Doravirine (DOR) in Human Immunodeficiency Virus (HIV)-Infected Children Ages 4 Weeks to <12 Years and <45 kg (MK-1439-066)

Human Immunodeficiency Virus (HIV) Infection Clinical Trial

Official title:

A Phase 2 Clinical Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Doravirine and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in Participants With HIV-1, Who Are 4 Weeks to Less Than 12 Years of Age and Weigh Less Than 45 kg

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04375800
• Other study ID #: 1439-066
• Secondary ID: MK-1439-0662019-
• Status: Recruiting
• Phase: Phase 2
• Start date: February 3, 2021
• Est. completion date: April 11, 2034

Study information

• Verified date: May 2024
• Source: Merck Sharp & Dohme LLC
• Contact: Toll Free Number
• Phone: 1-888-577-8839
• Email: Trialsites[@]merck.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a single-group, open-label, multi-site study in pediatric participants with human immunodeficiency virus type 1 (HIV-1) infection, aged 4 weeks to <12 years and weighing <45 kg, who are treatment-naive (TN) or have been virologically suppressed (VS) on stable combination antiretroviral therapy (cART) for ≥3 months with no history of treatment failure. The first primary objective is to evaluate the steady state pharmacokinetics (PK) of doravirine (DOR) [MK-1439] when given in combination with 2 nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) or as part of the fixed dose combination (FDC) of DOR/lamivudine (3TC)/tenofovir disproxil fumarate (TDF) in participants ≥6 to <12 years and weighing ≥14 to <45 kg. The second primary objective is to evaluate the safety and tolerability of DOR when given with 2 NRTIs or as part of the FDC of DOR/3TC/TDF, in participants ≥6 to 12 years and weighing ≥14 to <45 kg, through Week 24.

Description:

Participants who complete the Week 96 visit will be eligible to enroll in an Extension Study in which they may continue to receive DOR until it is commercially available, or for up to an additional 224 weeks (whichever comes first).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 84
• Est. completion date: April 11, 2034
• Est. primary completion date: March 4, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Weeks to 11 Years

Eligibility

Inclusion Criteria:

• Has HIV-1 infection confirmed at screening
• Has treatment history defined as either TN or with documented viral suppression (HIV-1 RNA <50 copies/mL) for =3 months on combination antiretroviral therapy (cART)
• Body weight is >3 kg to <45 kg
• If female, is not pregnant or breastfeeding, and one of the following applies:
• is not a woman of childbearing potential (WOCBP)
• is a WOCBP using an acceptable form of contraception, or is abstinent
• if a WOCBP must have a negative pregnancy test (urine or serum) within 24 hours of the first dose of study intervention

Study Extension Inclusion Criteria:

• Has completed the Week 96 visit.
• Is considered, in the opinion of the investigator, to have derived benefit from treatment with DOR plus the 2 NRTIs selected by the investigator, or DOR/3TC/TDF, by Week 96 of the study
• Is considered, in the opinion of the investigator, to be a clinically appropriate candidate for additional treatment with DOR plus 2 NRTIs selected by the investigator.
• Understands the procedures in the study extension and has provided (or have the participant's legally acceptable representative, if applicable, provide) documented informed consent/assent to enter the study extension and continue treatment with DOR plus 2 NRTIs selected by the investigator until DOR is available commercially in countries participating in the study or for up to an additional 224 weeks (whichever comes first).

Exclusion Criteria:

• Has evidence of renal disease
• Demonstrates evidence of liver disease
• Has clinical or laboratory evidence of pancreatitis
• Has any history of malignancy
• Has presence of any active acquired immunodeficiency syndrome (AIDS)-defining Opportunistic Infection
• Has an active diagnosis of hepatitis, including hepatitis B co-infection
• Has current active tuberculosis and/or is being treated with a rifampicin-containing regimen
• Has a medical condition that precludes absorption or intake of oral pellets/granules
• Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound results of the study or interfere with participating for the entire duration of the study
• Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or other prohibited therapy
• 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 treatment period
• Has a documented or known virologic resistance to DOR
• Has any history of viremia (HIV RNA >1000 copies/mL) after at least 3 months on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus (HIV) Infection
• Immunologic Deficiency Syndromes

Intervention

Drug:
• Doravirine
DOR capsules (3.2 to 100 mg); sachets (3.2 to 100 mg); or tablets (100 mg) taken once or twice daily by mouth.
• 2 NRTIs
Participants receive 2 NRTIs per local label by mouth for 96 weeks as background therapy.

Locations

Country	Name	City	State
Mexico	Unidad de Atencion Medica e Investigacion en Salud S.C. ( Site 0700)	Merida	Yucatan
Mexico	Hospital Infantil de Mexico Federico Gomez ( Site 0702)	Mexico City	Distrito Federal
Mexico	Instituto Nacional de Pediatria ( Site 0701)	Mexico City
Russian Federation	Kuzbasskiy Center for the Prevention and Control of AIDS ( Site 0506)	Kemerovo	Kemerovskaya Oblast
Russian Federation	Clinical Centre for Prevention and Control of AIDS ( Site 0504)	Krasnodar	Krasnodarskiy Kray
Russian Federation	Krasnoyarsk Regional Center for Prevention and Control of AIDS ( Site 0507)	Krasnoyarsk	Krasnoyarskiy Kray
Russian Federation	Infectious Clinical Hospital #2 ( Site 0501)	Moscow	Moskva
Russian Federation	FGU Republican Clinical Infectious Hospital of Roszdrav ( Site 0500)	Saint Petersburg	Sankt-Peterburg
South Africa	FARMOVS PTY LTD ( Site 0601)	Bloemfontein	Free State
South Africa	Family Clinic Research With UBUNTU ( Site 0605)	Cape Town	Western Cape
South Africa	King Edward Hospital ( Site 0600)	Durban	Kwazulu-Natal
South Africa	Empilweni Services and Research Unit ( Site 0604)	Johannesburg	Gauteng
South Africa	Perinatal HIV Research Unit ( Site 0602)	Johannesburg	Gauteng
South Africa	Wits Reproductive Health and HIV Institute (WRHI) ( Site 0603)	Johannesburg	Gauteng
South Africa	Be Part Yoluntu Centre ( Site 0606)	Paarl	Western Cape
Thailand	Siriraj Hospital ( Site 0901)	Bangkok	Krung Thep Maha Nakhon
Thailand	Research Institute for Health Sciences ( Site 0902)	Chiang Mai
Thailand	Faculty of Medicine - Khon Kaen University ( Site 0903)	Khon Kaen
United States	Emory Children's Center ( Site 0103)	Atlanta	Georgia
United States	University of Colorado at Denver ( Site 0108)	Aurora	Colorado

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Mexico,  Russian Federation,  South Africa,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under the concentration-time curve from 0 to 24 hours postdose (AUC0-24hr) of DOR with 2 NRTIs in plasma at steady-state	Plasma AUC0-24 hr of DOR with 2 NRTIs will be determined at steady-state.	Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42
Primary	Maximum concentration (Cmax) of DOR with 2 NRTIs in plasma at steady-state	Plasma Cmax of DOR with 2 NRTIs will be determined at steady-state.	Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42
Primary	Concentration at 24 hours (C24) of DOR with 2 NRTIs in plasma at steady-state	Plasma C24 of DOR with 2 NRTIs will be determined at steady-state.	24 hours postdose on Day 42
Primary	Time to maximum concentration (Tmax) of DOR with 2 NRTIs in plasma at steady-state	Plasma Tmax of DOR with 2 NRTIs will be determined at steady-state.	Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42
Primary	Percentage of participants with =1 adverse event (AE)	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.	Up to 24 weeks
Primary	Percentage of participants with a Grade 3 or 4 AE	Grade 3 or 4 AEs are "severe symptoms that cause inability to perform usual social and functional activities with intervention or hospitalization indicated (Grade 3), or "potentially life-threatenting events" (Grade 4).	Up to 24 weeks
Primary	Percentage of participants with overall mortality	The percentage of participants with mortality through 24 weeks will be determined.	Up to 24 weeks
Primary	Percentage of participants discontinuing from study treatment due to an AE	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.	Up to 24 weeks
Primary	Percentage of participants discontinuing from study treatment due to a drug-related AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, that is considered to be related to DOR.	Up to 24 weeks
Secondary	Plasma concentration of DOR	The DOR plasma concentration will be determined with sparse PK sampling.	Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose
Secondary	Plasma concentration of 3TC	The 3TC plasma concentration will be determined with sparse PK sampling.	Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose
Secondary	Plasma concentration of TFV	The TFV plasma concentration will be determined with sparse PK sampling.	Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose
Secondary	AUC0-24hr of 3TC	Plasma AUC0-24 hr of 3TC will be determined at steady-state.	Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42
Secondary	AUC0-24hr of TFV	Plasma AUC0-24 hr of TFV will be determined at steady-state.	Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42
Secondary	Cmax of 3TC	Plasma Cmax of 3TC will be determined.	Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose
Secondary	Cmax of TFV	Plasma Cmax of TFV will be determined.	Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose
Secondary	Percentage of participants with =1 AE	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.	Up to 48 weeks
Secondary	Percentage of participants with =1 AE	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.	Up to 96 weeks
Secondary	Percentage of participants with Grade 3 or 4 AE	Grade 3 or 4 AEs are "severe symptoms that cause inability to perform usual social and functional activities with intervention or hospitalization indicated (Grade 3), or "potentially life-threatenting events" (Grade 4).	Up to 48 weeks
Secondary	Percentage of participants with Grade 3 or 4 AE	Grade 3 or 4 AEs are "severe symptoms that cause inability to perform usual social and functional activities with intervention or hospitalization indicated (Grade 3), or "potentially life-threatenting events" (Grade 4).	Up to 96 weeks
Secondary	Percentage of participants with overall mortality	The percentage of participants with mortality through 48 weeks will be determined.	Up to 48 weeks
Secondary	Percentage of participants with overall mortality	The percentage of participants with mortality through 96 weeks will be determined.	Up to 96 weeks
Secondary	Percentage of participants discontinuing from study treatment due to AE	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.	Up to 48 weeks
Secondary	Percentage of participants discontinuing from study treatment due to AE	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.	Up to 96 weeks
Secondary	Percentage of participants discontinuing from study treatment due to drug-related AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, that is considered to be related to DOR.	Up to 48 weeks
Secondary	Percentage of participants discontinuing from study treatment due to drug-related AE	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, that is considered to be related to DOR.	Up to 96 weeks
Secondary	Percentage of participants with human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) <50 copies/mL	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time polymerase chain reaction (PCR) assay with a lower limit of detection of 40 copies/mL.	Up to 24 weeks
Secondary	Percentage of participants with HIV-1 RNA <50 copies/mL	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Up to 48 weeks
Secondary	Percentage of participants with HIV-1 RNA <50 copies/mL	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Up to 96 weeks
Secondary	Percentage of participants with HIV-1 RNA <200 copies/mL	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Up to 24 weeks
Secondary	Percentage of participants with HIV-1 RNA <200 copies/mL	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Up to 48 weeks
Secondary	Percentage of participants with HIV-1 RNA <200 copies/mL	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Up to 96 weeks
Secondary	Percentage of virologically-suppressed (VS) participants with HIV-1 RNA =50 copies/mL	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Up to 24 weeks
Secondary	Percentage of VS participants with HIV-1 RNA =50 copies/mL	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Up to 48 weeks
Secondary	Percentage of VS participants with HIV-1 RNA =50 copies/mL	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Up to 96 weeks
Secondary	Percentage of treatment-naive (TN) participants with log10 change from baseline in HIV-1 RNA	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Day 1 and Week 24
Secondary	Percentage of TN participants with log10 change from baseline in HIV-1 RNA	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Day 1 and Week 48
Secondary	Percentage of TN participants with log10 change from baseline in HIV-1 RNA	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Day 1 and Week 96
Secondary	Change from baseline in cluster of differentiation 4+ (CD4+) T-cell counts	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Day 1 and Week 24
Secondary	Change from baseline in CD4+ T-cell counts	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Day 1 and Week 48
Secondary	Change from baseline in CD4+ T-cell counts	Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real-time PCR assay with a lower limit of detection of 40 copies/mL.	Day 1 and Week 96
Secondary	Viral resistance-associated substitutions (RASs) to DOR or other treatment components	The presence of viral RASs to DOR or other treatment components will be monitored for up to 96 weeks.	Up to 96 weeks
Secondary	Percentage of participants adhering to DOR treatment regimen	Adherence to DOR will be monitored for up to 96 weeks.	Up to 96 weeks
Secondary	Assessment of palatability/acceptability of DOR pellets/granules	Palatability/acceptability will be based on scores on the 5-point facial hedonic scale (FHS). FHS scores will be tabulated, and summarized by mean and SD, on Day 28. The highest possible FHS score is 5, with higher scores indicative of greater palatability.	Day 28

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