First in Human Clinical Trial of a Next Generation, Long-acting Injectable, Combination Antiretroviral Therapy Platform
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- Co-primary pharmacokinetic outcome: Peak TLC-101 drug substance concentrations (Cmax) in plasma
研究概览
简要总结
This study is a prospective, open-label, single-site, first-in-human study of a long-acting, injectable combination antiretroviral therapy platform, with a pharmacologically-guided adaptive design for dose escalation, de-escalation, and study duration. The study is designed to learn whether the formulation can be used as a platform for other drugs for treatment of HIV. The formulation is a drug combination nanoparticle (DCNP). The study will be conducted by UW Positive Research. The sample size for this study is 12-16. The study population consists of healthy adults without HIV. The study duration is 57 days per participant at the start of the study.
详细描述
This study is a prospective, open-label, single-site, first-in-human study of a long-acting, injectable combination antiretroviral therapy platform, with a pharmacologically-guided adaptive design for dose escalation, de-escalation, and study duration. The study has two primary aims as follows:
- To characterize the plasma concentration-time course and pharmacokinetics (PK) of a single dose of the drug substances of TLC-ART 101 (lopinavir, ritonavir, and tenofovir) administered by subcutaneous injection within the drug combination nanoparticle.
- To characterize the safety and tolerability of a single subcutaneous injection of TLC-ART 101.
There are 4 exploratory mechanistic objectives (with related endpoints) as follows:
- To characterize the pharmacokinetics of the drug substances in human peripheral blood mononuclear cells (PBMCs)
- To characterize the concentrations of intracellular TFV-diphosphate (the active moiety of TFV) in PBMCs
- To explore whether the pharmacokinetic parameters of the 3 drug substances differ by sex following a single dose NB: This analysis not performed due to truncation of study to 3 cohorts and low ratio of female to male sex participants
- To compare lymphoid tissue mononuclear cell versus PBMC concentrations of the drug substances in TLC-ART 101.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy with a BMI between 18.5 to 29.9 kg/m2 (Amended through 31.9kg/m2)
- •Non-smoker or former smoker (defined as no smoking or no vaping or no use of tobacco cessation products for greater than 1 year)
- •Persons of any gender are eligible if they otherwise meet all other entry criteria.
- •Assessed by the study staff as being at low risk for HIV infection and committed to maintaining behavior consistent with low risk of HIV exposure until after completing the study.
- •Willing and able to give informed consent.
- •If participating in sexual activity that could lead to pregnancy, individuals of reproductive potential must agree to use specific forms of contraception throughout the study. At least two of the following must be used throughout the study:
- •Condom (male or female)
- •Diaphragm or cervical cap
- •Copper-based intrauterine device
- •Vasectomy in the male partner
- •Note: Select participants will have a 72-hour in-patient stay at UW Medical Center.
- •Note: Select participants will undergo an inguinal lymph node biopsy.
排除标准
- •Note the following criteria refer to values from the screening visit
- •Positive HIV-1 fourth generation antigen/antibody test
- •Positive hepatitis B surface antigen test
- •Active HCV infection Note: Participants that are positive for HCV antibody must have a negative HCV RNA
- •Any chronic medical condition deemed significant by the investigator (e.g., asthma, severe allergies, hypertension, heart disease, diabetes mellitus, hyperlipidemia)
- •Taking any chronic oral or systemic prescription medications (including indwelling hormonal implants or hormone-releasing intrauterine devices) within 30 days before the Entry visit
- •Taking any chronic oral or systemic non-prescription (over the counter, OTC) medications that cannot be safely stopped
- •Any clinically significant abnormal value of CBC, creatinine, AST, ALT, alkaline phosphatase, total bilirubin
- •PT/INR, PTT above the upper limit of normal
- •U/A with any clinically significant abnormality
- •Any clinically significant finding on ECG per physician review
- •Urine toxicology screen positive for any illicit drug (other than cannabis if the participant agrees to stop use of cannabis for 14 days prior to entering the study and for the duration of the study, and is believed to be credible in this promise in the opinion of the investigator)
- •BP > 140 systolic or > 90 diastolic mmHg
- •Known allergy/sensitivity or any hypersensitivity to LPV, RTV, TFV or either of the lipids in TLC-ART 101 (including anaphylaxis to a COVID-19 mRNA vaccine)
- •Active drug or alcohol use or dependence or psychiatric illness that, in the opinion of the site investigator, would interfere with adherence to study requirements
- •Acute or serious illness requiring systemic treatment, antibiotics, and/or hospitalization within 90 days prior to study entry
- •Scars or tattoos on the central abdomen that would interfere with administration of a subcutaneous injection or assessment of the location where the study medication is planned to be administered (within 1 inch of the umbilicus)
- •Diagnosis of syphilis, gonorrhea or chlamydia in the past year
- •People who are pregnant, intend to become pregnant, or are breastfeeding
- •Additional Exclusion Criteria for Participants who will Undergo Lymph Node Biopsy
- •Allergy to lidocaine or any related "-caine" drug
- •Chronic scars or tattoos in both inguinal areas that might interfere with performance of a lymph node biopsy or increase the likelihood of a poor cosmetic result
- •Anxiety or any other condition that has a high likelihood of interfering with the successful performance of a lymph node biopsy done under local anesthesia
- •Any coagulopathy or condition that would increase the potential for bleeding
研究组 & 干预措施
TLC-ART 101 Dosage 2A
In the scenario in which the dosage in Arm 1 produces insufficient pharmacokinetics (PK), the dosage will be increased 2 fold in Arm 2A and administered to 4 participants.
If Arm 2A shows ideal PK parameters, and additional 8 participants will be enrolled in this arm, for a total study size of 16 participants.
干预措施: TLC-ART (Drug)
TLC-ART 101 Dosage 3A
In the scenario in which the dosage in Arm 2A produces insufficient drug levels, the dosage may be further increased by 2-fold from Arm 2A dosage (4x total dosage increase) and administered to an additional 4 participants.
If Arm 3A shows ideal PK parameters, and additional 4 participants will be enrolled in this arm, for a total study size of 16 participants
干预措施: TLC-ART (Drug)
TLC-ART 101 Initial Dosage
The arms will all receive the nanoparticle suspension of lopinavir, ritonavir, and tenofovir (TLC-ART 101). The arms are also called cohorts. The dose a participant receives will vary, depending upon the study results and the time of when they enroll in the study.
The initial dosage administered to 4 participants will contain:
lopinavir 15.6 mg, ritonavir 4.2 mg, and tenofovir 9.15 mg in 1.5mL of the formulation
If the initial dose is appropriate, an additional 8 participants will be enrolled in Arm 1, for a total study size of 12 participants.
干预措施: TLC-ART (Drug)
TLC-ART 101 Dosage 2B
In the scenario in which the dosage in Arm 1 produces excessive drug levels, the dosage will be decreased by up to 2-5 fold (2-5x descending dose) and administered to 4 participants.
If Arm 2B shows ideal PK parameters, and additional 8 participants will be enrolled in this arm, for a total study size of 16 participants.
干预措施: TLC-ART (Drug)
TLC-ART 101 Dosage 3B
In the scenario in which the dosage in Arm 2B produces excessive drug levels, the dosage may be further decreased further by up to 2-5-fold from Arm 2B dosage (4-10x dose decrease) and administered to 4 participants.
If Arm 3B shows ideal PK parameters, and additional 4 participants will be enrolled in this arm, for a total study size of 16 participants
干预措施: TLC-ART (Drug)
结局指标
主要结局
Co-primary pharmacokinetic outcome: Peak TLC-101 drug substance concentrations (Cmax) in plasma
时间窗: duration of follow-up in days for this study (anticipated to be 57 days per participant)
The maximum drug substance plasma concentrations of lopinavir, ritonavir, and tenofovir obtained following a single administration
Co-primary pharmacokinetic outcome: Time to maximum TLC-101 concentration (Tmax) of drug substances in plasma
时间窗: duration of follow-up in days for this study (anticipated to be 57 days per participant)
Time taken to reach the maximum concentrations of lopinavir, ritonavir, and tenofovir over the timecourse after a single administration
Co-primary pharmacokinetic outcome: Total TLC-101 drug substance exposure (area under the curve or AUC) in plasma
时间窗: duration of follow-up in days for this study (anticipated to be 57 days per participant)
Area under the curve of plasma concentrations of lopinavir, ritonavir, and tenofovir over the study timecourse after a single administration
Co-primary pharmacokinetic outcome: Half-life (T 1/2) of TLC-101 drug substance concentrations in plasma
时间窗: duration of follow-up in days for this study (anticipated to be 57 days per participant)
The half-life of drug substance plasma concentrations of lopinavir, ritonavir, and tenofovir after a single administration
Primary safety outcome
时间窗: 57 days of study follow-up, or if reported subsequent to study completion
Treatment emergent adverse events related to TLC-ART 101 as graded by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Corrected Version 2.1 - July 2017)
Co-primary Pharmacokinetic Outcome: Peak TLC-101 Drug Substance Concentrations (Cmax) in Plasma
时间窗: Duration of follow-up in days for this study (57 days in Cohort 1 and 64 days in Cohorts 2A/2B)
The maximum drug substance plasma concentrations of lopinavir, ritonavir, and tenofovir obtained following a single administration. Sampling for drug concentrations was performed at 15-, 30-, and 45-minutes post-dosing; at 1, 3, 5, 8, and 24 hours; and after 2, 3, 7, 10, 14, 21, 28, 35, 49, and 57 days in Cohort 1. Cohort 2A/2B members had an additional sample drawn at 64 days.
Co-primary Pharmacokinetic Outcome: Time to Maximum TLC-101 Concentration (Tmax) of Drug Substances in Plasma
时间窗: Duration of follow-up in days for this study (57 days in Cohort 1 and 64 days in Cohorts 2A/2B)
Time (hours) to reach the maximum concentrations of lopinavir, ritonavir, and tenofovir after a single administration of TLC-ART-101. Sampling for drug concentrations was performed at 15-, 30-, and 45-minutes post-dosing; at 1, 3, 5, 8, and 24 hours; and after 2, 3, 7, 10, 14, 21, 28, 35, 49, and 57 days in Cohort 1. Cohort 2A/2B members had an additional sample drawn at 64 days.
Co-primary Pharmacokinetic Outcome: Total TLC-101 Drug Substance Exposure (Area Under the Curve or AUC) in Plasma
时间窗: Duration of follow-up in days for this study (57 days in Cohort 1 and 64 days in Cohorts 2A/2B)
Area under the curve of plasma concentrations of lopinavir, ritonavir, and tenofovir over the study timecourse after a single administration. Sampling for drug concentrations was performed at 15-, 30-, and 45-minutes post-dosing; at 1, 3, 5, 8, and 24 hours; and after 2, 3, 7, 10, 14, 21, 28, 35, 49, and 57 days in Cohort 1. Cohort 2A/2B members had an additional sample drawn at 64 days.
Co-primary Pharmacokinetic Outcome: Estimated Half-life (T 1/2) of TLC-101 Drug Substance Concentrations in Plasma
时间窗: Duration of follow-up in days for this study (57 days in Cohort 1 and 64 days in Cohorts 2A/2B)
The apparent terminal half-life of drug substance plasma concentrations of lopinavir, ritonavir, and tenofovir after a single administration. Sampling for drug concentrations was performed at 15-, 30-, and 45-minutes post-dosing; at 1, 3, 5, 8, and 24 hours; and after 2, 3, 7, 10, 14, 21, 28, 35, 49, and 57 days in Cohort 1. Cohort 2A/2B members had an additional sample drawn at 64 days. The apparent terminal half-life T1/2,z was computed by regression on at least 3 detectable points if Tlast was at 57 or 64 days (end of study) or 2 detected and the first undetectable if Tlast \< 57 or 64 days; detectable timepoints following undetectable plasma levels were excluded from the T1/2 estimation.
Primary Safety Outcome
时间窗: Duration of follow-up in days for this study (57 days in Cohort 1 and 64 days in Cohorts 2A/2B)
Treatment emergent adverse events related to TLC-ART 101 as graded by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Corrected Version 2.1 - July 2017). Only related injection site reactions (ISRs) or other related systemic events are reported here. Comprehensive adverse events, related and unrelated, are reported in the Adverse Event section.
次要结局
- Secondary pharmacokinetic outcome: Comparison of TLC-101 drug substance concentrations in peripheral blood mononuclear cells compared with plasma levels(duration of follow-up in days for this study (anticipated to be 57 days per participant))
- Secondary outcome of tenofovir active drug moiety(57 days of study follow-up)
- TLC-101 concentrations in lymphoid tissues(57 days of study follow-up)
研究者
Rachel Bender Ignacio
Associate Professor, School of Medicine
University of Washington