First in Human Study of TLC-ART 101 (ACTU 2001)

Human Immunodeficiency Virus Clinical Trial

Official title:

First in Human Clinical Trial of a Next Generation, Long-acting Injectable, Combination Antiretroviral Therapy Platform

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05850728
• Other study ID #: STUDY00007490
• Secondary ID: U01AI148055
• Status: Recruiting
• Phase: Phase 1
• Start date: April 1, 2023
• Est. completion date: December 1, 2025

Study information

• Verified date: May 2023
• Source: University of Washington
• Contact: UW Positive Research
• Phone: 206-773-7129
• Email: positiveresearch[@]uw.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 16
• Est. completion date: December 1, 2025
• Est. primary completion date: October 25, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Antiretroviral Therapy
• HIV Infections
• Human Immunodeficiency Virus
• Treatment

Intervention

Drug:
• TLC-ART
TLC-ART 101 contains lopinavir, ritonavir, and tenofovir in a combination nanoparticle suspension

Locations

Country	Name	City	State
United States	UW Positve Research, Harborview Medical Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
University of Washington	National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

References & Publications (7)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Co-primary pharmacokinetic outcome: Peak TLC-101 drug substance concentrations (Cmax) in plasma	The maximum drug substance plasma concentrations of lopinavir, ritonavir, and tenofovir obtained following a single administration	duration of follow-up in days for this study (anticipated to be 57 days per participant)
Primary	Co-primary pharmacokinetic outcome: Time to maximum TLC-101 concentration (Tmax) of drug substances in plasma	Time taken to reach the maximum concentrations of lopinavir, ritonavir, and tenofovir over the timecourse after a single administration	duration of follow-up in days for this study (anticipated to be 57 days per participant)
Primary	Co-primary pharmacokinetic outcome: Total TLC-101 drug substance exposure (area under the curve or AUC) in plasma	Area under the curve of plasma concentrations of lopinavir, ritonavir, and tenofovir over the study timecourse after a single administration	duration of follow-up in days for this study (anticipated to be 57 days per participant)
Primary	Co-primary pharmacokinetic outcome: Half-life (T 1/2) of TLC-101 drug substance concentrations in plasma	The half-life of drug substance plasma concentrations of lopinavir, ritonavir, and tenofovir after a single administration	duration of follow-up in days for this study (anticipated to be 57 days per participant)
Primary	Primary safety outcome	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)	57 days of study follow-up, or if reported subsequent to study completion
Secondary	Secondary pharmacokinetic outcome: Comparison of TLC-101 drug substance concentrations in peripheral blood mononuclear cells compared with plasma levels	To characterize the concentrations of the three drug substances in human peripheral blood mononuclear cells from the same blood samples as plasma analyses	duration of follow-up in days for this study (anticipated to be 57 days per participant)
Secondary	Secondary outcome of tenofovir active drug moiety	To characterize the concentrations of intracellular tenofovir-diphosphate (the active moiety of TFV) in peripheral blood mononuclear cells	57 days of study follow-up
Secondary	TLC-101 concentrations in lymphoid tissues	To compare lymphoid tissue mononuclear cell versus peripheral blood mononuclear cell concentrations of the drug substances in TLC-ART 101	57 days of study follow-up

External Links

•   TLC ART Program homepage
•   UW Positive Research website