Clinical trial NCT05850728: First in Human Study of TLC-ART 101 (ACTU 2001)
Official title: First in Human Clinical Trial of a Next Generation, Long-acting Injectable, Combination Antiretroviral Therapy Platform
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Human Immunodeficiency Virus
Treatment
Antiretroviral Therapy
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2023-05-09
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Pharmacologically-guided adaptive design, in which the dose is increased or decreased if needed, based on results from prior participant arms
Primary purpose: TREATMENT

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
4. To compare lymphoid tissue mononuclear cell versus PBMC concentrations of the drug substances in TLC-ART 101.

Eligibility criteria: Inclusion Criteria:

* Healthy with a BMI between 18.5 to 29.9 kg/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 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

Primary outcomes:
measure: Co-primary pharmacokinetic outcome: Peak TLC-101 drug substance concentrations (Cmax) in plasma
timeFrame: duration of follow-up in days for this study (anticipated to be 57 days per participant)
measure: Co-primary pharmacokinetic outcome: Time to maximum TLC-101 concentration (Tmax) of drug substances in plasma
timeFrame: duration of follow-up in days for this study (anticipated to be 57 days per participant)
measure: Co-primary pharmacokinetic outcome: Total TLC-101 drug substance exposure (area under the curve or AUC) in plasma
timeFrame: duration of follow-up in days for this study (anticipated to be 57 days per participant)
measure: Co-primary pharmacokinetic outcome: Half-life (T 1/2) of TLC-101 drug substance concentrations in plasma
timeFrame: duration of follow-up in days for this study (anticipated to be 57 days per participant)
measure: Primary safety outcome
timeFrame: 57 days of study follow-up, or if reported subsequent to study completion
Secondary outcomes:
measure: Secondary pharmacokinetic outcome: Comparison of TLC-101 drug substance concentrations in peripheral blood mononuclear cells compared with plasma levels
timeFrame: duration of follow-up in days for this study (anticipated to be 57 days per participant)
measure: Secondary outcome of tenofovir active drug moiety
timeFrame: 57 days of study follow-up
measure: TLC-101 concentrations in lymphoid tissues
timeFrame: 57 days of study follow-up
Other outcomes:
Locations:
city: Seattle
country: United States
facility: UW Positve Research, Harborview Medical Center
state: Washington
Study officials:
affiliation: University of Washington
name: Rachel A Bender Ignacio, MD MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Freeling JP, Koehn J, Shu C, Sun J, Ho RJ. Anti-HIV drug-combination nanoparticles enhance plasma drug exposure duration as well as triple-drug combination levels in cells within lymph nodes and blood in primates. AIDS Res Hum Retroviruses. 2015 Jan;31(1):107-14. doi: 10.1089/aid.2014.0210.
citation: McConnachie LA, Kinman LM, Koehn J, Kraft JC, Lane S, Lee W, Collier AC, Ho RJY. Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection. J Pharm Sci. 2018 Jul;107(7):1787-1790. doi: 10.1016/j.xphs.2018.03.005. Epub 2018 Mar 13.
citation: Kraft JC, McConnachie LA, Koehn J, Kinman L, Collins C, Shen DD, Collier AC, Ho RJ. Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma. AIDS. 2017 Mar 27;31(6):765-770. doi: 10.1097/QAD.0000000000001405.
citation: Kraft JC, Treuting PM, Ho RJY. Indocyanine green nanoparticles undergo selective lymphatic uptake, distribution and retention and enable detailed mapping of lymph vessels, nodes and abnormalities. J Drug Target. 2018 Jun-Jul;26(5-6):494-504. doi: 10.1080/1061186X.2018.1433681. Epub 2018 Feb 12.
citation: Perazzolo S, Shireman LM, McConnachie LA, Koehn J, Kinman L, Lee W, Lane S, Collier AC, Shen DD, Ho RJY. Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101. J Pharm Sci. 2020 May;109(5):1789-1801. doi: 10.1016/j.xphs.2020.01.016. Epub 2020 Jan 29.
citation: Perazzolo S, Shireman LM, Shen DD, Ho RJY. Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture. J Pharm Sci. 2022 Feb;111(2):529-541. doi: 10.1016/j.xphs.2021.10.007. Epub 2021 Oct 19.
citation: Perazzolo S, Shen DD, Ho RJY. Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 2: Model for the Drug-combination Nanoparticles. J Pharm Sci. 2022 Mar;111(3):825-837. doi: 10.1016/j.xphs.2021.10.009. Epub 2021 Oct 19.