Clinical Trial Result Information

Protocol number
NR16046

Title of Study
The drug interaction companion protocol to NR15961: A randomized, partially blinded, multicenter, phase III, three arm study evaluating the efficacy and safety of peginterferon alfa-2a monotherapy versus combination therapy of peginterferon alfa-2a with ribavirin versus combination therapy of interferon alfa-2a with ribavirin for 48 weeks and 24 weeks of follow-up in patients with chronic hepatitis C coinfected with human immunodeficiency virus.

Sponsor
Hoffmann-La Roche Ltd.

Company division
Pharmaceutical

Product name
PEGASYS

Generic name
peginterferon alfa-2a (40KD)

Therapeutic area
Hepatitis C, Chronic

Clinical study summary
This nested drug-interaction substudy of the parent phase III study NR15691 evaluated potential drug interactions between ribavirin and two nucleoside reverse transcriptase inhibitor (NRTI) regimens (zidovudine plus lamivudine and stavudine plus lamivudine) administered concomitantly with ribavirin or placebo in combination with PEGASYS (peginterferon alfa-2a (40KD)). Patients participating in the sub-study were randomized to receive PEGASYS plus ribavirin, or PEGASYS plus placebo (plus stable HAART) for the 12 week study period.

Study center(s)
11 centers in the USA (including Puerto Rico) and Spain

Phase of development
III

Objectives
Primary: To examine in vivo ribavirin's effect on the intracellular phosphorylation of the NRTIs zidovudine, lamivudine, and/or stavudine in chronic hepatitis C (CHC) patients coinfected with HIV.
Secondary: (1) To examine in vivo ribavirin's effect on the pharmacokinetics of zidovudine, lamivudine, and/or stavudine in CHC patients coinfected with HIV. (2) To examine ribavirin's pharmacokinetics after 12 weeks of multiple dosing of HCV and HAART therapy in CHC patients coinfected with HIV.

Methodology
After a screening period of up to 35 days, patients received weekly sc injections of PEGASYS (180μg) and daily oral placebo or ribavirin (800 mg) for 12 weeks. Patients received a consistent zidovudine plus lamivudine or stavudine plus lamivudine dosing regimen as part of their HAART for at least 6 weeks prior to entry into the study. During the 12 week study period, patients were maintained on a fixed antiretroviral regimen. Blood samples were collected at baseline at predose (0) and at intervals up to 12 hours after the morning dose of zidovudine, lamivudine, and/or stavudine and at week 12 at predose (0) and at intervals upto 12 hours after the morning dose of NRTIs and ribavirin. Patients followed the procedures outlined in the main protocol NR15961. Pharmacokinetic assessments included intracellular concentrations of phosphorylated NRTIs and endogenous nucleoside triphosphates; and plasma concentrations of NRTIs and ribavirin. Pharmacodynamic assessments included HCV RNA titers at weeks 4 and 12, HIV RNA titers at weeks 4, 8, and 12, and CD4+ and CD8+ cell counts at weeks 4, 8, and 12. Safety assessments at all study visits included clinical adverse events, laboratory test results, and vital signs. After 12 weeks in this substudy, patients continued in the longer parent study NR15961.

Number of patients (planned/analyzed)
60 patients from NR15961 planned; 56 enrolled.

Diagnosis and main criteria for inclusion
Inclusion Criteria: Male and female outpatients ≥18 years of age with serologically and histologically proven CHC, elevated ALT, detectable HCV RNA, serological evidence of HIV-1 infection, a CD4+ cell count of ≥ 100 cells/μL, and stable HIV disease with or without antiretroviral therapy.
Patients had to be taking zidovudine plus lamivudine or stavudine plus lamivudine for at least 6 weeks prior to baseline and their HAART regimen was expected to remain unaltered for the first 12 weeks of the study.

Exclusion Criteria: Excluded were patients with other forms of hepatitis; other forms of chronic liver disease; history or evidence of decompensated liver disease; evidence of hepatic malignancy; active HIV-related opportunistic infections.

Test product, dose and mode of administration or test procedure
PEGASYS 180µg, ribavirin 200mg. All patients received PEGASYS, but investigators and patients were blinded as to who was receiving ribavirin or placebo.

Duration of treatment
12 weeks

Reference therapy, dose and mode of administration or reference procedure
None

Criteria for evaluation (efficacy, safety)
Pharmacokinetics: Primary: Assessment in peripheral blood mononuclear cells (PBMCs) at baseline and week 12 of AUC0-12h of zidovudine triphosphate/AUC0-12h of deoxythymidine triphosphate AUC0-12h of lamivudine triphosphate/AUC0-12h of deoxycytidine triphosphate
AUC0-12h of stavudine triphosphate/AUC0-12h of deoxythymidine triphosphate.
Secondary: Plasma AUC0-12h and Cmax for zidovudine, lamivudine, and/or stavudine at baseline and after 12 weeks of ribavirin administration.
Plasma ribavirin AUC0-12h and Cmax after 12 weeks of ribavirin therapy in CHC patients coinfected with HIV.
Pharmacodynamics: HCV RNA titers, HIV RNA titers, CD4+ cell counts, CD8+ cell counts.
Safety: Clinical adverse events and laboratory adverse events, AIDS-defining events, laboratory test results, and vital signs.

Statistical methods
Pharmacokinetics: Analysis of covariance (ANCOVA) was used to analyze all primary and secondary pharmacokinetic parameters at week 12.
Pharmacodynamics: Descriptive statistics were used to summarize pharmacodynamic parameters by treatment group.
Safety: Descriptive statistics were used to summarize safety parameters by treatment group.

Summary (efficacy, safety, other results)
Pharmacokinetics: No statistically significant differences were seen at week 12 in the AUC0-12h ratios of lamivudine TP/deoxycytidine TP, stavudine TP/deoxythymidine TP, or zidovudine TP/deoxythymidine TP between the PEGASYS plus placebo arm and the PEGASYS plus ribavirin arm after adjustment for baseline covariates.
No statistically significant differences were seen at week 12 in the intracellular concentrations (AUC0-12h) of the endogenous nucleoside triphosphates, deoxythymidine triphosphate and deoxycytidine triphosphate, between the PEGASYS plus placebo arm and the PEGASYS plus ribavirin arm after adjustment for baseline covariates.
No statistically significant differences were seen at week 12 in the plasma AUC0-12h or Cmax values for lamivudine, stavudine, or zidovudine between the PEGASYS plus placebo arm and the PEGASYS plus ribavirin arm after adjustment for baseline covariates.

Pharmacodynamics: In both treatment arms, median HCV RNA titers decreased more rapidly during the first 4 weeks of treatment and then decreased more slowly from week 4 to week 12. The median change from baseline was smaller in the PEGASYS plus placebo arm than in the PEGASYS plus ribavirin arm both at week 4 and at week 12.
No evidence was seen suggesting loss of effectiveness of concomitant HIV antiretroviral therapy during the 12 weeks of CHC treatment. HIV RNA titers did not increase from baseline in either treatment arm. CD4+ cell counts and CD8+ cell counts decreased from baseline during the first 12 weeks of treatment in both treatment arms, and the decreases were smaller in the PEGASYS plus placebo arm than in the PEGASYS plus ribavirin arm. No patients developed AIDS-defining events during this 12-week study.

Safety: The majority of adverse events during the first 12 weeks of treatment were mild or moderate in intensity in both treatment arms, and the frequency of severe adverse events was similar in both treatment arms (29% vs 28%) There were no deaths, life-threatening adverse events, AIDS-defining events, or premature withdrawals for safety reasons during this 12-week substudy. The most common clinical adverse events in both treatment arms were those known to be associated with interferon therapy and included fatigue, headache, pyrexia, asthenia, and diarrhea.
The frequency of serious adverse events in both treatment arms during the first 12 weeks of treatment was low (≤ 10%) and was similar in both treatment arms. Two of the five serious adverse events (anemia and pancreatitis) were considered by the investigators to be related to the study drug. None of the serious adverse events led to premature withdrawal of the patient from the study; only pancreatitis resulted in modification of the dose of study drugs.
Dose modification of PEGASYS for adverse events or laboratory abnormalities during the first 12 weeks of treatment was higher in the PEGASYS plus placebo arm than in the PEGASYS plus ribavirin arm (45% and 32%). In both treatment arms, laboratory abnormalities were the main reason for modification of the PEGASYS dose, mainly for neutropenia (32% vs 24%) and less frequently for thrombocytopenia (13% vs 4%). A similar percentage of patients in the two treatment arms had their dose of placebo or ribavirin modified for adverse events or laboratory abnormalities (29% vs 32%).
A higher percentage of patients in the PEGASYS plus placebo arm than in the PEGASYS plus ribavirin arm had neutrophil counts <0.5 x 109/L (19% and 4%) at some time during the first 12 weeks of treatment. Three patients in the PEGASYS plus placebo arm, but no patients in the PEGASYS plus ribavirin group, had platelet counts <50 x109/L at some time during the first 12 weeks of the study. Three patients in the PEGASYS plus ribavirin arm, but no patients in the PEGASYS plus placebo arm, had hemoglobin concentrations <10 g/dL at some time during the first 12 weeks of treatment.

Conclusions
No evidence of a drug interaction was seen between ribavirin and the NRTIs zidovudine, lamivudine, or stavudine in HIV/CHC coinfected patients after 12 weeks of treatment. No statistically significant differences were seen between the PEGASYS plus placebo arm and the PEGASYS plus ribavirin arm after 12 weeks of treatment in the intracellular AUC0-12h ratios of the triphosphorylated NRTIs to the corresponding endogenous nucleoside triphosphates or in the intracellular concentrations of the endogenous nucleoside triphosphates.
In addition, ribavirin had no effect on the plasma AUC0-12h or Cmax of zidovudine, lamivudine, or stavudine. Plasma exposure of ribavirin did not appear to be affected by concomitant administration of NRTIs and was similar to that observed in CHC monoinfected patients.
No evidence was found in this substudy that the addition of ribavirin reduces the effectiveness of concomitant HIV antiretroviral therapy during the first 12 weeks of CHC treatment. HIV RNA titers did not increase from baseline in either treatment arm.
No unexpected differences in safety were observed with the concomitant use of ribavirin and NRTIs

Publications (references, if available)
Gries J-M, Torriani FJ, Rodriguez-Torres M, et al. Abstract from the 11th Congress on Retroviruses and Opportunistic Infections, February 8-11, 2004 (Abstract 136LB).

Date of report
3/1/2004