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

Study Overview
=================
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).

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

Conditions
-----------------
Human Immunodeficiency Virus (HIV) Infection

Intervention / Treatment
-----------------
* Drug: Doravirine
* Drug: 2 NRTIs


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 4 Weeks
Maximum Age: 11 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doravirine + 2 NRTIs<br>Participants receive DOR (3.2 mg to 100 mg based on weight) in combination with 2 NRTIs (based on local label) for 96 weeks. | Drug: Doravirine<br>* DOR capsules (3.2 to 100 mg); sachets (3.2 to 100 mg); or tablets (100 mg) taken once or twice daily by mouth.<br>* Other names: MK-1439;Drug: 2 NRTIs<br>* Participants receive 2 NRTIs per local label by mouth for 96 weeks as background therapy.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Percentage of participants with overall mortality | The percentage of participants with mortality through 24 weeks will be determined. | Up to 24 weeks | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Percentage of participants with overall mortality | The percentage of participants with mortality through 48 weeks will be determined. | Up to 48 weeks | 
| Percentage of participants with overall mortality | The percentage of participants with mortality through 96 weeks will be determined. | Up to 96 weeks | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Percentage of participants adhering to DOR treatment regimen | Adherence to DOR will be monitored for up to 96 weeks. | Up to 96 weeks | 
| 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 |