The primary objectives of this trial are the following:- to determine the dose dependency of the antiviral effect of TMC435350 during 1 week ofmonotherapy in treatment-naïve HCV-infected subjects;- to determine the dose dependency of the antiviral…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy parameter is the viral load drop at the end of the 4-week
treatment regimen.
Secondary outcome
Secondary parameters include:
- the proportion of subjects with viral load below the limit of quantification
and limit of detection respectively.
- Also the proportion of subjects per treatment regimen with viral breakthrough
will be assessed.
- The results of the viral genotype will be evaluated by the Sponsor
Virologist. Relevant changes
in the viral sequence, detected by the viral genome sequencing will be
tabulated and described.
Background summary
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide and has
become a focus of
considerable medical research. An estimated 170 million people (i.e., 3% of the
global
population) are infected with HCV. More than 50% of HCV infections become
chronic in nature.
This may lead to the development of liver fibrosis, cirrhosis, and occasionally
hepatocellular
carcinoma. Chronic HCV infection is the leading cause of liver failure
requiring liver
transplantation.
Current HCV therapies are based on peginterferon alpha-2a (PegIFN-*) in
combination with
ribavirin (RBV). This combination therapy yields a sustained virologic response
in
approximately 80% of subjects infected with genotypes 2 and 3 HCV, and in
approximately 45%
of subjects infected with genotype 1 HCV. In addition to the limited efficacy
on genotype 1
HCV, this combination therapy has significant side effects and is poorly
tolerated in some
subjects. Major side effects include influenza-like symptoms, hematologic
abnormalities, and
neuropsychiatric symptoms.
In recent clinical trials, new investigational drugs acting directly on the
virally encoded protease
target have demonstrated that significant reductions in HCV viral load can be
achieved during
short courses of monotherapy, or when administered in addition to PegIFN + RBV
combination
therapy. There is a need for HCV inhibitors that may overcome the disadvantages
of current
HCV therapy such as side effects, limited efficacy, the emerging resistance,
and compliance
failures.
Lead optimization has led to new compounds with a low EC50, including the
compound
TMC435350. TMC435350 was shown to be an inhibitor of HCV NS3/NS4A protease
activity in
enzymatic assays in vitro and of HCV replication using the cellular replicon
model. In vitro,
TMC435350 has an EC50 on HCV replication of 8nM (6 ng/mL) in the human hepatoma
cell line
(Huh7)-Luc cell line engineered with a genotype 1 HCV replicon sequence3
.
Study objective
The primary objectives of this trial are the following:
- to determine the dose dependency of the antiviral effect of TMC435350 during
1 week of
monotherapy in treatment-naïve HCV-infected subjects;
- to determine the dose dependency of the antiviral effect of TMC435350 during
combined
tritherapy with PegIFN*-2a and RBV in treatment-naïve HCV-infected subjects.
The secondary objectives of this trial are the following:
- to determine the safety, tolerability and pharmacokinetic profile of
TMC435350 during
1 week of monotherapy, and during combined tritherapy with PegIFN*-2a and RBV,
in
treatment-naïve HCV-infected subjects;
- to determine the 4-week efficacy and safety of 2 selected doses of TMC435350
given in
combination with PegIFN*-2a and RBV in treatment-experienced (prior
non-responders
to IFN-based therapy/relapsers, who did not discontinue anti-HCV therapy due to
AEs)
HCV-infected subjects;
- to determine the frequency, kinetics, and genetics of viral breakthrough of
HCV during
monotherapy and combination therapy; genetics of viral breakthrough will also be
determined during SoC treatment;
to follow-up rapid virologic response (RVR) in subjects at Week 4 until Week 24
(after
20 weeks of SoC treatment) or Week 48 (after 44 weeks of SoC treatment), to
determine
the incidence of sustained virologic response (SVR) at these time points and
during a
24-week treatment-free observation period;
- to study the potential drug-drug interaction by TMC435350 on RBV.
Study design
This trial is randomized and blinded (during the course of the investigational
treatment phase, the
Sponsor, Investigator, and the patient will remain blinded for treatment) to
allow for an objective
comparison of efficacy, tolerability, and safety between active TMC435350
treatment and
placebo. When the previous dose cohort was found safe and efficacious (data
review meeting,
see Section 6.2.6), the next dose level will be tested in a new dose cohort.
After completion of
each of the individual cohorts* the Sponsor will require access to the
treatment codes. The
Investigator will be provided access to the individual treatment code at Week
20.
Current HCV therapies are based on PegIFN-* in combination with RBV. This
combination
therapy yields a sustained virologic response in approximately 45% of subjects
chronically
infected with genotype-1 HCV, and is considered SoC.
Intervention
A first cohort of 48 treatment-naïve subjects will be randomized to low-dose
treatment or
placebo. This cohort will be equally distributed over Panels A and B. In this
first cohort, each
panel will consist of 2 dose groups of TMC435350 (25 or 75 mg; n = 9 subjects
each) and one
placebo group (n = 6 subjects). Subjects in Panel A will receive TMC435350 or
placebo in
monotherapy for 7 days. This 7-day monotherapy period will be followed by a
21-day combined
tritherapy period in which TMC435350 or placebo is coadministered with
PegIFN*-2a
(Pegasys®) and RBV (Copegus®). Subjects in Panel B will receive 4 weeks of
combinedtritherapy. Stopping rules for dose limiting toxicity and definitions
for determination of a
possible Maximum Tolerated Dose (MTD) have been defined. Data Review Meetings
will be
organized by the Sponsor with the Principal Investigator before dose escalation
as follows:
After a careful blinded review of the first-week safety, tolerability and, to
the available extent,
pharmacokinetic data of the low-dose cohort, a next cohort of 24
treatment-naïve subjects will be
randomized to middle dose treatment (200 mg) or placebo. This cohort will also
be equally
distributed over Panels A and B. In this second cohort, each panel will consist
of one
TMC435350 dose group (200 mg, n = 9 subjects) and one placebo group (n = 3
subjects).
Combined treatment with PegIFN*-2a and RBV in Panels A and B will happen as
described for
the first cohort.
After a careful blinded review of the safety, tolerability, and pharmacokinetic
data after
completion of the middle dose cohort, a third cohort of 24 treatment-naïve
subjects will be
randomized to high dose treatment (400 mg) or placebo. This cohort will again
be equally
distributed over Panels A and B. In this third cohort, each panel will consist
of one TMC435350
dose group (400 mg, or the final selected dose based on safety and PK data, not
exceeding
400mg; n = 9 subjects) and one placebo group (n = 3 subjects). Combined
treatment with
PegIFN*-2a and RBV in Panels A and B will happen as described for the first
cohort.
After a first-week blinded safety and PK review in the highest dose cohort of
treatment-naïve
subjects, the 24 treatment-experienced subjects (non-responders/relapsers) will
be randomized
over 2 TMC435350 dose groups (200 mg or 400 mg, or the final selected dose
based on safety,
tolerability, and pharmacokinetic data, not exceeding 400 mg; n = 9 subjects
each) or placebo
(n = 6 subjects) in Panel C. These subjects will receive 28-day combined
tritherapy.
Randomization in this cohort will be stratified for previous relapsers and
non-responders.
In addition, 10 HCV-infected non-responding/relapsing subjects having
participated in trial
TMC435350-TiDP16-C101 will be included in the last cohort. These subjects will
all receive
28-day combined tritherapy including active TMC435350 treatment at a dose of
400 mg (or the
final selected dose based on safety, tolerability and pharmacokinetic data, not
exceeding
400 mg), in combination with RBV and PegIFN*-2a after safe completion of the
400 mg dose in
Panel B.
After each 28-day treatment period, subjects will be offered free of charge
standard of care (SoC)
treatment containing PegIFN*-2a (Pegasys®) and RBV (Copegus®) until Week 48 (or
Week 24)
depending on the virologic response during the initial 20 weeks of treatment.
Study burden and risks
- Number of bloodsamples:
Panel A: 199 - 3.9 ml per sample
Panel B-C-D: 198 - 3.9 ml per sample
In case of drop out: 20 blood samples; 4,4ml per sample.
- Number of visits to the site: 46
- Physical examination: 14
- Risks: In healthy volunteers the following adverse events were reported (they
received either placebo or TMC435350): loose stool, diarrhea, flatulence, heavy
headedness, frequent defecation, light headedness, somnolence. Furthermore a
mild and transient readness of the skin after direct exposure of the skin to
the sun was reported by 3 people who received either placebo, either TMC435350.
Other risks: skin sensitivity to the sun; rash; known adverse events of the
Standard of Care treatment; possible blood draw risks.
- Justification of the study: The patient's health will be monitored closely.
After the 28 days 'experimental' phase (including 21 days in combination with
the Standard of Care), the Standard of Care treatment for HCV is provided for
24 or 48 weeks (depending on the response).
Roderveldlaan 1
2600 Berchem
BE
Roderveldlaan 1
2600 Berchem
BE
Listed location countries
Age
Inclusion criteria
1. Aged between 18 and 70 years, extremes included;
2. Documented chronic (diagnosis of hepatitis C > 6 months before the screening period) genotype 1a or 1b HCV infection (as assessed by line probe assay); treatment-naïve subjects or prior non-responding subjects/relapsers to previous treatment regimens (IFN/RBV or pegylated IFN/RBV), who did not discontinue anti-HVC therapy due to AEs; genotype 1 HCV patients with hemophilia or with stable methadone use may be enrolled; (subtyping in genotype 1a and 1b patients will also be done);
3. ICF signed voluntarily before the first trial related activity;
4. Able to comply with the protocol requirements and having good accessible veins;
5. HCV plasma viral load * 10,000 IU/mL at screening (as assessed by the Taqman assay);
6. Bodyweight as defined by a Quetelet Index (Body Mass Index [BMI], weight in kg divided by the square of height in meters) between 18 and 32 kg/m², extremes included.
Exclusion criteria
1. Evidence of Child Pugh B or C liver disease or Metavir score 4 at screening with a history or evidence of decompensated cirrhosis defined as prior or current history of ascites, hepatic encephalopathy, bleeding esophageal or gastric varices. Any other cause of significant liver disease in addition to hepatitis C; this may include but is not limited to hepatitis B, drug- or alcohol-related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson*s disease, non-alcoholic steatohepatitis, or primary biliary cirrhosis. Subjects with diagnosed or suspected hepatocellular carcinoma;
2. Subjects receiving or having received polymerase inhibitor or protease inhibitor treatment for HCV during the 6 months before screening;
3. Male subjects with female partners of childbearing potential not agreeing to use a reliable birth control method for 90 days after the last dosing of TMC435350 in the trial or as prescribed in the leaflet of the medication as administered in the SoC treatment period (when taking PegIFN*-2a in combination with RBV, all subjects must use effective birth control methods during treatment and for 7 months afterwards);
4. Female, except if postmenopausal for over 2 years, or posthysterectomy, or post-tubal ligation (without reversal operation);
5. History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drug use, which in the Investigator*s opinion would compromise the subject*s safety and/or compliance with the trial procedures (period of non-drug/alcoholic misuse must at least be 1 month before the first administration of study medication).
6. A positive urine drug test at screening. Urine will be tested to check the current use of amphetamines, cocaine, and opioids (with the exclusion of methadone).
7. Subjects with at least one of the following laboratory abnormalities as defined by the Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table at
screening:
- Bilirubin * 1.5x upper limit of laboratory normal range (ULN);
- Platelet count < 80,000/mm3;
- White blood cell (WBC) count < 2,000 cells/mm3;
- Any other lab toxicity found to be clinically significant by the Investigator.
8. Subjects coinfected with HIV-1 or HIV-2, or hepatitis A or B virus infection (confirmed by hepatitis A antibody immunoglobulin [IgM], or hepatitis B surface antigen [HBsAg]) at screening;
9. Subjects with a pathologically prolonged QTc value (> 500 ms) at screening, or any active clinically significant disease (e.g., tuberculosis, cardiac dysfunction), or medical history or physical examination findings during screening that, in the Investigator*s opinion, would compromise the outcome of the trial;
10. Subjects having uncontrolled/unstable diabetes, epilepsy, a manifest psychiatric disease;
11. Non-stable methadone use or subjects having any other unstable disease;
12. Subjects enrolled in another clinical trial within 90 days prior to screening;
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-003289-16-NL |
| CCMO | NL20160.018.07 |
| OMON | NL-OMON22664 |
| OMON | NL-OMON29020 |