Trial Outcomes & Findings for Three-year Follow-up of Participants After Administration of Boceprevir or Narlaprevir for the Treatment of Chronic Hepatitis C (P05063) (NCT NCT00689390)

Last Updated: 2018-09-11

Results Overview

Durability of response was assessed by the number of participants who relapsed during the LTFU among those that had achieved sustained virologic response (SVR) by 24 weeks after treatment with boceprevir or narlaprevir in a previous Phase 1, 2, or 3 treatment study. In the current LTFU, participants were classified based on the last Hepatitis C Virus ribonucleic acid (HCV-RNA) result available at the time of the data cut-off date as follows: A participant was classified as a sustained virologic responder at a given time point if serum HCV-RNA was undetectable at that time point and there had not been a positive HCV-RNA since the participant was determined to have achieved SVR in the previous study. A participant was classified as a relapser if they were a sustained virologic responder in the previous treatment study and became serum HCV-RNA positive with no subsequent negative results during LTFU.

Recruitment status

TERMINATED

Study phase

PHASE2/PHASE3

Target enrollment

1954 participants

Primary outcome timeframe

From End Of Treatment (EOT) date in the previous treatment study to the first date of a positive HCV RNA result for relapsers or the last contact date for non-relapsers in the LTFU (up to 3.5 years)

Results posted on

2018-09-11

Participant Flow

Participants were recruited from 9 boceprevir studies (P03523 \[NCT00423670\], P03659 \[NCT00160251\], P04487 \[No NCT\], P05101 \[NCT00708500\], P05216 \[NCT00705432\], P05411 \[NCT00959699\], P05514 \[NCT00910624\], P05685 \[NCT00845065\], and P06086 \[NCT01023035\]) and 1 narlaprevir study (P05104 \[NCT00797745\]).

1954 participants enrolled in this long-term follow-up (LTFU) study, with 1907 participants from 9 boceprevir studies and 47 participants from 1 narlaprevir study.

Participant milestones

Participant milestones
Measure	Participants From Boceprevir Studies Participants who previously participated in treatment studies in which boceprevir was administered were subsequently enrolled in Part 1 of the current follow-up study P05063 (NCT00689390). Participants may have received boceprevir or control peginterferon plus ribavirin (PR) in the previous treatment study. No treatment was administered in the current follow-up study.	Participants From Narlaprevir Studies Participants who previously participated in treatment studies in which narlaprevir was administered were subsequently enrolled in Part 2 of the current follow-up study P05063 (NCT00689390). Participants may have received narlaprevir or control PR in the previous treatment study. No treatment was administered in the current follow-up study.
Overall Study STARTED	1907	47
Overall Study COMPLETED	1481	37
Overall Study NOT COMPLETED	426	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Participants From Boceprevir Studies Participants who previously participated in treatment studies in which boceprevir was administered were subsequently enrolled in Part 1 of the current follow-up study P05063 (NCT00689390). Participants may have received boceprevir or control peginterferon plus ribavirin (PR) in the previous treatment study. No treatment was administered in the current follow-up study.	Participants From Narlaprevir Studies Participants who previously participated in treatment studies in which narlaprevir was administered were subsequently enrolled in Part 2 of the current follow-up study P05063 (NCT00689390). Participants may have received narlaprevir or control PR in the previous treatment study. No treatment was administered in the current follow-up study.
Overall Study Adverse Event	19	0
Overall Study Lost to Follow-up	179	7
Overall Study Withdrawal by Subject	117	3
Overall Study Withdrew Consent-Retreatment Opportunity	52	0
Overall Study Non-Compliance With Protocol	21	0
Overall Study Did Not Meet Protocol Eligibility	1	0
Overall Study Administrative	37	0

Baseline Characteristics

Three-year Follow-up of Participants After Administration of Boceprevir or Narlaprevir for the Treatment of Chronic Hepatitis C (P05063)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Participants From Boceprevir Studies n=1907 Participants Participants who previously participated in treatment studies in which boceprevir was administered were subsequently enrolled in Part 1 of the current follow-up study P05063 (NCT00689390). Participants may have received boceprevir or control peginterferon plus ribavirin (PR) in the previous treatment study. No treatment was administered in the current follow-up study.	Participants From Narlaprevir Studies n=47 Participants Participants who previously participated in treatment studies in which narlaprevir was administered were subsequently enrolled in Part 2 of the current follow-up study P05063 (NCT00689390). Participants may have received narlaprevir or control PR in the previous treatment study. No treatment was administered in the current follow-up study.	Total n=1954 Participants Total of all reporting groups
Age, Customized <40 years	173 participants n=5 Participants	5 participants n=7 Participants	178 participants n=5 Participants
Age, Customized 40 to <65 years	1651 participants n=5 Participants	42 participants n=7 Participants	1693 participants n=5 Participants
Age, Customized ≥65 years	83 participants n=5 Participants	0 participants n=7 Participants	83 participants n=5 Participants
Sex: Female, Male Female	785 Participants n=5 Participants	19 Participants n=7 Participants	804 Participants n=5 Participants
Sex: Female, Male Male	1122 Participants n=5 Participants	28 Participants n=7 Participants	1150 Participants n=5 Participants

PRIMARY outcome

Timeframe: From End Of Treatment (EOT) date in the previous treatment study to the first date of a positive HCV RNA result for relapsers or the last contact date for non-relapsers in the LTFU (up to 3.5 years)

Population: All participants who were sustained responders at 24 weeks post-treatment in the previous study and who had available data were included in the analysis.

Outcome measures

Outcome measures
Measure	Previous SVR on Boceprevir + PR n=1116 Participants Participants who previously received boceprevir plus PR in treatment studies and achieved sustained virologic response (SVR). No treatment was administered in the current follow-up study.	Previous SVR on Narlaprevir + PR n=40 Participants Participants who previously received narlaprevir plus PR in treatment studies and achieved SVR. No treatment was administered in the current follow-up study.	Previous SVR on PR Only n=144 Participants Participants who previously received PR only in boceprevir or narlaprevir treatment studies and achieved SVR. No treatment was administered in the current follow-up study
Number of Participants With Relapse During the LTFU Among Sustained Responders From Previous Treatment Studies With Boceprevir or Narlaprevir (Durability of Virologic Response)	8 participants	0 participants	1 participants

PRIMARY outcome

Timeframe: From EOT date in the previous treatment study to the first date of a positive HCV RNA result for relapsers or the last contact date for non-relapsers in the LTFU (up to 3.5 years)

Population: All participants who were sustained responders at 24 weeks post-treatment in the previous study and who had available data were included in the analysis.

The distribution of time to relapse was summarized using Kaplan-Meier estimates for all participants who were sustained responders at 24 weeks post-treatment in the previous study. Exposure Adjusted Relapse Rate = 1000 × (number of relapses) / (Total exposure time in years). Total exposure time in years = \[(total number of days from last day of treatment to the last follow-up day for all subjects who did not relapse) + (total number of days from last day of treatment to the day of relapse for those who relapsed)\] / 365.25 days \[for 1 year\].

Outcome measures

Outcome measures
Measure	Previous SVR on Boceprevir + PR n=1116 Participants Participants who previously received boceprevir plus PR in treatment studies and achieved sustained virologic response (SVR). No treatment was administered in the current follow-up study.	Previous SVR on Narlaprevir + PR n=40 Participants Participants who previously received narlaprevir plus PR in treatment studies and achieved SVR. No treatment was administered in the current follow-up study.	Previous SVR on PR Only n=144 Participants Participants who previously received PR only in boceprevir or narlaprevir treatment studies and achieved SVR. No treatment was administered in the current follow-up study
Kaplan-Meier Exposure-adjusted Relapse Rate	2.3 relapses per 1,000 person-years	0 relapses per 1,000 person-years	2.2 relapses per 1,000 person-years

PRIMARY outcome

Timeframe: From EOT in the previous treatment study to the last available date in the LTFU (up to 3.5 years)

Population: All participants with TE-RAVs who received at least one dose of study medication in a previous Phase 1, 2, or 3 boceprevir or narlaprevir clinical study. Participants could have had more than one TE-RAV. All TE-RAVs were observed in participants in the boceprevir studies (i.e. none of the participants in the narlaprevir study had a TE-RAV).

Plasma samples of all participants receiving at least one dose of study medication in a previous treatment protocol were evaluated by population sequencing and analyzed to detect amino acid variants in the NS3/4A protease known to be associated with reduced susceptibility to boceprevir and narlaprevir. RAVs in the NS3/4A protease gene were evaluated at 12 loci (V36, Q41, F43, T54, V55, V107, R155, A156, V158, D168, I/V170 and M175) on the basis of in vitro studies. A TE-RAV was defined as a RAV not present at baseline and that had not returned to wild type (WT) while the participant was still on treatment. The number of participants with TE-RAVS detected at the EOT in the previous treatment study are reported below, followed by those participants with TE-RAVS that returned to WT during the LTFU (among those with detected TE-RAVS).

Outcome measures

Outcome measures
Measure	Previous SVR on Boceprevir + PR n=308 Participants Participants who previously received boceprevir plus PR in treatment studies and achieved sustained virologic response (SVR). No treatment was administered in the current follow-up study.	Previous SVR on Narlaprevir + PR Participants who previously received narlaprevir plus PR in treatment studies and achieved SVR. No treatment was administered in the current follow-up study.	Previous SVR on PR Only Participants who previously received PR only in boceprevir or narlaprevir treatment studies and achieved SVR. No treatment was administered in the current follow-up study
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci V36L TE-RAVs detected	9 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __V36M TE-RAVs returned to WT (out of 142)	135 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __T54A TE-RAVs returned to WT (out of 40)	40 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci T54C TE-RAVs detected	2 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci T54S TE-RAVs detected	143 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __T54S TE-RAVs returned to WT (out of 143)	104 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci V55A TE-RAVs detected	5 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci V107I TE-RAVs detected	3 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __R155K TE-RAVs returned to WT (out of 183)	154 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __A156S TE-RAVs returned to WT (out of 37)	35 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci V158M TE-RAVs detected	1 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __V158M TE-RAVs returned to WT (out of 1)	1 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci D168N TE-RAVs detected	12 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __D168N TE-RAVs returned to WT (out of 12)	11 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __I170T TE-RAVs returned to WT (out of 3)	3 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci V170A TE-RAVs detected	27 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __V170A TE-RAVs returned to WT (out of 27)	24 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci M175L TE-RAVs detected	5 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci V36A TE-RAVs detected	6 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __V36A TE-RAVs returned to WT (out of 6)	6 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci V36G TE-RAVs detected	1 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __V36G TE-RAVs returned to WT (out of 1)	1 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __V36L TE-RAVs returned to WT (out of 9)	8 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci V36M TE-RAVs detected	142 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci F43C TE-RAVs detected	3 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __F43C TE-RAVs returned to WT (out of 3)	3 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci T54A TE-RAVs detected	40 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __T54C TE-RAVs returned to WT (out of 2)	2 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __V55A TE-RAVs returned to WT (out of 5)	3 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __V107I TE-RAVs returned to WT (out of 3)	2 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci R155K TE-RAVs detected	183 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci R155T TE-RAVs detected	22 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __R155T TE-RAVs returned to WT (out of 22)	20 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci A156S TE-RAVs detected	37 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci A156T TE-RAVs detected	4 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __A156T TE-RAVs returned to WT (out of 4)	4 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci V158I TE-RAVs detected	18 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __V158I TE-RAVs returned to WT (out of 16)	16 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci I170T TE-RAVs detected	3 participants	—	—
Number of Participants With HCV Treatment-Emergent Resistance Associated Variants (TE-RAVs) of NS3/4A Protease Loci __M175L TE-RAVs returned to WT (out of 5)	2 participants	—	—

PRIMARY outcome

Timeframe: From enrollment in the LTFU study to the last available date in the LTFU study (up to 3 years)

Population: All enrolled participants were included in safety analyses.

Long-term safety was assessed based on the SAEs reported during the LTFU period. An SAE was any adverse drug or biologic or device experience occurring at any dose that resulted in any of the following outcomes: death, life-threatening AE, persistent or significant disability/incapacity, required in-patient hospitalization or prolongs hospitalization, congenital anomaly or birth defect. Important medical events that did not result in any of these outcomes could still be considered SAEs if they jeopardized the participant and/or required medical/surgical intervention, based on appropriate medical judgment. Grade 4 laboratory abnormalities and out of normal range liver function tests that were not accompanied by clinical manifestations were NOT considered SAEs.

Outcome measures

Outcome measures
Measure	Previous SVR on Boceprevir + PR n=1907 Participants Participants who previously received boceprevir plus PR in treatment studies and achieved sustained virologic response (SVR). No treatment was administered in the current follow-up study.	Previous SVR on Narlaprevir + PR n=47 Participants Participants who previously received narlaprevir plus PR in treatment studies and achieved SVR. No treatment was administered in the current follow-up study.	Previous SVR on PR Only Participants who previously received PR only in boceprevir or narlaprevir treatment studies and achieved SVR. No treatment was administered in the current follow-up study
Number of Participants With Serious Adverse Events (SAEs) Reported During the LTFU	136 participants	2 participants	—

PRIMARY outcome

Timeframe: From enrollment in the LTFU study to the last available date in the LTFU study (up to 3 years)

Population: All enrolled participants were included in safety analyses.

An SAE was any adverse drug or biologic or device experience occurring at any dose that resulted in any of the following outcomes: death, life-threatening AE, persistent or significant disability/incapacity, required in-patient hospitalization or prolongs hospitalization, congenital anomaly or birth defect. Important medical events that did not result in any of these outcomes could still be considered SAEs if they jeopardized the participant and/or required medical/surgical intervention, based on appropriate medical judgment. Grade 4 laboratory abnormalities and out of normal range liver function tests that were not accompanied by clinical manifestations were NOT considered SAEs.

Outcome measures

Outcome measures
Measure	Previous SVR on Boceprevir + PR n=1907 Participants Participants who previously received boceprevir plus PR in treatment studies and achieved sustained virologic response (SVR). No treatment was administered in the current follow-up study.	Previous SVR on Narlaprevir + PR n=47 Participants Participants who previously received narlaprevir plus PR in treatment studies and achieved SVR. No treatment was administered in the current follow-up study.	Previous SVR on PR Only Participants who previously received PR only in boceprevir or narlaprevir treatment studies and achieved SVR. No treatment was administered in the current follow-up study
Number of Participants That Discontinued the LTFU Due to SAEs	19 participants	0 participants	—

Adverse Events

Participants From Boceprevir Studies

Serious events: 136 serious events

Other events: 0 other events

Deaths: 0 deaths

Participants From Narlaprevir Studies

Serious events: 2 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Principal Investigator (PI) agrees to provide to the sponsor 30 days prior to submission for publication or presentation, review results communications. Sponsor shall have editorial rights with respect to results communications and the right to review and comment on the data analysis and presentation with regard to proprietary information, the accuracy of the information contained in the publication, and to ensure that the presentation is fairly balanced and in compliance with FDA regulations.
Publication restrictions are in place

Restriction type: OTHER