Antiretroviral Therapy, Human Immunodeficiency Virus, Treatment
Conditions
Brief summary
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.
Detailed description
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: 1. 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. 2. 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: 1. To characterize the pharmacokinetics of the drug substances in human peripheral blood mononuclear cells (PBMCs) 2. To characterize the concentrations of intracellular TFV-diphosphate (the active moiety of TFV) in PBMCs 3. 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 4. To compare lymphoid tissue mononuclear cell versus PBMC concentrations of the drug substances in TLC-ART 101.
Interventions
DRUGTLC-ART
TLC-ART 101 contains lopinavir, ritonavir, and tenofovir in a combination nanoparticle suspension
Sponsors
University of Washington
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Pharmacologically-guided adaptive design, in which the dose is increased or decreased if needed, based on results from prior participant arms
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* 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.
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Co-primary Pharmacokinetic Outcome: Peak TLC-101 Drug Substance Concentrations (Cmax) in Plasma | 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 | 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 | 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 | 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 | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRachel A Bender Ignacio, MD MPH
University of Washington
Participant flow
Recruitment details
Approximately 240 healthy volunteers without HIV or hepatitis B or C made contact with the study and/or were pre-screened for this study. 20 persons signed informed consent 8 persons were ineligible to enter the study due to either meeting exclusionary criteria or enrollment of planned cohort size.
Pre-assignment details
Enrollment into the cohorts was sequential in this adaptive dose escalation de-escalation study. Therefore only one cohort was enrolling at any time and the cohort assignment was known prior to an individual enrollment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 38.8 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 3 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 5 | 0 / 3 |
| other Total, other adverse events | 4 / 4 | 5 / 5 | 3 / 3 |
| serious Total, serious adverse events | 0 / 4 | 1 / 5 | 0 / 3 |
Outcome results
None listed