Primary Objective:This research study is designed to assess the effectiveness of the combination of study drugs (ASV + DCV) being used to treat the hepatitis C virus (HCV). The best way to assess this aim is to measure the amount of virus in…
ID
Source
Brief title
Condition
- Other condition
- Viral infectious disorders
Synonym
Health condition
Hepatitis C
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
Proportion of treated subjects with SVR-12, defined as HCV RNA < LOQ at post
treatment Week 12, for subjects who are prior null or partial responders to P/R
or are treatment-naive.
Secondary outcome
Secondary Endpoints
* Proportion of treated subjects with SVR12, defined as HCV RNA < LOQ at
post-treatment Week 12, for subjects who are intolerant or ineligible to P/R;
* On treatment safety, as measured by frequency of SAEs and discontinuations
due to AEs through the end of treatment plus 7 days;
* Differences in rates of selected grade 3-4 laboratory abnormalities during
the first 12 weeks between treatments (ASV + DCV vs Placebo) for naive subjects;
* Proportion of genotype 1b subjects with SVR12 (HCV RNA < LOQ at post
treatment Week 12) by the rs12979860 SNP in the IL28B gene for each cohort;
* Proportion of genotype 1b subjects with HCV RNA undetectable at each of the
following time points: Weeks 1, 2, 4, 6, 8 and 12; at both Weeks 4 and 12
[eRVR]; EOT (up to 24 weeks), post-treatment Week 12, or post-treatment Week 24
for each cohort;
* Proportion of genotypes 1b subjects with HCV RNA < LOQ at each of the
following time points: weeks 1, 2, 4, 6, 8 and 12; at both Weeks 4 and 12
[VR(4&12)]; EOT (up to 24 weeks), post-treatment Week 24 (SVR24) for each
cohort.
Background summary
Approximately 170 million people worldwide are chronically infected with
hepatitis C virus (HCV). The majority of individuals infected progress to
chronic hepatitis, which can lead to cirrhosis, liver failure and
hepatocellular carcinoma (HCC). HCV is the leading indication for liver
transplantation in most countries and a major cause of HCC.
There are 6 major HCV genotypes with many subtypes based on sequence
heterogeneity of the genome. Genotypes 1 - 3 have a worldwide distribution
(with genotype 1 being the major genotype in the United States, Europe, Japan,
and South America, genotypes 4 and 5 are found principally in Africa, and
genotype 6 is distributed primarily in Asia. Although genotype does not predict
the outcome of infection, different genotypes are associated with differential
responses to treatment, and allow dosage of current interferon-based treatment
to be tailored to the genotype being treated.
The standard of care therapy for patients with Genotype 1 HCV infection is the
combination of a direct acting antiviral (DAA) and peg-Interferon plus
ribavirin (P/R). The recently approved DAAs include the two NS3/4A protease
inhibitors boceprevir (BOC) and telaprevir (TVR). These drugs are administrated
for either 24 weeks (naive early responders) or 48 weeks (previous
peg-Interferon Alfa-2 and ribavirin treatment failures and naive late
responders) achieving sustained virologic response (SVR) rates of ~60 - 80% in
naive patients and ~30% - 80% among previous treatment (P/R) failures. Despite
this improvement in SVR rates and the option of short treatment duration,
adverse events occurred more frequently in patients treated with DAA + P/R than
in those treated with P/R therapy alone. In the BOC trials, the most common
adverse events were anemia and dysgeusia in the BOC arms compared with P/R
arms, while in the TVR trials, rash, anemia, pruritus, nausea and diarrhea
developed more commonly among those who received TVR compared with those who
received P/R therapy.
The emergence of antiviral resistant variants during the use of a single DAA
administrated in combination with P/R has been associated with the occurrence
of both virologic failure and relapse in clinical trials. Mutations that confer
either high or low level resistance to BOC and TVR cluster around the catalytic
site of the NS3/4A serine protease. Similar variants were detected in both BOC
and TVR-treated subjects, suggesting that some degree of cross-resistance
exists between the two DAAs. Emergent resistance substitutions are detected in
the majority of isolates from subjects who did not achieve SVR (> 60%) ie, in
almost 100% of subjects who failed after receiving 12 weeks of treatment with
TVR plus P/R and in the majority (> 60%) of subjects who failed therapy or
relapsed after Week 12 of TVR plus P/R followed by 12 weeks of P/R. HCV
genotype 1 subtype-associated patterns of TVR treatment-emergent amino acid
substitutions were observed in these subjects and varied by genotype; genotype
1a predominately had V36M and R155K or the combination of these two variants,
while subjects with genotype 1b
predominately had V36A, T54A/S, and A156S/T variants. A comparable scenario is
observed among those subjects who failed BOC regimens; subjects with genotype
1a commonly had V36M, T54S, R155K, while for subjects with genotype 1b, the
most frequent variants detected were T54A, T54S, V55A, A156S, I/V170A. P/R
retreatment of patients with prior non-response to P/R was unsuccessful, with
SVR rates of only 6% to 9%.
Null-responders are the subset of non-responders who have responded most poorly
to P/R, and their urgent need for more potent therapies has prompted evaluation
of regimens containing DAA agents. SVR rates of 27% (genotype 1a) and 37%
(genotype 1b) were achieved in null responders with a regimen combining TVR
plus P/R in a study of non-responders.
These results suggest that DAA-containing regimens can benefit this population,
but greater antiviral potency is needed to increase response rates further.
Combinations of two DAAs may overcome interferon non-responsiveness in
null-responders by increasing antiviral activity and reducing the risk of
developing resistance-associated variants. Marked anti-viral effects have been
observed in subjects treated with DUAL DAAs in studies that included genotype
1b null-responders, supporting the development of DUAL DAA therapy proposed in
this study.
Study objective
Primary Objective:
This research study is designed to assess the effectiveness of the combination
of study drugs (ASV + DCV) being used to treat the hepatitis C virus (HCV). The
best way to assess this aim is to measure the amount of virus in patients*
blood 12 weeks after ceasing study the study medication which is 24 weeks in
duration. If a patient has achieved undetectable HCV in their blood 12 weeks
after ceasing treatment they are said to have achieved a "Sustained Virological
Response" (Abbreviated as SVR-12).
Secondary Objectives:
1/ To measure how well the study medications work by assessing the proportion
of patients who achieve HCV RNA below the LOQ (Limit of Quantification of 25
IU/mL)for patients who are intolerant or ineligible to P/R;
2/ To assess the safety of the study medications. This will be assessed by
measuring the number of serious adverse events (SAEs) and study medication
discontinuations*
3/ To estimate the differences in rate of occurence of selected serious lab
abnormalities (hematologic and liver function) during the first 12 weeks
between treatments (ASV + DCV versus Placebo) for treatment-naïve subjects;
4/ To assess the relationship between the efficacy of the study drugs and
changes in the HCV genome responsible for drug resistance.
5/ To assess the efficacy of the study drugs as determined by:
* Undetectable HCV RNA at the following time points throughout the trial: At
Weeks 1, 2, 4, 6, 8, and 12; at both Weeks 4 and 12 [Extended rapid virological
response (eRVR) - which means that the virus is undetectable at treatment weeks
4 and 12.]; at End-Of-Treatment (up to 24 weeks), and at Post-treatment Week 12
or Post-treatment Week 24.
Study design
Approximately 625 genotype 1b subjects will receive ASV + DCV and approximately
100 genotype 1b subjects will receive PBO in this study. As indicated in Figure
3.1 on Page 35 of the Protocol, subjects in the open-label null or partial
responder and intolerant or ineligible cohorts will be treated with ASV + DCV
for 24 weeks. Subjects in the double-blind treatment naive cohort will be
randomized 2:1 to receive ASV + DCV for 24 weeks or placebo (PBO) for 12 weeks
followed by ASV + DCV for 24 weeks in protocol AI444-026. Randomization in this
cohort will be stratified by cirrhosis status (absent or present). At Week 12,
subjects in the treatment-naive cohort will be unblinded to treatment
assignment and will have the option to transfer to protocol AI444-026 and
receive active treatment (ASV + DCV) for 24 weeks.
Subjects meeting pre-specified rescue criteria in the treatment naive cohort
and in the null or partial responder cohort may have therapeutic rescue
instituted with QUAD regimen (ASV + DCV plus P/R).
Subjects will enroll into one of the following three cohorts of genotype 1b
based on eligibility:
* Null or Partial Responder to P/R (n = 200), and;
* Intolerant to or Ineligible for P/R (up to 225), and;
* Treatment-naive (n = 300).
Subjects in the treatment-naive cohort will be randomized 2:1 to either:
* ASV + DCV for 24 weeks (n = 200), or;
* ASV-PBO + DCV-PBO for 12 weeks followed by ASV + DCV for 24 weeks in protocol
AI444026 (n = 100).
Subjects in the P/R intolerant or ineligible cohort will fall in to one of
three subgroups:
* Anemia or neutropenia (up to 75), or;
* Compensated advanced fibrosis/cirrhosis (F3 or F4) with thrombocytopenia (up
to 75), or;
* Depression (up to 75).
Subjects in the null or partial responder and intolerant or ineligible cohorts
will receive 24 weeks of 100 mg BID ASV soft capsule and 60 mg QD DCV tablet,
followed by 24 weeks of follow-up after completion of treatment or upon early
discontinuation of treatment.
Subjects in the null or partial responder cohort or the active arm of the
treatment-naive cohort meeting pre-specified rescue criteria may have
therapeutic rescue instituted with QUAD regimen for an additional 24 weeks.
(QUAD regimen = ASV and DCV plus P/R).
Subjects in the treatment-naive cohort will be randomized 2:1 to receive ASV +
DCV for 24 week or ASV-PBO + DCV-PBO for 12 weeks followed by ASV + DCV for 24
Weeks in protocol AI444-026. It is expected that all subjects who are on-study
will complete the protocol defined durations for treatment and follow-up. If
alternative HCV therapy is initiated in the post-treatment period for any
reason, subject must withdraw from the study once the post-treatment Week 4
visit has occurred.
The last visit will be considered the date of the last post-treatment visit.
The end of the study will be considered the last subject*s last visit date, or
the date the last data point required for statistical analysis is received from
the last subject in the null or partial
responder or treatment-naive cohort, whichever is later.
Following completion of the follow-up period of the study, subjects may be
asked to enroll into a separate observational study (AI444046) for an
additional 3-year follow-up to assess long-term SVR, natural history of the HCV
resistance, and liver-related complications.
An analysis will be conducted after all subjects (excluding those who receive
rescue therapy) in the null or partial responder cohort and the ASV + DCV arm
of the treatment-naive cohort reach post-treatment Week 12. Subjects who
receive rescue therapy will be counted as treatment failures. The primary
analysis will occur when at least the subjects in the null or partial responder
and treatment naive cohorts (excluding those who receive rescue therapy)
complete post-treatment Week 12. The final analysis will occur once all
subjects complete post-treatment Week 24.
Intervention
In this protocol, investigational products are:
* asunaprevir (ASV, BMS-650032) 100 mg soft capsules and matching placebo
capsules;
* daclatasvir (DCV, BMS-790052) 60 mg tablets and matching placebo tablets;
* peg-Interferon-alfa-2a (for subjects who initiate rescue therapy);
* RBV (for subjects who initiate rescue therapy).
Selection and timing of dose for each subject are as follows (with the
exceptions
described below):
* ASV: ASV soft capsules (or matching placebo) should be taken twice daily (1
capsule per dose) for the duration of assigned treatment. ASV may be taken with
or without a meal, and for subjects on rescue therapy, may be taken with RBV.
* DCV: DCV tablets (or matching placebo) should be taken once daily (1 tablet)
for the duration of assigned treatment. DCV may be taken with or without a
meal, and for subjects on rescue therapy, may be taken with RBV.
* For Rescue Therapy ONLY:
* Peg-Interferon-alfa-2a (pegIFN*-2a) : Rescue subjects will self-administer
180 *g pegIFN*-2a injection subcutaneously once weekly throughout the entire
dosing period.
* Ribavirin (RBV): Rescue subjects will take RBV twice daily with food. For
subjects weighing < 75 kg the total dose is 1000 mg per day and for those
weighing * 75 kg the dose is 1200 mg per day.
PegIFN*-2a/RBV will be supplied by Bristol-Myers Squibb, but may be locally
sourced if necessary. PegINF*-2a/RBV will only be used for rescue therapy,
pending eligibility criteria are met and at the discretion of the investigator.
Study burden and risks
BURDEN AND RISKS:
The burden and risks are summarised in Sections E4 and E9 above.
BENEFITS:
The study drugs (ASV + DCV) will hopefully help research participants to
achieve a virologic response to treatment, and hence, prevent their HCV from
progressing to liver cirrhosis (scarring), liver cancer or end stage liver
disease which may require a liver transplant. However, this cannot be
guaranteed.
During the study, subjects will be monitored closely by the study doctor (who
is an experienced clinician) and his/her team. Subjects may benefit from being
seen more frequently by a experienced clinicians and nursing staff, and from
receiving increased emotional support from the research team.
Although not of direct benefit to research participants, the information
learned from this study may help other subjects with chronic HCV infection in
the future.
Vijzelmolenlaan 9
Woerden 3447 GX
NL
Vijzelmolenlaan 9
Woerden 3447 GX
NL
Listed location countries
Age
Inclusion criteria
* Males and females, * 18 years of age;;* HCV Genotype 1b who previously failed treatment with peginterferon alfa and ribavirin, classified as previous null or partial responders based on previous therapy, OR intolerant or ineligible to P/R due to neutropenia, anemia, depression or thrombocytopenia with cirrhosis, OR treatment naive;;* HCV RNA * 104 IU/mL (10,000 IU/mL);;* Seronegative for HIV and HBsAg;;* Subjects with compensated cirrhosis are permitted (compensated cirrhotics are capped at approximately 25% of treated population).
Exclusion criteria
* Prior treatment of HCV with HCV direct acting antiviral (DAA); ;* Evidence of a medical condition contributing to chronic liver disease other than HCV;;* Evidence of decompensated liver disease including, but not limited to, a history or presence of ascites, bleeding varices, or hepatic encephalopathy;;* Diagnosed or suspected hepatocellular carcinoma or other malignancies;;* Uncontrolled diabetes or hypertension;
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-005446-35-NL |
| ClinicalTrials.gov | NCT01581203 |
| CCMO | NL39753.018.12 |