Trial Outcomes & Findings for Pharmacokinetics of Islatravir in Participants With Severe Renal Impairment (MK-8591-026) (NCT NCT04303156)

NCT ID: NCT04303156

Last Updated: 2021-10-28

Results Overview

Participants were treated with islatravir (ISL), and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 12 participants
• Primary outcome timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose
• Results posted on: 2021-10-28

Participant Flow

Male and females with severe renal impairment between the ages of 18 and 75 years old (inclusive), and healthy matched controls were enrolled in this study.

Participant milestones

Measure	Severe Renal Impairment Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form.	Healthy Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Overall Study STARTED	6	6
Overall Study COMPLETED	6	6
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pharmacokinetics of Islatravir in Participants With Severe Renal Impairment (MK-8591-026)

Baseline characteristics by cohort

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form.	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.	Total n=12 Participants Total of all reporting groups
Age, Continuous	57.7 Years STANDARD_DEVIATION 12.9 • n=5 Participants	58.8 Years STANDARD_DEVIATION 5.5 • n=7 Participants	58.3 Years STANDARD_DEVIATION 9.5 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with islatravir (ISL), and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Plasma Islatravir (ISL)	14.4 hr*μM Interval 11.8 to 17.6	6.54 hr*μM Interval 4.77 to 8.98

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Area Under the Curve From Time 0 to Last Sampling Time (AUC0-last) of Plasma ISL	11.0 hr*μM Interval 9.17 to 13.1	5.68 hr*μM Interval 4.06 to 7.94

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Maximum Concentration (Cmax) of Plasma ISL	1.23 μM Interval 1.06 to 1.42	1.19 μM Interval 0.699 to 2.04

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The Tmax of plasma ISL was expressed as a median.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Time of Maximum Concentration (Tmax) of Plasma ISL	1.03 Hours Interval 1.0 to 2.0	0.75 Hours Interval 0.5 to 1.0

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The Geometric Coefficient of Variation was expressed as a percent (%CV), and is calculated from the square root of corresponding estimated variance obtained for each population in fixed effect model multiplied by 100.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Apparent Terminal Half-life (t1/2) of Plasma ISL	127 Hours Geometric Coefficient of Variation 7.7	72.0 Hours Geometric Coefficient of Variation 15.5

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Apparent Clearance (CL/F) of Plasma ISL	14.2 L/hr Interval 11.6 to 17.4	31.3 L/hr Interval 22.8 to 42.9

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of plasma ISL. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Apparent Volume of Distribution (Vz/F) of Plasma ISL	2610 Liters Interval 2170.0 to 3140.0	3250 Liters Interval 2100.0 to 5030.0

SECONDARY outcome

Timeframe: Pre-dose, 4, 24, 48, 96, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL, and peripheral blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
AUC0-inf of ISL Triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMC)	5810 hr*pmol/10^6 cells Interval 3890.0 to 8700.0	3920 hr*pmol/10^6 cells Interval 2830.0 to 5420.0

SECONDARY outcome

Timeframe: Pre-dose, 4, 24, 48, 96, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL and peripheral blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
AUC0-last of ISL-TP in PBMC	5200 hr*pmol/10^6 cells Interval 3670.0 to 7370.0	3780 hr*pmol/10^6 cells Interval 2720.0 to 5230.0

SECONDARY outcome

Timeframe: Pre-dose, 4, 24, 48, 96, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL and peripheral blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Cmax of ISL-TP in PBMC	20.3 pmol/10^6 cells Interval 15.1 to 27.4	21.6 pmol/10^6 cells Interval 13.7 to 34.1

SECONDARY outcome

Timeframe: Pre-dose, 4, 24, 48, 96, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL and peripheral blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The Tmax of ISL-TP was expressed as a median.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Tmax of ISL-TP in PBMC	36.00 Hours Interval 24.0 to 240.12	24.00 Hours Interval 4.0 to 239.78

SECONDARY outcome

Timeframe: 24 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL and peripheral blood samples were collected at 24 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Concentration at 24 Hours Post Dose (C24) of ISL-TP in PBMC	18.4 pmol/10^6 cells Interval 14.2 to 23.8	19.0 pmol/10^6 cells Interval 12.9 to 28.2

SECONDARY outcome

Timeframe: 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations. One sample was missing for a Healthy participant.

Participants were treated with ISL and peripheral blood samples were collected at 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=5 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Concentration at 168 Hours Post Dose (C168) of ISL-TP in PBMC	8.06 pmol/10^6 cells Interval 4.69 to 13.9	4.43 pmol/10^6 cells Interval 0.938 to 20.9

SECONDARY outcome

Timeframe: 672 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL and peripheral blood samples were collected at 672 hours post-dose to determine the concentration of ISL-TP in PBMCs. The 95% confidence interval was derived from a fixed effects model performed on natural log-transformed values.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Concentration at 672 Hours Post Dose (C672) of ISL-TP in PBMC	1.96 pmol/10^6 cells Interval 0.982 to 3.92	0.730 pmol/10^6 cells Interval 0.489 to 1.09

SECONDARY outcome

Timeframe: Pre-dose, 4, 24, 48, 96, 168 hours post-dose

Population: Participants who comply with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of important protocol deviations.

Participants were treated with ISL, and blood samples were collected from pre-dose up to 168 hours post-dose to determine the concentration of ISL-TP in PBMCs. The t1/2 of plasma ISL was expressed as a geometric mean. The Geometric Coefficient of Variation was expressed as a percent (%CV), and is calculated from the square root of corresponding estimated variance obtained for each population in fixed effect model multiplied by 100.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
T1/2 of ISL-TP in PBMC	181 Hours Geometric Coefficient of Variation 48.4	131 Hours Geometric Coefficient of Variation 19.0

SECONDARY outcome

Timeframe: Up to Day 29

Population: All participants who received at least one dose of treatment.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Percentage of Participants With an Adverse Event (AE)	16.7 Percentage of participants	0.0 Percentage of participants

SECONDARY outcome

Timeframe: Up to Day 29

Population: All participants who received at least one dose of treatment.

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

Outcome measures

Measure	Severe Renal Impairment n=6 Participants Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form	Healthy n=6 Participants Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Percentage of Participants Who Discontinued From the Study Due to an AE	0.0 Percentage of participants	0.0 Percentage of participants

Adverse Events

Severe Renal Impairment

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Healthy

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Severe Renal Impairment n=6 participants at risk Participants with severe renal impairment received a single oral dose of 60 mg Islatravir administered in capsule form.	Healthy n=6 participants at risk Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Musculoskeletal and connective tissue disorders Pain in extremity	16.7% 1/6 • Number of events 1 • Adverse Events (AEs) from day of treatment (Day 1) up to day 29. All-cause mortality from day of randomization (Day 1) up to day 29. For AEs the population analyzed consisted of all participants who received at least one dose of treatment. For All-cause mortality the population analyzed consisted of all randomized participants.	0.00% 0/6 • Adverse Events (AEs) from day of treatment (Day 1) up to day 29. All-cause mortality from day of randomization (Day 1) up to day 29. For AEs the population analyzed consisted of all participants who received at least one dose of treatment. For All-cause mortality the population analyzed consisted of all randomized participants.

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: ClinicalTrialsDisclosure@merck.com

Results disclosure agreements

• Principal investigator is a sponsor employee If publication activity is not directed by the Sponsor, the investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission.
• Publication restrictions are in place

Restriction type: OTHER