Clinical trial NCT02886624: Short Duration Therapy of Acute Hepatitis C Genotypes 1 or 4
Official title: Short Duration Therapy of Acute Hepatitis C Genotypes 1 or 4: Efficacy and Tolerability of Grazoprevir 100mg/Elbasvir 50mg During 8 Weeks
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Hepatitis C
HIV
Lead sponsor: Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2016-09-01
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the rate of sustained virological response (SVR) 12 weeks after 8-week oral treatment with grazoprevir 100mg/elbasvir 50mg (MRK-combo) in patients with acute hepatitis C genotype1 or 4.

Detailed description: Increasing rates of acquisition of HCV in men who have sex with men (MSM) have been reported since 2001 in Western European countries and particularly in France. Observational studies have recently reported that HIV-infected gay and bisexual men with sexually transmitted hepatitis C have shown unexpectedly rapid liver disease progression in a relatively short period of time.

It is therefore admitted that, in the absence of a spontaneous HCV clearance within 3 months of acute HCV infection, treatment should be initiated. Pegylated interferon in combination with weight-adapted ribavirin is still recommended as the treatment of choice for all HCV genotypes in an acute setting. For patients developing a rapid virologic response, treatment duration of 24 weeks is recommended. If antiviral therapy was initiated within 24 weeks after diagnosis, sustained virologic response rates of 60 to 80% have been observed at the price of a high side effects burden.

However, short course therapies with new direct acting antivirals are likely to be safer and more efficient. But their efficacy in acute hepatitis C has still to be established. To date, US- and Europe- based trials are ongoing in this setting with the association of sofosbuvir and ribavirine, sofosbuvir / ledipasvir or sofosbuvir / simeprevir, for a duration of 4, 6, 8 or 12 weeks. Preliminary results are very diverse, with SVR12 ranging from 56% to 95%. MSD has been evaluating the efficacy and safety of a double drug combination (grazoprevir + elbasvir) in HIV-infected patients which exhibits paramount efficacy and excellent tolerance in a diverse range of genotypes, including 1 and 4 HCV strains, which are those mainly encountered in the French acute HCV epidemics in MSM. This association has the potential to be used for short treatment duration especially with regards to the fact that patients will have no fibrosis at the time of treatment initiation. This MRK-combo would therefore be an ideal candidate for treating acute hep C due to GT1 or 4 in a "test and treat" approach in high-risk population such as MSM.

Eligibility criteria: Inclusion Criteria:

1. Adult ≥18 years.
2. A recent acute HCV infection \[defined by (i) detectable HCV RNA within 6 months after a negative HCV RNA or HCV serology test OR (ii) detectable HCV RNA and acute clinical hepatitis within 5 months prior to screening visit (ALT ≥250 IU/L with normal ALT within the preceding 8 months OR ALT ≥500 IU/L with either no measured ALT or with abnormal ALT within the preceding 8 months)\] or reinfection \[defined by documented de novo infection after prior clearance post-treatment (defined by one negative HCV RNA ≥6 months after end of treatment) or spontaneously (defined by two negative HCV RNA a minimum of 6 months apart OR documented infection with a new viral strain, confirmed by phylogenetic or genotypic analysis)\] within 5 months prior screening OR (iii) patients having reported a risk factor for HCV contamination (traumatic sexual intercourse, intranasal, rectal or intravenous drug use) ≥6 months AND presenting a negative HCV RNA or HCV serology test within 12 months.
3. Infection with HCV genotype 1 or 4 (confirmed at screening visit or by using a previous biological test performed 1 to 4 weeks before week 0).
4. Plasma HCV-RNA ≥ 1000 IU/mL (confirmed at screening visit or by using a previous biological test performed 1 to 4 weeks before week 0).
5. Confirmed HIV infection (only for HIV co-infected patients).
6. Without HIV treatment or with an authorized stable HIV treatment for at least two weeks (only for HIV co-infected patients).
7. Body weight ≥40 kg and ≤125 kg.
8. Female patients with child-bearing potential and their heterosexual partners must use adequate contraception from the date of screening until 30 days after administration of the last dose of study drug. Male participants must agree to consistently and correctly use a condom, while their female partner must use adequate contraception from the date of screening until 30 days after administration of the last dose of study drug.
9. Informed and signed consent.
10. Patients with Health insurance (Sécurité Sociale or Couverture Médicale Universelle).

Exclusion Criteria:

1. Opportunistic infections (stage C), active or occurred within 6 months prior to baseline.
2. Primary HIV infection.
3. Co-infection with Hepatitis B virus (HBsAg-positive) without appropriate treatment (TDF or TAF) for at least 2 weeks.
4. Confirmed cirrhosis (before acute HCV diagnosis).
5. Any other causes of acute hepatitis.
6. Pregnant or breast-feeding women.
7. Liver transplant recipients.
8. Evolutive malignancy.
9. Patients with a history of non-adherence, who will be at risk of being unable to respect the study follow-up timetable.
10. Patients participating in another clinical trial (with an experimental treatment) or within an exclusion period of a previous clinical trial at screening.
11. Patients under legal gardianship or incarcerated.
12. Hemaglobulin \<10 g/dL (female) or \<11g/dL (male).
13. Platelet count \<50,000/mm3.
14. Neutrophil count \< 750/mm3.
15. Other antiretroviral drugs than those allowed in the study.
16. Contra-indications to grazoprevir and/or elbasvir or to any of the excipients listed in the summary of the product characteristics.
17. Contra-indicated treatment likely to interfere with the study drugs as listed in the summary of the product characteristics.

Primary outcomes:
measure: Sustained Virological Response 12 Weeks Post-treatment (SVR12)
timeFrame: 12 weeks
Secondary outcomes:
measure: Virological Failure
timeFrame: 12 weeks
measure: Treatment Adherence
timeFrame: 8 weeks
measure: Number of Participants With Undetectable HIV RNA
timeFrame: 12 weeks
measure: CD4 Cell Count
timeFrame: 12 weeks
measure: Incidence of HCV Re-infection
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Lyon
country: France
facility: CHU de Lyon
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Paris
country: France
facility: Hôpital La Pitié-Salpêtrière
city: Paris
country: France
facility: Hôpital Bichat
city: Paris
country: France
facility: Hôpital Tenon
Study officials:
affiliation: Hôpital Saint-Antoine, Service des maladies infectieuses et tropicales
name: Karine Lacombe, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gambotti L, Batisse D, Colin-de-Verdiere N, Delaroque-Astagneau E, Desenclos JC, Dominguez S, Dupont C, Duval X, Gervais A, Ghosn J, Larsen C, Pol S, Serpaggi J, Simon A, Valantin MA, Velter A; Acute hepatitis C collaborating group. Acute hepatitis C infection in HIV positive men who have sex with men in Paris, France, 2001-2004. Euro Surveill. 2005 May;10(5):115-7.
citation: Fierer DS, Dieterich DT, Fiel MI, Branch AD, Marks KM, Fusco DN, Hsu R, Smith DM, Fierer J. Rapid progression to decompensated cirrhosis, liver transplant, and death in HIV-infected men after primary hepatitis C virus infection. Clin Infect Dis. 2013 Apr;56(7):1038-43. doi: 10.1093/cid/cis1206. Epub 2012 Dec 21.
citation: European AIDS Treatment Network (NEAT) Acute Hepatitis C Infection Consensus Panel. Acute hepatitis C in HIV-infected individuals: recommendations from the European AIDS Treatment Network (NEAT) consensus conference. AIDS. 2011 Feb 20;25(4):399-409. doi: 10.1097/QAD.0b013e328343443b. No abstract available.
citation: Rockstroh JK, Nelson M, Katlama C, Lalezari J, Mallolas J, Bloch M, Matthews GV, Saag MS, Zamor PJ, Orkin C, Gress J, Klopfer S, Shaughnessy M, Wahl J, Nguyen BY, Barr E, Platt HL, Robertson MN, Sulkowski M. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV. 2015 Aug;2(8):e319-27. doi: 10.1016/S2352-3018(15)00114-9. Epub 2015 Jul 9.