A Multipart, Open-label Study to Evaluate the Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir With and Without Dasabuvir Coadministered With and Without Ribavirin in Adults With Genotype 1 or 4 Chronic Hepatitis C Virus Infection and Human Immunodeficiency Virus, Type 1 Coinfection (TURQUOISE-I)

Study ID
STU 082013-062

Cancer Related
No

Healthy Volunteers
No

Study Sites

  • UT Southwestern-Clinical Translational Research Center (CTRC)
  • Parkland Health & Hospital System

Contact
Jesse Tarbutton
214/590-0610
jesse.tarbutton@utsouthwestern.edu

Principal Investigator
Mamta Jain

Summary

This is a Phase 2/3, multipart open-label, multicenter study evaluating the safety and efficacy of aBT-450/r/aBT-267 with and without aBT-333 coadministered with and without RBV for 12 or 24 weeks in adults with HCV GT 1 or GT 4/HiV-1 coinfection who are HCV treatment-naive or HCV treatment-experienced, 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+ T-cell count [GreaterThanorequalTo] 200 cells/mm3 (Part 1 only) or a CD4+ T-cell % [GreaterThanorequalTo] 14% (Part 1 only) while on a stable atazanavir (aTV), raltegravir (RaL), dolutegravir (DTG) or darunavir (DRV) containing HiV-1
aRT regimen will be eligible.

Part 1b consists of approximately 30 subjects who are currently stable on an HiV-1 aRT regimen containing the protease inhibitor (Pi) DRV QD. Subjects meeting eligibility criteria will be randomized in a 1:1 ratio to receive either DRV 800 mg QD (arm C) or switch to DRV 600 mg 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. Randomized subjects in Part 1b will be stratified by prior HiV treatment history (previously Pi-naive subjects [i.e., no Pi exposure other than DRV] and previously Pi-experienced subjects [i.e., received
non-DRV Pi prior to current DRV treatment]).

Part 2, the Phase 3 cohort, further evaluates the safety and efficacy of aBT-450/r/aBT-267 with and without aBT-333 coadministered with and without RBV for 12 and 24 weeks. approximately 210 additional HCV GT 1 and 20 GT 4/HiV-1 coinfected adults with and without compensated cirrhosis who are HCV treatment-naive or HCV treatment-experienced (iFn or pegiFn with RBV, pegiFn/RBV plus SoF, or SoF plus RBV) and currently on a stable HiV-1 regimen containing aTV, RaL, DTG, DRV will be assigned to receive aBT-450/r/aBT-267 with and without aBT-333 coadministered with
and without RBV for 12 weeks or 24 weeks based on HCV genotype/subtype, cirrhotic status and previous treatment with SoF.

The primary efficacy endpoint is the percentage of subjects in GT 1 analysis Group 1 in Part 2 achieving SVR12 (HCV Rna [Less Than] LLoQ 12 weeks after the last actual dose of study drug) compared to the historical SVR12 rate for sofosbuvir plus RBV as reported in the PHoTon-1 study. The percentage of subjects achieving SVR12 will be calculated and a 2-sided 95% confidence interval (Ci) of the percentage will be computed using the Wilson score method for the binomial proportion. The lower confidence bound of the 2-sided 95% Ci (LCB) for the percentage of subjects achieving SVR12 must exceed 74% to achieve non-inferiority.

Participant Eligibility

For Part 1b

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 or as directed by the local RBV label. (Note: Ethinyl estradiol-containing hormonal contraceptives, including oral, injectable, implantable, patch and ring 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 randomization, and


* at the Enrollment Day by urine specimen (prior to randomization)

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.

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 Note: Genotype 1a, prior pegIFN/RBV null responders with cirrhosis will not be eligible for enrollment in Part 1b.


* 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 treatment response was documented between Weeks 10 x 16 of treatment), but failed to achieve
HCV RNA undetectable at or after Week 20 of treatment; or


* Relapser: received at least 36 weeks of pegIFN/RBV for the treatment of HCV and was undetectable at or after Week 36 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. Interferon-based therapy (e.g., pegIFN/RBV) 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 test result for anti-Human Immunodeficiency Virus antibody (HIV Ab) 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+ T-cell count >= 200 cells/mm3 or CD4+T-cell % >= 14% during screening.

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 the following ritonavir-boosted protease inhibitors.

The nucleoside/nucleotide reverse transcriptase inhibitor combinations in the stable qualifying HIV-1 ART regimen must be either:


* Tenofovir disoproxil fumarate (TDF) PO QD plus emtricitabine (FTC) PO QD (Individual components or as the fixed dose combination TDF/FTC, Truvada(RegisteredTM)), or


* Tenofovir disoproxil 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 inhibitors in the stable qualifying HIV-1 ART regimen must be:


* Darunavir (DRV) PO QD coadministered with ritonavir (RTV) PO QD. 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 FibroScan result of < 12.5 kPa (FibroScan must be approved by the local regulatory agency to qualify for entrance criteria); or


* A screening FibroTest score of <= 0.72 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) <= 2 (Subjects with a screening FibroTest result that is <= 0.72 and an APRI > 2, or a FibroTest result that is >= 0.73 and an APRI <= 2 must have a FibroScan or liver biopsy to determine the presence or
absence of cirrhosis).

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; or


* A screening FibroScan score >= 12.5 kPa (FibroScan must be approved by the local regulatory agency to qualify for entrance criteria); or


* A screening FibroTest result that is >= 0.73 and an APRI > 2 (Subjects with a screening FibroTest result that is <= 0.72 and an APRI > 2, or a FibroTest result that is >= 0.73 and an APRI <= 2 must have a FibroScan or liver biopsy to determine the presence or absence of cirrhosis).

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) within 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.


For Part 2

1. Male or female at least 18 years of age at the time of screening.

2. Female who is:


* practicing total abstinence (true abstinence) from sexual intercourse, where recognized per local guidelines as an acceptable method. Abstinence is only acceptable as a method of birth control when it is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal or post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal (coitus interrupts) are not acceptable methods of contraception. Total abstinence must be practiced for the duration of treatment and for 30 days after stopping study drug, or for 7 months after
stopping study drug if receiving RBV (or as directed by local RBV label); or


* 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 agrees 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 30 days after stopping study drug, or for 7 months after stopping study drug, if receiving ribavirin or as directed by the local RBV label. (Note: Ethinyl estradiol-containing hormonal contraceptives, including oral, injectable, implantable, patch and ring 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 randomization, and


* at Study Day 1 (Baseline, prior to dosing) by urine specimen.

4. Males who are not surgically sterile and who are 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 30 days after stopping study drug, or for 7 months after stopping study drug if receiving RBV or as directed by the local RBV label.

5. Subjects must be able to understand and adhere to the study visit schedule and all other protocol requirements.

6. 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.

7. Chronic HCV infection at screening defined as:


* Positive for anti-HCV antibody (Ab) or,


* HCV RNA > 1,000 IU/mL at Screening.

8. Screening laboratory result indicating HCV genotype 1 or 4-infection.

9. Positive test result for anti-Human Immunodeficiency Virus antibody (HIV Ab) at Screening.

10. 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 once during the 12 months, prior to screening.

11. On a stable, qualifying HIV-1 ART regimen for at least 8 weeks prior to screening.

The HIV-1 ART regimen must include at least one of the following ARV agents:


* Atazanavir (ATV) PO QD coadministered with ritonavir (RTV) PO QD (for GT1 and GT4 subjects),

* Raltegravir (RAL) PO BID (for GT1 and GT4 subjects),

* Dolutegravir (DTG) PO QD or PO BID (for GT1 and GT4 subjects),

* Darunavir (DRV) PO QD coadministered with ritonavir (RTV) PO QD (for GT 4 subjects only).

In addition to the above medications, subjects may take a nucleoside/nucleotide reverse transcriptase inhibitor (N(t)RTI) backbone containing any of the following:


* Tenofovir disoproxil fumarate (TDF) PO,

* Emtricitabine (FTC) PO,

* Lamivudine (3TC) PO,

* Abacavir (ABC) PO.

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:

12. 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 FibroScan performed within 3 months prior to or during screening with a score of < 12.5 kPa (FibroScan must be approved by the local regulatory agency to qualify for entrance criteria); or


* A screening FibroTest score of <= 0.72 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) <= 2 (Subjects with a screening FibroTest result that is <= 0.72 and an APRI > 2, or a FibroTest result that is >= 0.73 and an APRI <= 2 must have a FibroScan or liver biopsy performed during screening to
determine the presence or absence of cirrhosis).

Subjects will be considered to have compensated cirrhosis and included in the study if the following criteria are met:

13. 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; or


* A FibroScan performed within 3 months prior to or during screening with a score of >= 12.5 kPa (FibroScan must be approved by the local regulatory agency to qualify for entrance criteria); or


* A screening FibroTest result that is >= 0.73 and an APRI > 2 (Subjects with a screening FibroTest result that is <= 0.72 and an APRI > 2, or a FibroTest result that is >= 0.73 and an APRI <= 2 must have a FibroScan or liver biopsy performed during screening to determine the presence or absence of cirrhosis).

14. Compensated cirrhosis defined as Child-Pugh score of <= 6 at Screening. Subjects on ATV and/or subjects receiving chronic anticoagulation therapy with a Child-Pugh score of > 6 at screening may be enrolled with prior approval from AbbVie Study Designated Physician.

15. Absence of hepatocellular carcinoma (HCC) as indicated by a negative ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI) within 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.