A Randomized, Open-label Study to Evaluate the Safety and Efficacy of ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection and Human Immunodeficiency Virus, Type 1 (HIV-1) Coinfection (TURQUOISE-I)
This is a Phase 2/3, randomized, open-label, multicenter study evaluating the safety and efficacy of aBT-450/r/aBT-267 and aBT-333 coadministered with RBV for 12 or 24 weeks in adults with HCV GT 1/HiV-1 coinfection who are HCV treatment-naive or pegiFn/RBVxexperienced with and without compensated cirrhosis.
This study will consist of a Phase 2 pilot cohort (Part 1a and Part 1b) and a Phase 3 cohort (Part 2). Both Part 1 and Part 2 of this study will consist of a Treatment Period and a Post-Treatment Period. in addition, Part 1b will consist of a lead-in period (Pre-Treatment Period) for approximately 2 weeks prior to the initiation of the Treatment Period. Patients with an unquantifiable plasma HiV-1 Rna and a CD4+ count [GreaterThanorequalTo] 200 cells/mm3 or a CD4+% [GreaterThanorequalTo] 14% while on a stable atazanavir (aTV), raltegravir (RaL), or darunavir (DRV) containing HiV-1 aRT regimen will be eligible.
Please note that Part 1a has already been completed so we will only be performing Part 1b and Part 2.
For Part 1b, participants will be randomized to receive DRV 800 mg QD (arm C) or switch to DRV
600 mg twice daily (BiD) administration (arm D) for a minimum of 14 days prior to starting study
treatment. Beginning on Study Day 1, subjects in Part 1b will also receive aBT-450/r/aBT-267 and
aBT-333 coadministered with RBV for 12 weeks.
For Part 2, participants will be randomized into 1 of 2 treatment arms:
arm a (12-Week Treatment arm):
* aBT-450/r/aBT-267, aBT-333, RBV,
arm B (24-Week Treatment arm):
* aBT-450/r/aBT-267, aBT-333, RBV
The primary efficacy endpoints are the percentage of subjects with SVR12 (HCV Rna [Less Than] LLoQ 12 weeks after the last actual dose of study drug) within each treatment arm. The percentage of subjects achieving SVR12 within each treatment arm will be calculated and a 2-sided 97.5% confidence interval (Ci) of the percentage will be computed using the normal approximation to the binomial distribution. a gatekeeping testing procedure will be used to control the Type i error rate at 0.05 and the primary endpoints will be tested separately within each arm:
a1. SVR12: Superiority of arm a to the historical SVR rate for pegiFn and RBV therapy; the Lower Confidence Bound (LCB) of the 97.5% Ci for the percentage of subjects with SVR12 in arm a must exceed 36% to achieve superiority.
B1. SVR12: Superiority of arm B to the historical SVR rate for pegiFn and RBV therapy; the LCB of the 97.5% Ci for the percentage of subjects with SVR12 in arm B must exceed 36% to achieve superiority.
1. Male or female and age is between 18 and 70 years, inclusive, at time of screening.
2. Female who is:
* practicing total abstinence from sexual intercourse (minimum 1 complete menstrual cycle),
* sexually active with female partners only,
* of childbearing potential and sexually active with male partner(s):
- currently using at least one effective method of birth control at the time of screening and agree
to practice two effective methods of birth control while receiving study drugs (as outlined in the
subject information and consent form or other subject information documents), starting with Study
Day 1 and for 7 months after stopping study drug as directed by the local ribavirin label. (Note:
Hormonal contraceptives, including oral, topical, injectable or implantable varieties, may not be
used during study drug treatment).
* not of childbearing potential, defined as:
- postmenopausal for at least 2 years prior to screening (defined as amenorrheic for longer than 2
years, age appropriate, and confirmed by a follicle-stimulating hormone [FSH] level indicating a
postmenopausal state), or
- surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or
has a vasectomized partner(s),
3. Females must have negative results for pregnancy tests performed:
* at Screening by serum specimen within 35 days prior to initial study drug administration
* at Study Day 1 (Baseline, prior to dosing) by urine specimen.
4. Sexually active males must be surgically sterile or have male partners only or if sexually active with female partner(s) of childbearing potential must agree to practice two effective forms of birth control (as outlined in the subject informed consent or other subject information documents) throughout the course of the study, starting with Study Day 1 and for 7 months after stopping study drug or as directed by the local ribavirin label. (Note: Hormonal contraceptives may be
considered effective if used by the female partners of male subjects.)
5. Subjects must be HCV treatment-naive or pegIFN/RBV-experienced. If pegIFN/RBV-experienced, subject must have documentation that they were adherent to prior pegIFN/RBV combination therapy and meet one of the following categories:
* Null responder:
1. received at least 12 weeks of pegIFN/RBV for the treatment of HCV and failed to achieve a 2
log10 IU/mL reduction in HCV RNA at Week 12 (Subjects will be considered to meet this
definition if the lack of treatment response was documented between Weeks 10 x 16 of
treatment ); or
2. received at least 4 weeks of pegIFN/RBV for the treatment of HCV and achieved a < 1 log10
IU/mL reduction in HCV RNA at Week 4 (Subjects will be considered to meet this definition if the
lack of treatment response was documented after >= 25 days of treatment); or
* Partial responder: received at least 20 weeks of pegIFN/RBV for the treatment of HCV and achieved >= 2 log10 IU/mL reduction in HCV RNA at Week 12 (Subjects will be considered to meet this definition if the lack of treatment response was documented between Weeks 10 x 16 of treatment), but failed to achieve HCV RNA undetectable at the end of treatment; or
* Relapser: received at least 36 weeks of pegIFN/RBV for the treatment of HCV and was undetectable at or after the end of treatment, but HCV RNA was detectable within 52 weeks of treatment follow-up.
HCV RNA levels that serve as documentation to support the type of prior response should have been obtained in relation to the previous pegIFN/RBV treatment. PegIFN/RBV therapy must have been completed no less than 2 months prior to the Screening Visit.
6. Subjects must be able to understand and adhere to the study visit schedule and all other protocol requirements.
7. Body Mass Index (BMI) is from >= 18 to < 38 kg/m2 at the time of screening. BMI is calculated as weight measured in kilograms (kg) divided by the square of height measured in meters (m).
8. Must voluntarily sign and date an informed consent form, approved by an IRB/IEC, prior to the initiation of any screening or study specific procedures.
9. Chronic HCV infection prior to study enrollment. Chronic HCV infection is defined as one of the following:
* Positive for anti-HCV antibody (Ab) or HCV RNA at least 6 months before Screening, and positive for HCV RNA and anti-HCV Ab at the time of Screening; or
* Positive for anti-HCV Ab and HCV RNA at the time of Screening with a liver biopsy consistent with chronic HCV infection.
10. Screening laboratory result indicating HCV genotype 1-infection.
11. Subject has HCV RNA level > 10,000 IU/mL at Screening.
12. Positive past test result for anti-Human Immunodeficiency Virus antibody (HIV Ab) or HIV-1 infection documented by a plasma HIV-1 RNA (viral load), rapid HIV test or any licensed HIV-1 ELISA test confirmed by another test using a different method including but not limited to a rapid HIV-1 Ab test, HIV-1 Western Blot, HIV-1 culture, HIV-1 antigen, or HIV-1 proviral DNA at any time prior to screening, and positive HIV Ab test at Screening.
13. Plasma HIV-1 RNA < 40 copies/mL during screening using Abbott RealTime HIV-1 assay, and plasma HIV-1 RNA below LLOQ by an approved plasma HIV-1 RNA quantitative assay (including but not limited to: COBAS(RegisteredTM) Ampliprep/COBAS(RegisteredTM) Taqman(RegisteredTM) HIV-1 Test, v 2.0 or Abbott RealTime HIV-1 assay) at least twice during the 24 weeks prior to screening including one qualifying result at least 8 weeks prior to screening.
Subjects with a solitary (unconfirmed) plasma HIV-1 RNA above LLOQ and < 200 copies/mL within 24 weeks of screening may be eligible for enrollment with approval of the AbbVie Study Designated Physician.
14. CD4+ count >= 200 cells/mm3 or CD4+% >= 14% during screening and at each timepoint measured during the 24 weeks prior to screening.
Subjects with a solitary CD4+ count < 200 cells/mm3 or CD4+% < 14% within 24 weeks of screening may be eligible for enrollment with approval of the AbbVie Study Designated Physician.
15. On a stable, qualifying HIV-1 ART regimen for at least 8 weeks prior to screening. The HIV-1 ART regimen must include two nucleoside/nucleotide reverse transcriptase inhibitors plus either the ritonavir-boosted protease inhibitor, atazanavir, or the integrase inhibitor, raltegravir.
The nucleoside/nucleotide reverse transcriptase inhibitor combinations in the stable qualifying HIV-1 ART regimen must be either:
* Tenofovir disproxil fumarate (TDF) PO QD plus emtricitabine (FTC) PO QD (Individual components or as the fixed dose combination TDF/FTC, Truvada(RegisteredTM)), or
* Tenofovir disproxil fumarate (TDF) PO QD plus lamivudine (3TC) PO QD or 3TC PO BID (Individual components or as the fixed dose combination TDF/3TC).
The ritonavir boosted protease inhibitor in the stable qualifying HIV-1 ART regimen must be:
* Atazanavir (ATV) PO QD coadministered with ritonavir (RTV) PO QD
The integrase inhibitor in the stable qualifying HIV-1 ART regimen must be:
* Raltegravir (RAL) PO BID.
Subjects receiving any other HIV-1 ART in addition to those noted above would not be eligible for enrollment in the study.
Subjects will be considered to be non-cirrhotic and included in the study if the following criteria are met:
16. Per local standard practice, documented results of one of the following:
* A liver biopsy within 24 months prior to or during screening demonstrating the absence of cirrhosis, e.g., a METAVIR Score of 3 or less, Ishak score of 4 or less; or
* A screening FibroTest score of <= 0.72 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) <= 2; or
* A screening FibroScan result of < 12.5 kPa (FibroScan must be approved by the local regulatory agency to qualify for entrance criteria).
- Subjects with a screening FibroScan result that is >= 12.5 kPa and < 14.6 kPa, a FibroTest
result that is <= 0.72 and an APRI > 2, or a FibroTest result that is >= 0.73 and an APRI <= 2 should
have a liver biopsy to determine the presence or absence of cirrhosis. If the liver biopsy
demonstrates the absence of cirrhosis, the subject will be considered noncirrhotic
and will be eligible for study participation.
Subjects will be considered to have compensated cirrhosis and included in the study
if the following criteria are met:
17. Per local standard practice, documentation of cirrhosis by one of the following methods:
* Previous histologic diagnosis of cirrhosis on liver biopsy, e.g., Metavir Score of > 3 (including 3 x 4 or 3/4), Ishak score of > 4 or on a liver biopsy conducted during screening,
* A screening FibroTest result that is >= 0.73 and an APRI > 2,
* A screening FibroScan score >= 14.6 kPa (FibroScan must be approved by the local regulatory agency to qualify for entrance criteria).
18. Compensated cirrhosis defined as Child-Pugh score of <= 6 at Screening.
19. Absence of hepatocellular carcinoma (HCC) as indicated by a negative ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI) 3 months prior to Screening or a negative ultrasound at Screening. Subjects who have an ultrasound with results suspicious of HCC followed by a subsequent negative CT or MRI of the liver will be eligible for the study.