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Cirrhosis Outcomes Better When Tx Guidelines Followed - below is full text Editorial and full text article, attached is pdf of published study
MedPage Today
Published: August 31, 2010
Action Points
* Explain that current guidelines recommend screening liver cirrhosis patients for esophageal varices and beta-blocker treatment or variceal ligation -- for those patients found to be at risk for bleeding -- along with periodic follow-up endoscopy.
* Explain to interested patients that following screening and treatment guidelines led to lower-than-expected rates of variceal hemorrhage.
Routinely screening liver cirrhosis patients for esophageal varices and treating them according to published guidelines led to lower-than-expected rates of subsequent variceal hemorrhage, researchers found.
A review of patient charts in a center that showed strong compliance with cirrhosis management guidelines found that the actuarial two-year likelihood of variceal bleeding was 13% -- compared with a predicted rate of 27% calculated on the basis of liver dysfunction severity, variceal size, and so-called "red wale markings" seen on endoscopy (P<0.05), according to Jayavani Moodley, MD, of the Cleveland Clinic, and colleagues.
"In our population, management according to principles endorsed by a recently published practice guideline was associated with a lower bleeding rate than that expected in untreated patients," Moodley and co-authors wrote in the August issue of Clinical Gastroenterology and Hepatology.
Guidelines issued in 2007 jointly by the American Gastroenterological Association and the American Association for the Study of Liver Disease call for screening cirrhosis patients for esophageal varices and beta-blocker treatment or variceal ligation for patients found to be at risk for bleeding, along with periodic follow-up endoscopy.
Moodley's team reviewed charts from 179 patients evaluated for cirrhosis at the Cleveland Clinic from 2003 to 2006 and found that 80% had endoscopic screens for esophageal varices within six months of their initial visit, and a total of 94% had such screens at some point during treatment at the clinic.
A chart review of endoscopy results revealed that 83 patients had varices -- including 35 with medium to large lesions.
The review also indicated that treatments conforming to the AGA/AASLD guidelines were given to 91% of patients with medium or large varices. On the other hand, compliance with the guidelines was lower (60%) among patients with small varices.
Of those patients without bleeding episodes during follow-up, 82% had their screening endoscopy within six months of their initial visit -- whereas only 50% of the patients suffering hemorrhages received such prompt screening (P=0.016).
Hemorrhage from esophageal varices occurred in nine patients with varices at screening of 12 total bleeding episodes that occurred during the follow-up period.
Moodley and colleagues had calculated a two-year actuarial probability of 13% that patients with varices would have hemorrhages. In comparison -- under the standard North Italian Endoscopy Club model for predicting variceal hemorrhage rates -- 27% of the Cleveland Clinic patients with varices would have been expected to develop hemorrhages in two years. This model takes into account the severity of liver dysfunction, the size of varices, and whether red wale markings are present.
Moodley and colleagues noted that 80% of the clinic's patients with medium to large varices underwent ligation procedures as opposed to beta-blocker therapy.
In their report, they wrote that the clinic's institutional preference was "influenced by two meta-analyses which indicate superiority of esophageal variceal ligation in preventing initial bleeding." But they also noted that a study published last year found better outcomes for beta-blockers.
"This finding, if verified, will likely alter our treatment strategy in the future," Moodley and colleagues commented.
In an accompanying editorial, two physicians at Boston's Beth Israel Deaconess Medical Center noted an odd paradox in the study's findings.
Although the rate of variceal hemorrhage was low in patients receiving guideline-compliant recommendations (8%), wrote Michelle Lai, MD, MPH, and Nezam Afdhal, MD, it was even lower (6%) among 54 patients who were screened but did not receive the recommended treatment.
Lai and Afdhal also suggested that findings at a tertiary care center such as the Cleveland Clinic may not apply to community gastroenterology practices. As a result, they indicated, "the findings, therefore, need to be confirmed ... in future studies."
Primary source: Clinical Gastroenterology and Hepatology
Source reference:
Moodley J, et al "Compliance with practice guidelines and risk of a first esophageal variceal hemorrhage in patients with cirrhosis" Clin Gastrenterol Hepatol 2010; 8: 703-708.
Additional source: Clinical Gastroenterology and Hepatology
Source reference:
Lai M, et al "Health care quality measurement in the care of patients with cirrhosis" Clin Gastrenterol Hepatol 2010; 8: 650-651.
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EDITORIAL
Health Care Quality Measurement in the Care of Patients With Cirrhosis
* Michelle Lai, MD, MPH
* Nezam H. Afdhal, MD
published online 17 May 2010.
In recent years, there has been increasing emphasis by the US government on health care quality assessment and improvement. Increased funding for the Agency for Healthcare Research and Quality has led to new initiatives by the agency to achieve its mission of improving the quality, safety, efficiency, and effectiveness of health care for Americans. After expanding its support of health information technology initiatives in 2004, the agency established the Effective Health Care Program in 2005 to conduct comparative effectiveness reviews and provide understandable and actionable information for patients, clinicians, and policy makers. The Patient Safety and Quality Improvement Act of 2005 established a system of patient safety organizations and a national patient safety database. More recently, the American Recovery and Reinvestment Act of 2009, known as the “Stimulus Package,” created the Federal Coordinating Council for Comparative Effectiveness and Research and allocated $1.1 billion for “comparative effectiveness research” to provide patients, clinicians, and others with evidence-based information to make informed decisions about health care.
Third-party payors have followed the governmental agencies in their emphasis on quality assessment and improvement as shown by a move toward an outcomes and quality-based reimbursement model. This pay-for-performance model of payment links quality of care with the level of payment for health care services. California leads the way with the California Pay for Performance Program, now the largest pay-for-performance program in the country. Medicare also launched various pay-for-performance initiatives in physician offices, clinics, and hospitals. More than 100 private and federal pilot pay-for-performance programs are under way.
According to criteria defined by the Institute of Medicine, cirrhosis (and its complications) is recognized as a chronic disease that requires quality of care measurement to reduce practice variation and improve clinical outcomes.1 Although clinical guidelines put forth by a panel of experts who have reviewed all the evidence (ie, comparative effectiveness review) is an important first step in evidence-based health care quality assessment and improvement, they are not, in themselves, assessment of health care quality. Currently, there are limited data on how to define and measure quality of care for patients with cirrhosis. Recent data show that, despite the existence of evidence-based practice guidelines, there is poor adherence (54%) to the clinical guidelines of the use of β-blockers for primary and secondary prevention of esophageal variceal hemorrhage (EVH).2, 3, 4, 5, 6, 7 It also remains to be seen whether compliance with the guidelines leads to improved patient outcomes. It is important to go one step further and translate these guidelines into a quality-assessment tool. Two articles in this current issue of Clinical Gastroenterology and Hepatology address quality assessment in the care of patients with cirrhosis. Moodley et al8 examines the association of compliance with guidelines to patient outcome whereas Kanwal et al9 identify quality indicators in the care of patients with cirrhosis.
Although there have been studies examining the compliance rate with clinical guidelines on the management of varices,7, 10 Moodley et al report on whether compliance leads to improved patient outcome. They examined the compliance with practice guidelines for screening of esophageal varices (EV) in patients with cirrhosis and intervention to prevent EVH as well as the impact of compliance on the rate of first EVH. The authors reviewed the charts of a random sample of 179 adult patients newly evaluated for cirrhosis at a tertiary liver unit, excluding patients with a previous history of EV, EVH, or treatment with β-blockers. They looked at the association of compliance with practice guidelines to subsequent esophageal variceal hemorrhage rates. Moodley et al found a high rate of compliance with screening guidelines (94%; and 80% in the first 6 months) at this tertiary liver unit. Compliance with intervention guidelines (ie, β-blockers, esophageal variceal ligation, or follow-up esophagogastroduodenoscopy [EGD]) was 68% in all screened patients and higher (91%) in patients with large varices. Twelve of the 179 patients had an EVH. Of the 12 subjects who had an EVH, only 50% had a screening EGD within 6 months of evaluation compared with 82% of those without an EVH who had an EGD within 6 months. The authors concluded that this showed the effectiveness of early variceal screening. However, it appears that in the group of patient who were not screened (9%), there were no cases of EVH. All subjects who bled had undergone a screening EGD at some point and 75% also had practice guideline compliant management after the screening. In addition, patients screened but not compliant with practice guideline management had a lower rate of EVH (3 of 54; 5.6%) than subjects who were compliant with practice guideline management (9 of 114; 7.9%). These results are somewhat contradictory and suggest that more data are needed before concluding that early screening led to lower rates of first EVH. The high compliance rate found in this study likely is owing to the practice setting of a tertiary care center. The findings, therefore, need to be confirmed in community gastroenterology practices in future studies.
The second article by Kanwal et al is an ambitious study to identify a set of evidence-based quality indicators (QI) for cirrhosis in clinical practice. By using the RAND/UCLA Appropriateness method, a panel of 11 experts came up with a list of the 8 most important QIs in 3 domains: ascites, variceal bleeding, and hepatocellular carcinoma. A list of candidate QIs that were linked to clinically important outcomes was generated using existing clinical guidelines. A comprehensive literature review of data linking candidate QIs to outcomes then was performed and presented to the panel of experts. Through an iterative, evidence-based process, the panel of experts chose the final 8 QIs. There were 3 QIs in the ascites domain, which were timely antibiotic treatment for spontaneous bacterial peritonitis, management of ascites with diuretics and salt restriction, and diagnostic paracentesis for hospitalized patients with ascites. The 4 QIs in the domain of variceal bleeding were timely endoscopies for patients with cirrhosis and upper gastrointestinal bleeding, appropriate treatment of EVH, as well as both primary and secondary prevention of an esophageal variceal bleed. The quality indicator in the domain of hepatocellular carcinoma was adherence to the hepatocellular carcinoma screening guideline of imaging every 6 to 12 months. These quality indicators are constructed as “if–then” statements, where “if” characterizes the eligible patient population and “then” describes the care that should be given. This format allows them to be translated easily into a practical checklist to be used as a tool for practices to assess quality and improve quality. However, before the use of this list of QIs is implemented into quality-assessment processes, studies need to be performed to evaluate whether adherence to this list of QIs in clinical practice leads to improved patient outcome.
We have seen the current focus by both government agencies and payors of quality assessment and quality improvement. In light of this increasing emphasis on quality assessment and quality-based reimbursement models, it is important that researchers and professional societies identify the optimal tools for assessing health care quality and also tools for implementing guidelines. These 2 articles represent a good start toward identifying tools for assessing health care quality in the care of patients with cirrhosis.
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Compliance With Practice Guidelines and Risk of a First Esophageal Variceal Hemorrhage in Patients With Cirrhosis
Jayavani Moodley, Cleveland Clinic Foundation, Department of Gastroenterology and Hepatology, 9500 Euclid Avenue, Cleveland, Ohio 44195. fax: (216) 445-5477, Rocio Lopez , William Carey
published online 12 March 2010.
Background & Aims
Esophageal variceal hemorrhage (EVH) is a serious complication of cirrhosis, with 20% mortality per episode. The 2007 American Association for the Study of Liver Disease and American College of Gastroenterology practice guidelines regarding esophageal varices in patients with cirrhosis recommend screening and intervention to prevent EVH. We assessed practice guideline compliance and its impact on the rate of first EVH.
Methods
An institutional review board-approved retrospective chart review was conducted on a random sample of adult patients newly evaluated for cirrhosis at the Cleveland Clinic from 2003 to 2006 (n = 179). Exclusion criteria were a previous diagnosis of esophageal varices or EVH and/or treatment with β-adrenergic antagonists. Patients were followed for 23 months (range, 9–38 months). Conformity with practice guidelines and subsequent bleeding rates were determined. Observed bleeding rates were compared to the North Italian Endoscopy Club (NIEC) model.
Results
Of the patients, 94% had a screening endoscopy, 80% within 6 months of the initial visit. Varices were present in 50% of the patients; 68% of all patients screened and 91% with large varices received a practice guideline-recommended treatment. Twelve patients (7%) had an episode of EVH; 82% of subjects without bleeding had their screening endoscopy within 6 months versus 50% of those with bleeding (P = .016). Actuarial likelihood of bleeding at 2 years was 13% versus 27% predicted by the NIEC model (P < .05).
Conclusion
Compliance with practice guideline recommendations is associated with reduction in first EVH in the first 2 years.
The risk of developing gastroesophageal varices in patients with cirrhosis is between 50% and 66%1 and 30%–40% of patients with varices suffer a variceal hemorrhage.2 Although the mortality rate associated with an episode of esophageal variceal hemorrhage (EVH) has decreased almost 3-fold in the past 2 decades owing to the combined use of endoscopic and pharmacological interventions, it is still high at 15%–20%.3, 4 If untreated, variceal hemorrhage portends a 70% risk of death within 1 year2; this high mortality rate makes primary prevention of bleeding the best approach to improving outcomes for these patients. The American Association for the Study of Liver Disease (AASLD) jointly with the American College of Gastroenterology (ACG) recently published practice guidelines (PG) (Supplementary Appendix A) that recommend screening and intervention for high risk EV.5 In 1988 the North Italian Endoscopy Club (NIEC) defined high risk varices as a composite measure of 3 variables: the severity of liver disease as determined by the Child–Pugh Score (CPS); the size of varices, with large varices being the most ominous; and the presence and severity of red wale markings or red signs (longitudinal dilated venules on the varix, similar to whip marks)6 (Supplementary Appendix B). In 2004 Zaman et al documented that self-reported PG compliance among gastroenterologists improved from 18% to 54% following the publication of the 1997 American College of Gastroenterology guidelines for the management of varices.7 Four years later the compliance rate in the same population still sits at 54%.8 There have been, however, no studies evaluating the impact improved compliance has on clinical outcomes such as rates of variceal hemorrhage or mortality among patients with cirrhosis. We undertook this study to assess actual compliance rates of gastroenterologists at a large tertiary institution with the current AASLD/ACG practice guidelines concerning EV screening and management. We also aimed to elucidate whether compliance resulted in improved patient outcomes, namely decreased risk of first variceal hemorrhage.
Methods
An institutional review board-approved retrospective chart review was conducted on 179 adult patients (age >18 years), selected by computerized randomization from 468 eligible patients, newly evaluated for cirrhosis at the Cleveland Clinic from 2003–2006. Exclusion criteria were a previous diagnosis of EV or EVH and/or treatment with β-adrenergic antagonists. The diagnosis of cirrhosis was based on historical, clinical, and pathological data.
The electronic database EPIC was used to retrieve relevant information spanning hepatology outpatient visits, hospital admissions, endoscopic procedures, and laboratory and other pathology-related data. Our analysis aimed to determine whether or not patients underwent timely screening for varices after initial evaluation by a hepatologist, follow-up surveillance endoscopies, and if found, were varices appropriately managed. Patients were followed for an average of 23.0 months (range, 9.2–37.8 months). Our endpoint was first EVH or last EPIC encounter. Information about bleeding episodes that occurred at the Cleveland Clinic was obtained directly from endoscopy reports, laboratory data, or hospital discharge summaries. If an episode of EVH occurred at another institution the data were documented by the hepatologist in the patient's outpatient record. The NIEC index was calculated for the patients who bled from EV, and the observed bleeding rates were compared with the NIEC predicted rates at 1 and 2 years.
For the purpose of appropriate data collection the following variables were defined.
Practice Guideline Recommended Management
In compliance with the 2007 AASLD/ACG PG (Supplementary Appendix A), effective screening required that patients have their screening endoscopy within 6 months of their initial visit to a hepatologist; patients should be placed on a noncardio-selective beta blocker (BB) or have esophageal variceal ligations (EVL) when needed; follow-up upper intestinal endoscopy (EGD) should be performed at appropriate intervals post esophageal variceal ligation (EVL); and for routine surveillance, BB should be titrated to the maximum tolerated dose.
Clinically Significant Bleeding (Baveno IV Criteria)9
Transfusion requirement ≥2 units of blood within 24 hours of time zero, and systolic blood pressure <100 mm Hg or postural systolic change >20 mm Hg, and/or heart rate >100 beats/minute.
Endoscopic Findings and Description of Varices
The presence or absence of esophageal varices was noted. Varices were classified as small, medium, or large. A 5 mm diameter was used as the cutoff for designating small from medium and large varices. The presence or absence of gastric varices and red wale markings was also documented. Unlike in the NIEC study, red wale markings were not graded in the endoscopy records reviewed. For the purpose of calculating the NIEC index in patients who bled we assigned those with red wale markings to the mild category (Supplementary Appendix C). As such, patients with red wale markings may have been placed in a lower risk NIEC category.
Length of Follow-Up
Patients were followed until their first bleeding episode from EV or their last encounter in EPIC, with the average length of follow-up being 23.0 months (range, 9.2–37.8 months).
Statistical Analysis
Descriptive statistics were computed for all variables. These include median and percentiles for age and frequencies for categorical variables. Pearson's χ2 tests were used to assess association between compliance to practice guidelines and factors such as presence of varices and CPS. The same was done to study factors associated with the presence and size of varices. Kaplan–Meier estimates were used to study bleeding rates in patients with EV, and a log-rank test was used to compare NIEC groups. Time of follow-up was defined as months between EV diagnosis and either bleeding or last follow-up visit if no bleeding was observed. A P < .05 was considered statistically significant. SAS version 9.2 software (The SAS Institute, Cary, NC) and R version 2.4.1 (The R Foundation for Statistical Computing, Vienna, Austria) were used for all analyses.
Results
Records of 562 cirrhotic patients presenting for the first time to a tertiary care liver clinic were screened. Ninety-four were excluded because of a previous diagnosis of EV, having suffered an EVH, or being recently (within the previous 12 months) or currently treated with beta blockers. Of the remaining eligible 468 patients, 179 were randomly selected for detailed analysis.
Compliance With Practice Guidelines
Screening for varices was accomplished in 169 cases (94%), although only 143 (80%) were screened within 6 months of their first encounter with the hepatologist (Figure 1). Ten (6%) were never screened. Two thirds (68%) received PG recommended management after their screening endoscopy, 47 (28%) did not, and 7(4%) were lost to follow-up. PG compliance was found in 73.8% of patients with varices and 67.9% with no varices (P = .41). Ninety-one percent of patients with medium and large varices received a PG recommended treatment compared with 60% with small varices (P = .002). When stratified according to CPS, 75% of CPS A, 57% of CPS B, and 80% of CPS C received PG-recommended treatment (A vs B, P = .048; C vs B, P = .28). Failure of compliance to practice guidelines was noted in 57 patients. Reasons for fallout were due to physician-related factors in 47 patients (82%). Of these, 20 did not receive a follow-up surveillance endoscopy, 14 were not given BB (for CPS B/C with small varices), 10 did not have a screening EGD, and 3 did not receive either BB or EVL once diagnosed with varices. Eighteen percent (10 patients) had their subsequent EGD beyond the recommended interval due to nonphysician or indeterminate factors.
Findings at Screening Endoscopy
One hundred and sixty-nine patients had a screening EGD (Table 2). One was excluded because of incomplete records; there was no description of the size or appearance of varices in the endoscopy report. Eighty-four (50%) of the remaining 168 patients had varices. Seventy (58%) of CPS A had no varices while 6 (60%) of CPS C had medium/large varices. CPS A patients were more likely to have small varices than CPS B (P = .002) and CPS C (P = .003). The presence of red wale markings on varices was noted in 3 (2.5%) of CPS A patients and 2 (20%) of CPS C.
Bleeding
Twelve patients (7%) of the study population had an episode of clinically significant bleeding during the follow-up period. Nearly all (11/12) had either esophageal or gastric varices at the time of initial screening endoscopy. Thirteen percent (11/84) of those with varices at initial screening subsequently bled. Of the 9 patients with EV, 2 (17%) had small and 7 (58%) had medium or large varices. Eight subjects bled within 1 year, 3 in the second year, and 1 subject 2 years after their screening EGD. At screening, 6 (50%) patients with subsequent EVH were CPS A, 4 (33%) CPS B, and 2 (17%) CPS C. Six (50%) of the patients who bled had received a screening endoscopy within 6 months of initial diagnosis. Eighty-two percent (137/167) of subjects without bleeding had their screening EGD within 6 months of initial visit compared with 50% (6/12) of those with bleeding (P = .016). Seventy-five percent (9/12) of patients with EVH did receive a PG-recommended treatment after their screening EGD. There were 52 patients with a NIEC score ≤26 and 32 with a NIEC >26 (Table 3). Three patients (5.8%) in the lower NIEC category bled compared with 6 (18.8%) in the group with a NIEC >26 (P = .032), in conformity with previous predictions of increased bleeding risk with higher NIEC scores (Figure 2).6
Eleven percent (9/84) of subjects with EV had EVH compared with 26.5% in the NIEC study (P = .002). The cumulative actuarial likelihood of bleeding was 9.2% and 13.0% at 1 and 2 years respectively, significantly lower than predicted by the NIEC model namely 16% and 27% (P < .05). As the NIEC index was developed for patients with EV, only the 9 patients with EV were used in comparison studies with the original NIEC.
We observed no bleeding episodes attributable to band ligation. Eighteen percent of those with small varices were given beta blockers; eighty percent of those with medium/large varices were treated with EVL, indicating a preference in this facility for this management tool. Observed bleeding rates were not different between treatment groups.
Discussion
Our study confirms the high prevalence of esophageal varices (50%) in cirrhotic patients with no history of bleeding. Sixty-three percent of those with varices had features putting them at high risk for bleeding. These results are similar to findings in other screening programs.6 We further demonstrated that high compliance (80%–94%) with screening for esophageal varices among cirrhotic patients seen at a large tertiary care facility appears to translate into better patient outcomes. We are unaware of other published reports demonstrating actual compliance with esophageal varices screening practice guidelines. Two studies evaluating practice guideline compliance regionally and nationally among gastroenterologists found a low rate of reported adherence (54%).7, 8 These reports surveyed gastroenterologists (not hepatologists) from a variety of practice settings. Our study examined behavior of hepatologists in an academic center. Nearly all (94%) of newly diagnosed cirrhotic patients had a screening endoscopy, 80% within 6 months of being evaluated by a hepatologist. Endoscopic screening remains the gold standard for the diagnosis of varices.5 The ACG/AASLD PG recommend a screening EGD to assess the presence of EV when the diagnosis of cirrhosis is made. Subsequent management depends on the nature of the varices, that being their size and appearance, and the patient's CPS.
Both beta-blockers and EVL are advocated in the primary prophylaxis of first EVH, and use of these measures significantly reduces the risk of bleeding.10, 11, 12 Of the 168 patients who received a screening endoscopy (regardless of when) 114 (68%) received PG-recommended management including either beta-blockers, EVL and/or timely follow-up. Significantly, 91% of patients with medium or large varices compared with 60% with small varices were treated in compliance with PG (P = .002). This may reflect that practitioners consider small varices less threatening than larger ones and thus are less likely to treat them. However it is known that 4%–10% of small varices progress to large varices per year, and therefore appropriate and timely management is warranted.2
Our center prefers EVL to beta blocker therapy, a choice influenced by 2 meta-analyses which indicate superiority of EVL in preventing initial bleeding.12, 13 Of our patients with medium or large varices, 80% were treated with EVL and only 11% by beta-blocker therapy. Concern about major hemorrhage caused by EVL was not realized in this study population. There was no significant difference in early bleeding (within 3 months of initiation of treatment) in those who received EVL and BB (10% and 3.7%, respectively, P = .34) (Supplementary Table 4). We are aware of the recently published report of BB superiority compared with EVL in primary bleeding prophylaxis.14 This finding, if verified, will likely alter our treatment strategy in the future.
The most common reason for divergence from PG recommendations is lack of timely follow-up endoscopy for surveillance in patients with no or small esophageal varices, explained, in part, by the referral nature of this practice (Figure 3). Eighteen patients with Child–Pugh B or C had small varices, a group for whom intervention with beta blocker therapy (with dose titration) is recommended. In this group only 22% were given beta blockers. Reasons for noncompliance have not been systematically determined, but may relate to many factors including the complexity of the management algorithm, or unfamiliarity or disagreement with individual PG recommendations. More emphasis may be needed in the specific care of this subset of patients. Bringing to light these areas of noncompliance can help physicians identify those patients who fall into potential gray areas where management may be unclear.
The NIEC provides a rich and detailed prospective assessment of bleeding risk in cirrhotic patients with newly discovered varices.6 Based on this, a scoring system of bleeding risk has been constructed and validated.6, 15 Recently suggestions have been made that the original NIEC assigns too much weight to the CPS limiting its prognostic efficiency and accuracy.15, 16 Zoli et al16 propose that more leverage be assigned to the size and appearance of the varices instead and have proposed a revised NIEC index. The differences in predicted bleeding risk between the original and revised scoring systems seem small. Pending further studies, the original NIEC index remains the most widely used system and was selected for our analysis.
This study suggests that the significant reduction in observed bleeding rates may be related to adherence to PG-recommended care. Patients who did not bleed were more likely to have received their screening EGD within the 6 month window as compared with those who bled (82% vs 50%, P = .016), demonstrating the effectiveness of early variceal screening. Seventy-five percent of patients who bled (9/12) did actually receive PG-compliant management after their screening EGD. This finding underscores the fact that no currently available strategy will eliminate the risk of variceal hemorrhage. It is noteworthy that both patients found to have isolated gastric varices (IGV) suffered clinically significant bleeding from these culprit vessels. One patient was found to have bleeding from IGV at the time of initial EGD and subsequently underwent placement of a transjugular intrahepatic portosystemic shunt (Supplementary Table 4). Gastric varices are found in about 20% of patients with cirrhosis either alone as IGV or as gastroesophageal varices in direct continuity with their esophageal counterparts. IGV are less prevalent than gastroesophageal varices (10% versus 90%), but they have a greater propensity to bleed; bleeding is difficult to control and is associated with a high mortality rate.2, 17 Currently there is no consensus on optimum treatment of gastric varices, and therefore more studies are necessary to provide data for guidelines on appropriate prophylaxis.9, 17 In patients with IGV it is prudent to rule out the presence of splenic vein thrombosis.
Our data need to be confirmed and validated. Of note, our endoscopists most often describe red wale markings as either present or absent (rather than following the NIEC protocol of mild-moderate-severe), making use of the NIEC scoring system difficult and subject to possible interpretive errors (Supplementary Appendix B). We also note a discrepancy between the higher rates of red signs in the NIEC data, namely 41% in Child's A and 39% in Child's C patients compared with 2.5% and 20%, respectively, in our study. This may represent the possibility of underreporting of red signs by our endoscopists and pose a potential limitation of our study.
Retrospective studies sometimes lack “granularity,” ie, the ability to capture nuances such as reasons for clinical decision-making. Compliance depends on factors other than physician recommendations and includes patient understanding, motivation, family support, and logistical issues such as financial means. From our data set it is difficult to attribute definitively the cause of failure to the physician or patient. Nevertheless, the cumulative effect of physician recommendation plus patient factors has been shown in this population to be highly effective in achieving the goals of practice guideline compliance. A future study is planned to attempt to better understand the relative roles of patient, environment, and physician factors associated with noncompliance.
In conclusion, this study confirms the high prevalence of esophageal varices in patients with cirrhosis and also finds high compliance rates with practice guidelines among hepatologists at a large tertiary institution regarding the prevention and management of EV. In our population, management according to principles endorsed by a recently published practice guideline was associated with a lower bleeding rate than that expected in untreated patients. It is recommended that efforts to promote increased awareness of and compliance to PG for the screening and management of EV are warranted.
Monday, September 27, 2010
Inhibitex Successfully Completes Phase 1a Trial of INX-189
Inhibitex Successfully Completes Phase 1a Trial of INX-189
Proof-of-Concept Trial in Patients with Chronic Hepatitis C Planned for Q4 2010
press release
Sept. 1, 2010
ATLANTA, Sep 01, 2010 (BUSINESS WIRE) -- Inhibitex, Inc. /quotes/comstock/15*!inhx (INHX 1.42, -0.01, -0.70%) , announced today that it has successfully completed a Phase1a, first-in-man, single ascending dose trial of INX-189, its nucleotide polymerase inhibitor in development for the treatment of chronic hepatitis C (HCV) infections. In this trial, 42 healthy volunteers received either a single oral dose of INX-189, ranging from 3 mg to 100 mg, or placebo. The Company plans to present detailed results from this trial during a future scientific meeting. Preliminary data from the trial are as follows:
-- INX-189 was generally well tolerated at all dose levels;
-- No drug-related serious adverse events;
-- No dose-related trends in frequency or type of adverse events; adverse events occurring in more than one subject were headache and nasal congestion;
-- No grade II or higher laboratory abnormality adverse events or clinically significant changes in ECGs; and
-- Pharmacokinetic data supports INX-189's potential for once daily (QD) dosing.
"We are encouraged with the initial safety and pharmacokinetic profile of INX-189 in this first-in-man trial," stated Dr. Joseph Patti, Senior Vice President and Chief Scientific Officer of Inhibitex, Inc. "Based upon the pharmacokinetics observed in this study, we continue to believe that INX-189 has the potential to demonstrate antiviral activity with a low once-daily dose, and we look forward to assessing its ability to reduce HCV RNA viral loads in patients with chronic hepatitis C in a Phase 1b multiple ascending dose trial we plan to start in the fourth quarter."
About Inhibitex
Inhibitex, Inc., headquartered in Alpharetta, Georgia, is a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. The Company's pipeline includes FV-100, which is in Phase II clinical development for the treatment of shingles, and INX-189, a nucleotide polymerase inhibitor in development for the treatment of chronic hepatitis C infections. The Company also has additional HCV nucleotide polymerase inhibitors in preclinical development and has licensed the use of its proprietary MSCRAMM(R) protein platform to Pfizer for the development of staphylococcal vaccines. For additional information about the Company, please visit www.inhibitex.com.
Safe Harbor Statement
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than historical facts included in this press release, including statements regarding the Company's plans to present detailed results from the Phase 1a trial during a future medical meeting and its intention to initiate a Phase 1b multiple ascending dose trial in the fourth quarter of 2010 are forward looking statements. These intentions, expectations, or results may not be achieved in the future and various important factors could cause actual results or events to differ materially from the forward-looking statements that the Company makes, including the risk of: either the Company, the FDA, a data and safety monitoring board, or an investigational review board delaying, suspending or terminating the clinical de velopment of INX-189 for a lack of safety or antiviral activity, manufacturing-related issues, questions or issues regarding the design of the planned Phase 1b clinical study of INX-189, or any other reasons; the Company obtaining, maintaining and protecting the intellectual property incorporated into and supporting the commercial viability of INX-189; and other cautionary statements contained elsewhere herein and in its Annual Report on Form 10-K for the year ended December 31, 2009, as filed with the Securities and Exchange Commission, or SEC, on March 26, 2010, and its Quarterly Report on Form 10-Q for the quarter ended June 30, 2010, as filed with the SEC on August 12, 2010. Given these uncertainties, you should not place undue reliance on these forward-looking statements, which apply only as of the date of this press release.
There may be events in the future that the Company is unable to predict accurately, or over which it has no control. The Company's business, financial condition, results of operations and prospects may change. The Company may not update these forward-looking statements, even though its situation may change in the future, unless it has obligations under the Federal securities laws to update and disclose material developments related to previously disclosed information. The Company qualifies all of the information contained in this press release, and particularly its forward-looking statements, by these cautionary statements.
Inhibitex(R) and MSCRAMM(R) are registered trademarks of Inhibitex, Inc.
SOURCE: Inhibitex, Inc.
Inhibitex, Inc.
Russell H. Plumb
Chief Executive Officer
678-746-1136
rplumb@inhibitex.com
or
Lee M. Stern, CFA
The Trout Group
646-378-2922
lstern@troutgroup.com
Proof-of-Concept Trial in Patients with Chronic Hepatitis C Planned for Q4 2010
press release
Sept. 1, 2010
ATLANTA, Sep 01, 2010 (BUSINESS WIRE) -- Inhibitex, Inc. /quotes/comstock/15*!inhx (INHX 1.42, -0.01, -0.70%) , announced today that it has successfully completed a Phase1a, first-in-man, single ascending dose trial of INX-189, its nucleotide polymerase inhibitor in development for the treatment of chronic hepatitis C (HCV) infections. In this trial, 42 healthy volunteers received either a single oral dose of INX-189, ranging from 3 mg to 100 mg, or placebo. The Company plans to present detailed results from this trial during a future scientific meeting. Preliminary data from the trial are as follows:
-- INX-189 was generally well tolerated at all dose levels;
-- No drug-related serious adverse events;
-- No dose-related trends in frequency or type of adverse events; adverse events occurring in more than one subject were headache and nasal congestion;
-- No grade II or higher laboratory abnormality adverse events or clinically significant changes in ECGs; and
-- Pharmacokinetic data supports INX-189's potential for once daily (QD) dosing.
"We are encouraged with the initial safety and pharmacokinetic profile of INX-189 in this first-in-man trial," stated Dr. Joseph Patti, Senior Vice President and Chief Scientific Officer of Inhibitex, Inc. "Based upon the pharmacokinetics observed in this study, we continue to believe that INX-189 has the potential to demonstrate antiviral activity with a low once-daily dose, and we look forward to assessing its ability to reduce HCV RNA viral loads in patients with chronic hepatitis C in a Phase 1b multiple ascending dose trial we plan to start in the fourth quarter."
About Inhibitex
Inhibitex, Inc., headquartered in Alpharetta, Georgia, is a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. The Company's pipeline includes FV-100, which is in Phase II clinical development for the treatment of shingles, and INX-189, a nucleotide polymerase inhibitor in development for the treatment of chronic hepatitis C infections. The Company also has additional HCV nucleotide polymerase inhibitors in preclinical development and has licensed the use of its proprietary MSCRAMM(R) protein platform to Pfizer for the development of staphylococcal vaccines. For additional information about the Company, please visit www.inhibitex.com.
Safe Harbor Statement
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than historical facts included in this press release, including statements regarding the Company's plans to present detailed results from the Phase 1a trial during a future medical meeting and its intention to initiate a Phase 1b multiple ascending dose trial in the fourth quarter of 2010 are forward looking statements. These intentions, expectations, or results may not be achieved in the future and various important factors could cause actual results or events to differ materially from the forward-looking statements that the Company makes, including the risk of: either the Company, the FDA, a data and safety monitoring board, or an investigational review board delaying, suspending or terminating the clinical de velopment of INX-189 for a lack of safety or antiviral activity, manufacturing-related issues, questions or issues regarding the design of the planned Phase 1b clinical study of INX-189, or any other reasons; the Company obtaining, maintaining and protecting the intellectual property incorporated into and supporting the commercial viability of INX-189; and other cautionary statements contained elsewhere herein and in its Annual Report on Form 10-K for the year ended December 31, 2009, as filed with the Securities and Exchange Commission, or SEC, on March 26, 2010, and its Quarterly Report on Form 10-Q for the quarter ended June 30, 2010, as filed with the SEC on August 12, 2010. Given these uncertainties, you should not place undue reliance on these forward-looking statements, which apply only as of the date of this press release.
There may be events in the future that the Company is unable to predict accurately, or over which it has no control. The Company's business, financial condition, results of operations and prospects may change. The Company may not update these forward-looking statements, even though its situation may change in the future, unless it has obligations under the Federal securities laws to update and disclose material developments related to previously disclosed information. The Company qualifies all of the information contained in this press release, and particularly its forward-looking statements, by these cautionary statements.
Inhibitex(R) and MSCRAMM(R) are registered trademarks of Inhibitex, Inc.
SOURCE: Inhibitex, Inc.
Inhibitex, Inc.
Russell H. Plumb
Chief Executive Officer
678-746-1136
rplumb@inhibitex.com
or
Lee M. Stern, CFA
The Trout Group
646-378-2922
lstern@troutgroup.com
Roche Receives FDA Approval for Second-Generation Hepatitis B Viral Load Test
Roche Receives FDA Approval for Second-Generation Hepatitis B Viral Load Test
Roche Molecular Diagnostics announced today that the U.S. Food & Drug Administration (FDA) has approved the COBAS® AmpliPrep / COBAS® TaqMan® HBV Test v2.0 for use in the United States. The new Roche test provides a fully automated solution for the quantitative detection of hepatitis B virus (HBV) DNA in human plasma or serum for patients on HBV antiviral therapy.
"This new test enables clinicians to follow best practices in patient care with standardized viral load measurements, a broad range of detection, and high sensitivity," said Paul Brown, Ph.D., President and CEO of Roche Molecular Diagnostics. "The system is also carefully designed to protect the integrity of each patient result, so clinicians can make key medical decisions about therapy with confidence."
According to the Centers for Disease Control, an estimated 1.2 million people in the United States are living with chronic hepatitis B. Clinical practice guidelines for chronic HBV highlight the importance of monitoring the levels of circulating hepatitis B viral DNA as an indicator of when hepatitis B therapies should be started, and to measure response to treatment, including suppression of HBV replication.
"Viral load testing remains the gold-standard for the management of HBV antiviral therapy," said Teresa Wright, MD, Chief Medical Officer of Roche Molecular Diagnostics. "Roche's new HBV test provides accurate and reproducible results at the key medical decision points, allowing the clinician to optimize patient outcomes."
About the COBAS® AmpliPrep/COBAS® TaqMan® HBV Test v2.0
The Roche COBAS® AmpliPrep / COBAS® TaqMan® HBV Test v2.0 has been validated to quantify diverse samples from genotypes A-H and pre-core mutants across a broad linear dynamic range of 20 IU/mL to 1.7E+08 IU/mL. The new assay uses a reduced sample input volume of 650 uL of either serum or plasma specimens and is standardized against the World Health Organization (WHO) Standard for hepatitis B.
This test is designed for use on Roche's fully automated COBAS® AmpliPrep/COBAS® TaqMan® System that is used in more than 250 clinical laboratories across the U.S.
The platform combines the COBAS® AmpliPrep Instrument for automated sample preparation and the COBAS® TaqMan® Analyzer or the smaller COBAS® TaqMan® 48 Analyzer for automated real-time PCR amplification and detection.
"Sample in/results out" testing eliminates manual intervention between steps and configuration options allow for customizable solutions for throughput needs. For a flexible throughput solution, the test offers 72 tests per kit in self sealing, ready-to-use reagent cassettes. Roche's proprietary AmpErase enzymes are also included in each test and are designed to prevent cross-contamination of samples and labs.
About Hepatitis B
Approximately 4,500 cases of acute hepatitis B in the United States are reported to CDC each year and each year an estimated 43,000 persons are newly infected with HBV.(1) However, because many HBV infections are either asymptomatic or never reported, the actual number of new infections is estimated to be approximately tenfold higher.
The hepatitis B virus is spread through having unprotected sex, by sharing needles, or from an infected mother to her baby during child birth. Symptoms occur in about 70 percent of patients and include jaundice, fatigue, abdominal pain, loss of appetite, nausea and vomiting.
About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2009, Roche had over 80,000 employees worldwide and invested almost 10 billion Swiss francs in R&D. The Group posted sales of 49.1 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.
Roche Molecular Diagnostics announced today that the U.S. Food & Drug Administration (FDA) has approved the COBAS® AmpliPrep / COBAS® TaqMan® HBV Test v2.0 for use in the United States. The new Roche test provides a fully automated solution for the quantitative detection of hepatitis B virus (HBV) DNA in human plasma or serum for patients on HBV antiviral therapy.
"This new test enables clinicians to follow best practices in patient care with standardized viral load measurements, a broad range of detection, and high sensitivity," said Paul Brown, Ph.D., President and CEO of Roche Molecular Diagnostics. "The system is also carefully designed to protect the integrity of each patient result, so clinicians can make key medical decisions about therapy with confidence."
According to the Centers for Disease Control, an estimated 1.2 million people in the United States are living with chronic hepatitis B. Clinical practice guidelines for chronic HBV highlight the importance of monitoring the levels of circulating hepatitis B viral DNA as an indicator of when hepatitis B therapies should be started, and to measure response to treatment, including suppression of HBV replication.
"Viral load testing remains the gold-standard for the management of HBV antiviral therapy," said Teresa Wright, MD, Chief Medical Officer of Roche Molecular Diagnostics. "Roche's new HBV test provides accurate and reproducible results at the key medical decision points, allowing the clinician to optimize patient outcomes."
About the COBAS® AmpliPrep/COBAS® TaqMan® HBV Test v2.0
The Roche COBAS® AmpliPrep / COBAS® TaqMan® HBV Test v2.0 has been validated to quantify diverse samples from genotypes A-H and pre-core mutants across a broad linear dynamic range of 20 IU/mL to 1.7E+08 IU/mL. The new assay uses a reduced sample input volume of 650 uL of either serum or plasma specimens and is standardized against the World Health Organization (WHO) Standard for hepatitis B.
This test is designed for use on Roche's fully automated COBAS® AmpliPrep/COBAS® TaqMan® System that is used in more than 250 clinical laboratories across the U.S.
The platform combines the COBAS® AmpliPrep Instrument for automated sample preparation and the COBAS® TaqMan® Analyzer or the smaller COBAS® TaqMan® 48 Analyzer for automated real-time PCR amplification and detection.
"Sample in/results out" testing eliminates manual intervention between steps and configuration options allow for customizable solutions for throughput needs. For a flexible throughput solution, the test offers 72 tests per kit in self sealing, ready-to-use reagent cassettes. Roche's proprietary AmpErase enzymes are also included in each test and are designed to prevent cross-contamination of samples and labs.
About Hepatitis B
Approximately 4,500 cases of acute hepatitis B in the United States are reported to CDC each year and each year an estimated 43,000 persons are newly infected with HBV.(1) However, because many HBV infections are either asymptomatic or never reported, the actual number of new infections is estimated to be approximately tenfold higher.
The hepatitis B virus is spread through having unprotected sex, by sharing needles, or from an infected mother to her baby during child birth. Symptoms occur in about 70 percent of patients and include jaundice, fatigue, abdominal pain, loss of appetite, nausea and vomiting.
About Roche
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world's largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche's personalized healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2009, Roche had over 80,000 employees worldwide and invested almost 10 billion Swiss francs in R&D. The Group posted sales of 49.1 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.
The Next Step for Taribavirin - Commentary
The Next Step for Taribavirin - Commentary
Hepatology Sept 24 2010
Paul Y Kwo and Rakesh Vinayek
Excerpts:
In this issue of Hepatology, Poordad and colleagues report the SVR rates of weight-based TBV compared to weight-based RBV in naïve genotype I HCV-infected patients. In this US Phase 2b randomized open-label controlled parallel group study, 278 naïve genotype I subjects were randomized to TBV 20, 25, or 30 mg/kg/day or RBV 800-1400 mg, pegIFN alfa-2b for 48 weeks. An early virologic response (EVR) defined as undetectable HCV RNA (< 39 I.U. at Week 12) or a 2 log reduction in baseline HCV RNA, the primary endpoint of the study, was comparable across all treatment arms. The SVR rate was also preserved across all treatment arms, ranging between 27 and 28%. The overall response rates in this trial were low though the high percentage of African Americans (20%) and those with advanced fibrosis may explain the lower SVR rates. It would be interesting to know the IL-28 composition of the treatment population as there may have been a high prevalence of unfavorable Il-28 CT or TT genotype patients present which could also explain in part the low SVR rates.
While SVR rates were not different between treatment arms, a lower relapse rate was seen with an incremental increase in the dose of TBV, similar to that observed with RBV. In addition, the per protocol SVR rates were substantially higher again demonstrating the importance of adherence to therapy to provide optimal SVR rates in the genotype I population. Lower anemia rates (defined as hemoglobin < 10 grams/dL) were seen in the TBV arms throughout the entire 48 weeks, with cumulative anemia rates being significantly lower across the two lower TBV arms (20 mg and 25 mg/kg) compared to weight-based RBV. However, as the dose of TBV was increased to 30 mg/kg, the anemia rate was numerically lower than with RBV but was not significant, other than at week 4, suggesting that higher doses TBV may lead to similar rates of anemia and other side effects observed with RBV. The pharmacokinetic analysis showed that this effect correlated with RBV plasma exposure. Furthermore, within the first 12 weeks of treatment when maintaining the dose of RBV has been shown to be most critical, significantly lower rates of anemia were observed with TBV compared with RBV (7-15% vs 24%, respectively) within the first 12 weeks of treatment although this translated clinically into comparable, not superior SVR rates in the TBV arms. Even though, fewer patients treated with TBV required dose reduction (13-28%) compared to 32% patients treated with RBV, it should also be noted that dropout rates for anemia were not different amongst the TBV arms compared to the RBV arms in this study, though this may be due to relatively small sample size. There does appear to be an increased rate of diarrhea in the TBV arms compared to RBV. This may be significant as some DAA agents are also associated with increased GI side effects and, as we enter an era where DAA agents and other drugs are combined, side effects could limit the efficacy of multi-drug combinations. Finally, while not statistically significant, insomnia was numerically higher in the TBV arms and should be a side effect of some concern in future trials. Thus, as significantly fewer dose reductions were noted only in the TBV 20 mg/kg arm as compared to the higher doses of TBV and RBV with similar SVR rates, the dose of 20 mg/kg may also require study in the future with DAA agents
So what does the future hold for taribavirin? Phase 2 and ongoing Phase 3 trials strongly suggest that DAA agents will be added to pegIFN and RBV to obtain higher SVR rates, albeit at the expense of higher rates of anemia and other side effects. Currently, the role of ESAs in the treatment of HCV with DAA agents is not yet precisely defined, though we await the results of ongoing trials. The inclusion of TBV into the HCV armamentarium may serve as an opportunity to combine with pegIFN and DAA agents to reduce the rates of anemia and avoid RBV dose reduction or introduction of ESAs. As RBV reduction or removal of RBV is associated with increased rates of breakthrough and development of resistance to DAA agents, TBV may have a role in populations particularly sensitive to ribavirin-related anemia , including those with advanced liver disease, older patients, patients who have undergone liver transplantation, HIV/HCV coinfected individuals, patients with hemoglobulinopathies and chronic renal failure 20. However, with the commencement of several trials comprising of multiple combinations of DAA agents with and without pegIFN/RBV, and the development of newer protease inhibitors with potentially lower rates of anemia, the role of TBV remains less precisely defined and could potentially have a finite life cycle. Studies with combinations of DAA agents with PEGIFN/RBV have been initiated and these studies will multiply. Whether or not RBV (and TBV) can be eliminated altogether remains to be determined.
Particularly in those patients with unfavorable treatment characteristics, RBV may remain a part of our therapeutic armamentarium for years to come; and, if so, TBV could be an option which has the potential to limit toxicity and potentially reduce costs. The ideal study may be to combine TBV with a DAA agent and pegIFN and compare it to RBV, to see if SVR rates can be preserved or improved by minimizing dose reductions and reducing the emergence of resistance. Given the long wait between the approval of pegIFN and RBV and yet unapproved DAA agents, one should not discount the potential contribution of TBV. Many promising agents have already been stopped in development due to lack of efficacy or toxicity 21-22. Thus, if TBV can be shown to preserve or improve efficacy rates in combination with DAAs and Peg IFN, with lower rates of anemia, the use of TBV in these clinical settings would be a welcome addition to the HCV armamentarium as we begin to expand the HCV populations that we treat.
Hepatology Sept 24 2010
Paul Y Kwo and Rakesh Vinayek
Excerpts:
In this issue of Hepatology, Poordad and colleagues report the SVR rates of weight-based TBV compared to weight-based RBV in naïve genotype I HCV-infected patients. In this US Phase 2b randomized open-label controlled parallel group study, 278 naïve genotype I subjects were randomized to TBV 20, 25, or 30 mg/kg/day or RBV 800-1400 mg, pegIFN alfa-2b for 48 weeks. An early virologic response (EVR) defined as undetectable HCV RNA (< 39 I.U. at Week 12) or a 2 log reduction in baseline HCV RNA, the primary endpoint of the study, was comparable across all treatment arms. The SVR rate was also preserved across all treatment arms, ranging between 27 and 28%. The overall response rates in this trial were low though the high percentage of African Americans (20%) and those with advanced fibrosis may explain the lower SVR rates. It would be interesting to know the IL-28 composition of the treatment population as there may have been a high prevalence of unfavorable Il-28 CT or TT genotype patients present which could also explain in part the low SVR rates.
While SVR rates were not different between treatment arms, a lower relapse rate was seen with an incremental increase in the dose of TBV, similar to that observed with RBV. In addition, the per protocol SVR rates were substantially higher again demonstrating the importance of adherence to therapy to provide optimal SVR rates in the genotype I population. Lower anemia rates (defined as hemoglobin < 10 grams/dL) were seen in the TBV arms throughout the entire 48 weeks, with cumulative anemia rates being significantly lower across the two lower TBV arms (20 mg and 25 mg/kg) compared to weight-based RBV. However, as the dose of TBV was increased to 30 mg/kg, the anemia rate was numerically lower than with RBV but was not significant, other than at week 4, suggesting that higher doses TBV may lead to similar rates of anemia and other side effects observed with RBV. The pharmacokinetic analysis showed that this effect correlated with RBV plasma exposure. Furthermore, within the first 12 weeks of treatment when maintaining the dose of RBV has been shown to be most critical, significantly lower rates of anemia were observed with TBV compared with RBV (7-15% vs 24%, respectively) within the first 12 weeks of treatment although this translated clinically into comparable, not superior SVR rates in the TBV arms. Even though, fewer patients treated with TBV required dose reduction (13-28%) compared to 32% patients treated with RBV, it should also be noted that dropout rates for anemia were not different amongst the TBV arms compared to the RBV arms in this study, though this may be due to relatively small sample size. There does appear to be an increased rate of diarrhea in the TBV arms compared to RBV. This may be significant as some DAA agents are also associated with increased GI side effects and, as we enter an era where DAA agents and other drugs are combined, side effects could limit the efficacy of multi-drug combinations. Finally, while not statistically significant, insomnia was numerically higher in the TBV arms and should be a side effect of some concern in future trials. Thus, as significantly fewer dose reductions were noted only in the TBV 20 mg/kg arm as compared to the higher doses of TBV and RBV with similar SVR rates, the dose of 20 mg/kg may also require study in the future with DAA agents
So what does the future hold for taribavirin? Phase 2 and ongoing Phase 3 trials strongly suggest that DAA agents will be added to pegIFN and RBV to obtain higher SVR rates, albeit at the expense of higher rates of anemia and other side effects. Currently, the role of ESAs in the treatment of HCV with DAA agents is not yet precisely defined, though we await the results of ongoing trials. The inclusion of TBV into the HCV armamentarium may serve as an opportunity to combine with pegIFN and DAA agents to reduce the rates of anemia and avoid RBV dose reduction or introduction of ESAs. As RBV reduction or removal of RBV is associated with increased rates of breakthrough and development of resistance to DAA agents, TBV may have a role in populations particularly sensitive to ribavirin-related anemia , including those with advanced liver disease, older patients, patients who have undergone liver transplantation, HIV/HCV coinfected individuals, patients with hemoglobulinopathies and chronic renal failure 20. However, with the commencement of several trials comprising of multiple combinations of DAA agents with and without pegIFN/RBV, and the development of newer protease inhibitors with potentially lower rates of anemia, the role of TBV remains less precisely defined and could potentially have a finite life cycle. Studies with combinations of DAA agents with PEGIFN/RBV have been initiated and these studies will multiply. Whether or not RBV (and TBV) can be eliminated altogether remains to be determined.
Particularly in those patients with unfavorable treatment characteristics, RBV may remain a part of our therapeutic armamentarium for years to come; and, if so, TBV could be an option which has the potential to limit toxicity and potentially reduce costs. The ideal study may be to combine TBV with a DAA agent and pegIFN and compare it to RBV, to see if SVR rates can be preserved or improved by minimizing dose reductions and reducing the emergence of resistance. Given the long wait between the approval of pegIFN and RBV and yet unapproved DAA agents, one should not discount the potential contribution of TBV. Many promising agents have already been stopped in development due to lack of efficacy or toxicity 21-22. Thus, if TBV can be shown to preserve or improve efficacy rates in combination with DAAs and Peg IFN, with lower rates of anemia, the use of TBV in these clinical settings would be a welcome addition to the HCV armamentarium as we begin to expand the HCV populations that we treat.
Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C
Virologic response rates of weight-based taribavirin versus ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C - pdf attached
Download the PDF here
Hepatology Sept 24 2010
Fred Poordad1,*,, Eric Lawitz2, Mitchell L. Shiffman3, Tarek Hassanein4, Andrew J. Muir5, Bruce R. Bacon6, Jamie Heise7, Deanine Halliman7, Eric Chun7, Janet Hammond7
"In conclusion, TBV administered in a weight-based fashion demonstrated similar rates of efficacy to RBV via SVR with significantly less anemia and lower rates of dose modification. The recommended dose of TBV for future development in patients with chronic hepatitis C genotype 1 is 25 mg/kg. These data suggest TBV may be an effective agent to substitute for RBV in the future and could be incorporated in upcoming trials using emerging small molecules for HCV treatment......However, diarrhea and insomnia were more common (>10% different) in the groups that received TBV, whereas anemia was more common (>10% different) in the RBV group (Table 3). The mean insomnia rate of the TBV arms was 35% compared to 24% for the RBV arm and was not considered clinically relevant. The mean TBV diarrhea rate was 39% versus 23% in the RBV group."
ABSTRACT
Ribavirin-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of patients with chronic hepatitis C. The study aimed to determine if weight-based dosing of taribavirin (TBV), an oral prodrug of ribavirin (RBV), demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration. A U.S. phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naive patients infected with genotype 1 who were stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800-1400 mg/day) with pegylated interferon alfa-2b for 48 weeks. The SVR rates in this difficult-to-cure patient demographics (mean age, 49 years; 61% male; 30% African American or Latino; high viral load; advanced fibrosis; and mean weight, 82 kg) were 28.4%, 24.3%, 20.6%, and 21.4% in the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. There were no statistical differences in the efficacy analyses. Anemia rates were significantly lower (P < 0.05) in the 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7%, respectively) compared to RBV (32.9%). The most common adverse events in all groups were fatigue, diarrhea, and insomnia. Diarrhea, reported in 38% of TBV patients versus 21% of RBV patients, was generally mild and not dose-limiting.
Conclusion: All TBV doses demonstrated efficacy and tolerability comparable to that of RBV; however, the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy. Anemia rates were significantly lower for TBV given at 20-25 mg/kg than RBV. These data suggest weight-based dosing with TBV provides a safe and effective treatment alternative to RBV for chronic hepatitis C.
Adverse Events Requiring Dose Modification or Discontinuation.
The percentages of patients with AEs leading to dose reduction or discontinuations are shown in Table 5. Dose modifications of TBV or RBV were most common in the TBV 30 mg/kg/day and RBV groups. Dose reductions were less frequent in the 20 and 25 mg/kg TBV groups compared to RBV by 21% and 12.9%, respectively. The proportion of patients withdrawn from the study as a result of adverse events were 12%, 25%, 19%, and 26% for the 20, 25, 30 mg/kg TBV groups and RBV group, respectively. The proportion of patients withdrawn for anemia adverse events was 1%, 4%, 4%, and 6%, for the 20, 25, and 30 mg/kg groups and the RBV group, respectively. The corresponding number of patients withdrawn for diarrhea AEs was 1%, 1%, 3%, and 0%. Dose reductions due to anemia were 7.5%, 12.9%, 20.6%, and 30% for the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. Stepwise reductions in peg-IFN, RBV, and TBV dosages were used primarily to manage anemia AEs.
Ribavirin (RBV) is essential for the treatment of chronic hepatitis C virus (HCV) infection. When used in combination with peginterferon alfa (peg-IFN alfa), it significantly enhances on-treatment virologic response and reduces relapse.1-3 RBV has been demonstrated to be essential in achieving high rates of sustained virologic response (SVR) when used in combination with direct-acting antiviral agents.4-6 One of the most significant toxicities of RBV is hemolytic anemia.5, 7 When used as monotherapy, RBV-induced hemolytic anemia is marginal because of a compensatory reticulocytosis.8, 9 However, peg-IFN alfa suppresses the bone marrow and significantly reduces reticulocytosis. Therefore, anemia associated with the combination of IFN and RBV therapy is much greater. Approximately 25%-30% of patients receiving peg-IFN and RBV develop a decline of 4 g or greater in hemoglobin (Hb).1, 2, 10 This significantly impairs quality of life and leads to dose reduction and premature discontinuation of treatment in 15%-30% of patients.1, 3, 11, 12 Decreasing the dose of RBV to below 10.6 mg/kg body weight/day during the first 12 weeks of treatment has been shown to increase relapse rates and reduce SVR in both treatment-naive patients and during retreatment.11, 13, 14
Taribavirin (TBV), formerly known as Viramidine, is a nucleoside analogue and oral prodrug of RBV that is converted from TBV to RBV by adenosine deaminase. Its structural difference from RBV, a positively charged carboxamidine group at position 3, significantly reduces the ability of this agent to enter red cells. Because accumulation of RBV within red blood cells is the primary mechanism causing hemolytic anemia, TBV should therefore be associated with significantly less anemia.
Two previous phase 3 clinical trials, ViSER 1 and ViSER 2 (Viramidine's Safety and Efficacy versus Ribavirin), compared a fixed dose of TBV 600 mg twice a day to weight-based dosing (WBD) of RBV 1000 mg/1200 mg (²75 kg/>75 kg body weight), in combination with either peg-IFN alfa-2b or peg-IFN alfa-2a, respectively.15, 16 Both ViSER studies met the primary safety endpoint defined as Hb < 10 g/dL or at least a 2.5 g/dL decrease from baseline at any time point during therapy. Statistically less anemia was observed in patients treated with TBV compared to RBV. However, the primary efficacy endpoint of these studies-a noninferior SVR between the TBV and RBV groups-was not achieved. Detailed subgroup analyses of the data suggested the reasons for the lower SVR in TBV-treated patients were: fixed dose as opposed to WBD and the selection of an inadequate dose. The present study explored several higher WBD regimens of TBV to determine a dosage regimen that was able to deliver comparable responses to RBV with less anemia.
RESULTS
Study Patients.
A total of 278 patients were randomized at 51 U.S. centers between March 2007 and October 2008. A total of 86 (41%) of patients in the TBV arms and 25 (36%) in the RBV arm completed treatment and follow-up. Overall, 122 (59%) patients withdrew prematurely in the TBV arms compared to 45 (64%) in the RBV group. The most commonly cited reasons for premature withdrawal were lack of response (29%) and adverse events (20%). Figure 1 shows the disposition of patients during treatment.
Baseline characteristics across the four treatment groups were similar (Table 1). The majority of patients were male (61%) with a mean weight of 82.1 kg and mean age of 49 years. African American or Latino patients accounted for 30% of the study population and 81% had high viral load defined as >400,000 IU/mL at baseline.
Efficacy.
The proportions of patients in the ITT population with an EVR, the primary endpoint of this study, were comparable between all groups with no statistical difference versus RBV. EVR was achieved in 64.2% (43 of 67) in the 20 mg/kg group, 57.1% (40 of 70) in the 25 mg/kg group, 54.4% (37 of 68) of the 30 mg/kg group and 51.4% (36 of 70) in the RBV group. Virologic response for TW4, 12, 24, and 48 as well as SVR are shown in Table 2. The proportion of patients with undetectable HCV RNA at every time point was similar between the TBV and RBV groups. Although responder rates were numerically lower at TW12 in the TBV 30 mg/kg group and somewhat higher at TW24 and TW48 in the TBV 20 mg/kg group, they were not significantly different for any of the TBV doses compared with RBV.
The relapse rates for the TBV groups (35%, 20 mg/kg; 21%, 25 mg/kg; 14%, 30 mg/kg) were inversely proportional to the TBV dose and are most likely indicative of the recognized effects of RBV dosing (Fig. 2). The lowest TBV dose resulted in the lowest RBV exposure and subsequently, the greatest relapse rate (35%).
The SVR rates observed in the per-protocol population were 60%, 64%, 62%, and 62% for the 20, 25, and 30 mg/kg/day TBV groups and the RBV group, respectively, and there were no statistically significant differences between the groups. These results were more than double the ITT SVR demonstrating maximal response as RBV or TBV exposure increases with adherence to therapy.
Safety.
The most common AEs were typical of those previously reported for chronic hepatitis C therapy with peg-IFN and RBV. However, diarrhea and insomnia were more common (>10% different) in the groups that received TBV, whereas anemia was more common (>10% different) in the RBV group (Table 3). The mean insomnia rate of the TBV arms was 35% compared to 24% for the RBV arm and was not considered clinically relevant. The mean TBV diarrhea rate was 39% versus 23% in the RBV group.
Diarrhea, which was previously noted to occur more frequently in the ViSER studies, was also reported more frequently in the current study. It occurred predominantly during the first 12 weeks of therapy and was generally mild, not dose-limiting and of short duration. Through FW24, cumulative diarrhea rates occurred in 40.3%, 37.1%, and 36.8% of patients on 20, 25, and 30 mg/kg/day TBV respectively. This indicates no apparent TBV dose relationship. In the majority of cases diarrhea classification was "mild" or "moderate." Serious diarrhea AEs (grade 3) were reported in two patients and were determined by their physician assessment as un-related to study medication and due to concomitant disease. There were no grade 4 diarrhea events reported. During the 24-week follow up period, the incidence of diarrhea returned to baseline at a frequency similar to that of RBV.
The cumulative incidence of anemia throughout the trial is shown in Table 4. The 20 and 25 mg/kg groups were statistically significantly lower than the RBV group (P < 0.05) at all time points. The anemia rate of TBV 30 mg/kg was lower than that observed with RBV but did not achieve statistical significance, other than at week 4. The pharmacokinetic analysis showed this effect correlated with RBV plasma exposure in the TBV group. Exposure of RBV associated with TBV dosing was consistently lower compared to RBV exposure due to RBV dosing by pharmacokinetic measures (data not shown) until after TW18. At that time, TBV 30 mg/kg/day generated RBV plasma trough levels that exceeded the levels observed due to RBV oral administration. In addition, the exposure of TBV and RBV due to TBV were dose linear over the dosage range 20-30 mg/kg/day evaluated.
Adverse Events Requiring Dose Modification or Discontinuation.
The percentages of patients with AEs leading to dose reduction or discontinuations are shown in Table 5. Dose modifications of TBV or RBV were most common in the TBV 30 mg/kg/day and RBV groups. Dose reductions were less frequent in the 20 and 25 mg/kg TBV groups compared to RBV by 21% and 12.9%, respectively. The proportion of patients withdrawn from the study as a result of adverse events were 12%, 25%, 19%, and 26% for the 20, 25, 30 mg/kg TBV groups and RBV group, respectively. The proportion of patients withdrawn for anemia adverse events was 1%, 4%, 4%, and 6%, for the 20, 25, and 30 mg/kg groups and the RBV group, respectively. The corresponding number of patients withdrawn for diarrhea AEs was 1%, 1%, 3%, and 0%. Dose reductions due to anemia were 7.5%, 12.9%, 20.6%, and 30% for the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. Stepwise reductions in peg-IFN, RBV, and TBV dosages were used primarily to manage anemia AEs.
DISCUSSION
The present study demonstrated that WBD TBV achieved comparable efficacy to RBV as demonstrated by SVR. This was observed in all three TBV WBD treatment groups, which met the study's primary endpoint. Notably, patients treated with TBV had less than half the anemia and a 13%-21% lower dose modification rate compared to RBV treated patients treated. These results suggest WBD of TBV can significantly improve the tolerability of HCV treatment while maintaining efficacy. Specifically, the 25 mg/kg dose offered the optimal balance of efficacy and safety in this patient population.
The relapse rates for the TBV groups were inversely proportional to the TBV dose and are most likely indicative of the recognized effects of RBV dosing. The similar SVR and higher relapse rates observed in the 20 mg/kg group are a reflection of higher end of treatment response rates. The high on-treatment response can be explained by the greater percentage of women and Caucasians randomized to this group. The higher relapse rate observed in the 20 mg/kg group is likely due to the lower TBV/RBV exposure.
The overall response rates observed in this trial appeared lower than expected for a Caucasian based genotype 1 trial. However, the demographics of this patient population were quite different than in many other controlled clinical trials reported to date. Approximately 20% of enrolled patients were African American, which was more than double many previous controlled clinical trials.1, 3 African Americans with genotype 1 HCV, have lower response rates to peg-IFN/RBV than Caucasians.17 Recent studies also demonstrated that African Americans have a much lower population frequency of a gene associated with SVR.18 A genetic predisposition for nonresponse in these patients is not likely to be overcome by a more favorable treatment, though the addition of direct acting antiviral agents should improve SVR rates in these populations. In addition to a high percentage of African and Latino races, other poor response characteristics present in the study population were: 81% of patients had high viral load; a higher age than reported in previous registration trials and up to 40% of patients had bridging fibrosis.1-3 The drop out rate in this trial was approximately 10% higher than other U.S.-based trials and this difference is likely related to the poor response characteristics described above.
Similar to dosing experiences with RBV, we found WBD with TBV provides optimal RBV exposure. The pharmacokinetics of TBV administered at doses of 20, 25, and 30 mg/kg/day demonstrated steady state by TW4 for both prodrug and parent drug. This is equivalent to what is seen of RBV exposure from a RBV weight adjusted dosage of 800-1400 mg/day. TBV pharmacokinetics were dose linear, predictable and consistently generated RBV plasma levels that were lower than seen by RBV administration, without an impact on efficacy. The lower RBV concentrations positively affected the critical safety concern for RBV-anemia. The TBV 25 mg/kg/day dose had similar efficacy results as WBD RBV with significantly lower anemia rates.
As was reported in previous TBV clinical trials, an increase in the frequency of diarrhea was observed in all TBV cohorts when compared to RBV. Diarrhea was considered an adverse event of special interest in this study, therefore a more rigorous medical history specific to diarrhea was collected prospectively and this likely accounted for increased reporting frequency. The majority of cases across all treatment groups were classified as common toxicity criteria grade 1, occurred early in therapy and were single episode. The exact mechanism of action leading to diarrhea in patients receiving TBV remains unknown. After the end of treatment, the incidence of diarrhea returned to baseline, suggesting it is treatment related, and reversible.
Anemia is considered to be significant when the Hb falls below 10 g/dL. Patients treated with TBV had lower rates of anemia throughout the entire 48 weeks of treatment. Within the first 12 weeks of treatment, when maintaining the dose of RBV has been shown to be most critical, significant anemia was observed in only 7%-15% of patients treated with TBV compared to 24% of patients treated with RBV. As a result, fewer patients treated with TBV required dose reductions (13%-28%) compared to 32% of patients treated with RBV. Less frequent dose modification in patients treated with TBV may alleviate the need to use ESAs. Several studies have now demonstrated the use of ESAs can significantly decrease the need to dose reduce RBV and leads to an improvement in the quality of life during HCV treatment,19-21 but fail to improve the SVR.22 However, the use of ESAs adds significant cost to HCV treatment and is associated with significant adverse events including thrombosis and red cell aplasia.19, 23 Thus, limiting anemia during HCV treatment is clearly desirable.
The future of HCV treatment will incorporate potent antiviral agents such as protease and polymerase inhibitors, with peg-IFN and RBV. Despite its toxicity, RBV remains critical to optimizing SVR rates of hepatitis C and is unlikely to be replaced by the first generation direct acting antiviral agents.4-6 Data from the new small molecule trials have demonstrated that anemia is a common consequence of treatment of protease inhibitors and when used with RBV there appears to be a significant need to either dose modify RBV or use ESAs to limit anemia.4-6 Therefore, TBV should be considered as a RBV substitution to future clinical trials with peg-IFN and protease inhibitors as it may yield a significant treatment advantage over RBV.
Other potential TBV opportunities that need to be explored in clinical trials would be in patients susceptible to anemia and where RBV is contraindicated (including chronic renal failure and hemoglobinopathies). Patients who are slow to respond and may require 72 weeks of treatment may also benefit from using TBV as opposed to RBV. The lower anemia rates associated with TBV may allow these patients to remain on a prolonged course to achieve SVR. Finally, TBV may be particularly useful in liver transplant recipients with recurrent HCV and in patients coinfected with HCV and human immunodeficiency virus. Many of these patients have preexisting anemia and this worsens considerably during treatment with peg-IFN and RBV. The low SVRs in these populations are at least in part secondary to anemia and the inability to optimize RBV dosage.
In conclusion, TBV administered in a weight-based fashion demonstrated similar rates of efficacy to RBV via SVR with significantly less anemia and lower rates of dose modification. The recommended dose of TBV for future development in patients with chronic hepatitis C genotype 1 is 25 mg/kg. These data suggest TBV may be an effective agent to substitute for RBV in the future and could be incorporated in upcoming trials using emerging small molecules for HCV treatment.
METHODS & PATIENTS
Study Patients.
Approximately 260 patients were planned for enrollment in the study, with approximately 65 patients in each of the four treatment groups. Eligible patients were treatment-naive, at least 18 years of age, diagnosed with chronic HCV genotype 1 infection (>2000 copies/mL or >780 IU/mL), and showed histologic changes consistent with chronic HCV as demonstrated on liver biopsy within 3 years of screening. Patients were excluded from the study if they had histologic evidence of cirrhosis (F4), low Hb concentrations (men, <13 g/dL; women, <12 g/dL), neutropenia (absolute neutrophil count <1200 x 103/µL), thrombocytopenia (<90 x 103 platelets/µL) or serum creatinine levels ³1.5 mg/dL. Additional exclusion criteria included chronic hepatic disease other than HCV, human immunodeficiency virus, or hepatitis B coinfection; severe psychiatric disorders; alcoholism or drug addiction within 1 year of screening; use of erythropoiesis-stimulating agents (ESAs); and presence of comorbid conditions considered significant by the investigator.
Study Design.
This was a phase 2b, multicenter, randomized, open-label, active-control, and parallel-group trial. Although the study was open-label, the sponsor was blinded to treatment allocation and viral load results until treatment week 12. Patients were enrolled at 51 centers in the United States. Patients were stratified by serum HCV RNA titers (²780,000 IU/mL or >780,000 IU/mL) and baseline weight (²75 or >75 kg). An interactive voice response system was used to randomize patients in a 1:1:1:1 ratio to receive weight-based TBV 20 mg/kg/day, 25 mg/kg/day, or 30 mg/kg/day (Valeant Pharmaceuticals North America, Aliso Viejo, CA) or weight-based RBV at 800, 1000, 1200, or 1400 mg/day (Copegus; Hoffmann-La Roche, Nutley, NJ) in combination with peg-IFN alfa 2b (PegIntron; Schering Corp., Kenilworth, NJ). All patients received doses twice daily with their morning and evening meals.
Patients were treated for 48 weeks, but treatment was discontinued for evidence of nonresponse defined as <2-log decline at week 12 or a positive viral load at week 24. Study treatment was initiated on day 1 and clinic visits occurred at treatment weeks (TWs) 1, 2, 3, 4, 8, 12, 18, 24, 30, 36, and 48, as well as posttreatment follow-up weeks (FWs) 4, 12, 20, and 24. All patients who completed treatment with study drug or discontinued treatment prematurely (except nonresponders) immediately entered a 24-week follow-up period.
The study protocol was approved by the institutional review boards of participating institutions and was conducted in accordance with the Declaration of Helsinki and provisions of Good Clinical Practices. All patients provided written informed consent.
Study Objective.
The objective of this study was to select an optimal dose of TBV by comparing the efficacy and safety of three TBV dose levels versus RBV based on body weight, both administered with peg-IFN alfa-2b to therapy-naive compensated patients with genotype 1 chronic hepatitis C.
Efficacy Assessments.
The primary efficacy endpoint was early virologic response (EVR) defined as the proportion of patients with at least a 2-log decrease from baseline in serum HCV RNA levels at TW12. Additional efficacy endpoints assessed in the trial included SVR; undetectable HCV RNA at TW4, TW24, and TW48; and viral relapse for those who were responders at the end of treatment. Subgroup analyses were carried out to determine the impact of various baseline demographic factors such as sex, age, race, weight, baseline HCV RNA, and fibrosis score on response.
Lack of efficacy was defined as less than a 2-log decrease of HCV RNA (IU/mL) at TW12 or detectable HCV RNA at TW24. Relapse rates were calculated by measuring the proportion of responding patients whose plasma HCV levels changed from undetectable at end of treatment to detectable at FW24.
Safety Assessments.
The primary safety endpoint was the proportion of patients with Hb < 10 g/dL at any time during the treatment period. Subgroup analyses were carried out to determine the impact of various baseline demographic factors such as sex, age, race, weight, baseline HCV RNA, and fibrosis score on safety. Safety assessments included laboratory values, vital signs, and monitoring of adverse events (AEs) at each study visit. Patients who discontinued therapy prematurely due to an AE were followed to study completion. Stepwise reductions in peg-IFN, RBV, and TBV dosages were allowed to manage AEs or laboratory abnormalities that had reached predetermined thresholds of severity. If a dose modification of TBV or RBV was required for nonhematologic AEs, the dose was decreased in a stepwise manner, starting with a reduction of approximately 20% of the assigned dose. Hematologic AEs, except anemia, initially required a dose reduction of 50%. Anemia AEs were managed according to presence or absence of cardiac disease. Upon AE resolution, increases of peg-IFN, RBV, or TBV dose in a reverse stepwise manner could be attempted at the investigator's discretion. Use of ESAs was prohibited.
Because diarrhea was identified as an AE of special interest in previous clinical trials, a more extensive diarrhea history was obtained at baseline, and a diarrhea-specific AE report form was developed and employed in this trial. Diarrhea was classified on the form by common toxicity criteria grades of 1 to 4 (mild to severe). A diarrhea management plan was developed and employed. An independent data monitoring committee convened at various time points during the study treatment period to assess safety but also to determine the risk-benefit ratio considering the higher dosages studied.
Pharmacokinetic Analyses.
Serial plasma samples for the determination of TBV and RBV concentrations were collected across the first dosing interval (0-12 hours) of the twice daily dosing regimen at TW4 and TW12 in a representative subset of the patients at select sites for noncompartmental pharmacokinetic analysis and assessment of dose linearity. In addition, predose plasma samples for determination of TBV and RBV concentrations were obtained at each treatment week with an assessment of steady state at TW4.
Statistical Analyses.
There were 275 patients enrolled in the study, with approximately 70 patients in each of the four treatment groups. The projected study power was 70% to detect a linear trend in proportions as well as to detect noninferiority of TBV versus RBV using a margin of 12%.
Analysis of the primary efficacy and safety variables used data from the intent-to-treat (ITT) population, defined as patients who were randomized and received at least one dose of study drug.
The per-protocol population, defined as ITT patients with no major protocol deviations, no use of prohibited concomitant medications, and who completed treatment with >80% compliance, was used for the sensitivity analysis at TW12, TW24, and TW48 and FW4, FW12, and FW24.
Unless otherwise noted, all tests of hypotheses were two-sided at the overall 5% level of significance. The trend test determined the dose response relationship of the three TBV treatment groups, and the Fisher's exact test was performed for the various treatment group comparisons. For each of these three comparisons, the difference in responder rate and associated 95% confidence interval was determined. Once the optimum TBV dose was identified, a test of noninferior efficacy was performed by comparing the proportions of responders at TW12 in the optimal TBV and RBV treatment arms. Chi-squared or the Fisher's exact test compared anemia rates between the TBV and RBV groups with a 95% confidence interval.
Secondary efficacy measures included the SVR defined as HCV RNA <100 copies/mL (39 IU/mL) and/or at least a 2-log decrease from baseline at TW4, TW24, TW48 and FW4 and FW12 and relapse rates at FW4, FW12, and FW24. Secondary safety measures included the comparison of incidence of treatment-emergent adverse events.
Subgroup analysis by HCV RNA levels at baseline, body weight, age, sex, race, and baseline fibrosis were performed using the trend test and the Fisher's exact test for the primary endpoint. In addition, the Cochran-Mantel-Haenszel procedure, with the Breslow-Day test was used to examine the homogeneity of treatment effect across strata.
The investigators and the sponsor managed the data for this study. The sponsor completed the statistical analysis. The authors had access to the clinical study report and have either written or provided intellectual input to the manuscript.
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Hepatology Sept 24 2010
Fred Poordad1,*,, Eric Lawitz2, Mitchell L. Shiffman3, Tarek Hassanein4, Andrew J. Muir5, Bruce R. Bacon6, Jamie Heise7, Deanine Halliman7, Eric Chun7, Janet Hammond7
"In conclusion, TBV administered in a weight-based fashion demonstrated similar rates of efficacy to RBV via SVR with significantly less anemia and lower rates of dose modification. The recommended dose of TBV for future development in patients with chronic hepatitis C genotype 1 is 25 mg/kg. These data suggest TBV may be an effective agent to substitute for RBV in the future and could be incorporated in upcoming trials using emerging small molecules for HCV treatment......However, diarrhea and insomnia were more common (>10% different) in the groups that received TBV, whereas anemia was more common (>10% different) in the RBV group (Table 3). The mean insomnia rate of the TBV arms was 35% compared to 24% for the RBV arm and was not considered clinically relevant. The mean TBV diarrhea rate was 39% versus 23% in the RBV group."
ABSTRACT
Ribavirin-induced hemolytic anemia can prompt dose reductions and lower sustained virologic response (SVR) rates in the treatment of patients with chronic hepatitis C. The study aimed to determine if weight-based dosing of taribavirin (TBV), an oral prodrug of ribavirin (RBV), demonstrated efficacy comparable to RBV while maintaining its previously demonstrated anemia advantage with fixed dose administration. A U.S. phase 2b randomized, open-label, active-controlled, parallel-group study was conducted in 278 treatment-naive patients infected with genotype 1 who were stratified by body weight and baseline viral load. Patients were randomized 1:1:1:1 to receive TBV (20, 25, or 30 mg/kg/day) or RBV (800-1400 mg/day) with pegylated interferon alfa-2b for 48 weeks. The SVR rates in this difficult-to-cure patient demographics (mean age, 49 years; 61% male; 30% African American or Latino; high viral load; advanced fibrosis; and mean weight, 82 kg) were 28.4%, 24.3%, 20.6%, and 21.4% in the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. There were no statistical differences in the efficacy analyses. Anemia rates were significantly lower (P < 0.05) in the 20 and 25 mg/kg/day TBV treatment groups (13.4% and 15.7%, respectively) compared to RBV (32.9%). The most common adverse events in all groups were fatigue, diarrhea, and insomnia. Diarrhea, reported in 38% of TBV patients versus 21% of RBV patients, was generally mild and not dose-limiting.
Conclusion: All TBV doses demonstrated efficacy and tolerability comparable to that of RBV; however, the 25 mg/kg dose demonstrated the optimal balance of safety and efficacy. Anemia rates were significantly lower for TBV given at 20-25 mg/kg than RBV. These data suggest weight-based dosing with TBV provides a safe and effective treatment alternative to RBV for chronic hepatitis C.
Adverse Events Requiring Dose Modification or Discontinuation.
The percentages of patients with AEs leading to dose reduction or discontinuations are shown in Table 5. Dose modifications of TBV or RBV were most common in the TBV 30 mg/kg/day and RBV groups. Dose reductions were less frequent in the 20 and 25 mg/kg TBV groups compared to RBV by 21% and 12.9%, respectively. The proportion of patients withdrawn from the study as a result of adverse events were 12%, 25%, 19%, and 26% for the 20, 25, 30 mg/kg TBV groups and RBV group, respectively. The proportion of patients withdrawn for anemia adverse events was 1%, 4%, 4%, and 6%, for the 20, 25, and 30 mg/kg groups and the RBV group, respectively. The corresponding number of patients withdrawn for diarrhea AEs was 1%, 1%, 3%, and 0%. Dose reductions due to anemia were 7.5%, 12.9%, 20.6%, and 30% for the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. Stepwise reductions in peg-IFN, RBV, and TBV dosages were used primarily to manage anemia AEs.
Ribavirin (RBV) is essential for the treatment of chronic hepatitis C virus (HCV) infection. When used in combination with peginterferon alfa (peg-IFN alfa), it significantly enhances on-treatment virologic response and reduces relapse.1-3 RBV has been demonstrated to be essential in achieving high rates of sustained virologic response (SVR) when used in combination with direct-acting antiviral agents.4-6 One of the most significant toxicities of RBV is hemolytic anemia.5, 7 When used as monotherapy, RBV-induced hemolytic anemia is marginal because of a compensatory reticulocytosis.8, 9 However, peg-IFN alfa suppresses the bone marrow and significantly reduces reticulocytosis. Therefore, anemia associated with the combination of IFN and RBV therapy is much greater. Approximately 25%-30% of patients receiving peg-IFN and RBV develop a decline of 4 g or greater in hemoglobin (Hb).1, 2, 10 This significantly impairs quality of life and leads to dose reduction and premature discontinuation of treatment in 15%-30% of patients.1, 3, 11, 12 Decreasing the dose of RBV to below 10.6 mg/kg body weight/day during the first 12 weeks of treatment has been shown to increase relapse rates and reduce SVR in both treatment-naive patients and during retreatment.11, 13, 14
Taribavirin (TBV), formerly known as Viramidine, is a nucleoside analogue and oral prodrug of RBV that is converted from TBV to RBV by adenosine deaminase. Its structural difference from RBV, a positively charged carboxamidine group at position 3, significantly reduces the ability of this agent to enter red cells. Because accumulation of RBV within red blood cells is the primary mechanism causing hemolytic anemia, TBV should therefore be associated with significantly less anemia.
Two previous phase 3 clinical trials, ViSER 1 and ViSER 2 (Viramidine's Safety and Efficacy versus Ribavirin), compared a fixed dose of TBV 600 mg twice a day to weight-based dosing (WBD) of RBV 1000 mg/1200 mg (²75 kg/>75 kg body weight), in combination with either peg-IFN alfa-2b or peg-IFN alfa-2a, respectively.15, 16 Both ViSER studies met the primary safety endpoint defined as Hb < 10 g/dL or at least a 2.5 g/dL decrease from baseline at any time point during therapy. Statistically less anemia was observed in patients treated with TBV compared to RBV. However, the primary efficacy endpoint of these studies-a noninferior SVR between the TBV and RBV groups-was not achieved. Detailed subgroup analyses of the data suggested the reasons for the lower SVR in TBV-treated patients were: fixed dose as opposed to WBD and the selection of an inadequate dose. The present study explored several higher WBD regimens of TBV to determine a dosage regimen that was able to deliver comparable responses to RBV with less anemia.
RESULTS
Study Patients.
A total of 278 patients were randomized at 51 U.S. centers between March 2007 and October 2008. A total of 86 (41%) of patients in the TBV arms and 25 (36%) in the RBV arm completed treatment and follow-up. Overall, 122 (59%) patients withdrew prematurely in the TBV arms compared to 45 (64%) in the RBV group. The most commonly cited reasons for premature withdrawal were lack of response (29%) and adverse events (20%). Figure 1 shows the disposition of patients during treatment.
Baseline characteristics across the four treatment groups were similar (Table 1). The majority of patients were male (61%) with a mean weight of 82.1 kg and mean age of 49 years. African American or Latino patients accounted for 30% of the study population and 81% had high viral load defined as >400,000 IU/mL at baseline.
Efficacy.
The proportions of patients in the ITT population with an EVR, the primary endpoint of this study, were comparable between all groups with no statistical difference versus RBV. EVR was achieved in 64.2% (43 of 67) in the 20 mg/kg group, 57.1% (40 of 70) in the 25 mg/kg group, 54.4% (37 of 68) of the 30 mg/kg group and 51.4% (36 of 70) in the RBV group. Virologic response for TW4, 12, 24, and 48 as well as SVR are shown in Table 2. The proportion of patients with undetectable HCV RNA at every time point was similar between the TBV and RBV groups. Although responder rates were numerically lower at TW12 in the TBV 30 mg/kg group and somewhat higher at TW24 and TW48 in the TBV 20 mg/kg group, they were not significantly different for any of the TBV doses compared with RBV.
The relapse rates for the TBV groups (35%, 20 mg/kg; 21%, 25 mg/kg; 14%, 30 mg/kg) were inversely proportional to the TBV dose and are most likely indicative of the recognized effects of RBV dosing (Fig. 2). The lowest TBV dose resulted in the lowest RBV exposure and subsequently, the greatest relapse rate (35%).
The SVR rates observed in the per-protocol population were 60%, 64%, 62%, and 62% for the 20, 25, and 30 mg/kg/day TBV groups and the RBV group, respectively, and there were no statistically significant differences between the groups. These results were more than double the ITT SVR demonstrating maximal response as RBV or TBV exposure increases with adherence to therapy.
Safety.
The most common AEs were typical of those previously reported for chronic hepatitis C therapy with peg-IFN and RBV. However, diarrhea and insomnia were more common (>10% different) in the groups that received TBV, whereas anemia was more common (>10% different) in the RBV group (Table 3). The mean insomnia rate of the TBV arms was 35% compared to 24% for the RBV arm and was not considered clinically relevant. The mean TBV diarrhea rate was 39% versus 23% in the RBV group.
Diarrhea, which was previously noted to occur more frequently in the ViSER studies, was also reported more frequently in the current study. It occurred predominantly during the first 12 weeks of therapy and was generally mild, not dose-limiting and of short duration. Through FW24, cumulative diarrhea rates occurred in 40.3%, 37.1%, and 36.8% of patients on 20, 25, and 30 mg/kg/day TBV respectively. This indicates no apparent TBV dose relationship. In the majority of cases diarrhea classification was "mild" or "moderate." Serious diarrhea AEs (grade 3) were reported in two patients and were determined by their physician assessment as un-related to study medication and due to concomitant disease. There were no grade 4 diarrhea events reported. During the 24-week follow up period, the incidence of diarrhea returned to baseline at a frequency similar to that of RBV.
The cumulative incidence of anemia throughout the trial is shown in Table 4. The 20 and 25 mg/kg groups were statistically significantly lower than the RBV group (P < 0.05) at all time points. The anemia rate of TBV 30 mg/kg was lower than that observed with RBV but did not achieve statistical significance, other than at week 4. The pharmacokinetic analysis showed this effect correlated with RBV plasma exposure in the TBV group. Exposure of RBV associated with TBV dosing was consistently lower compared to RBV exposure due to RBV dosing by pharmacokinetic measures (data not shown) until after TW18. At that time, TBV 30 mg/kg/day generated RBV plasma trough levels that exceeded the levels observed due to RBV oral administration. In addition, the exposure of TBV and RBV due to TBV were dose linear over the dosage range 20-30 mg/kg/day evaluated.
Adverse Events Requiring Dose Modification or Discontinuation.
The percentages of patients with AEs leading to dose reduction or discontinuations are shown in Table 5. Dose modifications of TBV or RBV were most common in the TBV 30 mg/kg/day and RBV groups. Dose reductions were less frequent in the 20 and 25 mg/kg TBV groups compared to RBV by 21% and 12.9%, respectively. The proportion of patients withdrawn from the study as a result of adverse events were 12%, 25%, 19%, and 26% for the 20, 25, 30 mg/kg TBV groups and RBV group, respectively. The proportion of patients withdrawn for anemia adverse events was 1%, 4%, 4%, and 6%, for the 20, 25, and 30 mg/kg groups and the RBV group, respectively. The corresponding number of patients withdrawn for diarrhea AEs was 1%, 1%, 3%, and 0%. Dose reductions due to anemia were 7.5%, 12.9%, 20.6%, and 30% for the 20, 25, and 30 mg/kg TBV groups and the RBV group, respectively. Stepwise reductions in peg-IFN, RBV, and TBV dosages were used primarily to manage anemia AEs.
DISCUSSION
The present study demonstrated that WBD TBV achieved comparable efficacy to RBV as demonstrated by SVR. This was observed in all three TBV WBD treatment groups, which met the study's primary endpoint. Notably, patients treated with TBV had less than half the anemia and a 13%-21% lower dose modification rate compared to RBV treated patients treated. These results suggest WBD of TBV can significantly improve the tolerability of HCV treatment while maintaining efficacy. Specifically, the 25 mg/kg dose offered the optimal balance of efficacy and safety in this patient population.
The relapse rates for the TBV groups were inversely proportional to the TBV dose and are most likely indicative of the recognized effects of RBV dosing. The similar SVR and higher relapse rates observed in the 20 mg/kg group are a reflection of higher end of treatment response rates. The high on-treatment response can be explained by the greater percentage of women and Caucasians randomized to this group. The higher relapse rate observed in the 20 mg/kg group is likely due to the lower TBV/RBV exposure.
The overall response rates observed in this trial appeared lower than expected for a Caucasian based genotype 1 trial. However, the demographics of this patient population were quite different than in many other controlled clinical trials reported to date. Approximately 20% of enrolled patients were African American, which was more than double many previous controlled clinical trials.1, 3 African Americans with genotype 1 HCV, have lower response rates to peg-IFN/RBV than Caucasians.17 Recent studies also demonstrated that African Americans have a much lower population frequency of a gene associated with SVR.18 A genetic predisposition for nonresponse in these patients is not likely to be overcome by a more favorable treatment, though the addition of direct acting antiviral agents should improve SVR rates in these populations. In addition to a high percentage of African and Latino races, other poor response characteristics present in the study population were: 81% of patients had high viral load; a higher age than reported in previous registration trials and up to 40% of patients had bridging fibrosis.1-3 The drop out rate in this trial was approximately 10% higher than other U.S.-based trials and this difference is likely related to the poor response characteristics described above.
Similar to dosing experiences with RBV, we found WBD with TBV provides optimal RBV exposure. The pharmacokinetics of TBV administered at doses of 20, 25, and 30 mg/kg/day demonstrated steady state by TW4 for both prodrug and parent drug. This is equivalent to what is seen of RBV exposure from a RBV weight adjusted dosage of 800-1400 mg/day. TBV pharmacokinetics were dose linear, predictable and consistently generated RBV plasma levels that were lower than seen by RBV administration, without an impact on efficacy. The lower RBV concentrations positively affected the critical safety concern for RBV-anemia. The TBV 25 mg/kg/day dose had similar efficacy results as WBD RBV with significantly lower anemia rates.
As was reported in previous TBV clinical trials, an increase in the frequency of diarrhea was observed in all TBV cohorts when compared to RBV. Diarrhea was considered an adverse event of special interest in this study, therefore a more rigorous medical history specific to diarrhea was collected prospectively and this likely accounted for increased reporting frequency. The majority of cases across all treatment groups were classified as common toxicity criteria grade 1, occurred early in therapy and were single episode. The exact mechanism of action leading to diarrhea in patients receiving TBV remains unknown. After the end of treatment, the incidence of diarrhea returned to baseline, suggesting it is treatment related, and reversible.
Anemia is considered to be significant when the Hb falls below 10 g/dL. Patients treated with TBV had lower rates of anemia throughout the entire 48 weeks of treatment. Within the first 12 weeks of treatment, when maintaining the dose of RBV has been shown to be most critical, significant anemia was observed in only 7%-15% of patients treated with TBV compared to 24% of patients treated with RBV. As a result, fewer patients treated with TBV required dose reductions (13%-28%) compared to 32% of patients treated with RBV. Less frequent dose modification in patients treated with TBV may alleviate the need to use ESAs. Several studies have now demonstrated the use of ESAs can significantly decrease the need to dose reduce RBV and leads to an improvement in the quality of life during HCV treatment,19-21 but fail to improve the SVR.22 However, the use of ESAs adds significant cost to HCV treatment and is associated with significant adverse events including thrombosis and red cell aplasia.19, 23 Thus, limiting anemia during HCV treatment is clearly desirable.
The future of HCV treatment will incorporate potent antiviral agents such as protease and polymerase inhibitors, with peg-IFN and RBV. Despite its toxicity, RBV remains critical to optimizing SVR rates of hepatitis C and is unlikely to be replaced by the first generation direct acting antiviral agents.4-6 Data from the new small molecule trials have demonstrated that anemia is a common consequence of treatment of protease inhibitors and when used with RBV there appears to be a significant need to either dose modify RBV or use ESAs to limit anemia.4-6 Therefore, TBV should be considered as a RBV substitution to future clinical trials with peg-IFN and protease inhibitors as it may yield a significant treatment advantage over RBV.
Other potential TBV opportunities that need to be explored in clinical trials would be in patients susceptible to anemia and where RBV is contraindicated (including chronic renal failure and hemoglobinopathies). Patients who are slow to respond and may require 72 weeks of treatment may also benefit from using TBV as opposed to RBV. The lower anemia rates associated with TBV may allow these patients to remain on a prolonged course to achieve SVR. Finally, TBV may be particularly useful in liver transplant recipients with recurrent HCV and in patients coinfected with HCV and human immunodeficiency virus. Many of these patients have preexisting anemia and this worsens considerably during treatment with peg-IFN and RBV. The low SVRs in these populations are at least in part secondary to anemia and the inability to optimize RBV dosage.
In conclusion, TBV administered in a weight-based fashion demonstrated similar rates of efficacy to RBV via SVR with significantly less anemia and lower rates of dose modification. The recommended dose of TBV for future development in patients with chronic hepatitis C genotype 1 is 25 mg/kg. These data suggest TBV may be an effective agent to substitute for RBV in the future and could be incorporated in upcoming trials using emerging small molecules for HCV treatment.
METHODS & PATIENTS
Study Patients.
Approximately 260 patients were planned for enrollment in the study, with approximately 65 patients in each of the four treatment groups. Eligible patients were treatment-naive, at least 18 years of age, diagnosed with chronic HCV genotype 1 infection (>2000 copies/mL or >780 IU/mL), and showed histologic changes consistent with chronic HCV as demonstrated on liver biopsy within 3 years of screening. Patients were excluded from the study if they had histologic evidence of cirrhosis (F4), low Hb concentrations (men, <13 g/dL; women, <12 g/dL), neutropenia (absolute neutrophil count <1200 x 103/µL), thrombocytopenia (<90 x 103 platelets/µL) or serum creatinine levels ³1.5 mg/dL. Additional exclusion criteria included chronic hepatic disease other than HCV, human immunodeficiency virus, or hepatitis B coinfection; severe psychiatric disorders; alcoholism or drug addiction within 1 year of screening; use of erythropoiesis-stimulating agents (ESAs); and presence of comorbid conditions considered significant by the investigator.
Study Design.
This was a phase 2b, multicenter, randomized, open-label, active-control, and parallel-group trial. Although the study was open-label, the sponsor was blinded to treatment allocation and viral load results until treatment week 12. Patients were enrolled at 51 centers in the United States. Patients were stratified by serum HCV RNA titers (²780,000 IU/mL or >780,000 IU/mL) and baseline weight (²75 or >75 kg). An interactive voice response system was used to randomize patients in a 1:1:1:1 ratio to receive weight-based TBV 20 mg/kg/day, 25 mg/kg/day, or 30 mg/kg/day (Valeant Pharmaceuticals North America, Aliso Viejo, CA) or weight-based RBV at 800, 1000, 1200, or 1400 mg/day (Copegus; Hoffmann-La Roche, Nutley, NJ) in combination with peg-IFN alfa 2b (PegIntron; Schering Corp., Kenilworth, NJ). All patients received doses twice daily with their morning and evening meals.
Patients were treated for 48 weeks, but treatment was discontinued for evidence of nonresponse defined as <2-log decline at week 12 or a positive viral load at week 24. Study treatment was initiated on day 1 and clinic visits occurred at treatment weeks (TWs) 1, 2, 3, 4, 8, 12, 18, 24, 30, 36, and 48, as well as posttreatment follow-up weeks (FWs) 4, 12, 20, and 24. All patients who completed treatment with study drug or discontinued treatment prematurely (except nonresponders) immediately entered a 24-week follow-up period.
The study protocol was approved by the institutional review boards of participating institutions and was conducted in accordance with the Declaration of Helsinki and provisions of Good Clinical Practices. All patients provided written informed consent.
Study Objective.
The objective of this study was to select an optimal dose of TBV by comparing the efficacy and safety of three TBV dose levels versus RBV based on body weight, both administered with peg-IFN alfa-2b to therapy-naive compensated patients with genotype 1 chronic hepatitis C.
Efficacy Assessments.
The primary efficacy endpoint was early virologic response (EVR) defined as the proportion of patients with at least a 2-log decrease from baseline in serum HCV RNA levels at TW12. Additional efficacy endpoints assessed in the trial included SVR; undetectable HCV RNA at TW4, TW24, and TW48; and viral relapse for those who were responders at the end of treatment. Subgroup analyses were carried out to determine the impact of various baseline demographic factors such as sex, age, race, weight, baseline HCV RNA, and fibrosis score on response.
Lack of efficacy was defined as less than a 2-log decrease of HCV RNA (IU/mL) at TW12 or detectable HCV RNA at TW24. Relapse rates were calculated by measuring the proportion of responding patients whose plasma HCV levels changed from undetectable at end of treatment to detectable at FW24.
Safety Assessments.
The primary safety endpoint was the proportion of patients with Hb < 10 g/dL at any time during the treatment period. Subgroup analyses were carried out to determine the impact of various baseline demographic factors such as sex, age, race, weight, baseline HCV RNA, and fibrosis score on safety. Safety assessments included laboratory values, vital signs, and monitoring of adverse events (AEs) at each study visit. Patients who discontinued therapy prematurely due to an AE were followed to study completion. Stepwise reductions in peg-IFN, RBV, and TBV dosages were allowed to manage AEs or laboratory abnormalities that had reached predetermined thresholds of severity. If a dose modification of TBV or RBV was required for nonhematologic AEs, the dose was decreased in a stepwise manner, starting with a reduction of approximately 20% of the assigned dose. Hematologic AEs, except anemia, initially required a dose reduction of 50%. Anemia AEs were managed according to presence or absence of cardiac disease. Upon AE resolution, increases of peg-IFN, RBV, or TBV dose in a reverse stepwise manner could be attempted at the investigator's discretion. Use of ESAs was prohibited.
Because diarrhea was identified as an AE of special interest in previous clinical trials, a more extensive diarrhea history was obtained at baseline, and a diarrhea-specific AE report form was developed and employed in this trial. Diarrhea was classified on the form by common toxicity criteria grades of 1 to 4 (mild to severe). A diarrhea management plan was developed and employed. An independent data monitoring committee convened at various time points during the study treatment period to assess safety but also to determine the risk-benefit ratio considering the higher dosages studied.
Pharmacokinetic Analyses.
Serial plasma samples for the determination of TBV and RBV concentrations were collected across the first dosing interval (0-12 hours) of the twice daily dosing regimen at TW4 and TW12 in a representative subset of the patients at select sites for noncompartmental pharmacokinetic analysis and assessment of dose linearity. In addition, predose plasma samples for determination of TBV and RBV concentrations were obtained at each treatment week with an assessment of steady state at TW4.
Statistical Analyses.
There were 275 patients enrolled in the study, with approximately 70 patients in each of the four treatment groups. The projected study power was 70% to detect a linear trend in proportions as well as to detect noninferiority of TBV versus RBV using a margin of 12%.
Analysis of the primary efficacy and safety variables used data from the intent-to-treat (ITT) population, defined as patients who were randomized and received at least one dose of study drug.
The per-protocol population, defined as ITT patients with no major protocol deviations, no use of prohibited concomitant medications, and who completed treatment with >80% compliance, was used for the sensitivity analysis at TW12, TW24, and TW48 and FW4, FW12, and FW24.
Unless otherwise noted, all tests of hypotheses were two-sided at the overall 5% level of significance. The trend test determined the dose response relationship of the three TBV treatment groups, and the Fisher's exact test was performed for the various treatment group comparisons. For each of these three comparisons, the difference in responder rate and associated 95% confidence interval was determined. Once the optimum TBV dose was identified, a test of noninferior efficacy was performed by comparing the proportions of responders at TW12 in the optimal TBV and RBV treatment arms. Chi-squared or the Fisher's exact test compared anemia rates between the TBV and RBV groups with a 95% confidence interval.
Secondary efficacy measures included the SVR defined as HCV RNA <100 copies/mL (39 IU/mL) and/or at least a 2-log decrease from baseline at TW4, TW24, TW48 and FW4 and FW12 and relapse rates at FW4, FW12, and FW24. Secondary safety measures included the comparison of incidence of treatment-emergent adverse events.
Subgroup analysis by HCV RNA levels at baseline, body weight, age, sex, race, and baseline fibrosis were performed using the trend test and the Fisher's exact test for the primary endpoint. In addition, the Cochran-Mantel-Haenszel procedure, with the Breslow-Day test was used to examine the homogeneity of treatment effect across strata.
The investigators and the sponsor managed the data for this study. The sponsor completed the statistical analysis. The authors had access to the clinical study report and have either written or provided intellectual input to the manuscript.
Amgen and Johnson & Johnson Recall Anemia Drugs EPO Procrit
Amgen and Johnson & Johnson Recall Anemia Drugs EPO Procrit
September 24, 2010
By ANDREW POLLACK
http://prescriptions.blogs.nytimes.com
Amgen’s anemia drugs have been embroiled in controversy about their safety for several years as evidence has mounted that their overuse can cause heart attacks or strokes or make cancer worse. Now comes yet another problem, though presumably a temporary one.
Amgen announced Friday morning that it and Johnson & Johnson were recalling various lots of their anemia drugs, Epogen and Procrit, because extremely thin, barely visible glass flakes have been found in the vials.
Amgen said the particles could cause clots and other problems if the drugs were given by intravenous infusion or lumps and immune system reactions if injected under the skin.
However, the company said it had received no complaints or had heard of no problems that could be “directly attributed to’’ the glass particles. A spokeswoman for Amgen, Emma Hurley, said the company’s evaluation “found a low potential to impact patients.’’
Amgen said the recall was being done in coordination with the Food and Drug Administration.
Both drugs are the same substance, a protein called erythropoietin, or epoetin alfa, which is made by Amgen in Puerto Rico. Amgen sells the protein as Epogen for the treatment of anemia in kidney dialysis patients.
Johnson & Johnson sells it as Procrit for other uses, such as for anemia caused by kidney disease that does not yet require dialysis and for anemia caused by cancer chemotherapy.
Ms. Hurley said Amgen did not anticipate that the problem would affect the availability of Epogen and would not have a material financial impact on Amgen. Johnson & Johnson also said supply of Procrit should not be affected.
Amgen discovered the flakes, she said, during a recent inspection of vials of the drug. The flakes were formed by the interaction of the drug formulation with the glass vials over the shelf life of the product.
Amgen has now reduced the shelf life to either 12 or 15 months, depending on the type of vial, from 36 months.
No recent change in the formulation of the drug would explain the problem, she said. That raises the possibility that the problem has been occurring undetected for a sometime. Epogen was first approved in 1989.
A third anemia drug, Amgen’s Aranesp, is a slightly different protein and is made separately from the other two.
Interactions between a drug and a vial are not unknown and can be serious. Several years ago, dozens of patients in Europe who were treated with Johnson & Johnson’s Eprex — basically the European version of Procrit — developed a serious condition called pure red cell aplasia, which left them dependent on blood transfusions. Johnson & Johnson eventually attributed the problem to a reaction between the drug formulation and the stoppers used in the vials.
The anemia drugs have all been huge sellers with sales of two billion dollars a year or more. But concerns have arisen in recent years that overuse of the drugs has contributed to problems like heart attacks and strokes and, in cancer patients, a worsening of the cancer.
Sales, particularly for use in treating cancer patients, have plummeted as the Food and Drug Administration has put extra warnings on the drugs’ labels and as Medicare has become more restrictive in paying for the drugs.
The F.D.A. will hold another advisory committee meeting on Oct. 18 to review the latest findings of possible harm to patients with kidney disease from the drugs.
September 24, 2010
By ANDREW POLLACK
http://prescriptions.blogs.nytimes.com
Amgen’s anemia drugs have been embroiled in controversy about their safety for several years as evidence has mounted that their overuse can cause heart attacks or strokes or make cancer worse. Now comes yet another problem, though presumably a temporary one.
Amgen announced Friday morning that it and Johnson & Johnson were recalling various lots of their anemia drugs, Epogen and Procrit, because extremely thin, barely visible glass flakes have been found in the vials.
Amgen said the particles could cause clots and other problems if the drugs were given by intravenous infusion or lumps and immune system reactions if injected under the skin.
However, the company said it had received no complaints or had heard of no problems that could be “directly attributed to’’ the glass particles. A spokeswoman for Amgen, Emma Hurley, said the company’s evaluation “found a low potential to impact patients.’’
Amgen said the recall was being done in coordination with the Food and Drug Administration.
Both drugs are the same substance, a protein called erythropoietin, or epoetin alfa, which is made by Amgen in Puerto Rico. Amgen sells the protein as Epogen for the treatment of anemia in kidney dialysis patients.
Johnson & Johnson sells it as Procrit for other uses, such as for anemia caused by kidney disease that does not yet require dialysis and for anemia caused by cancer chemotherapy.
Ms. Hurley said Amgen did not anticipate that the problem would affect the availability of Epogen and would not have a material financial impact on Amgen. Johnson & Johnson also said supply of Procrit should not be affected.
Amgen discovered the flakes, she said, during a recent inspection of vials of the drug. The flakes were formed by the interaction of the drug formulation with the glass vials over the shelf life of the product.
Amgen has now reduced the shelf life to either 12 or 15 months, depending on the type of vial, from 36 months.
No recent change in the formulation of the drug would explain the problem, she said. That raises the possibility that the problem has been occurring undetected for a sometime. Epogen was first approved in 1989.
A third anemia drug, Amgen’s Aranesp, is a slightly different protein and is made separately from the other two.
Interactions between a drug and a vial are not unknown and can be serious. Several years ago, dozens of patients in Europe who were treated with Johnson & Johnson’s Eprex — basically the European version of Procrit — developed a serious condition called pure red cell aplasia, which left them dependent on blood transfusions. Johnson & Johnson eventually attributed the problem to a reaction between the drug formulation and the stoppers used in the vials.
The anemia drugs have all been huge sellers with sales of two billion dollars a year or more. But concerns have arisen in recent years that overuse of the drugs has contributed to problems like heart attacks and strokes and, in cancer patients, a worsening of the cancer.
Sales, particularly for use in treating cancer patients, have plummeted as the Food and Drug Administration has put extra warnings on the drugs’ labels and as Medicare has become more restrictive in paying for the drugs.
The F.D.A. will hold another advisory committee meeting on Oct. 18 to review the latest findings of possible harm to patients with kidney disease from the drugs.
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