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WIN-R Study: final results of Weight-Based dosing study of ribavirin in treatment-naive patients
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WIN-R: Weight Based Interferon and Ribavirin trial.
Reported by Jules Levin
The final study results were reported at AASLD Nov 2005 (San Francisco) in a Late Breaker oral session by Ira Jacobson (Weill Medical College of Cornell University, New York, NY).
Comments from Jules Levin: there appear to be several confounders in interpreting the study results. 4900 patients were enrolled, 4200 were in the ITT analysis. A high 30% of patients discontinued study therapy for adverse events or 'non-medical' reasons, 37% overall (7% for lack of efficacy); the overall ITT SVR rates were low 41% (fixed dose) - 44% (weight-based dose), probably due to high discontinuation rates. More patients receiving WBD had hemoglobin <11 mg/dL (32% FD vs 46% WBD). There appeared to be more dose reductions due to anemia in WIN-R, but no more discontinuations. The study results found benefit to weight-based dosing in hard to treat patient populations: African-Americans, genotype 1 high viral load, but not in genotypes 2/3 or in genotype 1 low viral load. However, weight-based dosing of ribavirin has been in use by doctors and care providers. Typically, doctors prescribe 800, 1000, or 1200 mg daily of RBV based on a patient’s weight. Still, a key question remaining: The WIN-R study investigators concluded that 1400 mg was more effective in patients weighing >105 kg (2.2 lbs per kg) 47% SVR vs 34%. This study result is confounded because of the high discontinuation rates, the differences in hemoglobin <11 between FD & WBD, and the differences between enrollment numbers & the number of patients in the ITT analysis.
The trial of Manns (Lancet 2001) established PEG IFN alfa-2b 1.5 ug/kg/wk plus ribavirin (RBV) as an option for the treatment of chronic hepatitis C (CHC). Logistic regression analysis (post-study analysis) demonstrated a relationship between RBV dose in mg/kg and SVR. This analysis was conducted after the study was completed & was not accepted by the FDA as a basis for weight-based dosing of ribavirin. So the FDA requested Schering conduct a prospective study to answer the question: does weight based dosing of ribavirin improve SVR. Ribavirin dosing, however, is already and has always been since by weight: patients receive 800, 1000, or 1200 mg daily based on weight. The WIN-R study incorporated a dose of 1400 mg for heavy weight patients.
The aim of this study: "To compare prospectively the efficacy and safety of RBV administered as a flat dose 800 mg/day (FD) versus RBV 800-1400 mg/day (WBD) in combination with PEG IFN alfa-2b 1.5 ug/kg/week in the treatment
of CHC in treatment-naive patients."
Patients in a community setting with CHC were randomized to PEG IFN alfa-2b 1.5 ug/kg once weekly plus RBV 800 mg/day or RBV based on weight: <65 kg - 800 mg/day, 65 to <85 kg - 1000mg/day, 85 to <105 kg - 1200 mg/day, and 105-125 kg - 1400 mg/day. Treatment was 48 weeks for patients with HCV G1
while patients with G2 or 3 were randomized to 24 or 48 weeks. Follow-up for all patients was 24 weeks. HCV RNA was determined by PCR (Taqman/SPRI, sensitivity 29 IU/ml) at weeks 24, 48 and 72. Dose reduction of RBV was required for hemoglobin (Hgb) <10 gm/dl and discontinuation for Hgb 8.5.
225 sites enrolled 4913 patients (2444 FD, fixed dose, and 2469 WBD, weight based dose) who received at least one dose of drug, resulting in the largest
HCV therapeutic trial to date.
Patients weighing <65 kg were allowed into trial & received 800 mg RBV.
Primary Efficacy Analysis:
Comparison of all patients dosed differently (≥65 kg), which represents 86% of patients entered into the study. All patients who received at least 1 dose of drug (ITT analysis).
BASELINE CHARACTERISTICS: 63% male; 45 yrs mean age; 83 kg weight; mean BMI: 28 kg/m3; 62% genotype 1; 45-49% HCV RNA>600,000 IU/mL; 30% stage 3-4. No apparent differences between FD & WBD arms.
11% of patients at baseline were >105 kg; 34% >86 - 105; 41% 65-85; 14% <65 kg. (n=4913)
The Primary Efficacy (ITT) Analysis was based on 4,223 patients. The program abstract book reported 1,808 patients (37%) discontinued therapy (15% for adverse events, 7% for lack of efficacy, 15% for 'non-medical' reasons). 30% of patients discontinued therapy for adverse events or for 'non-medical' reasons).
The ITT analysis (based on n=4,223) (4,913 patients were enrolled) reported:
End Of Treatment (EOT)
57% FD
59% WBD
SVR (24 weeks following EOT)
41% FD
44% WBD
The study reported differences in SVR based on weight, but there are questions about some of these results. They reported:
-- 52% SVR for FD if <65 kg & 49% for WBD.
-- 44% for patients receiving FD if 65-85 kg vs 45% for WBD.
So far no differences between FD & WBD.
ANEMIA
In the program abstract book, they reported serious adverse events were similar in FD & WBD groups, but hemoglobin <11 gm/dL occurred in 32% FD patients vs 46% of WBD patients, but was comparable between all 4 WBD subgroups. The mean hemoglobin levels were lower in the WBD compared to FD group as displayed in graph in oral presentation. There appeared to be more dose reductions due to anemia in WIN-R, but not more discontinuations.
DISCONTINUATIONS
For patients >85-105 kg (2.2 lbs per kg), they reported 39% for FD vs 42% for WBD. And for patients >105 kg, they reported 34% for FD vs 47% for WBD.
However, considering the high 37% overall discontinuation rate & the high 30% discontinuation rate for AEs & 'non-medical' reasons, how do you interpret this data. The high discontinuation rates are reflected in the difference between the ITT analysis of SVR rates vs the On-treatment analysis, which does not include the 30% discontinuations: 41% FD vs 44% WBD (p=0.02) ITT; 51% FD vs 56% WBD On-Treatment (p=0.004).
In addition, ribavirin is already dosed by weight: 800, 1000, or 1200. A remaining question is: do you dose 1400 mg for patients >105 kg? Its very hard to interpret the data in this study when there is such a high discontinuation rate. Its hard to decipher if patients can tolerate such a high dose of ribavirin, or perhaps more important, is such a high dose relevant or helpful in improving response rates.
They reported no differences in discontinuations between FD & WBD: 14% for AEs for FD & 15% for WBD; 23% for FD & 21% for WBD for 'other' reasons. Reported in oral presentation.
Secondary Analysis SVR in Completers
They reported SVR in patients who completed therapy in study. Still, the 30-37% discontinuation rates and the difference between 5000 enrolled and 4200 in ITT. analysis.
ALL PATIENTs
ITT:
41% FD, 44% WBD
G1: 29% FD, 34% WBD
G2/3: 60% FD, 62% WBD
Completers SVR
55% FD, 59% WBD
G1: 42% FD, 48% WBD
G2/3: 76% FD, 79% WBD
SVR Genotype 1
Overall, WIN-R ITT analysis reported 34% HCV genotype 1 SVR. In high viral load patients, they reported a difference in SVR between FD & WBD: 27% vs 32% (p=0.047) for genotype 1 patients. But in patients with low viral load the difference was not significant: 34% vs 39% (p=0.173). But again, due to the high discontinuation rates how do you interpret a potential benefit for patients with high viral load. In addition, RBV is already weight-based dosed, so in theory does this supposed benefit to WBD apply to all weight groups or only to patients >105 kg, hard to interpret.
AFRICAN-AMERICANS with Genotype 1
The SVR (n=362) reported for FD was 10% vs 21% for WBD (p-0.0004). again, does this apply to all weight groups or only to >105 kg. Its hard to interpret if this benefit applies to individual weight groups or only to certain weight groups. The EOT response was 16% for FD & 29% for WBD (p=0.006).
HCV Genotype 2/3 Response by Treatment Duration
Overall SVR was 60% for FD vs 62% for WBD, no difference (p=ns).
With 24 weeks therapy: 65% for FD vs 68% for WBD. For 48 weeks therapy, 58% for FD vs 60% for WBD. (They said: more missing f/u PCR data in 48 week group accounts for lower SVR in ITT analysis.) my comment: This suggests that 48 week treatment is more difficult to tolerate than 24 week treatment.
RELAPSE: Negative at EOT, Positive at F/U
They reported for all treated: 19% for FD, 15% for WBD
HCV 1: 29% FD, 23% WBD
HCV 2/3: 8% FD, 7% WBD
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