Study of DAA Treatment for Children and Adolescents With Active HCV Infection in Cambodia (HEPEDIAC)

Pilot Therapeutic Study of DAA Treatment for Children and Adolescents With Active HCV Infection in Cambodia

The goal of this clinical trial is to evaluate the effectiveness of sofosbuvir/daclatasvir combination for children aged ≥ 6 years old and adolescents with active HCV infection in Cambodia

Study Overview

• Status: Recruiting
• Conditions: HCV Infection
• Intervention / Treatment: Drug: Sofosbuvir/Daclatasvir

Detailed Description

Non-comparative multicenter pilot therapeutic prospective study conducted in Phnom Penh and Siem Reap and divided in 2 phases:

Screening phase:

First, all children aged more than 6 years old and adolescents under 18 years old will be screened for HCV infection using Bioline HCV rapid test in two paediatric populations in Phnom Penh and Siem Reap: 1/ children born from HIV/HCV co-infected women followed in OI/ART sites 2/ children hospitalized in paediatric department of Kantha Bopha Foundation Children's Hospitals and of the National Pediatric Hospital.

HCV RNA will be performed in case of HCV rapid test positivity. A case-control study will be performed to evaluate the risk factors associated to HCV acquisition. Cases will be defined as children with positive HCV RDT and controls as children with negative HCV RDT. Four controls will be randomly selected for one case.

Therapeutic phase:

Children and adolescents confirmed with active HCV infection (positive HCV RNA) during the first phase will be referred to a specific consultation in Kantha Bopha hospital or National Pediatric Hospital for treatment after evaluation of liver disease. Patients with a weight > 25 kg will be treated with a sofosbuvir/daclatasvir combination for 12 weeks with adult dose (400/60 mg), children with a weight between 14 and 25 kg will be treated with the same sofosbuvir/daclatasvir combination with the half adult dose (200/30 mg) for 12 weeks. For all children and adolescents, residual plasma concentrations (trough concentrations) of the drugs will be assessed after 2 weeks of treatment. For the first 20 children and adolescents included (10 children weighing between 14 and 25 kg and 10 weighing more than 25 kg), whatever their HIV status and ARV treatment, a complete pharmacokinetic analysis will be performed prior to drug administration and +1h, +2h, +6h and +10h after drugs intake. A non-compartimental analysis using Phoenix WinNonlin 8.1 (Certara, Princeton, NJ, USA) will be performed to estimate the pharmacokinetic parameters of sofosbuvir, GS-331007 and daclatasvir. Maximal concentration (Cmax), trough concentration at steady state (Ct), minimal concentration (Cmin) and the time required to reach Cmax (Tmax) are the observed parameters. The area under the curve (AUCtau) will be estimated by the linear up log down trapezoidal method using the predose concentration as 24-hour postdose concentrations.

• Study Type: Interventional
• Enrollment (Estimated): 21000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Fatoumata COULIBALY; Phone Number: +33 0144236110; Email: fatoumata.coulibaly@anrs.fr

Study Locations

• Cambodia
  • Battambang, Cambodia
    • Not yet recruiting
    • Battambang Provincial Hospital
    • Contact: Nathalie DE REKENEIRE, Dr; Email: nderekeneire@pasteur-kh.org
    • Principal Investigator: CHEA PEUV, Dr
  • Phnom Penh, Cambodia
    • Recruiting
    • National Pediatric Hospital
    • Contact: Nathalie DE REKENEIRE, Dr; Email: nderekeneire@pasteur-kh.org
    • Principal Investigator: HUOT CHANTHEANY, Prof
  • Phnom Penh, Cambodia
    • Recruiting
    • Kantha Bopha
    • Contact: Nathalie DE REKENEIRE, Dr; Email: nderekeneire@pasteur-kh.org
    • Principal Investigator: KY SANTY, Prof
  • Siem Reap, Cambodia
    • Recruiting
    • Jayavarman VII Hospital
    • Contact: Nathalie DE REKENEIRE, Dr; Email: nderekeneire@pasteur-kh.org
    • Principal Investigator: YAY CHANTANA, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Screening phase Inclusion criteria

• Aged ≥ 6 years old with weight ≥ 14 kg
• Aged <18 years old
• Hospitalized in one of the 3 paediatric departments of Kantha Bopha hospitals in Phnom Penh, Jayavarman VII hospital in Siem Reap OR in the pediatric department of the National Pediatric hospital OR born from HIV/HCV co-infected women followed in OI/ART sites in Phnom Penh
• Informed consent obtained with information sheet given and explained before the inclusion visit, the consent form signed by at least one of the 2 parents or legal guardians and oral assent collected if the child ≥ 13 years old, at the latest the day of the inclusion

Non-inclusion criteria

- Any medical condition requiring intensive care and/or acute surgery

Therapeutic phase Inclusion criteria

• Aged ≥ 6 years old with weight ≥ 14 kg
• Aged < 18 years old
• HCV RNA detectable
• HCV treatment naive

• In case of HIV coinfection,

  • HIV-1 infection confirmed according to Cambodian screening policies
  • On ART for more than 6 months
  • CD4 cell-count> 100 cells/μL and > 15% and HIV viral load < 1000 copies/mL at inclusion visit
• Informed consent obtained with information sheet given and explained before the inclusion visit and the consent form signed by at least one of the 2 parents and oral assent collected if the child ≥ 13 years old, before any sample or drug administration corresponding to the therapeutic phase.

Non-inclusion Criteria:

• Suspicion of evidence of hepato-cellular carcinoma (HCC) or any other neoplasia
• Decompensated cirrhosis
• Co-infection with HBV (positive HBsAg)
• Advanced/terminal renal disease defined as serum creatinine clearance < 30 mL/min
• Active tuberculosis under treatment

• In case of HIV coinfection,

  • Repeated ART failures and impossibility of prescription of an effective ART regimen
  • Active opportunistic infection (OI)
• Current pregnancy or breast feeding
• Use of any drug known to interact with Sofosbuvir or Daclatasvir and for which temporary cessation or dose modification would be impossible
• Any concomitant medical condition that, according to the clinical site investigator, would contraindicate participation in the study
• Concurrent participation in any other clinical trial without written agreement of the two study investigators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Therapeutic phase; Children and adolescents confirmed with active HCV infection (positive HCV RNA) during the screening phase will be referred to a specific consultation in Kantha Bopha hospital and in the National Pediatric Hospital for treatment after evaluation of liver disease. Patients with a weight > 25 kg will be treated with a sofosbuvir/daclatasvir combination for 12 weeks with adult dose (400/60 mg), children with a weight between 14 and 25 kg will be treated with the same sofosbuvir/daclatasvir combination with the half adult dose (200/30 mg) for 12 weeks. For all children and adolescents, residual plasma concentrations (trough concentrations) of the drugs will be assessed after 2 weeks of treatment.

Drug: Sofosbuvir/Daclatasvir; Patients with a weight > 25 kg will be treated with a sofosbuvir/daclatasvir combination for 12 weeks with adult dose (400/60 mg), children with a weight between 14 and 25 kg will be treated with the same sofosbuvir/daclatasvir combination with the half adult dose (200/30 mg) for 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of the effectiveness of sofosbuvir/daclatasvir combination for children aged ≥ 6 years old and adolescents with active HCV infection in Cambodia	The proportion of patients with sustained virologic response defined by HCV RNA below the lower limit of quantification range of the viral load (undetectable viral load) 12 weeks after discontinuation of study drugs (SVR12). Detectable HCV RNA at the SVR12 study visit, permanent discontinuation of DAA, death, discontinuation of the study (loss to follow-up, transfer-out) will be considered as failures.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of the liver-related events	Proportion of patients with symptomatic cirrhosis and evaluation of Child-Pugh score; Proportion of patients with APRI (AST to Platelet Index Ratio) score > 2 and/or FIB-4 (Fibrosis-4) score > 3.25; Proportion of patients with liver elasticity > 9 kPa; Proportion of patients with hepato-cellular carcinoma	24 months
Occurrence of grade 3-4 adverse events (ANRS grading table);	Frequency, type and time to grade 3 or 4 adverse clinical or biological events. All adverse events will be graded according to the Division of AIDS ( DAIDS) grading table;; Frequency, type and time to drug-related clinical or biological adverse reactions of grade 3 or 4 or leading to treatment interruption	24 months
Adherence	The adherence to DAA treatment will be assessed by accountability (drug pill count)	24 months
Maximal Plasma Concentration (Cmax) of DAA	Cmax of Sofosbuvir, GS-331007 and Daclatasvir measured in plasma samples	24 months
Area under the plasma concentration versus time curve over the dosing interval (AUCtau) of DAA	AUCtau of Sofosbuvir, GS-331007 and Daclatasvir will be estimated by the linear up log down trapezoidal method	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk factors of HCV acquisition through questionnaire	Case-control study to evaluate the risk factors associated to HCV acquisition. The questionnaire include information on family disease history, medical care received (injections, blood transfusion, surgery), dental care, tatoos, injecting drug user, use of traditional medicine, and sharing of hygiene tools.	24 months

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2023
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: June 28, 2023
• First Submitted That Met QC Criteria: August 7, 2023
• First Posted (Actual): August 15, 2023

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Disease Attributes; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Infections; Communicable Diseases; Hepatitis C; Anti-Infective Agents; Antiviral Agents; Sofosbuvir
• Other Study ID Numbers: ANRS 12420 HEPEDIAC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No