Clinical Trials Register

Summary
EudraCT Number:	2019-003597-10
Sponsor's Protocol Code Number:	MK-8591A-028
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2020-11-16
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2019-003597-10

A.3

Full title of the trial

A Phase 2 Clinical Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Doravirine/Islatravir in Pediatric Participants with HIV-1 Infection who are Virologically Suppressed or Treatment-Naïve, are Less Than 18 Years of Age, and Weigh Greater Than or Equal to 35 kg

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

DOR/ISL in Adolescents with HIV-1, ≥12 to <18 years of Age and ≥35 kg

A.3.2

Name or abbreviated title of the trial where available

DOR/ISL in Adolescents with HIV-1, ≥12 to <18 years of Age and ≥35 kg

A.4.1

Sponsor's protocol code number

MK-8591A-028

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/395/2020

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc
B.5.2	Functional name of contact point	Jason Kim
B.5.3	Address:
B.5.3.1	Street Address	One Merck Drive P.O. Box 100
B.5.3.2	Town/ city	Whitehouse Station, New Jersey
B.5.3.3	Post code	08889-0100
B.5.3.4	Country	United States
B.5.4	Telephone number	+1267 3032189
B.5.6	E-mail	jason.kim@merck.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Doravirine/Islatravir
D.3.2	Product code	MK-8591A
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MK-8591
D.3.9.3	Other descriptive name	MK-8591
D.3.9.4	EV Substance Code	SUB130009
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.75
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DORAVIRINE
D.3.9.2	Current sponsor code	MK-1439
D.3.9.3	Other descriptive name	Doravirine is part of the authorised products: Delstrigo and Pifeltro
D.3.9.4	EV Substance Code	SUB177834
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

HIV-1 Infection

E.1.1.1

Medical condition in easily understood language

HIV-1: human immunodifiency virus 1

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10068341
E.1.2	Term	HIV-1 infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To evaluate the steady-state plasma pharmacokinetic profile of islatravir (ISL) as assessed by intensive pharmacokinetic (PK) sampling on Day 28 in the Intensive PK Cohort.
2. To evaluate the steady-state intracellular pharmacokinetic profile of ISL-triphosphate in peripheral blood mononuclear cells (PBMCs) on Day 28 in the Intensive PK Cohort.
3. To evaluate the safety and tolerability of DOR/ISL as assessed by review of the accumulated safety data through Week 24

E.2.2

Secondary objectives of the trial

1. To evaluate the safety and tolerability of DOR/ISL as assessed by review of the accumulated safety data through study duration.
2. To evaluate the antiretroviral activity of DOR/ISL in virologically suppressed (VS) and treatment-naïve (TN) participant cohorts, separately, as assessed by the percentage of participants with the following at Weeks 24, 48, and 96: 1) HIV-1 RNA ≥50 copies/mL (VS only), and 2) HIV-1 RNA <50 copies/mL (VS and TN).
3. To evaluate the immunologic effect of DOR/ISL in TN and VS cohorts separately as measured by change from baseline in CD4+ T-cell count at Weeks 24, 48, and 96.
4. To evaluate the development of viral drug resistance to DOR or ISL in participants who receive DOR/ISL.
5. To evaluate the acceptability/palatability of the DOR/ISL tablet.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Meets one of the following: a) Virologically Suppressed: Is HIV-1 positive at screening with plasma HIV-1 RNA <50 copies/mL at screening AND Has been receiving continuous, stable oral 2-drug or 3-drug combination ART (± PK booster) with documented viral suppression (HIV-1 RNA <50 copies/mL) for ≥3 months prior to providing documented informed consent/assent and has no history of prior virologic treatment failure on any past or current regimen. OR b) Treatment-Naïve: Is HIV-1 positive with plasma HIV-1 RNA ≥500 copies/mL at screening AND Is naïve to ART defined as having received ≤10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection, except for use of PrEP or PEP.
2. Able and willing to swallow available tablet formulation
3. Is male or female <18 years of age and weighing ≥35 kg at the time of signing the informed consent/assent
4. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: - Is not a WOCBP OR - Is a WOCBP and using an acceptable contraceptive method, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 6 weeks, corresponding to the time needed to eliminate any study intervention(s) (eg, 5 terminal half-lives)] after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention - A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours before the first dose of study intervention - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive - The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
5. The participant and legally acceptable representative have provided documented informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research

E.4

Principal exclusion criteria

1. Has HIV-2 infection
2. Has hypersensitivity or other contraindication to any of the components of the study drugs as determined by the investigator
3. Has an active diagnosis of hepatitis due to any cause, including active HBV infection (defined as HBsAg-positive or HBV DNA positive)
4. Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or cutaneous Kaposi’s sarcoma
5. Has a history or current evidence of any condition (including active tuberculosis infection), therapy, laboratory abnormality or other circumstance (including drug or alcohol use or dependence) that might, in the opinion of the investigator, confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate
6. Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or any prohibited therapies from 45 days prior to Day 1 through the study treatment period
7. Is currently taking long-acting cabotegravir-rilpivirine
8. Is currently participating in or has participated in an interventional clinical study with an investigational compound or device from 45 days prior to Day 1 through the study treatment period
9. Has a documented or known virologic resistance to components of DOR/ISL, as demonstrated by any of the following: - DOR resistance substitutions in reverse transcriptase: V106A/M, V108I, Y188L, H221Y, P225H, F227C/L, M230I/L, L234I, P236L, or Y318F - ISL resistance substitution in reverse transcriptase: M184V/I
10. Has exclusionary laboratory values (completed by the central laboratory) within 45 days prior to Day 1
11. Is female and expecting to conceive or donate eggs at any time during the study

E.5 End points

E.5.1

Primary end point(s)

1. Area under the plasma drug concentration-time curve from 0 to 24 hours post-dose (AUC0-24) of ISL
2. Maximum plasma concentration (Cmax) of ISL
3. Time to reach maximum plasma concentration (Tmax) of ISL
4. Apparent total clearance from plasma (CL/F) of ISL
5. Apparent volume of distribution during terminal phase (Vz/F) of ISL
6. Apparent plasma terminal half-life (t1/2) of ISL
7. AUC0-24 of ISL-triphosphate (ISL-TP) in PBMCs
8. Cmax of ISL-TP in PMBCs
9. C24 of ISL-TP in PBMCs
10. Percentage of participants experiencing ≥1 adverse event (AE)
11. Percentage of participants discontinuing from study treatment due to an AE

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
2. Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
3. Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
4. Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
5. Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
6. Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
7. Pre-dose, and 4, and 24 hours post-dose on Day 28
8. Pre-dose, and 4, and 24 hours post-dose on Day 28
9. 24 hours post-dose on Day 28
10. Up to 24 weeks
11. Up to 24 weeks

E.5.2

Secondary end point(s)

Note: As of amendment 028-03, the safety, tolerability, and antiviral activity of DOR/ISL will not be evaluated at Weeks 48 and 96 as dosing has been discontinued in all participants.
1. Percentage of participants discontinuing from study treatment due to an AE
2. Percentage of participants experiencing ≥1 adverse event (AE)
3. Percentage of VS participants with human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) ≥50 copies/mL
4. Percentage of VS participants with HIV-1 RNA ≥50 copies/mL
5. Percentage of VS participants with HIV-1 RNA ≥50 copies/mL
6. Percentage of VS participants with HIV-1 RNA <50 copies/mL
7. Percentage of VS participants with HIV-1 RNA <50 copies/mL
8. Percentage of VS participants with HIV-1 RNA <50 copies/mL
9. Percentage of TN participants with HIV-1 RNA <50 copies/mL
10. Percentage of TN participants with HIV-1 RNA <50 copies/mL
11. Percentage of TN participants with HIV-1 RNA <50 copies/mL
12. Change from baseline in cluster of differentiation 4+ (CD4+) T-cells in VS participants
13. Change from baseline in CD4+ T-cells in VS participants
14. Change from baseline in CD4+ T-cells in VS participants
15. Change from baseline in CD4+ T-cells in TN participants
16. Change from baseline in CD4+ T-cells in TN participants 1
7. Change from baseline in CD4+ T-cells in TN participants
18. Incidence of viral drug resistance to DOR
19. Incidence of viral drug resistance to ISL
20. Score on a palatability/acceptability scale of DOR/ISL whole tablet
21. Score on a palatability/acceptability scale of DOR/ISL split table

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Up to 48 weeks
2. Up to 48 weeks
3. Week 24
4. Week 48
5. Week 96
6. Week 24
7. Week 48
8. Week 96
9. Week 24
10. Week 48
11. Week 96
12. Baseline (Day 1) and Week 24
13. Baseline (Day 1) and Week 48
14. Baseline (Day 1) and Week 96
15. Baseline (Day 1) and Week 24
16. Baseline (Day 1) and Week 48
17. Baseline (Day 1) and Week 96
18. Up to 48 weeks
19. Up to 48 weeks
20. Day 1 and Day 28

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Mexico

Russian Federation

South Africa

Thailand

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At the end of Week 48, provided development of DOR/ISL continues, there will be a mechanism for all eligible participants to continue receiving study intervention without interruption until it becomes commercially accessible. Eligible participants are those who have completed the last scheduled study visit and are considered by the investigator to derive clinical benefit from continued administration of DOR/ISL.

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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