Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute Hepatitis C Virus (HCV) Infection

NCT02128217 | Completed Phase 1 Results DMC

• 2 other identifiers: ACTG A5327UM1AI068636
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 12

Brief Summary

Early identification of acute HCV infection is essential to prevent chronic infections and the long-term liver disease complications that may occur. Early identification and treatment of HCV during the acute phase can result in significantly higher response rates with shorter durations of therapy. Pegylated-interferon alfa (PEG-IFN) was the typical treatment for HCV infection. Participants subcutaneously inject PEG-IFN where the average duration of treatment was approximately 20 weeks. With the advancement of direct-acting antivirals (DAAs), it was possible to see if a new DAA might be non-inferior compared to (PEG-IFN). The study was designed to see if a fixed-dose combination tablet can replace the old HCV treatments by being more effective, safer and better tolerated in HIV-infected participants with new HCV infection. The study was a Phase I, open-label, two cohort clinical trial, in which 44 acutely HCV-infected HIV-1 positive participants were enrolled. Participants in each cohort were evaluated in two steps: on treatment (Step 1) and follow-up after discontinuing study treatment (Step 2). The cohorts were enrolled sequentially. Participants in Cohort 1 were enrolled and administered oral Sofosbuvir (SOF) in combination with weight-based ribavirin (RBV). Participants in Cohort 2 were enrolled and administered an oral fixed dose combination of Ledipasvir/Sofosbuvir (LDV/SOF).

Conditions

HIV-1 Infection; Hepatitis

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Sustained Virologic Response 12 (SVR12)

  SVR12 was defined as HCV RNA undetectable less than the lower limit of quantification, Target Not Detected (\<LLOQ TND) of the assay at 12 weeks after date of last dose of study treatment. For both Cohort 1 and Cohort 2, the 12 week measurement used for determining SVR12 was the measurement obtained closest to 84 days (i.e. 12\*7 days), within the window 79 to 112 days inclusive. If a participant did not have an HCV RNA measurement within this window, then the participant was considered as having detectable HCV RNA at 12 weeks unless the preceding and subsequent HCV RNA measurements were both undetectable (\<LLOQ TND). A two-sided 90% confidence interval was calculated for this percentage using the Blyth-Still-Casella method.

  At 12 weeks after date of last dose of study treatment. The duration of study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively.

• Percentage of Participants With an Occurrence of a Grade ≥ 2 Adverse Event, Serious AE According to ICH Criteria, or Treatment-limiting AE.

  Any adverse event occurring after initiation of study treatment through to 28 days after the date of last dose of study treatment was included (except that an event that was ongoing at the same grade from before start of study treatment was excluded). Adverse events consisted of Grade ≥ 2 primary diagnosis, primary sign/symptoms, and primary laboratory abnormality. It also included any serious adverse event according to ICH criteria and any treatment-limiting AE (ie, an AE reported as the reason for permanent discontinuation of study treatment). A two-sided 90% confidence interval was calculated for the percentage using the Blyth-Still-Casella method.

  From initiation of study treatment to 28 days after last dose of study treatment. The duration for study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively.

Secondary Outcomes (17)

• Percentage of Participants With HCV RNA Undetectable During Study Treatment

  1, 2, 4, 8 and, for the 12-week regimen, 12 weeks after starting study treatment.

• Percentage of Participants With HCV RNA Undetectable After End of Study Treatment

  2, 4, 8 and 24 weeks after last dose of study treatment. The duration of study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively.

• Number of Participants Who Had HCV Virologic Relapse

  From end of study treatment through to 24 weeks after end of study treatment. The duration of study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively.

• Percentage of HCV Virologic Failure Participants That Developed SOF- or LDV-Associated Resistance Mutations

  At time of HCV virologic failure; any time from start of study treatment to 24 weeks after end of study treatment. Duration of study treatment for Cohort 1 and 2 were 12 and 8 weeks, respectively.

• Count and Percentage of Participants With an Adverse Event by Type.

  Any time from start of treatment to 28 days after date of last dose of study treatment. The duration of study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively.

Study Arms (2)

Cohort 1: SOF+weight-based RBV for 12 wks

EXPERIMENTAL

Participants in Cohort 1 were assigned Sofosbuvir (SOF)+weight-based ribavirin (RBV) for 12 weeks. Follow-up visits occurred through to 24 weeks after the end of treatment.

Drug: Sofosbuvir; Drug: Ribavirin

Cohort 2: LDV/SOF for 8 wks

EXPERIMENTAL

Participants in Cohort 2 were assigned Ledipasvir/Sofosbuvir for 8 weeks. Follow-up visits occurred through to 24 weeks after the end of treatment.

Drug: Ledipasvir/Sofosbuvir

Interventions

Sofosbuvir DRUG

Participants received one 400 mg tablet of sofosbuvir (SOF) orally every morning with food

Also known as: SOF

Cohort 1: SOF+weight-based RBV for 12 wks

Ribavirin DRUG

Participants received weight-based ribavirin RBV orally, 2 times a day, every morning and every evening, with food. Weight under 75 kg, 600 mg (3 tablets) morning and 400 mg (2 tablets) evening. Weight over 75 kg, 600 mg (3 tablets) morning and 600 mg (3 tablets) evening. The dose of RBV was based on subject's weight at entry. Changes in weight after entry did not require a change in dose. Doses were only changed for toxicity management.

Also known as: RBV

Cohort 1: SOF+weight-based RBV for 12 wks

Ledipasvir/Sofosbuvir DRUG

Participants received one daily fixed-dose combination tablet orally every morning of 90 mg of Ledipasvir (LDV) and 400 mg of SOF.

Also known as: LDV/SOF

Cohort 2: LDV/SOF for 8 wks

Eligibility Criteria

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

You may qualify if:

• HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or plasma HIV-1 RNA viral load. \[NOTE: The term "licensed" refers to a FDA-approved kit, which is required for all IND studies.\] WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
• A documented confirmation of acute HCV infection within 6 months prior to A5327 entry or HCV reinfection as described below:
• New (\<24 weeks prior to initial A5327 entry) ALT elevation to ≥5X upper limit of normal (ULN) OR \>250 U/L in patients with documented normal ALT in the preceding 12 months or ≥10X ULN OR \>500 U/L in patients with abnormal or no measured ALT baseline in the preceding 12 months with detectable HCV RNA excluding those with any prior positive anti-HCV. OR
• Detectable HCV RNA with prior negative anti-HCV Ab or undetectable HCV RNA within the preceding 6 months.
• New (\<24 weeks prior to initial A5327 entry) ALT elevation to ≥5X ULN OR \>250 U/L in patients with documented normal ALT in the preceding 12 months or ≥10X ULN OR \>500 U/L in patients with abnormal or no measured ALT baseline in the preceding 12 months with detectable HCV RNA. OR
• Positive HCV RNA with prior negative HCV RNA within the preceding 6 months.
• HCV RNA confirmed to be detectable \>12 weeks after first laboratory evidence of acute HCV and still within the \<24 week from first laboratory evidence of acute HCV infection window. First laboratory evidence of infection was defined as date of first elevated liver enzymes or date of first serologic evidence of HCV seroconversion and/or viremia (whichever occurs first). \[NOTE: If the screening visit occurred less than 12 weeks from the first laboratory evidence of infection, then the participant was required a pre-entry study visit to confirm detectable HCV RNA at least 12 weeks from the first laboratory evidence of infection had passed. It was optimal for this pre-entry visit to occur as close as possible to 12 weeks from first laboratory evidence to ensure timely treatment. Potential participants who entered screening but who had an undetectable HCV RNA (\<LLOQ TND) at the pre-entry visit (when required) exhibited evidence of possible spontaneous clearance and will not meet the entry criteria.\]
• Body mass index (BMI) ≥ 18 kg/m\^2
• Screening electrocardiogram (ECG) without clinically significant abnormalities as determined by the investigator.
• Willing and able to provide written informed consent.
• Men and women age ≥ 18 years.
• All participants agreed not to participate in a conception process (eg, active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). \[NOTE: Female candidates who were pregnant or breastfeeding were not eligible. A male candidate who had a pregnant female partner was not eligible for the study.\]
• When participating in sexual activity that could lead to pregnancy, all participants must agree to use at least two reliable forms of contraceptive simultaneously while receiving protocol-specified medications, and for 6 months after stopping the medications. Such methods included:
• Condoms (male or female) with or without a spermicidal agent
• Diaphragm or cervical cap with spermicide

You may not qualify if:

• Received investigational drug or device within 60 days prior to study entry.
• Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson's disease, α1 antitrypsin deficiency, primary sclerosing cholangitis).
• Presence of active or acute AIDS-defining opportunistic infections within 30 days prior to study entry. \[NOTE: A list of AIDS-defining opportunistic infections as defined by the CDC, can be found in Appendix B of the following document: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm\]
• Active, serious infection (other than HIV-1 or HCV) requiring parenteral antibiotics, antivirals, or antifungals within 30 days prior to study entry.
• Infection with hepatitis B virus (HBV) defined as HBsAg positive.
• Evidence of acute hepatitis A infection defined as HAV IGM positive.
• Chronic use of systemically administered immunosuppressive agents (eg, prednisone equivalent \> 10 mg/day).
• History of solid organ transplantation.
• Current or prior history of clinical hepatic decompensation (eg, ascites, encephalopathy or variceal hemorrhage).
• History of a gastrointestinal disorder (or post operative condition) that could interfere with the absorption of the study drug.
• History of significant or symptomatic pulmonary disease, cardiac disease, or porphyria.
• History of difficulty with blood collection and/or poor venous access for the purposes of phlebotomy.
• History of clinically significant illness or any other major medical disorder that may interfere with participant treatment, assessment, or compliance with study requirements, which may included active drug or alcohol use or dependence.
• Use of any prohibited concomitant medications within 30 days prior to study entry.
• Prior exposure to a direct-acting antiviral (DAA) targeting the HCV NS5B polymerase. \[NOTE: DAAs include but are not limited to: mericitabine, ABT-333, ABT-072, BI-207127, BMS-791325, VX-222, tegobuvir, IDX719, setrobuvir, GS-9669, VX-135.\]

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (12)

701 University of California, San Diego AntiViral Research Center CRS

San Diego, California, 92103, United States

Location

801 University of California, San Francisco HIV/AIDS CRS

San Francisco, California, 94110, United States

Location

Whitman Walker Health CRS (31791)

Washington D.C., District of Columbia, 20009, United States

Location

2701 Northwestern University CRS

Chicago, Illinois, 60611, United States

Location

Rush Univ. Med. Ctr. ACTG CRS (2702)

Chicago, Illinois, 60612, United States

Location

101 Massachusetts General Hospital (MGH) CRS

Boston, Massachusetts, 02114, United States

Location

7804 Weill Cornell Chelsea CRS

New York, New York, 10010, United States

Location

7803 Weill Cornell Upton CRS

New York, New York, 10065, United States

Location

2401 Cincinnati CRS

Cincinnati, Ohio, 45267-0405, United States

Location

6201 Penn Therapeutics CRS

Philadelphia, Pennsylvania, 19104, United States

Location

31443 Trinity Health and Wellness Center CRS

Dallas, Texas, 75208, United States

Location

31473 Houston AIDS Research Team (HART) CRS

Houston, Texas, 77030, United States

Location

Related Publications (2)

• Naggie S, Fierer DS, Hughes MD, Kim AY, Luetkemeyer A, Vu V, Roa J, Rwema S, Brainard DM, McHutchison JG, Peters MG, Kiser JJ, Marks KM, Chung RT; Acquired Immunodeficiency Syndrome Clinical Trials Group (ACTG) A5327 Study Team. Ledipasvir/Sofosbuvir for 8 Weeks to Treat Acute Hepatitis C Virus Infections in Men With Human Immunodeficiency Virus Infections: Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals. Clin Infect Dis. 2019 Jul 18;69(3):514-522. doi: 10.1093/cid/ciy913.

  PMID: 31220220 DERIVED

• Naggie S, Marks KM, Hughes M, Fierer DS, Macbrayne C, Kim A, Hollabaugh K, Roa J, Symonds B, Brainard DM, McHutchison JG, Peters MG, Kiser JJ, Chung R; AIDS Clinical Trials Group (ACTG) A5327 Study Team. Sofosbuvir Plus Ribavirin Without Interferon for Treatment of Acute Hepatitis C Virus Infection in HIV-1-Infected Individuals: SWIFT-C. Clin Infect Dis. 2017 Apr 15;64(8):1035-1042. doi: 10.1093/cid/cix025.

  PMID: 28329053 DERIVED

Related Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014
• Aids Clinical Trial Group Network

MeSH Terms

Conditions

Hepatitis

Interventions

Sofosbuvir; Ribavirin; ledipasvir, sofosbuvir drug combination

Condition Hierarchy (Ancestors)

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; Ribonucleosides; Nucleosides

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Raymond T Chung, M.D.

  Massachusetts General Hospital

  STUDY CHAIR

• Susanna Naggie, M.D.

  Duke University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2014
• First Posted: May 1, 2014
• Study Start: May 30, 2014
• Primary Completion: February 28, 2017
• Study Completion: May 9, 2017
• Last Updated: April 27, 2018
• Results First Posted: March 30, 2018

Record last verified: 2018-03

Locations

US (12)