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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 84
- 试验地点
- 45
- 主要终点
- Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Postdose (AUC0-24hr) of Doravirine (DOR) Following Once-Daily Dosing in Plasma at Steady-State
研究概览
简要总结
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 primary objectives are:
- 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.
- 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.
详细描述
Participants who complete the Week 96 visit will be eligible to enroll in an Extension Study and receive DOR until it is commercially available, or for up to an additional 224 weeks (whichever comes first).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 4 Weeks 至 11 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Has human immunodeficiency virus type 1 (HIV-1) infection confirmed at screening
- •Has appropriate treatment history defined as treatment-naïve (TN) or with documented virologic suppression (HIV-1 ribonucleic acid [RNA] <50 copies/mL) on stable combination antiretroviral therapy (cART) for ≥3 months
- •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 doravirine (DOR) plus the 2 nucleoside/nucleotide analog reverse transcriptase inhibitor (NRTIs) selected by the investigator, or doravirine/lamivudine/tenofovir disoproxil fumarate (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 regimens (DOR plus 2 NRTIs selected by the investigator or DOR/3TC/TDF)
- •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 regimens (DOR plus 2 NRTIs selected by the investigator or DOR/3TC/TDF) until it is available locally in countries participating in the study or for up to an additional 224 weeks (whichever comes first)
排除标准
- •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
研究组 & 干预措施
Doravirine as a single entity plus 2 NRTIs or Doravirine as a FDC with 3TC and TDF
Participants receive doravirine (DOR) at 7.2 mg to 100 mg, based on weight, PLUS 2 nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs), based on local label, for 96 weeks, OR a fixed-dose combination (FDC) of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF), based on weight, for 96 weeks.
干预措施: 2 NRTIs (Drug)
Doravirine as a single entity plus 2 NRTIs or Doravirine as a FDC with 3TC and TDF
Participants receive doravirine (DOR) at 7.2 mg to 100 mg, based on weight, PLUS 2 nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs), based on local label, for 96 weeks, OR a fixed-dose combination (FDC) of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF), based on weight, for 96 weeks.
干预措施: DOR/3TC/TDF (Drug)
Doravirine as a single entity plus 2 NRTIs or Doravirine as a FDC with 3TC and TDF
Participants receive doravirine (DOR) at 7.2 mg to 100 mg, based on weight, PLUS 2 nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs), based on local label, for 96 weeks, OR a fixed-dose combination (FDC) of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF), based on weight, for 96 weeks.
干预措施: Doravirine (Drug)
结局指标
主要结局
Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Postdose (AUC0-24hr) of Doravirine (DOR) Following Once-Daily Dosing in Plasma at Steady-State
时间窗: Intensive pharmacokinetic sampling: at designated timepoints up to 24 hours postdose
Per protocol, intensive pharmacokinetic (PK) sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine AUC0-24hr.
Maximum Concentration (Cmax) of DOR Following Once-Daily Dosing in Plasma at Steady-State
时间窗: Intensive pharmacokinetic sampling: at designated timepoints up to 24 hours postdose
Per protocol, intensive PK sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine Cmax.
Concentration at 24 Hours (C24) of DOR Following Once-Daily Dosing in Plasma at Steady-State
时间窗: Intensive pharmacokinetic sampling: at designated timepoints up to 24 hours postdose
Per protocol, intensive PK sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine C24.
Time to Maximum Concentration (Tmax) of DOR Following Once-Daily Dosing in Plasma at Steady-State
时间窗: Intensive pharmacokinetic sampling: at designated timepoints up to 24 hours postdose
Per protocol, intensive PK sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine Tmax.
AUC From 0 to 12 Hours Postdose (AUC0-12hr) of DOR Following Twice-Daily Dosing in Plasma at Steady-State
时间窗: Intensive pharmacokinetic sampling: at designated timepoints up to 12 hours postdose
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine AUC0-12hr.
Cmax of DOR Following Twice-Daily Dosing in Plasma at Steady-State
时间窗: Intensive pharmacokinetic sampling: at designated timepoints up to 12 hours postdose
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine Cmax.
Concentration at 12 Hours (C12) of DOR Following Twice-Daily Dosing in Plasma at Steady-State
时间窗: Intensive pharmacokinetic sampling: at designated timepoints up to 12 hours postdose
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine C12.
Tmax of DOR Following Twice-Daily Dosing in Plasma at Steady-State
时间窗: Intensive pharmacokinetic sampling: at designated timepoints up to 12 hours postdose
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine Tmax.
Percentage of Participants With ≥1 Adverse Event (AE)
时间窗: 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 interventions.
Percentage of Participants With a Grade 3 or 4 AE
时间窗: 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-threatening events" (Grade 4).
Percentage of Participants With Events of Death
时间窗: Up to 24 weeks
The percentage of participants with events of death at Week 24 will be reported.
Percentage of Participants Discontinuing From Study Intervention Due to an AE
时间窗: 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 interventions.
Percentage of Participants Discontinuing From Study Intervention Due to a Drug-Related AE
时间窗: 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 the study interventions.
次要结局
- Percentage of Participants With Events of Death at Week 48(Up to 48 weeks)
- Percentage of Participants With Events of Death at Week 96(Up to 96 weeks)
- Plasma Concentration of DOR(Sparse pharmacokinetic sampling: at designated timepoints up to 24 weeks)
- Plasma Concentration of Lamivudine (3TC) Following Once-Daily Dosing of Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) as an Age-Appropriate Fixed-Dose Combination (FDC)(Sparse pharmacokinetic sampling: at designated timepoints up to 24 weeks)
- Plasma Concentration of Tenofovir (TFV) Following Once-Daily Dosing of DOR/3TC/TDF as an Age-Appropriate FDC(Sparse pharmacokinetic sampling: at designated timepoints up to 24 weeks)
- AUC0-24hr of 3TC Following Once-Daily Dosing of DOR/3TC/TDF as an Age-Appropriate FDC(Intensive pharmacokinetic sampling: at designated timepoints up to 24 hours postdose)
- AUC0-24hr of TFV Following Once-Daily Dosing of DOR/3TC/TDF as an Age-Appropriate FDC(Intensive pharmacokinetic sampling: at designated timepoints up to 24 hours postdose)
- Cmax of 3TC Following Once-Daily Dosing of DOR/3TC/TDF as an Age-Appropriate FDC(Intensive pharmacokinetic sampling: at designated timepoints up to 24 hours postdose)
- Cmax of TFV Following Once-Daily Dosing of DOR/3TC/TDF as an Age-Appropriate FDC(Intensive pharmacokinetic sampling: at designated timepoints up to 24 hours postdose)
- Percentage of Participants With ≥1 AE at Week 48(Up to 48 weeks)
- Percentage of Participants With ≥1 AE at Week 96(Up to 96 weeks)
- Percentage of Participants With Grade 3 or 4 AE at Week 48(Up to 48 weeks)
- Percentage of Participants With Grade 3 or 4 AE at Week 96(Up to 96 weeks)
- Percentage of Participants Discontinuing From Study Intervention Due to AE at Week 48(Up to 48 weeks)
- Percentage of Participants Discontinuing from Study Intervention Due to AE at Week 96(Up to 96 weeks)
- Percentage of Participants Discontinuing From Study Intervention Due to Drug-Related AE at Week 48(Up to 48 weeks)
- Percentage of Participants Discontinuing From Study Intervention Due to Drug-Related AE at Week 96(Up to 96 weeks)
- Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/mL at Week 24(Up to 24 weeks)
- Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 48(Up to 48 weeks)
- Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 96(Up to 96 weeks)
- Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 24(Up to 24 weeks)
- Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 48(Up to 48 weeks)
- Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 96(Up to 96 weeks)
- Percentage of Participants With HIV-1 RNA ≥50 copies/mL at Week 24(Up to 24 weeks)
- Percentage of Participants With HIV-1 RNA ≥50 Copies/mL at Week 48(Up to 48 weeks)
- Percentage of Participants With HIV-1 RNA ≥50 Copies/mL at Week 96(Up to 96 weeks)
- Percentage of Participants With Log10 Drop in Plasma HIV-1 RNA From Baseline at Week 24(Baseline (Day 1) and Week 24)
- Percentage of Participants With Log10 Drop in Plasma HIV-1 RNA From Baseline at Week 48(Baseline (Day 1) and Week 48)
- Percentage of Participants With Log10 Drop in Plasma HIV-1 RNA From Baseline at Week 96(Baseline (Day 1) and Week 96)
- Change From Baseline in Cluster of Differentiation 4+ (CD4+) T-Cell Counts at Week 24(Baseline (Day 1) and Week 24)
- Change From Baseline in CD4+ T-Cell Counts at Week 48(Baseline (Day 1) and Week 48)
- Change From Baseline in CD4+ T-Cell Counts at Week 96(Baseline (Day 1) and Week 96)
- Viral Resistance-Associated Substitutions (RASs) to DOR or Other Treatment Components(Up to 96 weeks)
- Percentage of Participants Adhering to DOR or to the FDC of DOR/3TC/TDF(Up to 96 weeks)
- Assessment of Palatability/Acceptability of Oral Pellets/Granules of DOR or the FDC of DOR/3TC/TDF(Day 28)