An Open-label, Single Arm, Phase 2 Study to Evaluate ABT-450/r/ABT-267 and ABT-333 With Ribavirin (RBV) in Adults With Genotype 1 HCV Infection Taking Methadone or Buprenorphine

• Sponsor: AbbVie (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01911845
• Collaborator: (none)
• Enrollment: 38
• Arm: 1
• Duration (Months): 17

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267; ABT-450 also known as paritaprevir; ABT-267 also known as ombitasvir) and ABT-333 (also known as dasabuvir) coadministered with ribavirin (RBV) in hepatitis C virus (HCV) genotype 1-infected adults taking methadone or buprenorphine ± naloxone.

Condition or Disease	Intervention/Treatment	Phase
Chronic Hepatitis C Infection; Chronic Hepatitis C	Drug: ABT-450/r/ABT-267; Drug: ABT-333; Drug: Ribavirin (RBV)	Phase 2

Detailed Description

This study consisted of 2 periods: a 12-week treatment period and a 48-week post-treatment period (for all participants who received study drugs). All participants who received at least 1 dose of study drug were to be followed for 48 weeks post-treatment to monitor for safety, HCV RNA, the emergence and/or persistence of resistant viral variants, and assessment of patient-reported outcome (PRO) instruments.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Single-Arm, Phase 2 Study to Evaluate the Combination of ABT-450/r/ABT-267 and ABT-333 Coadministered With Ribavirin (RBV) in Adults With Genotype 1 Hepatitis C Virus (HCV) Infection Taking Methadone or Buprenorphine
• Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ABT-450/r/ABT-267 and ABT-333, plus RBV ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks	Drug: ABT-450/r/ABT-267; Tablet; ABT-450 coformulated with ritonavir and ABT-267; Other Names: ABT-450 also known as paritaprevir; ABT-267 also known as ombitasvir ; Drug: ABT-333; Tablet; Other Names: dasabuvir ; Drug: Ribavirin (RBV); Tablet

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment [12 weeks after the last actual dose of study drug]

   The percentage of participants with sustained virologic response (plasma hepatitis C virus ribonucleic acid [HCV RNA] level less than the lower limit of quantification [< LLOQ]) 12 weeks after the last dose of study drug.

Secondary Outcome Measures

1. Percentage of Participants With Virologic Failure During Treatment [Baseline (Day 1), and Treatment Weeks 1, 2, 4, 6, 8, 10, and 12]

   Virologic failure during treatment was defined as rebound (confirmed HCV RNA greater than or equal to the lower limit of quantitation [≥ LLOQ] after HCV RNA < LLOQ during treatment, or confirmed increase from the lowest value post baseline in HCV RNA [2 consecutive HCV RNA measurements > 1 log(subscript)10(subscript) IU/mL above the lowest value post baseline] at any time point during treatment) or fail to suppress (HCV RNA ≥ LLOQ) persistently during treatment with at least 6 weeks [≥ 36 days] of treatment.

2. Percentage of Participants With Virologic Relapse Post-treatment [From the end of treatment through 12 weeks after the last actual dose of study drug]

   Participants were considered to have virologic relapse after treatment if they had confirmed quantifiable plasma Hepatitis C virus ribonucleic acid (HCV RNA) ≥ lower limit of quantification (LLOQ) between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA < LLOQ at the end of treatment. Completion of treatment was defined as a study drug duration ≥ 77 days.

3. Area Under the Plasma Concentration-time Curve (AUC) for ABT-450, Ritonavir, ABT-267, ABT-333, ABT-333 M1 Metabolite, and Ribavirin [Pre-dose (time 0) and 2, 4, 6, and 24 hours post-dose]

   Blood samples were collected pre-dose (time 0) and at 2, 4, 6, and 24 hours post-dose at one visit between treatment week 2 and treatment week 12, and were analyzed using validated analytical methods. A total of 22/38 participants consented for intensive pharmacokinetic blood sampling. Area under the plasma concentration-time curve from time 0 to 24 hours (AUC24 in ng*hr/mL)] was estimated using noncompartmental analyses. For ABT-450, ritonavir, and ABT-267, the AUC from time 0 to the last measureable concentration (AUCt in ng*hr/mL) was calculated instead of AUC24 due to time deviations at 24 hours. The AUCt values are approximately equivalent to AUC24. For ABT-333, ABT-333 M1, and RBV, the AUC from time 0 to 12 hours (AUC12 in ng*hr/mL) after the morning dose was calculated using the 24-hour concentration as the 12-hour concentration as dosing was twice a day and a 12-hour sample was not collected in this study.

4. Maximum Plasma Concentration (Cmax) for ABT-450, Ritonavir, ABT-267, ABT-333, ABT-333 M1 Metabolite, and Ribavirin [Pre-dose (time 0) and 2, 4, 6, and 24 hours post-dose]

   Blood samples were collected pre-dose (time 0) and at 2, 4, 6, and 24 hours post-dose at one visit between treatment week 2 and treatment week 12, and were analyzed using validated analytical methods. A total of 22/38 participants consented for intensive pharmacokinetic blood sampling. Maximum plasma concentration (Cmax; measured in ng/mL) was directly determined from the concentration-time data.

5. Time to Maximum Plasma Concentration (Tmax) for ABT-450, Ritonavir, ABT-267, ABT-333, ABT-333 M1 Metabolite, and Ribavirin [Pre-dose (time 0) and 2, 4, 6, and 24 hours post-dose]

   Blood samples were collected pre-dose (time 0) and at 2, 4, 6, and 24 hours post-dose at one visit between treatment week 2 and treatment week 12, and analyzed using validated analytical methods. A total of 22/38 participants consented for intensive pharmacokinetic blood sampling. The time to maximum plasma concentration (Tmax; measured in hours) was directly determined from the concentration-time data.

6. Plasma Trough Concentration (Ctrough) for ABT-450, Ritonavir, ABT-267, ABT-333, ABT-333 M1 Metabolite, and Ribavirin [Pre-dose (time 0) and 2, 4, 6, and 24 hours post-dose]

   Blood samples were collected pre-dose (time 0) and at 2, 4, 6, and 24 hours post-dose at one visit between treatment week 2 and treatment week 12, and analyzed using validated analytical methods. A total of 22/38 participants consented for intensive pharmacokinetic blood sampling. Minimum plasma concentration (C trough; measured in ng/mL) was directly determined from the concentration-time data.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Females must be practicing specific forms of birth control on study treatment, or be postmenopausal for more than 2 years or surgically sterile.

• Chronic HCV infection prior to study enrollment.

• Screening laboratory result indicating HCV genotype 1-infection.

• Subject must be treatment naive or previous pegylated interferon/ribavirin treatment experienced.

• Subjects must be on a stable opioid replacement therapy of methadone or buprenorphine ± naloxone for at least 6 months prior to screening.

Exclusion Criteria:

• Positive test result for Hepatitis B surface antigen (HBsAg) or anti-Human Immunodeficiency virus antibody (HIV Ab) at screening.

• Prior therapy with direct acting antiviral agents for the treatment of HCV, including telaprevir and boceprevir.

• Females who are pregnant or plan to become pregnant, or breastfeeding, or males whose partners are pregnant or planning to become pregnant within 7 months (or per local RBV label) after their last dose of study drug.

• Any current or past clinical evidence of cirrhosis such as ascites or esophageal varices, or prior biopsy showing cirrhosis, e.g., a Metavir Score of >3 or Ishak score of > 4.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• AbbVie

Investigators

• Study Director: Dan Cohen, MD, AbbVie

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT01911845
• Other Study ID Numbers: M14-103
• First Posted: Jul 30, 2013
• Last Update Posted: May 30, 2018
• Last Verified: Aug 1, 2015

• Keywords provided by AbbVie: HCV Genotype 1; Hepatitis Genotype 1; Interferon Free; methadone; HCV; Buprenorphine; Hepatitis C; Viekira Pak; paritaprevir; Viekira; ombitasvir; dasabuvir
• Additional relevant MeSH terms: Infections; Communicable Diseases; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic; Ribavirin

Study Results

Participant Flow

Arm/Group Title	ABT-450/r/ABT-267 and ABT-333, Plus RBV
Arm/Group Description	ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks
Period Title: Overall Study
STARTED	38
Completed Study Drug	37
COMPLETED	32
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	ABT-450/r/ABT-267 and ABT-333, Plus RBV
Arm/Group Description	ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks
Overall Participants	38
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.2 (11.0)
Sex: Female, Male (Count of Participants)
Female	13 34.2%
Male	25 65.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment
Description	The percentage of participants with sustained virologic response (plasma hepatitis C virus ribonucleic acid [HCV RNA] level less than the lower limit of quantification [< LLOQ]) 12 weeks after the last dose of study drug.
Time Frame	12 weeks after the last actual dose of study drug

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	ABT-450/r/ABT-267 and ABT-333, Plus RBV
Arm/Group Description	ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks
Measure Participants	38
Number (95% Confidence Interval) [Percentage of participants]	97.4 256.3%

2. Secondary Outcome

Title	Percentage of Participants With Virologic Failure During Treatment
Description	Virologic failure during treatment was defined as rebound (confirmed HCV RNA greater than or equal to the lower limit of quantitation [≥ LLOQ] after HCV RNA < LLOQ during treatment, or confirmed increase from the lowest value post baseline in HCV RNA [2 consecutive HCV RNA measurements > 1 log(subscript)10(subscript) IU/mL above the lowest value post baseline] at any time point during treatment) or fail to suppress (HCV RNA ≥ LLOQ) persistently during treatment with at least 6 weeks [≥ 36 days] of treatment.
Time Frame	Baseline (Day 1), and Treatment Weeks 1, 2, 4, 6, 8, 10, and 12

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	ABT-450/r/ABT-267 and ABT-333, Plus RBV
Arm/Group Description	ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks
Measure Participants	38
Number [Percentage of participants]	0 0%

3. Secondary Outcome

Title	Percentage of Participants With Virologic Relapse Post-treatment
Description	Participants were considered to have virologic relapse after treatment if they had confirmed quantifiable plasma Hepatitis C virus ribonucleic acid (HCV RNA) ≥ lower limit of quantification (LLOQ) between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA < LLOQ at the end of treatment. Completion of treatment was defined as a study drug duration ≥ 77 days.
Time Frame	From the end of treatment through 12 weeks after the last actual dose of study drug

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug with HCV RNA < LLOQ at the final treatment visit who completed treatment.

Arm/Group Title	ABT-450/r/ABT-267 and ABT-333, Plus RBV
Arm/Group Description	ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks
Measure Participants	37
Number [Percentage of participants]	0 0%

4. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve (AUC) for ABT-450, Ritonavir, ABT-267, ABT-333, ABT-333 M1 Metabolite, and Ribavirin
Description	Blood samples were collected pre-dose (time 0) and at 2, 4, 6, and 24 hours post-dose at one visit between treatment week 2 and treatment week 12, and were analyzed using validated analytical methods. A total of 22/38 participants consented for intensive pharmacokinetic blood sampling. Area under the plasma concentration-time curve from time 0 to 24 hours (AUC24 in ng*hr/mL)] was estimated using noncompartmental analyses. For ABT-450, ritonavir, and ABT-267, the AUC from time 0 to the last measureable concentration (AUCt in ng*hr/mL) was calculated instead of AUC24 due to time deviations at 24 hours. The AUCt values are approximately equivalent to AUC24. For ABT-333, ABT-333 M1, and RBV, the AUC from time 0 to 12 hours (AUC12 in ng*hr/mL) after the morning dose was calculated using the 24-hour concentration as the 12-hour concentration as dosing was twice a day and a 12-hour sample was not collected in this study.
Time Frame	Pre-dose (time 0) and 2, 4, 6, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Participants who consented for intensive pharmacokinetic blood sampling

Arm/Group Title	Buprenorphine ± Naloxone	Methadone
Arm/Group Description	Participants were on a stable opioid replacement therapy of buprenorphine ± naloxone during the Treatment Period, and for at least six months prior to screening.	Participants were on a stable opioid replacement therapy of methadone during the Treatment Period, and for at least six months prior to screening.
Measure Participants	12	10
ABT-450	27438.94 (34380.77)	37174.89 (49655.37)
Ritonavir	14303.27 (8367.86)	11375.38 (5586.62)
ABT-267	1523.48 (4444.58)	1486.72 (519.84)
ABT-333	5666.15 (2550.86)	5021.41 (2353.06)
ABT-333 M1 metabolite	3086.73 (1807.51)	2950.36 (2094.61)
Ribavirin	33362.24 (10340.16)	33499.39 (10697.75)

5. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) for ABT-450, Ritonavir, ABT-267, ABT-333, ABT-333 M1 Metabolite, and Ribavirin
Description	Blood samples were collected pre-dose (time 0) and at 2, 4, 6, and 24 hours post-dose at one visit between treatment week 2 and treatment week 12, and were analyzed using validated analytical methods. A total of 22/38 participants consented for intensive pharmacokinetic blood sampling. Maximum plasma concentration (Cmax; measured in ng/mL) was directly determined from the concentration-time data.
Time Frame	Pre-dose (time 0) and 2, 4, 6, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Participants who consented for intensive pharmacokinetic blood sampling

Arm/Group Title	Buprenorphine ± Naloxone	Methadone
Arm/Group Description	Participants were on a stable opioid replacement therapy of buprenorphine ± naloxone during the Treatment Period, and for at least six months prior to screening.	Participants were on a stable opioid replacement therapy of methadone during the Treatment Period, and for at least six months prior to screening.
Measure Participants	12	10
ABT-450	3269.50 (4388.48)	2973.30 (3371.83)
Ritonavir	1261.92 (657.35)	888.70 (409.56)
ABT-267	102.00 (27.21)	95.98 (35.56)
ABT-333	805.08 (354.04)	671.90 (302.08)
ABT-333 M1 metabolite	469.92 (271.13)	439.64 (272.91)
Ribavirin	3389.17 (1064.98)	3232.00 (948.39)

6. Secondary Outcome

Title	Time to Maximum Plasma Concentration (Tmax) for ABT-450, Ritonavir, ABT-267, ABT-333, ABT-333 M1 Metabolite, and Ribavirin
Description	Blood samples were collected pre-dose (time 0) and at 2, 4, 6, and 24 hours post-dose at one visit between treatment week 2 and treatment week 12, and analyzed using validated analytical methods. A total of 22/38 participants consented for intensive pharmacokinetic blood sampling. The time to maximum plasma concentration (Tmax; measured in hours) was directly determined from the concentration-time data.
Time Frame	Pre-dose (time 0) and 2, 4, 6, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Participants who consented for intensive pharmacokinetic blood sampling

Arm/Group Title	Buprenorphine ± Naloxone	Methadone
Arm/Group Description	Participants were on a stable opioid replacement therapy of buprenorphine ± naloxone during the Treatment Period, and for at least six months prior to screening.	Participants were on a stable opioid replacement therapy of methadone during the Treatment Period, and for at least six months prior to screening.
Measure Participants	12	10
ABT-450	4.38 (1.45)	6.81 (6.04)
Ritonavir	4.18 (1.33)	7.01 (5.97)
ABT-267	4.69 (1.00)	5.26 (0.98)
ABT-333	4.25 (2.74)	4.05 (1.40)
ABT-333 M1 metabolite	4.40 (0.84)	4.65 (1.11)
Ribavirin	3.72 (2.95)	5.83 (4.34)

7. Secondary Outcome

Title	Plasma Trough Concentration (Ctrough) for ABT-450, Ritonavir, ABT-267, ABT-333, ABT-333 M1 Metabolite, and Ribavirin
Description	Blood samples were collected pre-dose (time 0) and at 2, 4, 6, and 24 hours post-dose at one visit between treatment week 2 and treatment week 12, and analyzed using validated analytical methods. A total of 22/38 participants consented for intensive pharmacokinetic blood sampling. Minimum plasma concentration (C trough; measured in ng/mL) was directly determined from the concentration-time data.
Time Frame	Pre-dose (time 0) and 2, 4, 6, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Participants who consented for intensive pharmacokinetic blood sampling

Arm/Group Title	Buprenorphine ± Naloxone	Methadone
Arm/Group Description	Participants were on a stable opioid replacement therapy of buprenorphine ± naloxone during the Treatment Period, and for at least six months prior to screening.	Participants were on a stable opioid replacement therapy of methadone during the Treatment Period, and for at least six months prior to screening.
Measure Participants	12	10
ABT-450	170.01 (368.36)	458.53 (988.11)
Ritonavir	167.35 (406.50)	136.87 (273.44)
ABT-267	33.75 (17.28)	32.78 (14.11)
ABT-333	223.76 (246.63)	147.95 (115.20)
ABT-333 M1 metabolite	86.98 (110.35)	71.10 (83.23)
Ribavirin	2555.83 (1115.82)	2632.00 (1039.54)

Adverse Events

Time Frame	Adverse events were collected from the time of study drug administration until 30 days after the last dose, up to 16 weeks. Serious adverse events were collected from the time of informed consent until the end of participation in the study (65 weeks).
Arm/Group Title	ABT-450/r/ABT-267 and ABT-333, Plus RBV
Arm/Group Description	ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks
All Cause Mortality
	ABT-450/r/ABT-267 and ABT-333, Plus RBV
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	ABT-450/r/ABT-267 and ABT-333, Plus RBV
	Affected / at Risk (%)	# Events
Total	2/38 (5.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE MYELOID LEUKAEMIA	1/38 (2.6%)
SARCOMA	1/38 (2.6%)
Nervous system disorders
CEREBROVASCULAR ACCIDENT	1/38 (2.6%)
Other (Not Including Serious) Adverse Events
	ABT-450/r/ABT-267 and ABT-333, Plus RBV
	Affected / at Risk (%)	# Events
Total	35/38 (92.1%)
Blood and lymphatic system disorders
ANAEMIA	4/38 (10.5%)
Gastrointestinal disorders
ABDOMINAL PAIN	2/38 (5.3%)
DIARRHOEA	3/38 (7.9%)
GASTROOESOPHAGEAL REFLUX DISEASE	3/38 (7.9%)
GINGIVAL PAIN	2/38 (5.3%)
NAUSEA	19/38 (50%)
VOMITING	4/38 (10.5%)
General disorders
FATIGUE	18/38 (47.4%)
IRRITABILITY	4/38 (10.5%)
OEDEMA PERIPHERAL	2/38 (5.3%)
PYREXIA	3/38 (7.9%)
Infections and infestations
NASOPHARYNGITIS	3/38 (7.9%)
ORAL HERPES	2/38 (5.3%)
TOOTH ABSCESS	2/38 (5.3%)
UPPER RESPIRATORY TRACT INFECTION	2/38 (5.3%)
Investigations
HAEMOGLOBIN DECREASED	2/38 (5.3%)
Metabolism and nutrition disorders
DECREASED APPETITE	2/38 (5.3%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	5/38 (13.2%)
BACK PAIN	3/38 (7.9%)
MUSCLE SPASMS	3/38 (7.9%)
MUSCULOSKELETAL PAIN	2/38 (5.3%)
Nervous system disorders
DIZZINESS	2/38 (5.3%)
HEADACHE	12/38 (31.6%)
MIGRAINE	2/38 (5.3%)
PARAESTHESIA	2/38 (5.3%)
Psychiatric disorders
ANXIETY	5/38 (13.2%)
CONFUSIONAL STATE	2/38 (5.3%)
DEPRESSION	3/38 (7.9%)
INSOMNIA	7/38 (18.4%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	2/38 (5.3%)
Skin and subcutaneous tissue disorders
RASH	6/38 (15.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.