Doravirine (DOR) in Human Immunodeficiency Virus (HIV)-Infected Children Ages 4 Weeks to <12 Years and <45 kg (MK-1439-066)
- Conditions
- Human Immunodeficiency Virus (HIV) Infection
- Interventions
- Drug: 2 NRTIs
- Registration Number
- NCT04375800
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief 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.
- Detailed 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 & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 84
- 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).
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Doravirine + 2 NRTIs 2 NRTIs Participants receive DOR (3.2 mg to 100 mg based on weight) in combination with 2 NRTIs (based on local label) for 96 weeks. Doravirine + 2 NRTIs Doravirine Participants receive DOR (3.2 mg to 100 mg based on weight) in combination with 2 NRTIs (based on local label) for 96 weeks.
- Primary Outcome Measures
Name Time Method Area under the concentration-time curve from 0 to 24 hours postdose (AUC0-24hr) of DOR with 2 NRTIs in plasma at steady-state Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42 Plasma AUC0-24 hr of DOR with 2 NRTIs will be determined at steady-state.
Maximum concentration (Cmax) of DOR with 2 NRTIs in plasma at steady-state Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42 Plasma Cmax of DOR with 2 NRTIs will be determined at steady-state.
Percentage of participants with a Grade 3 or 4 AE Up to 24 weeks 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).
Percentage of participants discontinuing from study treatment due to a drug-related AE Up to 24 weeks 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.
Concentration at 24 hours (C24) of DOR with 2 NRTIs in plasma at steady-state 24 hours postdose on Day 42 Plasma C24 of DOR with 2 NRTIs will be determined at steady-state.
Time to maximum concentration (Tmax) of DOR with 2 NRTIs in plasma at steady-state Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42 Plasma Tmax of DOR with 2 NRTIs will be determined at steady-state.
Percentage of participants with ≥1 adverse event (AE) Up to 24 weeks 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.
Percentage of participants with overall mortality Up to 24 weeks The percentage of participants with mortality through 24 weeks will be determined.
Percentage of participants discontinuing from study treatment due to an AE Up to 24 weeks 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.
- Secondary Outcome Measures
Name Time Method Cmax of 3TC Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose Plasma Cmax of 3TC will be determined.
Plasma concentration of DOR Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose The DOR plasma concentration will be determined with sparse PK sampling.
Plasma concentration of TFV Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose The TFV plasma concentration will be determined with sparse PK sampling.
Plasma concentration of 3TC Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose The 3TC plasma concentration will be determined with sparse PK sampling.
AUC0-24hr of TFV Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42 Plasma AUC0-24 hr of TFV will be determined at steady-state.
Percentage of participants with ≥1 AE Up to 96 weeks 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.
Percentage of participants with Grade 3 or 4 AE Up to 96 weeks 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).
Percentage of participants with HIV-1 RNA <200 copies/mL Up to 96 weeks 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.
Percentage of VS participants with HIV-1 RNA ≥50 copies/mL Up to 96 weeks 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.
Change from baseline in CD4+ T-cell counts Day 1 and Week 96 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.
AUC0-24hr of 3TC Predose and 1, 2, 4, 12, and 24 hours postdose on Day 42 Plasma AUC0-24 hr of 3TC will be determined at steady-state.
Cmax of TFV Day 1 predose, Week 4 predose, Week 8 random, Week 12 random, and Week 24 predose and 0.5-2 hours postdose Plasma Cmax of TFV will be determined.
Percentage of participants with overall mortality Up to 96 weeks The percentage of participants with mortality through 96 weeks will be determined.
Percentage of participants discontinuing from study treatment due to AE Up to 96 weeks 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.
Percentage of participants discontinuing from study treatment due to drug-related AE Up to 96 weeks 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.
Percentage of participants with human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) <50 copies/mL Up to 24 weeks 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.
Percentage of treatment-naive (TN) participants with log10 change from baseline in HIV-1 RNA Day 1 and Week 24 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.
Viral resistance-associated substitutions (RASs) to DOR or other treatment components Up to 96 weeks The presence of viral RASs to DOR or other treatment components will be monitored for up to 96 weeks.
Percentage of participants adhering to DOR treatment regimen Up to 96 weeks Adherence to DOR will be monitored for up to 96 weeks.
Percentage of participants with HIV-1 RNA <50 copies/mL Up to 96 weeks 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.
Percentage of virologically-suppressed (VS) participants with HIV-1 RNA ≥50 copies/mL Up to 24 weeks 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.
Percentage of TN participants with log10 change from baseline in HIV-1 RNA Day 1 and Week 96 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.
Change from baseline in cluster of differentiation 4+ (CD4+) T-cell counts Day 1 and Week 24 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.
Assessment of palatability/acceptability of DOR pellets/granules Day 28 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.
Trial Locations
- Locations (24)
University of Colorado at Denver ( Site 0108)
🇺🇸Aurora, Colorado, United States
Emory Children's Center ( Site 0103)
🇺🇸Atlanta, Georgia, United States
Clinica Somer ( Site 1003)
🇨🇴Rionegro., Antioquia, Colombia
Ciensalud Ips S A S ( Site 1001)
🇨🇴Barranquilla, Atlantico, Colombia
CEIP - Centro de Estudios en Infectología Pediátrica ( Site 1002)
🇨🇴Cali, Valle Del Cauca, Colombia
Hospital Infantil de Mexico Federico Gomez ( Site 0702)
🇲🇽Mexico City, Distrito Federal, Mexico
Unidad de Atencion Medica e Investigacion en Salud S.C. ( Site 0700)
🇲🇽Merida, Yucatan, Mexico
Instituto Nacional de Pediatria ( Site 0701)
🇲🇽Mexico City, Mexico
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, Russian Federation
FARMOVS PTY LTD ( Site 0601)
🇿🇦Bloemfontein, Free State, 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
Empilweni Services and Research Unit ( Site 0604)
🇿🇦Johannesburg, Gauteng, South Africa
King Edward Hospital ( Site 0600)
🇿🇦Durban, Kwazulu-Natal, South Africa
Family Clinic Research With UBUNTU ( Site 0605)
🇿🇦Cape Town, Western Cape, South Africa
Be Part Yoluntu Centre ( Site 0606)
🇿🇦Paarl, Western Cape, South Africa
Tsitsikamma Clinical Research Initiative (TCRI) ( Site 0607)
🇿🇦Plettenberg Bay, Western Cape, South Africa
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, Thailand