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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03833362
Other study ID # CJ05013008
Secondary ID
Status Completed
Phase Phase 3
First received
Last updated
Start date May 7, 2014
Est. completion date February 21, 2017

Study information

Verified date February 2019
Source R-Pharm
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The purpose of this study was to confirm that combination of narlaprevir (NVR) and ritonavir (RTV) used as a metabolic inhibitor with pegylated interferon (PEG-INF) and ribavirin (RBV) leads to a superior Sustained Virological Response (SVR) rate compared to treatment with pegylated interferon and ribavirin in treatment-naïve and treatment failure patient populations.


Description:

The study included 3 time periods:

- Screening period with duration up to 3 weeks during which study eligibility was confirmed.

- Double-blind treatment period: all eligible patients divided into Treatment naive and Previous treatment failure subpopulations were randomized in one of the two parallel treatment arms in 2:1 ratio:

1. Arm 1: All patients received the combination of NVR/RTV + PEG-INF/RBV for 12 weeks that was followed by PEG-INF and RBV for 12 weeks (total treatment duration of 24 weeks).

2. Arm 2: Therapy with PEG-INF and RBV (standard of care) for 48 weeks with placebo equivalent for NVR and RTV for the first 12 weeks.

Different types of pegylated interferon could be used for treatment. The assignment to the pegylated interferon alfa-2a or pegylated interferon alfa-2b treatment will be also performed using web system, in a 1:1 ratio.

Clinical efficacy of each arm were assessed 24 weeks after the end of treatment with undetectable hepatitis C virus (HCV) RNA by lower limit of detection (LOD) 24 weeks following the end of treatment. In case of serum HCV-RNA levels were greater than or equal to 100 IU/mL at Week 12 of treatment (Arm 1) or serum HCV RNA declined from baseline less than 2 log after 12 weeks of treatment or serum HCV-RNA levels ≥LOD at week 24 of treatment (Arm 2) patients were considered non-responders and discontinued participation in the study. In case of satisfactory treatment response all patients were additionally administered with PEG-INF/RBV for 12 weeks (total of 24 weeks of treatment) in Arm 1, and for 36 weeks (total of 48 weeks of treatment) in Arm 2.

- Follow-up period during which patients do not receive any study medication. The duration of the follow-up period after the end of study treatment will be 24 weeks.

Overall, each patient will participate in the study for approximately up to 75 weeks from the time the patient signs the Informed Consent Form through the final visit


Recruitment information / eligibility

Status Completed
Enrollment 420
Est. completion date February 21, 2017
Est. primary completion date March 23, 2016
Accepts healthy volunteers No
Gender All
Age group 18 Years to 70 Years
Eligibility Inclusion Criteria:

- Body weight = 40 and = 125 kg;

- Documented infection with HCV genotype 1 (Mixed infections with other genotypes are not eligible):

1. treatment naïve (to interferon and ribavirin); or

2. treatment failure patients (patients must have received interferon/ribavirin at standard doses for a minimum of 12 weeks);

- Minimum HCV-RNA level of =10,000 IU at baseline;

- No evidence of cirrhosis; availability at Baseline of at least one of the following tests negative results:

1. Liver biopsy showing no cirrhosis (not later than within 3 years prior to Baseline) or

2. FibroScan elasticity score < 12.5 kPa 12 months prior to baseline or

3. FibroTest < 0.75 12 months prior to baseline and aspartate aminotransferase (AST)/platelet ratio (APRI) of = 1 during screening

- Using acceptable contraception methods for both partners from enrollment into the study until 6 months following the end of treatment;

- Willingness to give written informed consent.

Exclusion Criteria:

- Previous treatment with any HCV NS3-specific protease inhibitor and/ or other direct antiviral agents (e.g. HCV polymerase inhibitors);

- Treatment for HCV infection 30 days before the enrolment;

- Use of prohibited medications within 2 weeks prior to start of study medications (inducers or substrates of CYP3A4);

- Findings suspicious for hepatocellular carcinoma (HCC);

- Hepatic failure at present or in history;

- Auto-immune hepatitis in history;

- Anti-nuclear antibodies (ANA) titers > 1:320;

- Evidence of gallstones, choledocholithiasis and calcified gallbladder;

- HBsAg positive;

- HIV positive;

- Serum hemoglobin of <13g/dL for males and <12g/dL for females;

- Neutrophils <1500/mm3 (<1,5?109/L) at Screening;

- Platelets <150000/mm3 (<150?109/L) at Screening (patients with a platelet count >100,000/mm3 (>100?109/L) but less than 150,000/mm3 (150?109/L) can be included in the study in case a Fibroscan or FibroTest or liver biopsy during the study screening period shows no cirrhosis)

- Total bilirubin >1.6 mg/dL (>27.36 µmol/L) unless history of Gilbert's disease. If Gilbert's disease is the proposed etiology, this must be documented in the subject's chart;

- Direct bilirubin >1.5 x upper limit of normal (ULN) of the laboratory reference range at Screening;

- Serum albumin < lower limit of normal (LLN) of laboratory reference range at Screening;

- Serum creatinine >ULN of the laboratory reference at Screening;

- Serum aspartate aminotransferase (AST) / alanine aminotransferase (ALT) >5 x ULN of the laboratory reference range at Screening;

- Thyroid stimulating hormone (TSH) >1.2 ULN or <0.8 LLN;

- Contraindications to pegylated interferon, ribavirin and/or ritonavir treatment;

- Hypersensitivity to any of the study drugs;

- Active or suspected cancer;

- Psychiatric disease (moderate or severe depression, schizophrenia, bipolar disorder et al);

- Previous suicide attempt or suicidal ideation;

- Drug addiction;

- Opiate agonist substitution therapy;

- History of active gout within the past year;

- Organ transplant (except of cornea and hair transplant);

- Pregnant or nursing women;

- Men whose female partners are pregnant or planning pregnancy;

- Any medical condition that could interfere with the patient's participation and completion of the study;

- Use of other investigational drugs/ participation in other clinical trial within 30 days before the enrolment.

Study Design


Intervention

Drug:
Narlaprevir
yellow film-coated 100 mg. tablets
Ritonavir
100 mg tablets encapsulates in gelatin capsules (for blinding purposes)
Placebo Narlaprevir
yellow film-coated 100 mg. tablets identical to Narlaprevir tablets
Placebo Ritonavir
100 mg lactose/ cellulose tablets encapsulated in gelatin capsules (for blinding purposes) identical to Ritonavir capsules
Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b
180µg for subcutaneous injections in 0.5 ml syrettes / 1.5 µg/kg for subcutaneous injections in 50µkg, 80µkg,100µkg, 120µkg, 150µkg in vials
Ribavirin
hard gelatin, white 200mg. capsules Weight-based dose was 1000 mg/day (patient weight <75 kg) or 1200 mg/day (patient weight =75 kg) with Peginterferon alfa-2a and 800 mg/day (patient weight <65 kg) - 1400 (patient weight >105 kg) mg/day with Peginterferon alfa-2b

Locations

Country Name City State
Russian Federation South-Ural State Medical University, Clinic of Medical Academy, Infectious Diseases Department Chelyabinsk
Russian Federation Kazan State Medical Academy, Republican Clinical Hospital of Infectious Diseases n.a. A.F. Agafonov Kazan
Russian Federation Federal Budget Science Institution Central Science and Research Institute of Epidemiology of RosPotrebNadzor Moscow
Russian Federation Federal State Budget Healthcare Institution Central Clinical Hospital of Russian Academy of Science Moscow
Russian Federation First Moscow State Medical University n.a. I.M. Sechenov, Clinic of Nephrology, Internal and Professional Diseases n.a. E.M. Tarleev Moscow
Russian Federation First Moscow State Medical University n.a. I.M. Sechenov, Propedeutics of Internal Diseases Department Moscow
Russian Federation Moscow State Medical Stomatological University n.a. A. I. Evdokimov, Clinical Infectious Hospital #1, Clinical Infections Department Moscow
Russian Federation Public Corporation "Clinical Hospital of Centrosouze" Moscow
Russian Federation Public Corporation "MedElitConsulting" Moscow
Russian Federation State Budget Healthcare Moscow Institution Clinical Scientific Center of Healthcare Department of Moscow Moscow
Russian Federation State Budgetary Healthcare Organization Clinical city hospital #24 Moscow
Russian Federation Novosibirsk State Medical University, Clinical city hospital #12, Therapeutic Department Novosibirsk
Russian Federation Military Medical Academy of Ministry of Defense of Russian Federation n.a. S.M. Kirov, Infectious Diseases Department Saint Petersburg
Russian Federation Saint Petersburg State Budget Healthcare Institution Center of AIDS and Infectious Diseases Prevention and Control Saint Petersburg
Russian Federation Saint Petersburg State Budgetary Healthcare Institution Clinical Hospital of Infectious Diseases n.a. S.P. Botkin Saint Petersburg
Russian Federation Clinic of Samara State Medical University, Department of Infectious Diseases Samara
Russian Federation Public corporation Medical company "Gepatolog" Samara
Russian Federation Municipal Healthcare Institution Clinical city hospital #2 n.a. V.I. Razumovsky, Infectious Diseases Department Saratow
Russian Federation Stavropolsky Krai Clinical Hospital, Gastroenterology Department related to Hospital Therapy Department Stavropol'
Russian Federation Stavropolsky State Medical University, Clinic of Gastroenterology, Hepatology and Pancreatology Stavropol'

Sponsors (1)

Lead Sponsor Collaborator
R-Pharm

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type Measure Description Time frame Safety issue
Primary Number of patients with Sustained Virologic Response (SVR24) HCV RNA undetectable by Limit of detection (LOD) Week 24 after the end of treatment
Secondary Number of patients who achieve the Rapid Virological Response (RVR) HCV RNA < LOD Week 4 of treatment
Secondary Number of patients who achieve the Early Virological Response (EVR) HCV RNA Week 12 of treatment
Secondary Number of patients who achieve the End of Treatment Response (ETR) HCV RNA Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
Secondary Number of patients who achieve the SVR12 HCV RNA undetectable (by LOD) Week 12 after the end of treatment
Secondary Number of patients who develop viral breakthrough Greater than or equal to 1 log10 increase in HCV-RNA above nadir, or detectable HCV-RNA, while on treatment after an initial drop below detection Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
Secondary Number of patients who develop relapse HCV RNA undetectable by LOD at end of treatment with subsequent detectable HCV RNA Week 24 after the end of treatment
Secondary Number of patients who develop anemia Anemia is defined as as Hb <10g/dL Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
Secondary Number of patients who develop neutropenia Neutropenia is defined as neutrophils <0.75x109/L Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
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