Efficacy and Safety of Combinations of AL-335, Odalasvir (ODV) and Simeprevir (SMV) in the Treatment of Chronic Hepatitis C Infection

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02765490
• Collaborator: (none)
• Enrollment: 365
• Locations: 28
• Arms: 2
• Actual Duration (Months): 12.2
• Patients Per Site: 13
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy (proportion of subjects with SVR12), safety, tolerability and pharmacokinetics of an 8- and 6-week treatment regimen of AL-335, odalasvir (ODV) and simeprevir (SMV) in chronic HCV genotype 1, 2, 4, 5 or 6 infected subjects without cirrhosis.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C, Chronic	Drug: AL-335; Drug: Odalasvir; Drug: Simeprevir	Phase 2

Detailed Description

This is a Phase 2b multicenter study. The study will include a screening period of maximum 6 weeks, a treatment period of 6 or 8 weeks and a 24-weeks post-treatment follow-up period. The total study duration for each subject will be 36 to 38 weeks. This study investigates a 3 direct-acting antiviral agent (DAA) combination of AL-335 (HCV NS5B inhibitor), odalasvir (ODV) (a second generation HCV NS5A inhibitor) and simeprevir (SMV) (HCV NS3A4 protease inhibitor). The results of this study will enable the selection of treatment and duration to be further developed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 365 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2b, Multicenter, Randomized, Open-label Study to Investigate the Efficacy, Safety and Pharmacokinetics of Different Treatment Regimens of AL-335, Odalasvir, and Simeprevir in Treatment-naive and Treatment-experienced Subjects With Chronic Hepatitis C Virus Genotype 1, 2, 4, 5, and 6 Infection Without Cirrhosis
• Actual Study Start Date: Nov 9, 2016
• Actual Primary Completion Date: Aug 9, 2017
• Actual Study Completion Date: Nov 16, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A AL-335 (800 mg), odalasvir (25 mg) and simeprevir (75 mg) once daily during 6 weeks.	Drug: AL-335; AL-335 800 mg (2*400) tablet will be administered once daily.; Drug: Odalasvir; Odalasvir 25 mg tablet will be administered once daily.; Drug: Simeprevir; Simeprevir 75 mg capsule will be administered once daily.
Experimental: Group B AL-335 (800 mg), odalasvir (25 mg) and simeprevir (75 mg) once daily during 8 weeks.	Drug: AL-335; AL-335 800 mg (2*400) tablet will be administered once daily.; Drug: Odalasvir; Odalasvir 25 mg tablet will be administered once daily.; Drug: Simeprevir; Simeprevir 75 mg capsule will be administered once daily.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Treatment (EOT) (SVR12) [Week 12 (Follow-Up Phase)]

   The SVR 12 was defined as hepatitis C virus ribonucleic acid (HCV RNA) less than (<) lower limit of quantification (LLOQ; 15 international unit per milliliter [IU/mL]) detectable or undetectable 12 weeks after actual EOT.

Secondary Outcome Measures

1. Percentage of Participants With Sustained Virologic Response 24 Weeks After End of Treatment (SVR24) [Week 24 (Follow-Up Phase)]

   The SVR24 was defined as HCV RNA <LLOQ (detectable or undetectable) 24 weeks after End of Treatment (EOT).

2. Number of Participants With Viral Relapse [End of Treatment up to Week 24 (Follow up phase)]

   Viral Relapse: Participants who did not achieve SVR12, with HCV RNA <LLOQ at the EOT and confirmed HCV RNA greater than or equal to (>=) LLOQ during follow-up.

3. Number of Participants With Late Viral Relapse [Up to Week 24 (Follow-up Phase)]

   Late Viral Relapse: Participants who achieved SVR12 but had confirmed HCV RNA>=LLOQ afterwards during follow-up.

4. Percentage of Participants With On-treatment Failure [EOT up to Week 12 (Follow up Phase)]

   On-treatment failure: Participants who did not achieve SVR12 and with confirmed HCV RNA>=LLOQ at the End of Treatment (EOT).

5. Percentage of Participants With Sustained Virologic Response 4 Weeks After End of Treatment (EOT) [Week 4 (Follow-Up Phase)]

   The SVR 4 was defined as participants were considered to have reached SVR4, if 4 weeks after the actual EOT, HCV RNA was <LLOQ (detectable or undetectable).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Individuals with chronic hepatitis C virus (HCV) genotype 1, 2, 4, 5 or 6 infection

• Documented as treatment naive or experienced with a prior regimen consisting of Interferon (IFN) +/-Ribavirin (RBV) regimen without achieving sustained viral response

• Absence of cirrhosis

• Screening laboratory values within defined thresholds

• Must use specific contraceptive methods if female of childbearing potential or sexually active male

Exclusion Criteria:

• Co-infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV)

• Prior exposure to an HCV direct-acting antiviral agent (DAA), either in combination with pegylated interferon (PegIFN) or IFN-free

• Current or prior history of clinical hepatic decompensation

• History of clinically significant illness or any other medical disorder including cardiovascular conditions that may interfere with individual's treatment, assessment or compliance with the protocol

• Pregnant or a nursing female

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Antwerpen		Belgium
2		Bruxelles		Belgium
3		Edegem		Belgium
4		Gent		Belgium
5		Kortrijik		Belgium
6		Leuven		Belgium
7		Vancouver	British Columbia	Canada
8		Victoria	British Columbia	Canada
9		Toronto	Ontario	Canada
10		Vaughan	Ontario	Canada
11		Monteral	Quebec	Canada
12		Montreal	Quebec	Canada
13		Berlin		Germany
14		Essen		Germany
15		Frankfurt		Germany
16		Hamburg		Germany
17		Leipzig		Germany
18		Lodz		Poland
19		Lublin		Poland
20		Mysłowice		Poland
21		Warszawa		Poland
22		Wroclaw		Poland
23		Singapore		Singapore
24		Barcelona		Spain
25		Madrid		Spain
26		Málaga		Spain
27		Seville		Spain
28		Valencia		Spain

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

• Study Protocol - Apr 10, 2017
• Statistical Analysis Plan - Jun 27, 2017

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT02765490
• Other Study ID Numbers: CR108070; 64294178HPC2001; 2015-004200-38
• First Posted: May 6, 2016
• Last Update Posted: Nov 20, 2019
• Last Verified: Nov 1, 2019

• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Janssen Research & Development, LLC: Hepatitis C, Chronic; AL-335; Odalasvir; Simeprevir; ODV; SMV; ACH-3102; ACH-0143102; TMC435
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Simeprevir; Odalasvir

Study Results

Participant Flow

Arm/Group Title	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks	Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
Arm/Group Description	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 6 weeks.	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 8 weeks.
Period Title: Overall Study
STARTED	183	182
COMPLETED	182	179
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks	Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks	Total
Arm/Group Description	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 6 weeks.	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 8 weeks.	Total of all reporting groups
Overall Participants	183	182	365
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	48	49	49
Sex: Female, Male (Count of Participants)
Female	88 48.1%	94 51.6%	182 49.9%
Male	95 51.9%	88 48.4%	183 50.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	9 4.9%	14 7.7%	23 6.3%
Native Hawaiian or Other Pacific Islander	1 0.5%	0 0%	1 0.3%
Black or African American	9 4.9%	10 5.5%	19 5.2%
White	161 88%	153 84.1%	314 86%
More than one race	0 0%	2 1.1%	2 0.5%
Unknown or Not Reported	3 1.6%	3 1.6%	6 1.6%
Region of Enrollment (Count of Participants)
Belgium	46 25.1%	35 19.2%	81 22.2%
Canada	33 18%	30 16.5%	63 17.3%
Germany	15 8.2%	17 9.3%	32 8.8%
Spain	27 14.8%	31 17%	58 15.9%
Italy	24 13.1%	29 15.9%	53 14.5%
Poland	32 17.5%	29 15.9%	61 16.7%
Singapore	6 3.3%	11 6%	17 4.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Sustained Virologic Response 12 Weeks After End of Treatment (EOT) (SVR12)
Description	The SVR 12 was defined as hepatitis C virus ribonucleic acid (HCV RNA) less than (<) lower limit of quantification (LLOQ; 15 international unit per milliliter [IU/mL]) detectable or undetectable 12 weeks after actual EOT.
Time Frame	Week 12 (Follow-Up Phase)

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) population included all randomized participants who took at least 1 dose of the study drug [that is AL-335, Odalasvir (ODV) or Simeprevir (SMV)].

Arm/Group Title	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks	Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
Arm/Group Description	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 6 weeks.	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 8 weeks.
Measure Participants	183	182
Number (95% Confidence Interval) [Percentage of Participants]	98.9 54%	97.8 53.7%

2. Secondary Outcome

Title	Percentage of Participants With Sustained Virologic Response 24 Weeks After End of Treatment (SVR24)
Description	The SVR24 was defined as HCV RNA <LLOQ (detectable or undetectable) 24 weeks after End of Treatment (EOT).
Time Frame	Week 24 (Follow-Up Phase)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who took at least 1 dose of the study drug (i.e., AL-335, ODV or SMV). Last Observation Carried Forward (LOCF) method was used to impute the missing values.

Arm/Group Title	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks	Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
Arm/Group Description	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 6 weeks.	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 8 weeks.
Measure Participants	183	182
Number (95% Confidence Interval) [Percentage of Participants]	98.9 54%	97.3 53.5%

3. Secondary Outcome

Title	Number of Participants With Viral Relapse
Description	Viral Relapse: Participants who did not achieve SVR12, with HCV RNA <LLOQ at the EOT and confirmed HCV RNA greater than or equal to (>=) LLOQ during follow-up.
Time Frame	End of Treatment up to Week 24 (Follow up phase)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who took at least 1 dose of the study drug (i.e, AL-335, ODV or SMV).

Arm/Group Title	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks	Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
Arm/Group Description	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 6 weeks.	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 8 weeks.
Measure Participants	183	182
Number [Participants]	1 0.5%	4 2.2%

4. Secondary Outcome

Title	Number of Participants With Late Viral Relapse
Description	Late Viral Relapse: Participants who achieved SVR12 but had confirmed HCV RNA>=LLOQ afterwards during follow-up.
Time Frame	Up to Week 24 (Follow-up Phase)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who took at least 1 dose of the study drug (i.e, AL-335, ODV or SMV).

Arm/Group Title	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks	Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
Arm/Group Description	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 6 weeks.	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 8 weeks.
Measure Participants	183	182
Number [Participants]	0 0%	1 0.5%

5. Secondary Outcome

Title	Percentage of Participants With On-treatment Failure
Description	On-treatment failure: Participants who did not achieve SVR12 and with confirmed HCV RNA>=LLOQ at the End of Treatment (EOT).
Time Frame	EOT up to Week 12 (Follow up Phase)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who took at least 1 dose of the study drug (i.e, AL-335, ODV or SMV).

Arm/Group Title	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks	Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
Arm/Group Description	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 6 weeks.	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 8 weeks.
Measure Participants	183	182
Number [Percentage of Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Percentage of Participants With Sustained Virologic Response 4 Weeks After End of Treatment (EOT)
Description	The SVR 4 was defined as participants were considered to have reached SVR4, if 4 weeks after the actual EOT, HCV RNA was <LLOQ (detectable or undetectable).
Time Frame	Week 4 (Follow-Up Phase)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants who took at least 1 dose of the study drug (i.e, AL-335, ODV or SMV).

Arm/Group Title	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks	Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
Arm/Group Description	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 6 weeks.	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 8 weeks.
Measure Participants	183	182
Number (95% Confidence Interval) [Percentage of Participants]	99.5 54.4%	98.4 54.1%

Adverse Events

Time Frame	Screening up to Follow-up (Week 24)
Arm/Group Title	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks		Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
Arm/Group Description	Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 6 weeks.		Participants received AL-335 800 milligram (mg) (2*400) tablets, Odalasvir (ODV) 25 mg tablet, and Simeprevir (SMV) 75 mg capsule once daily (qd) orally in the morning for 8 weeks.
All Cause Mortality
	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks		Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/183 (0%)		1/182 (0.5%)
Serious Adverse Events
	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks		Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/183 (3.8%)		4/182 (2.2%)
Gastrointestinal disorders
Intestinal Obstruction	1/183 (0.5%)		0/182 (0%)
Intestinal Strangulation	1/183 (0.5%)		0/182 (0%)
Hepatobiliary disorders
Cholelithiasis	1/183 (0.5%)		0/182 (0%)
Infections and infestations
Infective Keratitis	0/183 (0%)		1/182 (0.5%)
Lower Respiratory Tract Infection	0/183 (0%)		1/182 (0.5%)
Musculoskeletal and connective tissue disorders
Back Pain	1/183 (0.5%)		0/182 (0%)
Bursitis	1/183 (0.5%)		0/182 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign Breast Neoplasm	0/183 (0%)		1/182 (0.5%)
Glioblastoma	0/183 (0%)		1/182 (0.5%)
Nervous system disorders
Ivth Nerve Paresis	1/183 (0.5%)		0/182 (0%)
Parkinsonism	1/183 (0.5%)		0/182 (0%)
Respiratory, thoracic and mediastinal disorders
Choking	1/183 (0.5%)		0/182 (0%)
Vascular disorders
Hypertension	1/183 (0.5%)		0/182 (0%)
Other (Not Including Serious) Adverse Events
	Arm A: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 6 Weeks		Arm B: AL-335 800 mg+ODV 25 mg+SMV 75 mg qd for 8 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	83/183 (45.4%)		85/182 (46.7%)
Gastrointestinal disorders
Diarrhoea	7/183 (3.8%)		10/182 (5.5%)
Nausea	13/183 (7.1%)		5/182 (2.7%)
General disorders
Asthenia	11/183 (6%)		8/182 (4.4%)
Fatigue	27/183 (14.8%)		21/182 (11.5%)
Infections and infestations
Viral Upper Respiratory Tract Infection	13/183 (7.1%)		19/182 (10.4%)
Musculoskeletal and connective tissue disorders
Back Pain	8/183 (4.4%)		12/182 (6.6%)
Myalgia	10/183 (5.5%)		13/182 (7.1%)
Nervous system disorders
Headache	40/183 (21.9%)		40/182 (22%)
Psychiatric disorders
Insomnia	15/183 (8.2%)		15/182 (8.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.