PRIORITIZE: Pragmatic, Randomized Study of Oral Regimens for Hepatitis C: Transforming Decision-Making for Patients, Providers, and Stakeholders
Location(s): United States
Background: Important patient groups underrepresented in hepatitis C virus (HCV) clinical trials include African Americans, older adults (> age 65), persons with active drug and alcohol use, persons with mental illness, and patients with multiple co-morbidities. The generalizability of results to these populations is therefore unknown. Data regarding the effectiveness of new treatments in these and other patient groups is critical to inform the use of these regimens in clinical practice, particularly given the high financial cost of the regimens and the need to efficiently allocate resources. Important questions must be addressed to allow patients and clinicians to make the best treatment decisions: What is the sustained virologic response (SVR) rate in a population of diverse patients, and does SVR equal cure? What are the side effects for these regimens in sicker populations or in those with co-morbid psychiatric and substance use disorders? How do lower adherence rates impact SVR?
Study: In order to learn whether oral regimens for treating HCV work equally well under real-world conditions when delivered to a broad spectrum of patients, the proposed study will utilize a randomized pragmatic clinical trial design to compare the effectiveness of standard of care medications for HCV genotype 1 (Harvoni®, Regimen A; and Viekira Pak™, Regimen B) with the next all-oral therapy anticipated to be approved in early 2016 (Merck fixed-dose combination tablet, Regimen C). The study will collect and analyze comprehensive data to address the multifaceted outcomes and measures that our patients and stakeholders identified as being most important when making HCV treatment decisions.
Aims: The primary aims are to compare Regimens A, B, and C on the following patient-centered outcomes:
- treatment effectiveness (that is, cure); and
- drug side effects.
The secondary aims are to compare Regimens A, B, and C on the following outcomes:
- treatment adherence, persistence, and out-of-pocket costs;
- amelioration of systemic HCV-associated symptoms post-treatment;
- functional status during and after treatment;
- post-treatment progression and regression of liver disease; and
- persistence of viral cure for three years after treatment.
Study Population and Proposed Inclusion and Exclusion Criteria: All patients infected with HCV genotype 1 who are being considered for HCV therapy will be invited to consent to have their HCV treatment and outcomes observed. Among the patients who consent to be observed, most will meet inclusion criteria to participate in the randomized cohort:
- in the provider’s opinion, the patient can begin treatment with Regimen A or B, or C, without significant risk or harm; and
- the patient is willing to consent to have his or her HCV treatment assigned randomly and to complete patient surveys.
We anticipated that some patients (up to 10 percent) will not meet these inclusion criteria. Those patients will be followed as an observational cohort. Randomization will be stratified by cirrhosis status (based on biopsy or markers of cirrhosis) and by subtype 1a or 1b. Randomized subjects who depart from protocol will remain in the randomized cohort. These 5 to 20 percent include subjects who decide to choose a different regimen and subjects who cannot gain access to the assigned regimen—even with help from our pharmaceutical partners’ patient assistance programs.
Comparators: Regimen A consists of Sofosbuvir/Ledipasvir fixed-dose combination tablet once daily. Regimen B consists of Paritaprevir/Ritonavir/Ombiatisvir fixed-dose combination tablet once daily + Dasabuvir tablet twice daily + Ribavirin tablets twice daily for patients with subtype 1a, which equates to most patients needing to take six pills in the morning with food and four pills in the evening with food. Regimen C is the Grazoprevir/Elbasvir fixed-dose combination tablet once daily with no food requirement.
Analytic Methods: The main analyses for the primary outcomes (for example, SVR12 or side effect scores) will rely on statistical models that depend on carefully defined covariates representing cirrhosis, treatment naïve, genotype 1a, age group, race, sex, and treatment regimen received, along with the interactions of treatment regimen with cirrhosis status, genotype, and race. For SVR12, we hypothesize that Regimens A, B, and C will have similar cure rates in patients with cirrhosis, patients with genotype 1a, and African-American patients. Within-subgroup differences in SVR between treatment arms are expected to be within the range of 0 to 6 percent. In other words, we hypothesize that for SVR treatment-by-subgroup interactions are negligible. We also hypothesize that patients with cirrhosis, patients with genotype 1a, and African-American patients will have lower SVR rates across the therapies. For drug side effects, we hypothesize that treatment differences related to cirrhosis—for example, Regimen B (with ribavirin)—will yield higher frequency and severity of drug side effects, especially in patients with cirrhosis. We further hypothesize that medication nonadherence will be greater for Regimen B than for Regimen A or C due to drug side effects and daily pill burden.
PRIORITIZE is led by an inclusive and representative team, with patients and patient organizations at its core, complemented by experts from the University of Florida, University of North Carolina, Johns Hopkins University, University of Michigan, and University of Chicago. All are united by a shared commitment to improve outcomes and access to care for all patients with HCV. Our team is uniquely positioned to rapidly initiate the proposed project using our fully operational infrastructure for HCV-TARGET, an observational HCV registry we established in 2011 with more than 45 high-enrolling sites nationwide and a partnership with the Food and Drug Administration.