Study of Oral Treatments for Hepatitis C

Chronic Hepatitis C Clinical Trial

— PRIORITIZE  

Official title:

THE PRIORITIZE STUDY: A Pragmatic, Randomized Study of Oral Regimens for Hepatitis C: Transforming Decision-Making for Patients, Providers, and Stakeholders

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02786537
• Other study ID #: 16-1234
• Secondary ID: PCORI-1503-27891
• Status: Completed
• Phase: Phase 4
• Start date: June 2016
• Est. completion date: September 2, 2020

Study information

• Verified date: December 2021
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase 1 of this study compared the effectiveness of 3 approved DAA (direct-acting antiviral) HCV treatment regimens to learn whether they worked equally well under real-world conditions. Phase 2 of this study began early 2017 with removal of 1 DAA regimen, limiting randomization to just 2 FDA approved DAA regimens. Patients receiving HCV therapy in community and academic clinics were offered the opportunity to consent to be randomly assigned to one of three (phase 1) or one of two (phase 2) regimens and observed for outcomes. Once randomized, all medical care, laboratory testing, and any disease or side effect management were assumed by usual care conditions, and patient-reported outcomes were collected outside clinic in keeping with pragmatic design principles.

Description:

In Phase 1 of this study, consented patients were randomized to 1 of the following 3 HCV DAA treatments: 1) Harvoni® (SOF/LDV) 2) Viekira Pak™ (PrOD) 3) Zepatier™ (EBR/GZR) with the optional addition of Ribavirin (RBV) and the length of treatment determined by the individual provider.

In Phase 2 of this study, consented patients were randomized to 1 of 2 FDA approved HCV treatments: Harvoni® or Zepatier™. Both Phase 1 and Phase 2 subjects had up to 1 tablespoon of blood drawn for HCV resistance testing and future biorepository testing (following appropriate additional consent). The results of testing determined whether a genotype 1a subject randomized to Zepatier would be provided 12 or 16 wks of Zepatier.

Following enrollment/randomization, participants completed patient reported outcome questionnaires (PROs) via electronic device or telephone. Following baseline/randomization, participants were asked to complete surveys again at Wk 4 of treatment, End of Treatment, 1 and 3 year post treatment. Patients continued standard medical care throughout study. Data was abstracted from test results and medical records throughout treatment and for up to 3 years post treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1275
• Est. completion date: September 2, 2020
• Est. primary completion date: June 13, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• HCV Genotype 1a or 1b

• Adult patients (age 18 years or older)

• Patients being prescribed HCV treatment who can begin treatment with any of the three HCV treatments being studied (Harvoni (SOF/LDV), Viekira Pak (PrOD) (Phase 1 only), or Zepatier (EBR/GZR))

Exclusion Criteria:

• Inability to provide written informed consent

• HARVONI® is not a covered drug on benefits formulary

• Current or historical evidence of hepatic decompensation (variceal bleeding, hepatic encephalopathy, or ascites)

• Child Pugh (CTP) B or C Cirrhosis (documented CTP calculation is required)

• Pregnant or breastfeeding women

Related Conditions & MeSH terms

• Chronic Hepatitis C
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic

Intervention

Drug:
• SOF/LDV (sofosbuvir/ledipasvir)
Sofosbuvir/Ledipasvir (400/90 mg) for approximately 12 to 24 weeks (treatment duration and use of ribavirin is per discretion of HCV provider)
• PrOD (ombitasvir/paritaprevir/ritonavir with dasabuvir) (Phase 1 only)
Ombitasvir/paritaprevir/ritonavir (12.5/75/50mg) (2 tablets taken orally) and Dasabuvir (250 mg tablet) (1 tablet twice daily) with food for 12 to 24 weeks (treatment duration as per HCV provider)
• EBR/GZR (elbasvir/grazoprevir)
Elbasvir/grazoprevir (50/100mg) tablet once daily with or without food with or without RBV for 12 to 16 weeks
• Ribavirin
200 mg pills (1-3 pills, 1-2 times per day)

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Internal Medicine Associates of Wellstar Atlanta Medical Center	Atlanta	Georgia
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	GI Associates & Endoscopy Center	Flowood	Mississippi
United States	University of Florida	Gainesville	Florida
United States	Research Specialist of Texas	Houston	Texas
United States	Indiana University Medical Center	Indianapolis	Indiana
United States	University of Florida, Jacksonville	Jacksonville	Florida
United States	Liver Wellness Center	Little Rock	Arkansas
United States	John Hopkins University	Lutherville	Maryland
United States	University of Miami/Schiff Center for Liver Diseases	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Yale University Digestive Diseases	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	Mt. Sinai Beth Israel	New York	New York
United States	New York Langone Medical Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	University of Nebraska Medical Ctr	Omaha	Nebraska
United States	Orlando Immunology Center	Orlando	Florida
United States	Stanford University	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Bon Secours St. Mary 's Hospital of Richmond (Liver Institute of Virginia)	Richmond	Virginia
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Saint Louis University	Saint Louis	Missouri
United States	UCSD Medical Center	San Diego	California
United States	UCSF/Zuckerberg San Francisco General Hospital and Trauma Center	San Francisco	California
United States	Univ of California, San Francisco	San Francisco	California
United States	Southwest CARE Center	Santa Fe	New Mexico
United States	University of Washington	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Mountain View Medical Center	Valatie	New York
United States	Georgetown University	Washington	District of Columbia
United States	Howard University	Washington	District of Columbia

Sponsors (4)

Lead Sponsor	Collaborator
University of Florida	AbbVie, Merck Sharp & Dohme Corp., Patient-Centered Outcomes Research Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sustained Virologic Response (SVR12) mITT With Imputation-Phase 1 and 2 EBR/GZR, SOF/LDV	SVR (Sustained Virologic Response) 12 will be defined as undetectable hepatitis C virus (HCV) RNA at 12 week follow-up visit (12 -24 weeks after HCV treatment discontinuation at discretion of provider).; mITT with imputation (missing=failure). Total number of subjects reflects participants from EBR/GZR with or without RBV and SOF/LDV with or without RBV randomized during Phase 1 and Phase 2.	12 weeks post-treatment
Primary	Phase 1/2 Number of Participants With Sustained Virologic Response (SVR12-mITT Without Imputation)	SVR (Sustained Virologic Response) 12 will be defined as undetectable hepatitis C virus (HCV) RNA at 12 week follow-up visit (12 -24 weeks after HCV treatment discontinuation as dictated by standard of care at each individual site).; Number of subjects reflects participants who started EBR/GZR or SOF/LDV- based treatment (with or without RBV) during Phase 1 and 2.	12-24 weeks post HCV treatment
Primary	Phase 1-Sustained Virologic Response (SVR12) mITT With Imputation	SVR (Sustained Virologic Response) 12 will be defined as patients who have undetectable hepatitis C virus (HCV) RNA at 12 week follow-up visit (12 -24 weeks after HCV treatment discontinuation as dictated by standard of care at each individual site).; mITT with imputation (missing=failure). Total number of subjects reflects participants from Phase 1 only.	12 weeks post-treatment
Primary	Phase 1 Number of Participants With Sustained Virologic Response (SVR12-mITT Without Imputation)	SVR (Sustained Virologic Response) 12 will be defined as undetectable hepatitis C virus (HCV) RNA at 12 week follow-up visit (12 -24 weeks after HCV treatment discontinuation as dictated by standard of care at each individual site).; Number of subjects reflects participants randomized during Phase 1 only.	12 -24 weeks post-treatment
Primary	Mean Change in Headache-PRO Scores -Phase 1	Headache was evaluated by the HIT-6 score, a validated, Patient Reported Outcomes survey (PROs) 'PROMIS Headache Impact Test (HIT)' with scores ranging from 36 to 78 with higher score reflecting greater impact. Mean change in headache side effect was evaluated using difference between baseline value of HIT-6 score to the highest (worst) score during treatment. Estimates of mean change and differences obtained from a constrained longitudinal linear mixed-effects model that treated baseline score as one of outcomes. Negative values for mean change represent improvement in symptom.	Baseline to On-Treatment
Primary	Mean Change in Headache-EBR/GZR and SOF/LDV	Headache was evaluated by the HIT-6 score, a validated, Patient Reported Outcomes survey (PROs) 'PROMIS Headache Impact Test (HIT)' with scores ranging from 36 to 78 with higher score reflecting greater impact. Mean change in headache side effect was evaluated using difference between baseline value of HIT-6 score to the highest (worst) score during treatment. Estimates of mean change and differences obtained from a constrained longitudinal linear mixed-effects model that treated baseline score as one of outcomes. Negative values for mean change represent improvement, while negative values for 'difference' indicate LDV/SOF performed better than PrOD	Baseline to On-Treatment
Primary	Median Change in Headache -Phase 1	Headache was evaluated by the HIT-6 score, a validated, Patient Reported Outcomes survey (PROs) 'PROMIS Headache Impact Test (HIT)' with scores ranging from 36 to 78 with higher score reflecting greater impact. Median change in headache side effect was evaluated using difference between baseline value of HIT-6 score to the highest (worst) score during treatment. Estimates of mean change and differences obtained from a constrained longitudinal linear mixed-effects model that treated baseline score as one of outcomes. Negative values for change represent improvement, while negative values for 'difference' indicate LDV/SOF performed better than PrOD	12 weeks (Baseline and Average On-treatment Score)
Primary	Median Change in Headache-Phase 2	Headache was evaluated by the HIT-6 score, a validated, Patient Reported Outcomes survey (PROs) 'PROMIS Headache Impact Test (HIT)' with scores ranging from 36 to 78 with higher score reflecting greater impact. Median change in headache side effect was evaluated using difference between baseline value of HIT-6 score to the highest (worst) score during treatment. Estimates of median change and differences obtained from a constrained longitudinal linear mixed-effects model that treated baseline score as one of outcomes. Negative values for mean change represent improvement, while negative values for 'difference' indicate LDV/SOF performed better than PrOD	Baseline -on Treatment (12-16 weeks)
Primary	Mean Change in Nausea/Vomiting PRO Score -Phase 1	Patients completed the PROMIS® Nausea Short Form at Baseline (T1) and on-treatment. PROMIS raw scores from each of the completed questionnaires were converted to standardized T-scores. Change was calculated as the difference between baseline and on-treatment score. T-scores for the PROMIS Nausea and Vomiting 4a scale range from 45.0 - 80.1. Higher scores indicate worse nausea. Negative values for mean change represent improvement.; The estimates of mean change and differences were obtained from a constrained longitudinal linear mixed-effects model that treated the baseline score as one of the outcomes. The model expressed mean score as a function of DAA regimen, cirrhosis status, HCV genotype, sex, age, race, and previous treatment status.	Baseline to On-Treatment
Primary	Mean Change in Nausea/Vomiting PROMIS Score -EBR/GZR vs. LDV/SOF	Participants completed the Patient Reported Outcomes surveys (PROs) 'PROMIS Nausea/Vomiting -4 Short Form' at baseline and during treatment. Raw scores are converted to standardized T-scores with a range of 45.0-80.1. Higher scores indicate worse nausea/vomiting.; Results presented as mean difference from baseline to average of on Treatment Scores (highest/worst) score during treatment.; A negative (-) PROMIS change score is suggestive of symptom improvement or lack of drug side effect. Estimates of mean change were obtained from a constrained longitudinal linear mixed-effects model that treated the baseline score as one of the outcomes.	Baseline and Average On-Treatment Score
Primary	Median Change in Nausea PRO Score -Phase 1	Patients completed the PROMIS® Nausea Short Form at Baseline (T1) and on-treatment. PROMIS raw scores from each of the completed questionnaires were converted to standardized T-scores. Change was calculated as the difference between baseline and on-treatment score. T-scores for the PROMIS Nausea and Vomiting 4a scale range from 45.0 - 80.1. Higher scores indicate worse nausea. Negative values for mean change represent improvement.; The estimates of change and differences were obtained from a constrained longitudinal linear mixed-effects model that treated the baseline score as one of the outcomes.	Baseline to end of treatment
Primary	Median Change in Nausea PROMIS Score-EBR/GZR SOF/LDV	Patients completed the PROMIS® Nausea Short Form at Baseline (T1) and on-treatment. PROMIS raw scores from each of the completed questionnaires were converted to standardized T-scores. Change was calculated as the difference between baseline and on-treatment score. T-scores for the PROMIS Nausea and Vomiting 4a scale range from 45.0 - 80.1. Higher scores indicate worse nausea. Negative values for change represent improvement.; The estimates of change and differences were obtained from a constrained longitudinal linear mixed-effects model that treated the baseline score as one of the outcomes.	Baseline- On Treatment (up to 16 weeks)
Primary	Mean Change in Fatigue PRO Score -Phase 1	Fatigue severity collected from validated, Patient Reported Outcomes survey (PROs), 'PROMIS Fatigue Short Form'. PROMIS® T-scores were computated to compare difference between baseline value of PROMIS score to the highest (worst) score during treatment. Results presented as computated t-score from baseline to average of on Treatment Scores. A positive (+) score suggests improvements in functional well-being. A negative (-) PRO change score is suggestive of symptom improvement or lack of drug side effect. PROMIS Fatigue Score scale per question: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always with 7 questions for a total maximum score of 35.	Baseline to On-treatment
Primary	Mean Change in Fatigue PRO -EBR/GZR vs SOF/LDV	Fatigue severity collected from validated, Patient Reported Outcomes survey (PROs), 'PROMIS Fatigue Short Form'. PROMIS® T-scores were computated to compare difference between baseline value of PROMIS score to the highest (worst) score during treatment. Results presented as computated t-score from baseline to average of on Treatment Scores. A positive (+) score suggests improvements in functional well-being. A negative (-) PRO change score is suggestive of symptom improvement or lack of drug side effect. PROMIS Fatigue Score scale per question: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always with 7 questions for a total maximum score of 35.	Baseline and Average On-Treatment Score
Primary	Median Change in Fatigue -Phase 1	Fatigue severity collected from validated, Patient Reported Outcomes survey (PROs), 'PROMIS Fatigue Short Form'. PROMIS® T-scores were computated to compare difference between baseline value of PROMIS score to the highest (worst) score during treatment. Results presented as computated t-score from baseline to average of on Treatment Scores. A positive (+) score suggests improvements in functional well-being. A negative (-) PRO change score is suggestive of symptom improvement or lack of drug side effect. PROMIS Fatigue Score scale per question: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always with 7 questions for a total maximum score of 35.	Baseline to End of Treatment
Primary	Median Change in Fatigue-Phase 2	Fatigue severity collected from validated, Patient Reported Outcomes survey (PROs), 'PROMIS Fatigue Short Form'. PROMIS® T-scores were computated to compare difference between baseline value of PROMIS score to the highest (worst) score during treatment. Results presented as computated t-score from baseline to average of on Treatment Scores. A positive (+) score suggests improvements in functional well-being. A negative (-) PRO change score is suggestive of symptom improvement or lack of drug side effect. PROMIS Fatigue Score scale per question: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always with 7 questions for a total maximum score of 35.	Baseline-On Treatment (up to 16 weeks)
Primary	Mean Change in HCV- PRO- Phase 1	HCV-PRO, a survey for patients with HCV that measures physical, emotional, and social functioning, productivity, intimacy, and perception of quality of life, was used to assess 'overall functioning and well-being'. In general, lower score is worst outcome and higher scores indicate greater well-being and functioning. However, for ease of interpretation, HCV-PRO scale has been transformed by using '100 - HCV-PRO' ultimately revising the score to mean 0 (lowest score) is best to 100 (worst outcome). A positive change (End of treatment to baseline) suggests improvements in functional well-being.; Total score = (SUM-N)/(4*N)*100, where N is the number of questions answered.	Baseline to End of Treatment
Primary	Median Change in HCV-PRO (Overall Well Being) -Phase 1	HCV-PRO, a survey for patients with HCV that measures physical, emotional, and social functioning, productivity, intimacy, and perception of quality of life, was used to assess 'Overall Functioning and Well-being'. In general, lower score is worst outcome and higher scores indicate greater well-being and functioning. However, for ease of interpretation, HCV-PRO scale has been transformed by using '100 - HCV-PRO' ultimately revising the score to mean 0 (lowest score) is best to 100 (worst outcome). A positive change (End of treatment to baseline) suggests improvements in functional well-being.; Total score = (SUM-N)/(4*N)*100, where N is the number of questions answered.	Baseline to End of Treatment
Primary	Mean Change in HCV-PRO (Functional Well-being) EBR/GZR vs. SOF/LDV Score-Phase 2	HCV-PRO, a survey designed to assess functional status of patients with HCV and measures physical, emotional, and social functioning, productivity, intimacy, and perception of quality of life, was used to assess functional well-being. In general, lower score is worst outcome and higher scores indicate greater well-being and functioning. However, for ease of interpretation, HCV-PRO scale has been transformed by using '100 - HCV-PRO' ultimately revising the score to mean 0 (lowest score) is best to 100 (worst outcome). A positive change (End of treatment to baseline) suggests improvements in functional well-being.; Total score = (SUM-N)/(4*N)*100, where N is the number of questions answered. End of Treatment -Baseline were used to calculate CHANGE in outcome. Number of subjects reflects participants from both Phase 1 and 2.	End of Treatment - Baseline
Primary	16 Wk EBR/GZR With RBV Efficacy on Patients With HCV RASs	Efficacy of Hepatitis C Virus (HCV) Treatment with Zepatier (Elbasvir/Grazobevir) with Ribavirin (RBV) for 16 weeks when used in Genotype 1a patients with Baseline RASs (NS5a Resistance Associated Substitutions or RAPs -Resistance Associated Polymorphisms).; Efficacy defined as HCV RNA undetectable 12 weeks post treatment. Table excludes Genotype 1b patients.	12 weeks post treatment
Secondary	Treatment Non-Adherence Probability Estimates	The Voils Medication Adherence Survey (VMAS) was used to evaluate medication adherence during HCV treatment. Participants responded to three questions about the extent of adherence during the past seven days of treatment (during early and late on-treatment occasions). Participants responded using a five-point ordinal scale of missed dosing from 1 (none of the time) to 5 (all of the time). On each occasion participants were coded as being "Non-adherent" if any response was > 1, otherwise they were coded as "Adherent". Probability estimates of percentage of patients reporting non-adherence were calculated per HCV treatment (Direct Acting Antiviral-DAA) regimen: 1)EBR/GZV (elbasvir/grazoprevir, 2)SOF/LDV (sofosbuvir/ledipasvir), 3)PrOD	12-16 weeks of HCV treatment
Secondary	Change in HCV-associated Symptoms (PROMIS Measures) After HCV Treatment Initiation	Change in HCV-associated symptoms was calculated as the mean differences of mean scores from multiple surveys from the NIH Patient-Reported Outcomes Measurement Information System (PROMIS)-- Fatigue, nausea, belly pain, sleep disturbance, and diarrhea) and functional status (well-being) when comparing baseline to early post-treatment and late post treatment surveys. Mean change scores were calculated by comparing baseline to early post-treatment (1 yr) and late post-treatment (approximately 3 years) surveys. T-scores for the PROMIS Nausea and Vomiting 4a scale range from 45.0 - 80.1. Higher scores indicate worse nausea. Negative values for mean change represent improvement.Negative numbers suggest better symptoms (improvement in HCV-associated symptoms). PROMIS Fatigue Score scale per question: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, 5=Always with 7 questions for a total maximum score of 35.HCV-PRO positive estimates suggest baseline functional well-being improvement.	1 year post treatment discontinuation (Early post-tx)
Secondary	Post-treatment Progression/Regression of Liver Disease-Fib-4	Mean change (delta) in FIB-4, an indirect non-invasive measure of liver fibrosis, calculated as baseline median -long term follow up median, following SVR after any of the study treatment regimens. Change in FIB-4 where negative values indicate improvement in liver fibrosis score and positive values indicate worsening of fibrosis score. There is no upper or lower limit for change. FIB-4 = age (years) * AST(IU/L)/Platelets (10^3/L) * ALT^.5(IU/L). In general, Score of 0-1.29 is low risk for advanced fibrosis, 1.30-1.67: intermediate risk for advanced liver fibrosis, >2.67: high risk for advanced fibrosis.	Baseline to up to 3 years post treatment discontinuation
Secondary	Change in Functional Status (HCV-PRO) Within Treatment	HCV-PRO score, a validated PROMIS survey used to evaluate overall functioning and well-being in HCV patients, was utilized to compare long-term 'within treatment' changes of functional well-being. In general, lower score is worst outcome and higher scores indicate greater well-being and functioning. However, for ease of interpretation, HCV-PRO scale has been transformed by using '100 - HCV-PRO' ultimately revising the score to mean 0 (lowest score) is best to 100 (worst outcome). A positive estimate (Post treatment to baseline) suggests baseline functional well-being improvement.; Total score = (SUM-N)/(4*N)*100, where N is the number of questions answered.	Treatment start date up to 2 years post-treatment
Secondary	Number of Participants With Adverse Events That Caused Treatment Discontinuation-EBR/GZR vs. LDV/SOF	The number of participants with adverse events that led to early treatment discontinuation (defined as duration less than originally prescribed treatment regimen)	Treatment start date through treatment completion (up to 24 weeks)
Secondary	HCV SVR Durability -No Cirrhosis	Number/Percentage of patients with persistence of viral cure, SVR (SVR = Sustained Virologic Response)- defined as undetectable HCV RNA at least 24 weeks following HCV Treatment.	24 weeks post-end of treatment up to 153 weeks
Secondary	HCV SVR Durability-Patients With Cirrhosis	Percentage of Cirrhotic patients with persistence of viral cure, SVR, (SVR= Sustained Virologic Response) defined as undetectable HCV RNA at least 24 weeks following HCV Treatment.	Up to 132 weeks post HCV treatment
Secondary	Impact of Baseline NS5A RASs on Treatment Outcomes-Phase 2	Number of participants who achieved SVR (sustained virologic response), defined as undetectable HCV RNA 12 weeks post-treatment with RASs (Resistant Associated Substitutions) after treatment with EBR/GZR or SOF/LDV regimen	12 weeks post HCV treatment