Hepatitis C, HIV-1-infection, Liver Diseases
Conditions
Brief summary
To achieve global hepatitis C virus (HCV) elimination by 2030, 80% of the \ 71 million people with chronic HCV infection will need to be treated, necessitating simplification of treatment delivery and associated laboratory monitoring without compromising efficacy or safety. The COVID-19 pandemic has further highlighted the need for innovative models of health care delivery that minimize face-to-face patient-provider contact. The purpose of this study was to evaluate the feasibility, safety, and efficacy of a minimal monitoring (MINMON) strategy to deliver interferon- and RBV-free, pan-genotypic DAA therapy to treat active HCV in HCV treatment naïve participants.
Detailed description
This study evaluated the feasibility, safety, and efficacy of a minimal monitoring (MINMON) strategy of delivering interferon- and ribavirin (RBV)-free, pan-genotypic direct-acting antiviral (DAA) therapy to treat active hepatitis C virus (HCV) in HCV treatment naïve participants, with or without HIV-1 co-infection, and with no evidence of decompensated cirrhosis. The MINMON intervention included four components: 1) No pre-treatment HCV genotyping; 2) Entire 12-week treatment course (84 tablets) dispensed to participants at study entry; 3) No scheduled on-treatment laboratory monitoring or clinic visits prior to SVR evaluation scheduled 24 weeks following entry; 4) Remote contact with participants at week 4 for adherence counseling and locator update, and week 22 for scheduling of SVR visit and locator update. At study entry, all participants received a single-tablet, fixed-dose combination (FDC) of sofosbuvir/velpatasvir (SOF/VEL) for 12 weeks. The trial was designed to accrue 400 adult participants who may be co-infected with HIV-1 (limited to no more than 200 participants), and whose liver disease state is either no cirrhosis (defined by Fibrosis-4 score) or compensated cirrhosis (defined by Fibrosis-4 and Child-Turcotte-Pugh (CTP) scores, and limited to no more than 80 participants). Accrual from research sites in the United States was limited to no more than 132 participants. The study proceeded in two steps: Step 1: MINMON intervention and Step 2: post-MINMON follow up. During Step 1 (MINMON intervention), participants were contacted remotely at week 4 to inquire about study medication adherence and confirm locator information, and again at week 22 to schedule the sustained virologic response (SVR) evaluation and confirm locator information. Unplanned in-person clinic visits before week 22 were permissible to address common treatment toxicities that could not be managed remotely. The primary efficacy outcome measure, sustained virologic response (SVR), was evaluated starting at the week 24 study visit. Early discontinuation of treatment did not alter the timing of the SVR evaluation. If the week 24 visit was missed, SVR could be evaluated at any time up to 76 weeks following study entry. Following SVR evaluation, participants entered Step 2 for two additional post-SVR evaluation study visits at weeks 48 and 72. Participants were contacted remotely at weeks 42 and 68 to schedule such visits. The schedule of additional post-MINMON evaluation visits were dependent on the week of Step 2 entry. In version 1 of the study, total study duration was up to 76 weeks. Due to the COVID-19 Pandemic, the window of the week 72 visit was extended for participants who completed SVR evaluations and registered to Step 2 to October 31, 2020 for US sites and to February 28, 2021 for non-US sites. This extension did not alter the window for SVR evaluation. All scheduled in-clinic study visits included a physical exam, blood collection, and collection of plasma samples. For participants able to become pregnant, pregnancy testing was conducted at screening, entry, and at any in-clinic visit during Step 1 if pregnancy was suspected. Liver Elastography was an optional evaluation.
Interventions
400/100 mg fixed-dose combination (FDC) tablet administered orally once daily with or without food.
OTHERMinimal Monitoring (MINMON) Strategy
MINMON Strategy: 1. No pre-treatment HCV genotyping 2. Entire treatment course (84) tablets of SOF/VEL administered to participants at study entry 3. No scheduled on-treatment laboratory monitoring or clinic visits 4. Remote contact with participants at week 4 and week 22
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Active Hepatitis C (HCV) infection, defined by HCV RNA \>1000 international units (IU/mL) within 35 days prior to study entry * HCV treatment naïve * Liver disease staged as either non-cirrhotic (Fibrosis-4 (FIB-4) Score \<3.25) or compensated cirrhotic (FIB-4 Score ≥3.25 and Child-Turcotte-Pugh (CTP) ≤Score 6) within 35 days prior to study entry * HIV-1 negative, or HIV-1 positive with either a) Non-efavirenz containing antiretroviral therapy (ART) started at least 14 days prior to study entry with plasma HIV-1 RNA \<400 copies/mL within 90 days prior to study entry or b) not taking ART and CD4+ cell count \>350 cells/uL within 90 days prior to study entry * The following laboratory values obtained within 35 days prior to study entry: * Albumin \>3.0 g/L * Hemoglobin \>8.0 g/dL for women; \>9.0 g/dL for men * Platelet count \>50,000/mm\^3 * Calculated creatinine clearance (CrCl) \>30 mL/min * Aspartate aminotransferase (AST) \<10 times the upper limit of the normal range (ULN) * Alanine transaminase (ALT) \<10 times the ULN * Total bilirubin \<1.5 times the ULN for participants not on atazanavir (ATV); \<3 times the ULN for participants on ATV * International normalized ratio (INR) \<1.5 times the ULN * For females of reproductive potential, a negative serum or urine pregnancy test within 48 hours prior to study entry * All participants of reproductive potential must have agreed not to participate in conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) while on study treatment and for 6 weeks after stopping study treatment * If participating in sexual activity that could lead to pregnancy, the all participants of reproductive potential had to agree to use at least one reliable methods of contraception while on study treatment and for 6 weeks after stopping study treatment * Participants who were not of reproductive potential were eligible without requiring the use of contraceptives. * Life expectancy \>12 months * Ability and willingness to be contacted remotely * Ability and willingness of participant to provide informed consent.
Exclusion criteria
* Positive for hepatitis B virus (HBV) surface antigen * For cirrhotic participants, CTP score \>6 corresponding to Class B or C * Breastfeeding or pregnancy * Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation * Active drug or alcohol use or dependence and other conditions that, in the opinion of the site investigator, would interfere with adherence to study requirements. * Acute or serious illness requiring systemic treatment and/or hospitalization within 35 days prior to study entry * For HIV positive participants, presence of active or acute AIDS-defining opportunistic infections within 35 days prior to study entry * Any history of hepatic decompensation including ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, and/or bleeding esophageal varices * Use of prohibited medications within the past 14 days prior to study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 (SVR12) | From at least 22 weeks and up to 76 weeks from treatment initiation | SVR12 was defined as plasma HCV RNA less than the lower limit of quantification (LLOQ) from the earliest sample drawn at least 22 weeks following study treatment initiation (i.e. at a visit scheduled at least 10 weeks after scheduled end of study treatment). Participants without any HCV RNA result at least 22 weeks after treatment initiation will be considered as having HCV RNA greater than the LLOQ. LLOQ was defined as \<15 IU/mL for results tested at USA centralized testing laboratory Quest using the Roche COBAS® HCV Quantitative nucleic acid test for use on the COBAS® 6800/8800 assays for quantitation (and detection) of HCV, and \<12 IU/mL for results tested at regional international labs using Abbott RealTime HCV assay for quantitation (and detection) of HCV. A two-sided 95%, confidence interval was calculated for this percentage using the Wilson (score) method. |
| Percentage of Participants With an Occurrence of Serious Adverse Events According to International Council for Harmonization (ICH) Criteria | From treatment initiation to 28 weeks | Serious adverse events (SAEs) as defined by ICH guidelines. A two-sided, 95% confidence interval was calculated for the percentage using the Wilson (score) method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least One Unplanned Clinic Visit Prior to SVR12 Evaluation | From treatment initiation to 22 weeks | According to the study minimal monitoring intervention, there were no planned clinic visits prior to study week 24, when SVR12 was scheduled to be evaluated. An unplanned clinic visit was defined as an in-clinic visit occurring from treatment initiation to up to week 22. A two-sided, 95% confidence interval was calculated for the percentage using the Wilson (score) method. |
| Percentage of Participants With an Occurrence of One or More Non-serious, Grade >= 3 Adverse Event (AE), or Treatment Limiting AE. | From treatment initiation to 28 weeks | AEs included all primary diagnoses, primary signs/symptoms, and primary laboratory abnormalities that either had severity grade ≥ 3 or led to a change in study medication. Serious Adverse Events (SAE) by International Council for Harmonization (ICH) criteria were excluded as they contributed to the primary safety outcome measure. Severity grading was based on DAIDS AE Grading Table, Corrected Version 2.1. A two-sided, 95% confidence interval was calculated for the percentage using the Wilson (score) method. |
| Percentage of Participants Who Prematurely Discontinued HCV Study Medications | From at least 22 weeks and up to 76 weeks from treatment initiation | Since there were no planned clinic visits during the 12 week study medication period, the last dose of study treatment was self-reported by participants, and recorded at the SVR evaluation visit at 24 weeks. Premature treatment discontinuation was defined when the self-reported final dose date was \<11 weeks (\<77 days) after the date of initial dose (accounting for any reported treatment holds). Participants discontinuing study follow up without information about completion of HCV study medications were counted as having prematurely discontinued medications. A two-sided, 95% confidence interval was calculated for the percentage using the Wilson (score) method. |
Countries
Brazil, Puerto Rico, South Africa, Thailand, Uganda, United States
Participant flow
Recruitment details
Participants were enrolled from October 2018 to July 2019 at 38 sites in Brazil, South Africa, Thailand, Uganda, and the United States.
Pre-assignment details
There was no randomization in this study. Enrollment from sites located in the United States was restricted to 132 participants. Enrollment of participants having compensated cirrhosis was limited to no more than 80 participants, and enrollment of people living with HIV was limited to no more than 200 participants.
Participants by arm
| Arm | Count |
|---|---|
| MINMON 24 Weeks With SOF/VEL 12 Weeks Participants received Sofosbuvir/Velpatasvir (SOF/VEL \[Tradename: Epclusa®\]) tablet for 12 weeks with a minimal monitoring (MINMON) strategy for 24 weeks
Sofosbuvir/Velpatasvir (SOF/VEL): 400/100 mg fixed-dose combination (FDC) tablet administered orally once daily with or without food.
Minimal Monitoring (MINMON) Strategy: MINMON Strategy:
1. No pre-treatment HCV genotyping
2. Entire treatment course (84) tablets of SOF/VEL administered to participants at study entry
3. No scheduled on-treatment laboratory monitoring or clinic visits
4. Remote contact with participants at week 4 and week 22 | 399 |
| Total | 399 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Step 1: MINMON Intervention | Lost to Follow-up | 3 |
| Step 1: MINMON Intervention | Protocol Violation | 1 |
| Step 2:Post-MINMON | Death | 2 |
| Step 2:Post-MINMON | Lost to Follow-up | 30 |
| Step 2:Post-MINMON | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Age, Continuous | 47 years |
| Age, Customized 20 to 29 years | 33 Participants |
| Age, Customized 30 to 39 years | 95 Participants |
| Age, Customized 40 to 49 years | 100 Participants |
| Age, Customized 50 to 59 years | 97 Participants |
| Age, Customized 60 to 69 years | 55 Participants |
| Age, Customized 70 to 79 years | 18 Participants |
| Age, Customized 80+ years | 1 Participants |
| Cirrhosis Status Cirrhosis absent | 365 Participants |
| Cirrhosis Status Cirrhosis present | 34 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 95 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 289 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants |
| Gender Identity Cisgender | 377 Participants |
| Gender Identity Transgender Spectrum | 22 Participants |
| HCV Genotype Genotype 1 | 249 Participants |
| HCV Genotype Genotype 2 | 26 Participants |
| HCV Genotype Genotype 3 | 80 Participants |
| HCV Genotype Genotype 4 | 26 Participants |
| HCV Genotype Genotype 5 | 3 Participants |
| HCV Genotype Genotype 6 | 11 Participants |
| HCV Genotype Genotype 7 | 1 Participants |
| HCV Genotype Unknown Genotype | 3 Participants |
| HCV RNA | 6.1 Log10 IU/ml |
| HIV-infection Status HIV-1 infection absent | 233 Participants |
| HIV-infection Status HIV-1 infection present | 166 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 113 Participants |
| Race (NIH/OMB) Black or African American | 72 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 47 Participants |
| Race (NIH/OMB) White | 166 Participants |
| Region of Enrollment Brazil | 131 participants |
| Region of Enrollment South Africa | 12 participants |
| Region of Enrollment Thailand | 110 participants |
| Region of Enrollment Uganda | 15 participants |
| Region of Enrollment United States | 131 participants |
| Self Reported History of Substance Use Currently | 56 Participants |
| Self Reported History of Substance Use Never | 171 Participants |
| Self Reported History of Substance Use Not evaluated | 2 Participants |
| Self Reported History of Substance Use Previously | 170 Participants |
| Sex: Female, Male Female | 139 Participants |
| Sex: Female, Male Male | 260 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 397 |
| other Total, other adverse events | 58 / 397 |
| serious Total, serious adverse events | 31 / 397 |
Outcome results
Primary
Percentage of Participants With an Occurrence of Serious Adverse Events According to International Council for Harmonization (ICH) Criteria
Serious adverse events (SAEs) as defined by ICH guidelines. A two-sided, 95% confidence interval was calculated for the percentage using the Wilson (score) method.
Time frame: From treatment initiation to 28 weeks
Population: Participants who received first dose of study medication and had at least one post-entry evaluation for adverse events.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MINMON 24 Weeks With SOF/VEL 12 Weeks | Percentage of Participants With an Occurrence of Serious Adverse Events According to International Council for Harmonization (ICH) Criteria | 3.5 percentage of participants |
Primary
Percentage of Participants With Sustained Virologic Response 12 (SVR12)
SVR12 was defined as plasma HCV RNA less than the lower limit of quantification (LLOQ) from the earliest sample drawn at least 22 weeks following study treatment initiation (i.e. at a visit scheduled at least 10 weeks after scheduled end of study treatment). Participants without any HCV RNA result at least 22 weeks after treatment initiation will be considered as having HCV RNA greater than the LLOQ. LLOQ was defined as \<15 IU/mL for results tested at USA centralized testing laboratory Quest using the Roche COBAS® HCV Quantitative nucleic acid test for use on the COBAS® 6800/8800 assays for quantitation (and detection) of HCV, and \<12 IU/mL for results tested at regional international labs using Abbott RealTime HCV assay for quantitation (and detection) of HCV. A two-sided 95%, confidence interval was calculated for this percentage using the Wilson (score) method.
Time frame: From at least 22 weeks and up to 76 weeks from treatment initiation
Population: Participants who enrolled and received first dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MINMON 24 Weeks With SOF/VEL 12 Weeks | Percentage of Participants With Sustained Virologic Response 12 (SVR12) | 95.0 percentage of participants |
Secondary
Percentage of Participants Who Prematurely Discontinued HCV Study Medications
Since there were no planned clinic visits during the 12 week study medication period, the last dose of study treatment was self-reported by participants, and recorded at the SVR evaluation visit at 24 weeks. Premature treatment discontinuation was defined when the self-reported final dose date was \<11 weeks (\<77 days) after the date of initial dose (accounting for any reported treatment holds). Participants discontinuing study follow up without information about completion of HCV study medications were counted as having prematurely discontinued medications. A two-sided, 95% confidence interval was calculated for the percentage using the Wilson (score) method.
Time frame: From at least 22 weeks and up to 76 weeks from treatment initiation
Population: Participants who enrolled into study and received first dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MINMON 24 Weeks With SOF/VEL 12 Weeks | Percentage of Participants Who Prematurely Discontinued HCV Study Medications | 1.0 percentage of participants |
Secondary
Percentage of Participants With an Occurrence of One or More Non-serious, Grade >= 3 Adverse Event (AE), or Treatment Limiting AE.
AEs included all primary diagnoses, primary signs/symptoms, and primary laboratory abnormalities that either had severity grade ≥ 3 or led to a change in study medication. Serious Adverse Events (SAE) by International Council for Harmonization (ICH) criteria were excluded as they contributed to the primary safety outcome measure. Severity grading was based on DAIDS AE Grading Table, Corrected Version 2.1. A two-sided, 95% confidence interval was calculated for the percentage using the Wilson (score) method.
Time frame: From treatment initiation to 28 weeks
Population: Participants who received first dose of study medication and had at least one post-entry evaluation for adverse events.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MINMON 24 Weeks With SOF/VEL 12 Weeks | Percentage of Participants With an Occurrence of One or More Non-serious, Grade >= 3 Adverse Event (AE), or Treatment Limiting AE. | 5.8 percentage of participants |
Secondary
Percentage of Participants With at Least One Unplanned Clinic Visit Prior to SVR12 Evaluation
According to the study minimal monitoring intervention, there were no planned clinic visits prior to study week 24, when SVR12 was scheduled to be evaluated. An unplanned clinic visit was defined as an in-clinic visit occurring from treatment initiation to up to week 22. A two-sided, 95% confidence interval was calculated for the percentage using the Wilson (score) method.
Time frame: From treatment initiation to 22 weeks
Population: Participants who enrolled and received first dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MINMON 24 Weeks With SOF/VEL 12 Weeks | Percentage of Participants With at Least One Unplanned Clinic Visit Prior to SVR12 Evaluation | 3.8 percentage of participants |