Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability of Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets in HIV-1-Infected Children Less Than 12 Years of Age
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 57
- 试验地点
- 14
- 主要终点
- Geometric Mean Area Under the Plasma Concentration-time Curve Over 24 Hours (AUC0-24h) for ABC, DTG, and 3TC
研究概览
简要总结
The purpose of this study was to examine the pharmacokinetics, safety, and tolerability of abacavir/dolutegravir/lamivudine dispersible and immediate release tablets in children living with HIV less than 12 years of age.
详细描述
This study examined the pharmacokinetics (PK), safety, and tolerability of fixed-dose combination abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC) dispersible and immediate release tablets in children living with HIV less than 12 years of age.
Children were enrolled into one of five ABC/DTG/3TC dosing groups based on their weight. The first 5-7 children within each weight-band underwent intensive PK assessments 5-10 days after starting ABC/DTG/3TC to confirm dose selection. Children remained on their initial dose of ABC/DTG/3TC through Week 4. After Week 4, ABC/DTG/3TC dosing was adjusted based on PK results at the individual or weight-band level, and/or an individual child's growth and weight gain over time.
Follow-up study visits for all participants occurred at Weeks 1, 4, 12, 24, 36, and 48. If participants had a known M184 resistance mutation, they had additional study visits at Weeks 8, 16, and 20. Study visits included physical examination, study drug adherence and tolerability questionnaires, blood collection, and intensive PK sampling. Following the Week 48 study visit, some children were allowed to continue follow-up through up to 144 weeks if alternative post-study drug supply was not yet available.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 11 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Weight 6 kg to less than 40 kg at entry
- •Antiretroviral therapy (ART)-naïve at entry or has been taking a stable ART regimen for at least six consecutive months at entry
- •Note: For ART-naïve children, receipt of antiretroviral (ARV) prophylaxis prior to diagnosis of HIV infection is permitted. For these children, ascertainment of this criterion may be based on parent or guardian report only, but available medical records should also be reviewed in relation to this criterion.
- •Note: For ART-experienced children (on a stable ART regimen), dose and formulation changes (e.g., for growth) within the six months prior to entry are permitted. For these children, ascertainment of this criterion must be based on medical records.
- •For ART-experienced children (on a stable ART regimen), has had a suppressed HIV viral load (HIV-1 RNA less than 200 copies/mL) for at least six consecutive months prior to entry
- •Note: To fulfill this criterion, at least two documented HIV-1 RNA results less than 200 copies/mL must be available, one based on a specimen collected at least six months prior to entry and one based on a specimen collected within 30 days prior to entry.
- •Note: Any documented HIV-1 RNA result greater than or equal to 200 copies/mL based on a specimen collected within six months prior to entry is exclusionary (see exclusion criterion below).
- •At screening, has normal, Grade 1, or Grade 2 laboratory test results for all of the following, based on testing of specimens collected within 30 days prior to entry and grading per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (refer to the study protocol for guidance on severity grading):
- •Hemoglobin (greater than or equal to 8.5 g/dL or greater than or equal to 5.25 mmol/L)
- •Absolute neutrophil count (greater than or equal to 600 cells/mm^3 or greater than or equal to 0.600 x 10^9 cells/L)
- •Platelet count (greater than or equal to 50,000 cells/mm^3 or greater than or equal to 50.00 x 10^9 cells/L)
- •Estimated glomerular filtration rate (eGFR; bedside Schwartz formula; greater than or equal to 60 ml/min/1.73 m^2)
- •Alanine transaminase (ALT) (less than 5.0 x ULN)
- •Aspartate aminotransferase (AST) (less than 5.0 x ULN)
- •Total bilirubin (less than 2.6 x ULN)
- •Direct bilirubin (less than or equal to ULN)
- •Note: Laboratory tests may be repeated during the screening period (i.e., within 30 days prior to entry), with the latest results used for eligibility determination.
- •Note: For treatment-experienced children on an atazanavir-containing ART regimen, Grade 3 or higher total bilirubin is permitted.
- •At screening, has a negative test result for hepatitis B surface antigen based on testing of a specimen collected within 30 days prior to entry
- •Confirmed HIV-1-infection based on documented testing of two samples collected at different time points:
- •Sample #1 may be tested using any of the following:
- •Two rapid antibody tests from different manufacturers or based on different principles and epitopes
- •One enzyme immunoassay OR Western Blot OR immunofluorescence assay OR chemiluminescence assay
- •One HIV DNA polymerase chain reaction (PCR)*
- •One quantitative HIV RNA PCR (above the limit of detection of the assay)*
- •One qualitative HIV RNA PCR*
- •One HIV total nucleic acid test*
- •Sample #2 may be tested using any of the following:
- •Rapid antibody test. If this option is used in combination with two rapid tests for Sample #1, at least one of the three rapid tests must be United States Food and Drug Administration (FDA)-approved, and the third rapid test must be from a third manufacturer or based on a third principle or epitope.
- •One enzyme immunoassay OR Western Blot OR immunofluorescence assay OR chemiluminescence assay
- •One HIV DNA PCR*
- •One quantitative HIV RNA PCR (above the limit of detection of the assay)*
- •One qualitative HIV RNA PCR*
- •One HIV total nucleic acid test*
- •For participants who are less than two years of age, or who are two years of age and older with any exposure to breast milk in the past 28 days, HIV-1 infection must be confirmed using the tests indicated above with an asterisk (*) for Sample #1 and Sample #
- •Whole blood, plasma, or serum samples must be tested. If both samples are tested using antibody tests, at least one of the samples must be tested in a laboratory that operates according to Good Clinical Laboratory Practice guidelines and participates in an appropriate external quality assurance program. If nucleic acid testing is used, at least one test must be performed in a Clinical Laboratory Improvement Amendments (CLIA) certified (for US sites) or Virology Quality Assurance (VQA) certified (for non-US sites) laboratory. For tests performed in other settings, adequate source documentation including the date of specimen collection, date of testing, test performed, and test result must be available. FDA approved testing methods should be used when possible.
- •HLA-B*5701-negative based on documented testing at any time prior to entry
- •Note: Documented testing is required even if the potential participant has received ABC prior to study entry.
- •For females of reproductive potential (defined as having experienced menarche), not pregnant based on testing performed at screening
- •For females of reproductive potential who are engaging in sexual activity that could lead to pregnancy, willing to use two methods of contraception while receiving study drug, based on participant and parent or guardian report at entry
- •One of the two methods must be highly effective; highly effective methods include surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, tubal ligation, or salpingectomy) and the following:
- •Contraceptive intrauterine device or intrauterine system
- •Subdermal contraceptive implant
- •Progestogen injections
- •Combined estrogen and progestogen oral contraceptive pills
- •Percutaneous contraceptive patch
- •Contraceptive vaginal ring
- •The highly effective method must be initiated prior to study entry. The second method should ideally be a barrier method. Male or female condom use is recommended with all other methods of contraception for dual protection against pregnancy and to avoid transmission of HIV and other sexually transmitted infections.
- •Based on parent or guardian report at entry, child is expected to be available for 48 weeks of follow-up
- •Parent or legal guardian is willing and able to provide written informed consent for child's study participation and, when applicable per local institutional review board/ethics committee (IRB/EC) policies and procedures, child is willing and able to provide written informed assent for study participation
排除标准
- •Documented resistance to ABC, DTG, or 3TC
- •Note: Testing to rule out resistance is not required, and the M184V resistance mutation is not exclusionary.
- •For ART-experienced children (on a stable ART regimen), documented HIV-1 RNA result greater than or equal to 200 copies/mL based on a specimen collected within six months prior to entry
- •History of any of the following as determined by the site investigator based on participant/parent/guardian report and available medical records:
- •Malignancy (ever)
- •Hypersensitivity reaction to ABC (ever)
- •Receipt of any prohibited medication (refer to the study protocol for more information) within 30 days prior to study entry
- •Receipt of systemic interferon or any chronic systemic immunosuppressant medication within 30 days prior to study entry
- •Note: Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg) taken for replacement or short course therapy are permitted. Intranasal or inhaled steroid use is also permitted.
- •Has any of the following as determined by the site investigator based on participant/parent/guardian report and available medical records
- •Current clinical evidence of pancreatitis
- •Currently-active tuberculosis (TB) and/or currently receiving rifampicin-containing TB treatment
- •Currently-active AIDS-defining (WHO Clinical Stage 4) opportunistic infection
- •Has any documented or suspected clinically significant medical condition or any other condition that, in the opinion of the site investigator, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives
研究组 & 干预措施
Weight Band #1 (6 to less than 10 kg at study entry)
Children weighing 6 to less than 10 kg at study entry. These children received 3 dispersible tablets of ABC/DTG/3TC daily while weighing 6-<10 kg; as their weight increased, they received higher doses consistent with their new weight band.
干预措施: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Dispersible Tablets (Drug)
Weight Band #2 (10 to less than 14 kg at study entry)
Children weighing 10 to less than 14 kg at study entry. These children received 4 dispersible tablets of ABC/DTG/3TC daily while weighing 10-<14 kg; as their weight increased, they received higher doses consistent with their new weight band.
干预措施: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Dispersible Tablets (Drug)
Weight Band #3 (14 to less than 20 kg at study entry)
Children weighing 14 to less than 20 kg at study entry. These children received 5 dispersible tablets of ABC/DTG/3TC daily while weighing 14-<20 kg; as their weight increased, they received higher doses consistent with their new weight band.
干预措施: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Dispersible Tablets (Drug)
Weight Band #4 (20 to less than 25 kg at study entry)
Children weighing 20 to less than 25 kg at study entry. These children received 6 dispersible tablets of ABC/DTG/3TC daily while weighing 20-<25 kg; as their weight increased, they received higher doses consistent with their new weight band.
干预措施: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Dispersible Tablets (Drug)
Weight Band #5 (25 kg or greater at study entry)
Children weighing 25 kg or greater at study entry. These children received 1 immediate release tablet of ABC/DTG/3TC daily.
干预措施: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Immediate Release Tablets (Immediate release) (Drug)
结局指标
主要结局
Geometric Mean Area Under the Plasma Concentration-time Curve Over 24 Hours (AUC0-24h) for ABC, DTG, and 3TC
时间窗: Week 1; Blood samples were drawn at pre-dose and 1, 2, 3, 4, 6, 8, and 24 hours post dosing.
Based on analysis of intensive pharmacokinetic (PK) samples. The geometric mean AUC0-24h for each Weight Band was compared to the lower and upper reference values (in ug\*h/mL) for DTG (35.1, 134), ABC (6.3, 50.4), and 3TC (6.3, 26.5). Steady state was measured at Week 1, but was re-collected later for two participants due to a specimen handling error for the Week 1 specimens.
Geometric Mean Maximum Plasma Concentration (Cmax) for ABC, DTG, and 3TC
时间窗: Week 1; Blood samples were drawn at pre-dose and 1, 2, 3, 4, 6, 8, and 24 hours post dosing.
Based on analysis of intensive PK samples. Steady state was measured at Week 1, but was re-collected later for two participants due to a specimen handling error for the Week 1 specimens.
Percentage of Participants Who Had at Least One Grade 3 or Grade 4 Adverse Event Assessed as Related to Study Drug Through Week 24
时间窗: Measured from treatment initiation through Week 24
AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.
Geometric Mean Concentration at 24 Hours Post-dose (C24h) for ABC, DTG, and 3TC
时间窗: Week 1; Blood samples were drawn at pre-dose and 1, 2, 3, 4, 6, 8, and 24 hours post dosing.
Based on analysis of intensive PK samples. The geometric mean C24h for each Weight Band was compared to the lower and upper reference values (in ug/mL) for DTG (0.67, 2.97). Steady state was measured at Week 1, but was re-collected later for two participants due to a specimen handling error for the Week 1 specimens.
Percentage of Participants Who Had at Least One Adverse Event Through Week 24
时间窗: Measured from treatment initiation through Week 24
Adverse event (AE) grading was based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. AEs of any grade were reported.
Percentage of Participants Who Had a Grade 5 Adverse Event Assessed as Related to Study Drug Through Week 24
时间窗: Measured from treatment initiation through Week 24
AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.
Percentage of Participants Who Had at Least One Life-threatening Adverse Event Assessed as Related to Study Drug Through Week 24
时间窗: Measured from treatment initiation through Week 24
AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator. Life-threatening was defined according to Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual).
Percentage of Participants Who Had at Least One Serious Adverse Event Assessed as Related to Study Drug Through Week 24
时间窗: Measured from treatment initiation through Week 24
AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator. Seriousness was defined according to Version 2.0 of the DAIDS EAE Manual.
Percentage of Participants Who Had at Least One Adverse Event Assessed as Related to Study Drug That Led to Permanent Discontinuation of Study Drug Through Week 24
时间窗: Measured from treatment initiation through Week 24
AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.
次要结局
- Population PK: Geometric Mean AUC0-24h for ABC, DTG, and 3TC(Measured from Week 1 through Week 48 over 24 hours post-dose)
- Population PK: Geometric Mean Concentration at Time 0 (Pre-dose) (C0h) for ABC, DTG, and 3TC(Measured from Week 1 through Week 48 over 24 hours post-dose)
- Population PK: Geometric Mean Concentration at 24 Hours Post-dose (C24h) for ABC, DTG, and 3TC(Measured from Week 1 through Week 48 over 24 hours post-dose)
- Population PK: Geometric Mean Maximum Plasma Concentration (Cmax) for ABC, DTG, and 3TC(Measured from Week 1 through Week 48 over 24 hours post-dose)
- Population PK: Geometric Mean Time to Maximum Concentration (Tmax) for ABC, DTG, and 3TC(Measured from Week 1 through Week 48 over 24 hours post-dose)
- Population PK: Geometric Mean Apparent Oral Clearance (CL/F) for ABC, DTG, and 3TC(Measured from Week 1 through Week 48 over 24 hours post-dose)
- Population PK: Geometric Mean Half-life (t1/2) for ABC, DTG, and 3TC(Measured from Week 1 through Week 48 over 24 hours post-dose)
- Percentage of Participants With at Least One Adverse Event Through Week 48(Measured from treatment initiation through Week 48)
- Percentage of Participants Who Had at Least One Grade 3 or Grade 4 Adverse Event Assessed as Related to Study Drug Through Week 48(Measured from treatment initiation through Week 48)
- Percentage of Participants Who Had a Grade 5 Adverse Event Assessed as Related to Study Drug Through Week 48(Measured from treatment initiation through Week 48)
- Percentage of Participants Who Had at Least One Life-threatening Adverse Event Assessed as Related to Study Drug Through Week 48(Measured from treatment initiation through Week 48)
- Percentage of Participants Who Had at Least One Serious Adverse Event Assessed as Related to Study Drug Through Week 48(Measured from treatment initiation through Week 48)
- Percentage of Participants Who Had at Least One Adverse Event Assessed as Related to Study Drug That Led to Permanent Discontinuation of Study Drug Through Week 48(Measured from treatment initiation through Week 48)
- Percentage of Participants Who Had at Least One Adverse Event Through Week 60(Measured from treatment initiation through Week 60)
- Percentage of Participants Who Had at Least One Grade 3 or Grade 4 Adverse Event Assessed as Related to Study Drug Through Week 60(Measured from treatment initiation through Week 60)
- Percentage of Participants Who Had a Grade 5 Adverse Event Assessed as Related to Study Drug Through Week 60(Measured from treatment initiation through Week 60)
- Percentage of Participants Who Had at Least One Life-threatening Adverse Event Assessed as Related to Study Drug Through Week 60(Measured from treatment initiation through Week 60)
- Percentage of Participants Who Had at Least One Serious Adverse Event Assessed as Related to Study Drug Through Week 60(Measured from treatment initiation through Week 60)
- Percentage of Participants Who Had at Least One Adverse Event Assessed as Related to Study Drug That Led to Permanent Discontinuation of Study Drug Through Week 60(Measured from treatment initiation through Week 60)
- Percentage of Participants Who Experienced Virologic Failure Through Week 48(Measured from treatment initiation through Week 48)
- Percentage of Participants Who Experienced Virologic Failure Through Week 60(Measured from treatment initiation through Week 60)
- Percentage of Participants With HIV-1 RNA Less Than 200 Copies/mL(Weeks 4, 24, and 48)
- Percentage of Participants With Virologic Success of HIV-1 RNA Less Than 200 Copies/mL Using FDA Snapshot Algorithm(Weeks 4, 24, and 48)
- Percentage of Participants With Virologic Success of HIV-1 RNA Less Than 50 Copies/mL Using FDA Snapshot Algorithm(Weeks 4, 24, and 48)
- Median (Q1,Q3) Change From Baseline in Total Cholesterol(Baseline, Weeks 24 and 48)
- Median (Q1,Q3) Change From Baseline in Triglycerides(Baseline, Weeks 24 and 48)
- Median (Q1, Q3) CD4+ Cell Count(Weeks 4, 24, and 48)
- Median (Q1, Q3) CD4+ Percentage(Weeks 4, 24, and 48)
- Median (Q1,Q3) Change From Baseline in HDL(Baseline, Weeks 24 and 48)
- Parent/Guardian-reported Percent Adherence to Study Drug(Weeks 4, 24, and 48)
- Parent/Guardian-reported Number of Missed Doses of Study Drug(Weeks 4, 24, and 48)
- Parent/Guardian-reported Response of How Well the Person Usually Responsible Administered the Study Drug in the Way They Were Supposed to(Weeks 4, 24, and 48)
- Parent/Guardian-reported Response of How Often the Child Received the Study Drug in the Way They Were Supposed to(Weeks 4, 24, and 48)
- Parent/Guardian-reported Ease of Giving Study Drug(Weeks 4, 12, 24, and 48)
- Median (Q1,Q3) Change From Baseline in LDL(Baseline, Weeks 24 and 48)
- Parent/Guardian-reported Reason for Missed Doses of Study Drug(Weeks 4, 24, and 48)
- Parent/Guardian-reported Response of Child's Face When Taking Favorite Food(Weeks 4, 12, 24, and 48)
- Antiretroviral (ARV) Resistance Mutations(Entry and confirmation of virologic failure)
- Parent/Guardian-reported Response of Child's Face When Taking Study Drug(Weeks 4, 12, 24, and 48)
- Parent/Guardian-reported Time for Study Drug Tablets to Dissolve(Weeks 4, 12, 24, and 48)
- Parent/Guardian-reported Satisfaction With the Number of Study Drug Tablets to Dissolve(Weeks 4, 12, 24, and 48)