Therapy for Hepatitis C Virus (HCV) in Primary Treatment Failure in Pakistan

NCT05248919 | Enrolling By Invitation DMC

• 1 other identifier: HCVTreatmentFailure
• Study Type: interventional
• Target: 318
• Locations: 1 country
• Sites: 1

Brief Summary

This trial is linked to a largescale observational study determining the efficacy of sofosbuvir/daclatasvir in people in Pakistan (involving a separate protocol). The observational study will identify a cohort of patients who have not responded to first-line antiviral therapy (sofosbuvir plus daclatasvir) and the optimal treatment for these patients is unclear. This trial will address this issue by comparing two second-line treatment regimens to determine the preferred treatment option.

Conditions

Hepatitis C

Outcome Measures

Primary Outcomes (1)

• Determine sustained virological response rate (SVR)

  Sustained virological response (SVR) defined as proportion of patients who are HCV RNA negative with a sensitive molecular test (sensitivity \<100 IU/ml) 36 +/- 2 weeks from the time of randomisation. 2\. To determine the proportion of people with decompensated cirrhosis who achieve a sustained virological response (SVR) 36 weeks (+/-2 weeks) after first dose of medication (sofosbuvir/velpatasvir) administered.

  36+/- 2 weeks from the point of randomisation

Secondary Outcomes (3)

• Cost effectiveness of treatment

  24 weeks after randomisation

• Health care costs

  24 weeks after randomisation

• Determine viral polymorphisms in HCV

  12 months

Study Arms (3)

12 weeks - treatment with sofosbuvir/velpatasvir (usual regime)

ACTIVE COMPARATOR

134 first-line treatment failure patients randomly allocated to receive 12 weeks treatment with sofosbuvir/velpatasvir. 1:1 random allocation with stratification for the presence of cirrhosis

Drug: Epclusa (nucleotide HCV NS5B polymerase inhibitors).

24 weeks - treatment with sofosbuvir/velpatasvir (intervention)

ACTIVE COMPARATOR

134 first-line treatment failure patients randomly allocated to receive 24 weeks treatment with sofosbuvir/velpatasvir. 1:1 random allocation with stratification for the presence of cirrhosis

Drug: Epclusa (nucleotide HCV NS5B polymerase inhibitors).

Observational

NO INTERVENTION

50 patients with decompensated cirrhosis who will receive 24 weeks of sofosbuvir/velpatasvir.

Interventions

Epclusa (nucleotide HCV NS5B polymerase inhibitors). DRUG

Sofosbuvir (400mg/day) and Velpatasvir(100mg/day) for 12 weeks or 24 weeks

Also known as: Sofosbuvir 400 Mg and Velpatasvir 100 Mg Oral Capsules

12 weeks - treatment with sofosbuvir/velpatasvir (usual regime); 24 weeks - treatment with sofosbuvir/velpatasvir (intervention)

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to give written informed consent or sign consent forms with a fingerprint.
• Male or female, age ≥ 18 years.
• Willing to comply with study procedures
• Resident in the area and not planning to leave the region.
• Have a confirmed diagnosis at the time of screening of active hepatitis C infection - defined as detectable HCV RNA using a molecular diagnostic assay with a sensitivity of \>100IU/ml OR detectable HCV Core antigen using an assay with a sensitivity of \>1.5 pg/ml.
• Treatment experience within the last 24 months of antiviral therapy drugs recommended by the government program and administered in line with national recommendations. The current recommendations are that patients without cirrhosis should receive sofosbuvir 400 mg per day in combination with daclatasvir 60 mg per day for a total of 12 weeks and for patients with cirrhosis therapy should involve sofosbuvir 400 mg per day in combination with daclatasvir 60 mg per day for a total of 24 weeks. Patients who receive additional medication (including ribavirin) can be enrolled in the study but the additional medication should be noted.
• The subject's medical records must include sufficient detail of prior treatment to confirm eligibility.
• Have a stored sample of serum or plasma that is known to contain detectable HCV RNA and which can be made available to the study team or be willing to provide such a sample
• Have undergone, or be willing to undergo, an approved screening test for determining liver cirrhosis either by:
• APRI score - calculated from serum AST concentration in IU/L and platelet count /L (a result of ≥2 demonstrates presence of cirrhosis)
• Liver transient elastography assessment (a 'Fibroscan'). A result of ≥12.5 kPa will demonstrate cirrhosis.
• liver biopsy within 1 year of screening
• Females of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day 1 prior to enrolment.
• Lactating females must agree to discontinue nursing before starting study drug.
• Subjects must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments.

You may not qualify if:

• Unwilling or unable to give consent
• Clinically significant illness (other than HCV) or other major medical condition that may interfere with the subject's treatment, assessment or compliance with protocol.
• History of discontinuation the most recent regime due to an adverse event
• Co-morbidities limiting life expectancy to less than 12 months
• Gastrointestinal disorder that could interfere with the absorption of the study drugs
• Significant cardiac disease
• Unstable psychiatric condition
• Significant drug allergy (e.g. hepatotoxicity)
• Infection with hepatitis B virus (HBV) or Human immunodeficiency virus (HIV)
• Unable or unwilling to undergo the necessary procedures - undergoing blood testing and ultrasound/fibroscan scanning.
• Previous poor compliance with medication (defined as failure to take \>80% of the prescribed medication)
• Have undergone liver or other solid organ transplantation
• Have a current or recent diagnosis of hepatocellular carcinoma or any other malignancy

Sponsors & Collaborators

• Queen Mary University of London: lead
• Aga Khan University: collaborator
• Dow University of Health Sciences: collaborator
• University of Oxford: collaborator
• University of Bristol: collaborator

Study Sites (1)

Clinical trials unit

Karachi, Sindh, Pakistan

Location

Related Publications (9)

• El-Akel W, El-Sayed MH, El Kassas M, El-Serafy M, Khairy M, Elsaeed K, Kabil K, Hassany M, Shawky A, Yosry A, Shaker MK, ElShazly Y, Waked I, Esmat G, Doss W. National treatment programme of hepatitis C in Egypt: Hepatitis C virus model of care. J Viral Hepat. 2017 Apr;24(4):262-267. doi: 10.1111/jvh.12668. Epub 2017 Feb 1.

  PMID: 28145032 RESULT

• Smith D, Magri A, Bonsall D, Ip CLC, Trebes A, Brown A, Piazza P, Bowden R, Nguyen D, Ansari MA, Simmonds P, Barnes E; STOP-HCV Consortium. Resistance analysis of genotype 3 hepatitis C virus indicates subtypes inherently resistant to nonstructural protein 5A inhibitors. Hepatology. 2019 May;69(5):1861-1872. doi: 10.1002/hep.29837. Epub 2018 Apr 27.

  PMID: 29425396 RESULT

• Lim AG, Walker JG, Mafirakureva N, Khalid GG, Qureshi H, Mahmood H, Trickey A, Fraser H, Aslam K, Falq G, Fortas C, Zahid H, Naveed A, Auat R, Saeed Q, Davies CF, Mukandavire C, Glass N, Maman D, Martin NK, Hickman M, May MT, Hamid S, Loarec A, Averhoff F, Vickerman P. Effects and cost of different strategies to eliminate hepatitis C virus transmission in Pakistan: a modelling analysis. Lancet Glob Health. 2020 Mar;8(3):e440-e450. doi: 10.1016/S2214-109X(20)30003-6.

  PMID: 32087176 RESULT

• Zeuzem S, Foster GR, Wang S, Asatryan A, Gane E, Feld JJ, Asselah T, Bourliere M, Ruane PJ, Wedemeyer H, Pol S, Flisiak R, Poordad F, Chuang WL, Stedman CA, Flamm S, Kwo P, Dore GJ, Sepulveda-Arzola G, Roberts SK, Soto-Malave R, Kaita K, Puoti M, Vierling J, Tam E, Vargas HE, Bruck R, Fuster F, Paik SW, Felizarta F, Kort J, Fu B, Liu R, Ng TI, Pilot-Matias T, Lin CW, Trinh R, Mensa FJ. Glecaprevir-Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection. N Engl J Med. 2018 Jan 25;378(4):354-369. doi: 10.1056/NEJMoa1702417.

  PMID: 29365309 RESULT

• Foster GR, Afdhal N, Roberts SK, Brau N, Gane EJ, Pianko S, Lawitz E, Thompson A, Shiffman ML, Cooper C, Towner WJ, Conway B, Ruane P, Bourliere M, Asselah T, Berg T, Zeuzem S, Rosenberg W, Agarwal K, Stedman CA, Mo H, Dvory-Sobol H, Han L, Wang J, McNally J, Osinusi A, Brainard DM, McHutchison JG, Mazzotta F, Tran TT, Gordon SC, Patel K, Reau N, Mangia A, Sulkowski M; ASTRAL-2 Investigators; ASTRAL-3 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015 Dec 31;373(27):2608-17. doi: 10.1056/NEJMoa1512612. Epub 2015 Nov 17.

  PMID: 26575258 RESULT

• Esteban R, Pineda JA, Calleja JL, Casado M, Rodriguez M, Turnes J, Morano Amado LE, Morillas RM, Forns X, Pascasio Acevedo JM, Andrade RJ, Rivero A, Carrion JA, Lens S, Riveiro-Barciela M, McNabb B, Zhang G, Camus G, Stamm LM, Brainard DM, Subramanian GM, Buti M. Efficacy of Sofosbuvir and Velpatasvir, With and Without Ribavirin, in Patients With Hepatitis C Virus Genotype 3 Infection and Cirrhosis. Gastroenterology. 2018 Oct;155(4):1120-1127.e4. doi: 10.1053/j.gastro.2018.06.042. Epub 2018 Jun 27.

  PMID: 29958855 RESULT

• Wing PAC, Jones M, Cheung M, DaSilva S, Bamford C, Jason Lee WY, Aranday-Cortes E, Da Silva Filipe A, McLauchlan J, Smith D, Irving W, Cunningham M, Ansari A, Barnes E, Foster GR. Amino Acid Substitutions in Genotype 3a Hepatitis C Virus Polymerase Protein Affect Responses to Sofosbuvir. Gastroenterology. 2019 Sep;157(3):692-704.e9. doi: 10.1053/j.gastro.2019.05.007. Epub 2019 May 10.

  PMID: 31078622 RESULT

• Huang R, Rao H, Xie Q, Gao Z, Li W, Jiang D, Mo H, Massetto B, Stamm LM, Brainard DM, Wei L. Comparison of the efficacy of sofosbuvir plus ribavirin in Chinese patients with genotype 3a or 3b HCV infection. J Med Virol. 2019 Jul;91(7):1313-1318. doi: 10.1002/jmv.25454. Epub 2019 Apr 3.

  PMID: 30861150 RESULT

• Lim AG, Qureshi H, Mahmood H, Hamid S, Davies CF, Trickey A, Glass N, Saeed Q, Fraser H, Walker JG, Mukandavire C, Hickman M, Martin NK, May MT, Averhoff F, Vickerman P. Curbing the hepatitis C virus epidemic in Pakistan: the impact of scaling up treatment and prevention for achieving elimination. Int J Epidemiol. 2018 Apr 1;47(2):550-560. doi: 10.1093/ije/dyx270.

  PMID: 29309592 RESULT

MeSH Terms

Conditions

Hepatitis C

Interventions

sofosbuvir-velpatasvir drug combination; Sofosbuvir; velpatasvir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Uridine Monophosphate; Uracil Nucleotides; Pyrimidine Nucleotides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleotides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleotides

Study Officials

• Graham Foster, MBBS

  Queen Mary University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 268 patients accepted into the study will be divided into two groups (134 per group) and randomly allocated 1:1 (stratified by the presence or absence of cirrhosis) to receive: i) 12 weeks treatment with sofosbuvir/velpatasvir or ii) 24 weeks treatment with sofosbuvir/velpatasvir. Approximately an additional 50 patients with decompensated cirrhosis will form the observational group iii) who will receive 24 weeks of sofosbuvir/velpatasvir. Patients will be assessed for sustained virological response (SVR) from the point of randomisation at 12 (+/-1 week) and 24 weeks (+/-1 week) and then finally at 36 weeks (+/-2 weeks).

Study Record Dates

• First Submitted: June 30, 2021
• First Posted: February 21, 2022
• Study Start: June 1, 2023
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2027
• Last Updated: November 21, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

PA (1)