| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recent hepatitis C virus infection all genotypes. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recent hepatitis C infection is infection with the hepatitis C virus for less than 12 months. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019744 |
| E.1.2 | Term | Hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The main objective of the trial is to evaluate the proportion of patients with HCV RNA below the level of quantitation (target not detected [TND] or target detected, not quantifiable [TDnq]) at 12 weeks post end of treatment (SVR12) following sofosbuvir/velpatasvir therapy for 6 weeks (short treatment duration) as compared with 12 weeks (standard treatment duration) in people with recent HCV infection (duration of infection ≤12 months). |
|
| E.2.2 | Secondary objectives of the trial |
1 To evaluate the proportion of participants with HCV RNA below the level of quantitation at the end of treatment, 4 weeks after treatment completion and 24 weeks after treatment completion;
2 To evaluate the proportion of participants with undetectable HCV RNA through 2 years post treatment;
3 To evaluate the levels of adherence, factors associated with suboptimal adherence including HIV status & the impact of suboptimal adherence on therapeutic response;
4 To evaluate the impact of treatment on illicit drug use, injecting behaviour & sexual risk taking behaviour during treatment;
5 To evaluate safety & tolerability
6 To evaluate the change in HIV RNA & CD4 (on-treatment & end of treatment);
7 To evaluate the rate & risk factors for reinfection during & up to 2 years following treatment;
8 To evaluate the immunological factors associated with treatment induced clearance and reinfection
9 To evaluate patient interest & attitudes towards long acting parenteral
HCV therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Participants have voluntarily signed the informed consent form.
2) 18 years of age or older.
3) Detectable HCV RNA at screening (>10,000 IU/ml), and in the opinion of the investigator is unlikely to demonstrate spontaneous viral clearance
4) HCV genotypes 1-6
5) HBsAg negative
6) Negative pregnancy test at baseline (females of childbearing potential only)
7) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
8) Medically stable on the basis of physical examination, medical history and vital signs
9) Adequate literacy to provide reliable responses to the study questionnaires
10) All fertile males and females must be using effective contraception during treatment and during the 30 days after treatment end.
11) Recently acquired HCV infection (estimated duration of infection ≤12 months)*
Recently acquired HCV infection as defined by:
A)
i) First anti-HCV Ab or HCV RNA positive within the previous 6 months
and
ii) Documented anti-HCV Ab negative within the 12 months prior to anti-HCV antibody positive result
OR
B)
i) First anti-HCV Ab or HCV RNA positive within the previous 6 months
and
ii) Acute clinical hepatitis (jaundice or ALT> 10 X ULN) within the previous 12 months prior to first positive HCV antibody or HCV RNA, with no other cause of acute hepatitis identifiable
OR
C) For cases of recent HCV reinfection the following criteria are required:
Documented prior HCV antibody positive with HCV RNA negative on at least 2 occasions 6 months apart AND new HCV RNA positive within the previous 6 months
*Estimated duration of infection based on midpoint between last antibody negative or HCV RNA and first antibody positive or HCV RNA in the case of seroconversion and 6 weeks prior to date of maximum ALT in the case of acute hepatitis.
If co-infection with HIV is documented, the subject must meet the following criteria:
1) Antiretroviral (ARV) untreated for >8 weeks preceding screening visit with CD4 T cell count >500 cells/mm3
OR
2) On a stable ARV regimen for >8 weeks prior to screening visit, with CD4 T cell count >200 cells/mm3 and an undetectable plasma HIV RNA level.
• Suitable ARV include:
o Nucleos(t)ide reverse transcriptase inhibitors: Tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), emtricitabine (FTC)Non-nucleoside reverse transcriptase inhibitors: Rilpivirine
o Protease inhibitors: Atazanavir, darunavir, lopinavir, ritonavir
o Integrase inhibitors: Dolutegravir, raltegravir, elvitegravir/cobicistat
• Contraindicated ARV include:
o Efavirenz
50% reduction in velpatasvir (GS-5816) exposure
o Didanosine
o Zidovudine
o Tipranavir
Other ARV agents may be permissible at the time of study commencement pending further drug-drug interaction studies; please discuss with the Medical Monitor.
|
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the exclusion criteria are not to be enrolled in this study.
1) History of any of the following:
a. Clinically significant illness (other than HCV) or any other major medical disorder that may interfere with the participant treatment, assessment or compliance with the protocol; participants currently under evaluation for a potentially clinically significant illness (other than HCV) are also excluded.
b. History of chronic pulmonary disease associated with functional limitation, severe cardiac disease, major organ transplantation or other evidence of severe illness, malignancy, or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study
c. Solid organ transplant
d. Malignancy within 5 years prior to screening, with exception of specific cancers that may have been cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for possible malignancy are also excluded.
e. Significant drug allergy (such as anaphylaxis or hepatotoxicity).
2) Subject has a known or documented prior history of cirrhosis
3) Subject shows evidence of significant liver disease in addition to hepatitis C, which may include but is not limited to drug- or alcohol-related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, non-alcoholic steatohepatitis (NASH), or primary biliary cirrhosis
4) Any of the following lab parameters at screening:
a. Direct bilirubin > 1.5 x ULN
b. Platelets < 50,000/μL
c. Creatinine clearance (CLcr) < 50 mL/min
d. Haemoglobin < 10 g/dL
e. Albumin < 30g/L
f. International Normalised Ratio (INR) >1.5 (unless subject is on a stable anticoagulant regimen or has known coagulopathy
5) Pregnant or nursing female.
6) Use of prohibited concomitant medications as described in protoocl section 5.2
7) Chronic use of systemically administered immunosuppressive agents (e.g. prednisone equivalent > 10 mg/day)
8) Known hypersensitivity to velpatasvir, sofosbuvir or formulation excipients.
9) Therapy with any anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) ≤6 months prior to the first dose of study drug.
10) Any investigational drug ≤6 weeks prior to the first dose of study drug.
11) Previous failure of therapy with sofosbuvir or an NS5A inhibitor prior to the first dose of study drug.
12) Ongoing severe psychiatric disease as judged by the treating physician.
13) Frequent injecting drug use that is judged by the treating physician to compromise treatment safety.
14) Inability or unwillingness to provide informed consent or abide by the requirements of the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the proportion of participants with HCV RNA below the level of quantitation (target not detected [TND] or target detected, not quantifiable [TDnq]) at 12 weeks post end of treatment (SVR12). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks post end of treatment (SVR12) |
|
| E.5.2 | Secondary end point(s) |
1) Secondary virological endpoints
• The proportion of participants with:
a) ETR defined as HCV RNA below the level of quantitation at end of therapy
b) SVR 4 defined as HCV RNA below the level of quantitation 4 weeks post therapy
c) SVR 24 defined as HCV RNA below the level of quantitation 24 weeks post therapy
d) HCV RNA below the level of quantitation through 2 years post treatment
Results will be stratified by HCV genotype and HIV-coinfection.
2) 80/80 adherence: Defined as the receipt of >80% of scheduled doses for >80% of the scheduled treatment period.
3) 90/90 adherence: Defined as the receipt of >90% of scheduled doses for >90% of the scheduled treatment period.
4) 100/100 adherence: Defined as the receipt of 100% of scheduled doses for 100% of the scheduled treatment period.
5) On-treatment adherence: Calculated by subtracting the number of missed doses from the total number of doses of scheduled treatment and dividing by the total intended therapy duration. This measures the proportion of doses received from the time that treatment was initiated until treatment was discontinued or completed.
6) Toxicity: Proportion of participants with at least one severe or potentially life threatening (grade 3 or 4) adverse event.
7) Early treatment discontinuation: Discontinuation of therapy prior to the per-protocol planned end of treatment (6 or 12 weeks depending on study arm).
8) Resistance associated variants (RAVs): The proportion of treated subjects with development of RAVs following virological relapse or breakthrough.
9) Reinfection rate: Rates of HCV reinfection will be calculated using person-time of observation during and up to 48 months following end of treatment.
10) Baseline characteristics, on-treatment adherence, risk behaviours and toxicity will be evaluated among subjects withdrawing prior to randomisation. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1a) End of treatment (ETR)
1b) 4 weeks post end of treatment (SVR4)
1c) 24 weeks post end of treatment (SVR24)
1d) Week 102/108 (for 6 weeks treatment duration/for 12 weeks treatment duration)
2) ETR
3) ETR
4) ETR
5) ETR
6) SVR24
7) ETR
8) SVR24
9) Week 102/108 (for 6 weeks treatment duration/for 12 weeks treatment duration)
10) Week 102/108
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Germany |
| Netherlands |
| New Zealand |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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