Phase I/II Study of the Safety, Tolerability, Acceptability, and Pharmacokinetics of Oral and Long-Acting Injectable Cabotegravir and Rilpivirine in Virologically Suppressed Children Living With HIV-1, Two to Less Than 12 Years of Age
概览
- 阶段
- 1 期
- 干预措施
- Long acting CAB injectable + long acting RPV injectable
- 疾病 / 适应症
- HIV-1-infection
- 发起方
- National Institute of Allergy and Infectious Diseases (NIAID)
- 入组人数
- 90
- 试验地点
- 22
- 主要终点
- AUC (Cohort 1, tablets)
- 状态
- 招募中
- 最后更新
- 12天前
概览
简要总结
The purpose of the study is to evaluate the pharmacokinetics (PK), safety, tolerability, and acceptability of a long-acting injectable Cabotegravir and Rilpivirine in Virologically Suppressed Children Living with HIV-1, Two to Less Than 12 Years of Age
详细描述
This is a Phase I/II, multicenter, open-label, non-comparative study to evaluate the safety, tolerability, acceptability, and PK of oral CAB and oral RPV followed by long-acting injectable CAB (CAB LA) and long-acting injectable RPV (RPV LA) to propose the weight-band dosing in virologically suppressed children living with HIV-1 aged two to less than 12 years. The study will also assess the long-acting injectable regimen with and without an oral lead-in period in the same study population. Following completion of the study, if it is not possible for participants to access injections of CAB LA and RPV LA from non-study sources all participants may enter a Study Safety Extension (SSE) period. During the SSE period ongoing safety information to monitor for toxicities will be collected.
研究者
入排标准
入选标准
- •, Step 1: Entry for Cohort 1, Cohort 2a, and Cohort 2b
- •Parent or legal guardian is willing and able to provide written permission for child's study participation and, when applicable per institutional review board/ethics committee (IRB/EC) policies and procedures, child is willing and able to provide written assent for study participation.
- •Note: All sites must follow all applicable IRB/EC policies and procedures; for US sites, this includes single IRB (sIRB) policies and procedures.
- •Age two years old to less than 12 years old at entry
- •Body weight ≥10 kgs and \<40 kgs at entry
- •At entry, willing and able to comply with the study visit schedule and other study requirements, as determined by the site investigator or designee.
- •Confirmed HIV-1-infection based on documented testing of two samples collected from two separate blood collection tubes per Sample #1 and Sample #2 requirements. Test results may be obtained from medical records or from testing performed during the study screening period
- •Has been on a stable unchanged ART regimen consisting of two or more drugs from two or more antiretroviral drug classes for at least six consecutive months (defined as 180 consecutive days) prior to entry.
- •Has no prior history of switching ART regimens for reasons related to treatment failure based on parent/guardian report and/or available medical records.
- •Note: Participants undergoing dose modifications for growth or who have switched to a new formulation due to toxicity, tolerability, or changes in national treatment guidelines are considered eligible per this inclusion criterion. Treatment failure should be defined by local guidelines.
排除标准
- •, Step 1: Entry for Cohort 1, Cohort 2a, and Cohort 2b
- •Potential participants must be excluded from the study if any of the conditions specified below are identified during the screening period (i.e., within 28 days prior to study entry). The screening period begins when parental permission and informed assent (if applicable) are obtained and ends immediately prior to enrollment. For criteria involving a potential participant's medical history, it is expected that each exclusionary condition will be assessed at screening and subsequently reviewed and confirmed on the day of study entry, prior to enrollment. In these criteria, "at entry" is used to refer to the day of enrollment in the study
- •Within 6 months prior to entry, any HIV-1 RNA value \>400 copies/mL OR two consecutive "viral blips," defined as an HIV-1 RNA value ≥50 copies/mL but ≤400 copies/mL.
- •As determined by the IoR or designee, and based on available medical records, known or suspected resistance to NNRTIs.
- •Note: Prior receipt of NNRTIs for prophylaxis or treatment is not exclusionary
- •As determined by the IoR or designee, and based on available medical records, known or suspected resistance to INSTIs.
- •Ongoing congestive heart failure, symptomatic arrhythmia, or any current clinically significant cardiac disease, as determined by the IoR or designee, and based on available medical records.
- •Has any of the following, as determined by the IoR or designee based on participant/parent/guardian report and available medical records:
- •Current hepatitis C infection
- •Current clinically significant hepatic disease
研究组 & 干预措施
Cohort 2A
Cohort 2A: Once daily doses of oral CAB + oral RPV through the Week 4b visit, followed by Q4W or Q8W intramuscular injection doses of CAB LA + RPV LA.
干预措施: Long acting CAB injectable + long acting RPV injectable
Cohort 2B
Cohort 2B: Q4W or Q8W intramuscular injection doses of CAB LA + RPV LA.
干预措施: Long acting CAB injectable + long acting RPV injectable
Cohort 1
Cohort 1 will receive Once daily oral CAB + oral RPV through the Week 4b visit, followed by intramuscular injection doses of CAB LA + RPV LA every four weeks (Q4W dosing regimen) or every eight weeks (Q8W dosing regimen)
干预措施: Long acting CAB injectable + long acting RPV injectable
Cohort 2A
Cohort 2A: Once daily doses of oral CAB + oral RPV through the Week 4b visit, followed by Q4W or Q8W intramuscular injection doses of CAB LA + RPV LA.
干预措施: Once daily CAB tablet + RPV tablet
Cohort 1
Cohort 1 will receive Once daily oral CAB + oral RPV through the Week 4b visit, followed by intramuscular injection doses of CAB LA + RPV LA every four weeks (Q4W dosing regimen) or every eight weeks (Q8W dosing regimen)
干预措施: Once daily CAB tablet + RPV tablet
结局指标
主要结局
AUC (Cohort 1, tablets)
时间窗: At week 2
Area under the curve from start of dose to 8 hours post dose
CL/F (Cohort 1, tablets)
时间窗: At week 2
apparent clearance from start of dose to 8 hours post dose
Cmax (Cohort 1, tablets)
时间窗: At week 2
Peak concentration from start of dose to 8 hours post dose
Tmax (Cohort 1, tablets)
时间窗: At week 2
Time of maximal concentration from start of dose to 8 hours post dose
Week 5 concentrations (C5WK) (Cohort 1, injections)
时间窗: Through week5
Week 12 concentrations (C12WK) (Cohort 1, injections)
时间窗: Through week 12
Proportion of children who experience a drug related safety event during the CAB + RPV oral lead-in period (Cohort 1)
时间窗: Through week 4a
Proportion of children who experience a grade 3 of higher adverse event during the CAB + RPV oral lead-in period (Cohort 1)
时间窗: Through week 4a
Proportion of children who experience an SAE during the CAB + RPV oral lead-in period (Cohort 1)
时间窗: Through week 4a
Proportion of children who experience a drug-related safety failure event during the 24 weeks of CAB + RPV (oral and injectable) (Cohort 1)
时间窗: Week 4b through week 28
Pre-dose concentrations (C0) (Cohort 1, tablets)
时间窗: At week 2
Accumulation Ratio at week 24 and week 8 (Cohort 1, injections)
时间窗: At week 8 and 24
Trough concentrations (Ct) prior to IM doses through Week 24 (Cohort 1, injections)
时间窗: Through week 24
Proportion of children who experience premature permanent discontinuation study treatment due to an adverse event during the 24 weeks of CAB + RPV (oral and injectable) (Cohort 1)
时间窗: Week 4b through week 28
Proportion of children who experience premature permanent discontinuation study treatment due to an adverse event during the CAB + RPV oral lead-in period (Cohort 1)
时间窗: Through week 4a
Proportion of children who experience a grade 3 or higher adverse event during the 24 weeks of CAB + RPV (oral and injectable) (Cohort 1)
时间窗: Week 4b through week 28
Proportion of children who experience an SAE during the 24 weeks of CAB + RPV (oral and injectable) (Cohort 1)
时间窗: Week 4b through week 28
次要结局
- Accumulation ratios Wk 24:Wk 8 and Wk 48: Wk 8 (Cohort 2a), Wk 20:Wk4 and Wk 44: Wk 4 (Cohort 2b(At week 8, 48 and 72)
- Ct prior to IM doses through Week. 24 and Week. 48 (Cohort 2a)(At Week. 24 and Week. 48)
- Ct prior to IM doses through Wk. 20 and Wk. 44 (Cohort 2b)(At week 20 and 44)
- Proportion of children who experience a drug-related safety failure event through Weeks 48 and 72 of CAB + RPV (oral and injectable) (Cohort 1)(Through week 48 and 72)
- Proportion of children who experience a grade 3 or higher adverse event through Weeks 48 and 72 of CAB + RPV (oral and injectable) (Cohort 1)(Through week 48 and 72)
- Proportion of children who experience an SAE through Weeks 48 and 72 of CAB + RPV (oral and injectable) (Cohort 1)(Through week 48 and 72)
- Proportion of children who experience premature permanent discontinuation study treatment due to an adverse event through Weeks 48 and 72 of CAB + RPV (oral and injectable) (Cohort 1)(Through week 48 and 72)
- Proportion of children who have HIV-1 RNA <50 and ≥50, copies/ml at Weeks 24, 48, and 72 using the FDA Snapshot algorithm (Cohort 1)(At weeks 24, 48 and 72)
- Proportion of children who have HIV-1 RNA <200 and ≥200 copies/ml at Weeks 24, 48, and 72 using the FDA Snapshot algorithm (Cohort 1)(At weeks 24, 48 and 72)
- Proportion of children with confirmed virologic failure at Weeks 24, 48 and 72 while on CAB + RPV (Cohort 1)(At weeks 24, 48 and 72)
- Child and/or parent/caregiver responses to questionnaires about CAB or RPV side effects, pain associated with injections, and injection site reactions at Weeks 24, 48, and 72 (Cohort 1)(At Weeks 24, 48, and 72)
- Child and/or parent/caregiver reported attitudes about CAB or RPV, including willingness to use at Weeks 24, 48, and 72 (Cohort 1)(At weeks 24, 48 and 72)
- Proportion of participants who had genotypic and phenotypic resistance to CAB or RPV among children who experience virologic failure while on CAB + RPV (Cohort 1)(Through week 72)
- Median for CD4 count and percentage at Weeks 24, 48 and 72 (Cohort 1)(At weeks 24, 48 and 72)
- Median change from baseline CD4 count and percentage at Weeks 24, 48 and 72 (Cohort 1)(At weeks 24, 48 and 72)
- Child and/or parent/caregiver response to questionnaires (Cohort 2)(at week 44 and 48)
- Child and/or parent/caregiver reported attitudes about CAB (Cohort 2) or RPV, including willingness to use for children who are on 48 weeks of CAB + RPV (oral and injectable) OR 44 weeks of CAB LA + RPV LA (injectable)(At week 44 and 48)
- Proportion of children who experience a drug-related safety failure event during the 48 weeks of CAB + RPV (oral and injectable) OR the 44 weeks of CAB LA + RPV LA (injectable) (Cohort 2)(At week 44 and 48)
- Proportion of children who experience a grade 3 or higher adverse event during the 48 weeks of CAB + RPV (oral and injectable) OR the 44 weeks of CAB LA + RPV LA (injectable) (Cohort 2)(At week 44 and 48)
- Proportion of children who experience an SAE during the 48 weeks of CAB + RPV (oral and injectable) OR the 44 weeks of CAB LA + RPV LA (injectable) (Cohort 2)(At week 44 and 48)
- Proportion of children who experience premature permanent discontinuation study treatment due to an adverse event during the 48 weeks of CAB + RPV (oral and injectable) OR the 44 weeks of CAB LA + RPV (Cohort 2) LA (injectable)(At week 44 and 48)
- Proportion of children who have HIV-1 RNA <50 and ≥50, copies/ml using the FDA Snapshot algorithm for children who are on 48 weeks of CAB + RPV (oral and injectable) OR 44 weeks of CAB LA + RPV LA (injectable) (Cohort 2)(At week 44 and 48)
- Proportion of children who have HIV-1 RNA <200 and ≥200 copies/ml using the FDA Snapshot algorithm for children who are on 48 weeks of CAB + RPV (oral and injectable) OR 44 weeks of CAB LA + RPV LA (injectable) (Cohort 2)(At week 44 and 48)
- Proportion of children with confirmed virologic failure while on treatment for children who are on 48 weeks of CAB + RPV (oral and injectable) OR 44 weeks of CAB LA + RPV LA (injectable) (Cohort 2)(At week 44 and 48)
- Median and Interquartile Range for CD4 count and percentage for children who are on 48 weeks of CAB + RPV (oral and injectable) OR 44 weeks of CAB LA + RPV LA (injectable) (Cohort 2)(At week 44 and 48)
- Median and Interquartile Range change from baseline CD4 count and percentage for children who are on 48 weeks of CAB + RPV (oral and injectable) OR 44 weeks of CAB LA + RPV LA (injectable) (Cohort 2)(At week 44 and 48)
- Proportion of participants who had genotypic and phenotypic resistance to CAB and RPV among children who experience virologic failure while on 48 weeks of CAB + RPV (oral and injectable) OR while on 44 weeks of CAB LA + RPV LA (injectable) (Cohort 2)(At week 44 and 48)
- LA dosing: Ct prior to IM doses at Wk. 48 and Wk. 72 and accumulation ratios (Wk. 48:Wk. 8 and Wk. 72:Wk. 8) (Cohort 1)(At week 8 and 48)