THE PRIORITIZE STUDY: A Pragmatic, Randomized Study of Oral Regimens for Hepatitis C: Transforming Decision-Making for Patients, Providers, and Stakeholders
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 1,275
- 试验地点
- 37
- 主要终点
- Phase 1/2 Number of Participants With Sustained Virologic Response (SVR12-mITT Without Imputation)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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))
排除标准
- •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
研究组 & 干预措施
EBR/GZR (elbasvir/grazoprevir) with RBV
Patients received 1 EBR/GZR (elbasvir/grazoprevir) (Zepatier) tablet (50/100mg) once daily for 12 to 16 weeks (provider discretion) with Ribavirin (RBV) 200 mg/tablet, 1-3/day, taken 1-2 times per day (dosage at discretion of provider).
干预措施: EBR/GZR (elbasvir/grazoprevir) (Drug)
EBR/GZR (elbasvir/grazoprevir) with RBV
Patients received 1 EBR/GZR (elbasvir/grazoprevir) (Zepatier) tablet (50/100mg) once daily for 12 to 16 weeks (provider discretion) with Ribavirin (RBV) 200 mg/tablet, 1-3/day, taken 1-2 times per day (dosage at discretion of provider).
干预措施: Ribavirin (Drug)
EBR/GZR (elbasvir/grazoprevir)
Patients received 1 EBR/GZR (elbasvir/grazoprevir) tablet (50/100 mg) once daily for 12 to 16 weeks (provider discretion) (without Ribavirin)
干预措施: EBR/GZR (elbasvir/grazoprevir) (Drug)
SOF/LDV (sofosbuvir/ledipasvir) with RBV
Patients received 1 SOF/LDV (sofosbuvir/ledipasvir) (Harvoni) tablet (400/90 mg) orally once daily with or without food 12 to 24 weeks with ribavirin (RBV) (at discretion of provider). RBV taken as 200 mg/tablet(capsule), 1-3 pills/day, 1-2 times/day.
干预措施: SOF/LDV (sofosbuvir/ledipasvir) (Drug)
SOF/LDV (sofosbuvir/ledipasvir) with RBV
Patients received 1 SOF/LDV (sofosbuvir/ledipasvir) (Harvoni) tablet (400/90 mg) orally once daily with or without food 12 to 24 weeks with ribavirin (RBV) (at discretion of provider). RBV taken as 200 mg/tablet(capsule), 1-3 pills/day, 1-2 times/day.
干预措施: Ribavirin (Drug)
SOF/LDV (sofosbuvir/ledipasvir)
Patients received 1 SOF/LDV (sofosbuvir/ledipasvir) tablet (400/90 mg) orally once daily with or without food 12 to 24 weeks without ribavirin (RBV) (per discretion of provider)
干预措施: SOF/LDV (sofosbuvir/ledipasvir) (Drug)
PrOD (Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir) with RBV (Phase 1 only)
Patients received Pr0D (Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir) orally daily with food for 12 to 24 weeks with RBV (Ribavirin). Ombitasvir/Paritaprevir/Ritonavir (12.5/75/50 mg/tablet) -2 tablets once daily with food for 12 to 24 weeks and 1 dasabuvir tablet (250 mg) twice daily with food for 12 to 24 weeks.
RBV (200 mg/pill) 1-3 pills/day, 1-2 times/day (use and dosage at provider discretion). Total daily RBV dosage ranged from 200 to 1200 mg.
干预措施: PrOD (ombitasvir/paritaprevir/ritonavir with dasabuvir) (Phase 1 only) (Drug)
PrOD (ombitasvir/paritaprevir/ritonavir and dasabuvir)
Patients received 2 ombitasvir/paritaprevir/ritonavir tablets (12.5/75/50 mg) once daily and 1 dasabuvir (250 mg) tablet twice daily with food for 12 to 24 weeks without Ribavirin (as per provider instructions)
干预措施: PrOD (ombitasvir/paritaprevir/ritonavir with dasabuvir) (Phase 1 only) (Drug)
PrOD (ombitasvir/paritaprevir/ritonavir and dasabuvir)
Patients received 2 ombitasvir/paritaprevir/ritonavir tablets (12.5/75/50 mg) once daily and 1 dasabuvir (250 mg) tablet twice daily with food for 12 to 24 weeks without Ribavirin (as per provider instructions)
干预措施: Ribavirin (Drug)
结局指标
主要结局
Phase 1/2 Number of Participants With Sustained Virologic Response (SVR12-mITT Without Imputation)
时间窗: 12-24 weeks post HCV treatment
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.
Mean Change in Headache-PRO Scores -Phase 1
时间窗: Baseline to On-Treatment
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.
Phase 1-Sustained Virologic Response (SVR12) mITT With Imputation
时间窗: 12 weeks post-treatment
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.
Mean Change in Fatigue PRO -EBR/GZR vs SOF/LDV
时间窗: Baseline and Average On-Treatment Score
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.
Mean Change in HCV-PRO (Functional Well-being) EBR/GZR vs. SOF/LDV Score-Phase 2
时间窗: End of Treatment - Baseline
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.
16 Wk EBR/GZR With RBV Efficacy on Patients With HCV RASs
时间窗: 12 weeks post treatment
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.
Sustained Virologic Response (SVR12) mITT With Imputation-Phase 1 and 2 EBR/GZR, SOF/LDV
时间窗: 12 weeks post-treatment
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.
Phase 1 Number of Participants With Sustained Virologic Response (SVR12-mITT Without Imputation)
时间窗: 12 -24 weeks post-treatment
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.
Median Change in Headache -Phase 1
时间窗: 12 weeks (Baseline and Average On-treatment Score)
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
Median Change in Headache-Phase 2
时间窗: Baseline -on Treatment (12-16 weeks)
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
Median Change in Nausea PRO Score -Phase 1
时间窗: Baseline to end of treatment
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.
Mean Change in HCV- PRO- Phase 1
时间窗: Baseline to End of Treatment
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.
Mean Change in Headache-EBR/GZR and SOF/LDV
时间窗: Baseline to On-Treatment
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
Median Change in Nausea PROMIS Score-EBR/GZR SOF/LDV
时间窗: Baseline- On Treatment (up to 16 weeks)
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.
Mean Change in Fatigue PRO Score -Phase 1
时间窗: Baseline to On-treatment
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.
Median Change in Fatigue -Phase 1
时间窗: Baseline to End of Treatment
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.
Median Change in HCV-PRO (Overall Well Being) -Phase 1
时间窗: Baseline to End of Treatment
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.
Mean Change in Nausea/Vomiting PRO Score -Phase 1
时间窗: Baseline to On-Treatment
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.
Mean Change in Nausea/Vomiting PROMIS Score -EBR/GZR vs. LDV/SOF
时间窗: Baseline and Average On-Treatment Score
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.
Median Change in Fatigue-Phase 2
时间窗: Baseline-On Treatment (up to 16 weeks)
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.
次要结局
- Treatment Non-Adherence Probability Estimates(12-16 weeks of HCV treatment)
- Impact of Baseline NS5A RASs on Treatment Outcomes-Phase 2(12 weeks post HCV treatment)
- Post-treatment Progression/Regression of Liver Disease-Fib-4(Baseline to up to 3 years post treatment discontinuation)
- Change in HCV-associated Symptoms (PROMIS Measures) After HCV Treatment Initiation(1 year post treatment discontinuation (Early post-tx))
- Number of Participants With Adverse Events That Caused Treatment Discontinuation-EBR/GZR vs. LDV/SOF(Treatment start date through treatment completion (up to 24 weeks))
- HCV SVR Durability -No Cirrhosis(24 weeks post-end of treatment up to 153 weeks)
- HCV SVR Durability-Patients With Cirrhosis(Up to 132 weeks post HCV treatment)
- Change in Functional Status (HCV-PRO) Within Treatment(Treatment start date up to 2 years post-treatment)