A Phase 4 interventional study of Sofosbuvir/Velpatasvir (SOF/VEL) and Minimal Monitoring (MINMON) Strategy in Hepatitis C, HIV-1-infection and Liver Diseases, sponsored by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections. Completed at 38 sites in 6 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-02-04.
Sponsored by Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections · Phase 4, Interventional, and Treatment
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.
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.
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The following laboratory values obtained within 35 days prior to study entry:
Exclusion Criteria:
Participants received Sofosbuvir/Velpatasvir (SOF/VEL \[Tradename: Epclusa®\]) tablet for 12 weeks with a minimal monitoring (MINMON) strategy for 24 weeks
Drug: Sofosbuvir/Velpatasvir (SOF/VEL) · Other: Minimal Monitoring (MINMON) Strategy
400/100 mg fixed-dose combination (FDC) tablet administered orally once daily with or without food.
Also known as: Epclusa
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
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
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
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
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
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
Participants were enrolled from October 2018 to July 2019 at 38 sites in Brazil, South Africa, Thailand, Uganda, and the United States.
| Milestone | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Started | 400 |
| Completed | 396 |
| Not completed | 4 |
| Withdrew: Lost to follow-up | 3 |
| Withdrew: Protocol violation | 1 |
| Milestone | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Started | 396 |
| Completed | 362 |
| Not completed | 34 |
| Withdrew: Death | 2 |
| Withdrew: Lost to follow-up | 30 |
| Withdrew: Withdrawal by subject | 2 |
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 | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Percentage of Participants With Sustained Virologic Response 12 (SVR12) | 95.0 (92.4 to 96.7) |
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.
| percentage of participants | 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 (2.1 to 5.8) |
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 | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Percentage of Participants With at Least One Unplanned Clinic Visit Prior to SVR12 Evaluation | 3.8 (2.3 to 6.1) |
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 | 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 (5.1 to 6.6) |
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.
| percentage of participants | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Percentage of Participants Who Prematurely Discontinued HCV Study Medications | 1.0 (0.4 to 2.5) |
Collected over From treatment initiation to study completion at week 72. The week 72 window 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 in response to COVID-19, up to a maximum of 110 weeks.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| MINMON 24 Weeks With SOF/VEL 12 Weeks | 2/397 (0.5%) | 31/397 (7.8%) | 58/397 (14.6%) |
| Event | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| PneumoniaInfections and infestations | 2/397 |
| Haemoglobin decreasedInvestigations | 2/397 |
| Hepatocellular carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 2/397 |
| AnaemiaBlood and lymphatic system disorders | 1/397 |
| Acute myocardial infarctionCardiac disorders | 1/397 |
| Acute right ventricular failureCardiac disorders | 1/397 |
| Ischaemic cardiomyopathyCardiac disorders | 1/397 |
| Diverticular perforationGastrointestinal disorders | 1/397 |
| DyspepsiaGastrointestinal disorders | 1/397 |
| Urinary tract infectionInfections and infestations | 1/397 |
| Event | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Creatinine renal clearance decreasedInvestigations | 22/397 |
| Blood creatinine increasedInvestigations | 5/397 |
| Abnormal loss of weightMetabolism and nutrition disorders | 5/397 |
| Blood bilirubin increasedInvestigations | 3/397 |
| Weight decreasedInvestigations | 3/397 |
| Abdominal distensionGastrointestinal disorders | 2/397 |
| Alanine aminotransferase increasedInvestigations | 2/397 |
| Aspartate aminotransferase increasedInvestigations | 2/397 |
| Blood pressure increasedInvestigations | 2/397 |
| Back painMusculoskeletal and connective tissue disorders | 2/397 |
Participants who enrolled into study and received first dose of study medication.
| Age, Continuous(years) | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Median | 47 (37 to 57) |
| Age, Customized(Participants) | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| 20 to 29 years | 33 |
| 30 to 39 years | 95 |
| 40 to 49 years | 100 |
| 50 to 59 years | 97 |
| 60 to 69 years | 55 |
| 70 to 79 years | 18 |
| 80+ years | 1 |
| Sex: Female, Male(Participants) | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Female | 139 |
| Male | 260 |
| Ethnicity (NIH/OMB)(Participants) | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Hispanic or Latino | 95 |
| Not Hispanic or Latino | 289 |
| Unknown or Not Reported | 15 |
| Race (NIH/OMB)(Participants) | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 113 |
| Native Hawaiian or Other Pacific Islander | 1 |
| Black or African American | 72 |
| White | 166 |
| More than one race | 0 |
| Unknown or Not Reported | 47 |
| Region of Enrollment(participants) | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Brazil | 131 |
| South Africa | 12 |
| Thailand | 110 |
| Uganda | 15 |
| United States | 131 |
| Gender Identity(Participants) | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| Cisgender | 377 |
| Transgender Spectrum | 22 |
| HIV-infection Status(Participants) | MINMON 24 Weeks With SOF/VEL 12 Weeks |
|---|---|
| HIV-1 infection absent | 233 |
| HIV-1 infection present | 166 |
4 further baseline measures are reported on the registry.
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