LRAs United as a Novel Anti-HIV Strategy.

NCT03525730 | Completed Phase 1

• 1 other identifier: 2017-002837-48
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

A translational proof of concept study in humans on the primary research question whether novel anti-human immunodeficiency virus (HIV) latency strategies, including a BAF inhibitor and a histone deacetylase inhibitor, result in HIV reservoir reduction in HIV patients on antiretroviral therapy.

Conditions

HIV-1-infection

Keywords

HIV; Latency reversing agents; HDAC inhibitor; BAF inhibitor; HIV reservoir; HIV cure

Outcome Measures

Primary Outcomes (1)

• Cell associated HIV-RNA

  The change in cell associated HIV-RNA between treatment initiation (week 0) and at the end of study (week 6). The change wil be compared between the study arms.

  6 week

Secondary Outcomes (20)

• Tat/rev induced limiting dilution assay (TILDA)

  6 week

• Synergy

  6 week

• Cell associated HIV-RNA

  6 week

• Cell associated HIV-DNA

  6 week

• Plasma HIV-RNA

  6 week

Study Arms (4)

Control

NO INTERVENTION

This group receives no intervention.

Valproic acid

EXPERIMENTAL

This group receives valproic acid (enteric) for 14 days.

Drug: Valproic Acid

Pyrimethamine

EXPERIMENTAL

This group receives pyrimethamine for 14 days.

Drug: Pyrimethamine

Valproic acid and Pyrimethamine

EXPERIMENTAL

This group receives valproic acid and pyrimethamine for 14 days.

Drug: Valproic Acid; Drug: Pyrimethamine

Interventions

Valproic Acid DRUG

Valproic acid (enteric) 30mg/kg, divided over 2 doses per day, orally on day 1-14.

Also known as: Depakine

Valproic acid; Valproic acid and Pyrimethamine

Pyrimethamine DRUG

Pyrimethamine 200mg once daily (QD) orally on day 1 and 100mg on day 2-14.

Also known as: Daraprim

Pyrimethamine; Valproic acid and Pyrimethamine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1 infected patients ≥18 years.
• World Health Organization (WHO) performance status 0 or 1.
• Confirmed HIV-1 infection by 4th generation ELISA, Western Blot or PCR.
• Wild type HIV infection or polymorphisms associated with at highest low-level resistance to any class of ART according to Stanford HIV drug resistance database. Transmitted mutations and acquired mutations due to virological failure associated with resistance of at highest low-level resistance are allowed.
• On cART.
• Current plasma HIV-RNA \<50 copies/mL for at least 365 days and measured on at least 2 occasions of which at least 1 must be obtained within 365 and 90 days prior to study entry.
• Current CD4 T-cell count at study entry of ≥200 cells/mm3.
• Pre-cART HIV-RNA ≥10.000 copies/mL.

You may not qualify if:

• Previous virological failure, defined as either acquired resistance mutations (\>low level resistance) on cART or HIV-RNA \>1000 copies/mL on two consecutive measurements during cART.
• Uncontrolled hepatitis B or C co-infection. For hepatitis B: patients should be vaccinated, or on pre-exposure prophylaxis through the use of lamivudine/emtricitabine or tenofovir in their combination ART. Otherwise, standard serological testing should be available within the last 365 days for homosexual HIV positive men. For non-homosexual HIV positive persons, there should be at least one negative hepatitis B test (either by serology or PCR). For homosexual HIV positive men, a negative hepatitis C immunoglobulin G, hepatitis C (HCV) antigen, blot or HCV-RNA PCR should be available within the previous 365 days. For non-homosexual HIV positive persons, there should be at least one negative hepatitis C test (either IgG, blot or PCR) available.
• Prior exposure to any HDACi, BAFi or other known LRA.
• Prior exposure to cytotoxic myeloablative chemotherapy for hematological malignancies during cART.
• Concurrent exposure to strong interacting medication on glucuronidation.
• Exposure within 90 days prior to study entry to immunomodulators, cytokines, systemic antifungals, dexamethasone, vitamin K antagonists, anti-epileptics, antipsychotics, carbapenems, mefloquine, colestyramine, Any documented opportunistic infection related to HIV in the last 90 days.
• Inadequate blood counts, renal and hepatic function tests
• Haemoglobin \<6.5 mmol/L (males) or \<6.0 mmol/L (females), leucocytes \<2.5 x109/L, absolute neutrophil count \<1000 cells/mm3, thrombocytes \<100 x109/L, international standardized ratio \>1.6, activated partial thromboplastin time \>40 seconds.
• Estimated glomerular filtration rate \<50 mL/min (CKD-EPI),
• Alanine aminotransferase or total bilirubin \>2.5x upper limit of normal.
• All laboratory values must be obtained within 42 days prior to the baseline visit.
• Megaloblastic anemia due to folate deficiency.
• Pancreatitis in last 6 months, or chronic pancreatitis.
• Active malignancy during the past year with the exception of basal carcinoma of the skin, stage 0 cervical carcinoma, Kaposi Sarcoma treated with cART alone, or other indolent malignancies.
• Females in the reproductive age cannot participate. Males cannot participate if they refuse to abstain from sex or condom use in serodiscordant sexual contact during the study, except if their sexual partner(s) use pre-exposure prophylaxis.

Sponsors & Collaborators

• Erasmus Medical Center: lead

Study Sites (1)

Erasmus MC

Rotterdam, 3015 CN, Netherlands

Location

Related Publications (1)

• Bollen PDJ, Prins HAB, Colbers A, Velthoven-Graafland K, Rijnders BJA, de Vries-Sluijs TEMS, van Nood E, Nouwen J, Bax H, de Mendonca Melo M, Verbon A, Burger DM, Rokx C. The dolutegravir/valproic acid drug-drug interaction is primarily based on protein displacement. J Antimicrob Chemother. 2021 Apr 13;76(5):1273-1276. doi: 10.1093/jac/dkab021.

  PMID: 33544819 DERIVED

MeSH Terms

Interventions

Valproic Acid; Pyrimethamine

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Casper Rokx, MD PhD

  Erasmus Medical Center

  PRINCIPAL INVESTIGATOR

• Tokameh Mahmoudi, PhD

  Erasmus Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD PhD

Model Details: 6 week study, including 2 week intervention and 4 week post-treatment period.

Study Record Dates

• First Submitted: April 23, 2018
• First Posted: May 16, 2018
• Study Start: April 18, 2018
• Primary Completion: July 25, 2019
• Study Completion: October 1, 2020
• Last Updated: April 29, 2021

Record last verified: 2021-04

Locations

NL (1)