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

NCT05850728 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: STUDY00007490U01AI148055
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Human Immunodeficiency Virus; Treatment; Antiretroviral Therapy

Outcome Measures

Primary Outcomes (5)

• 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)

• 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)

• 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)

• 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 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 Outcomes (3)

• 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

Study Arms (5)

TLC-ART 101 Initial Dosage

EXPERIMENTAL

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.

Drug: TLC-ART

TLC-ART 101 Dosage 2A

EXPERIMENTAL

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.

Drug: TLC-ART

TLC-ART 101 Dosage 2B

EXPERIMENTAL

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.

Drug: TLC-ART

TLC-ART 101 Dosage 3A

EXPERIMENTAL

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

Drug: TLC-ART

TLC-ART 101 Dosage 3B

EXPERIMENTAL

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

Drug: TLC-ART

Interventions

TLC-ART DRUG

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

TLC-ART 101 Dosage 2A; TLC-ART 101 Dosage 2B; TLC-ART 101 Dosage 3A; TLC-ART 101 Dosage 3B; TLC-ART 101 Initial Dosage

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Washington: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

UW Positve Research, Harborview Medical Center

Seattle, Washington, 98104, United States

Location

Related 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.

  PMID: 25402233 BACKGROUND

• 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.

  PMID: 29548975 BACKGROUND

• 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.

  PMID: 28099191 BACKGROUND

• 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.

  PMID: 29388438 BACKGROUND

• 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.

  PMID: 32006525 BACKGROUND

• 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.

  PMID: 34673093 BACKGROUND

• 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.

  PMID: 34673094 BACKGROUND

Related Links

• TLC ART Program homepage
• UW Positive Research website

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• Rachel A Bender Ignacio, MD MPH

  University of Washington

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, School of Medicine

Model Details: Pharmacologically-guided adaptive design, in which the dose is increased or decreased if needed, based on results from prior participant arms

Study Record Dates

• First Submitted: March 23, 2023
• First Posted: May 9, 2023
• Study Start: April 1, 2023
• Primary Completion: June 28, 2024
• Study Completion: June 28, 2024
• Last Updated: December 11, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: 2025-2026

Locations

US (1)