Optimizing Reversal of HIV Latency With Combination Therapy

NCT06240520 | Unknown Phase 1

• 1 other identifier: 2024-511192-15-00
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 3

Brief Summary

The ORBIT trial is part of a worldwide search for a functional cure of HIV. One such cure strategy aims to reverse HIV in the reservoir from latency by increasing cell-associated HIV-RNA, which will lead to increased antigen presentation, trigger immune recognition, and facilitate the elimination of reservoir cells (so-called 'shock and kill' approach to HIV cure). Participants of the trial are adults with HIV with undetectable viral load that are able to give informed consent to participate in the trial, in total 49 patients will be recruited. The investigational medical compounds in this trial are panobinostat, lenalidomide and pyrimethamine. These are all licensed drugs for other conditions. Participants of this trial will receive a single dose of the IMPs, either as monotherapy or as combination therapy. Sampling will be performed before, during and after medical treatment to evaluate latency reversal, reservoir reduction and safety endpoints. Patients will be recruited from the Erasmus MC, Amsterdam university Medical Center and the University Medical Center Utrecht.

Conditions

Hiv

Keywords

HIV Cure; Shock and kill; Latency reversal; Combination therapy

Outcome Measures

Primary Outcomes (2)

• Cell-associated HIV RNA

  Fold change in cell-associated HIV RNA

  1 day

• Adverse events

  The number and severity of clinical and biochemical adverse events considered by the investigator to be related to any of the investigational drugs

  14 days

Secondary Outcomes (1)

• HIV reservoir

  120 days

Study Arms (7)

control

NO INTERVENTION

panobinostat

EXPERIMENTAL

Drug: Panobinostat 20 MG Oral Capsule

lenalidomide

EXPERIMENTAL

Drug: Lenalidomide 25 MG Oral Capsule

pyrimethamine

EXPERIMENTAL

Drug: Pyrimethamine 200mg Oral Tablet

panobinostat + lenalidomide

EXPERIMENTAL

Drug: Panobinostat 20 MG Oral Capsule; Drug: Lenalidomide 25 MG Oral Capsule

panobinostat + pyrimethamine

EXPERIMENTAL

Drug: Panobinostat 20 MG Oral Capsule; Drug: Pyrimethamine 200mg Oral Tablet

lenalidomide + pyrimethamine

EXPERIMENTAL

Drug: Pyrimethamine 200mg Oral Tablet; Drug: Lenalidomide 25 MG Oral Capsule

Interventions

Panobinostat 20 MG Oral Capsule DRUG

Panobinostat 20mg will be administered once orally

panobinostat; panobinostat + lenalidomide; panobinostat + pyrimethamine

Pyrimethamine 200mg Oral Tablet DRUG

Pyrimethamine 200mg will be administered once orally

lenalidomide + pyrimethamine; panobinostat + pyrimethamine; pyrimethamine

Lenalidomide 25 MG Oral Capsule DRUG

Lenalidomide 25mg will be administered once orally

lenalidomide; lenalidomide + pyrimethamine; panobinostat + lenalidomide

Eligibility Criteria

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

You may qualify if:

• Documented HIV-1 infection by 4th generation ELISA, Western Blot or PCR.
• ≥ 18 years old.
• World Health Organization (WHO) performance status 0 or 1.
• Current plasma HIV RNA \<50 copies/ml measured on the last 2 occasions, with measurements being at least 3 months apart.
• Uninterrupted prescribed ART for a minimum of two consecutive years.
• Considered \>95% adherent to ART by treating physician.
• Current blood CD4+T-cell count of ≥200 cells/mm3
• No clinical signs of cellular immunodeficiency or AIDS.
• Pre-ART plasma HIV RNA ≥1000 copies/mL.
• Confirmed HIV subtype B. People with a high likelihood of subtype B can participate if they live in a HIV subtype B endemic region with HIV acquired there and in whom no HIV sequencing is available or can be done on stored samples.
• People should be considered capable mentally and somatically by their treating physician to understand the informed consent procedure and undergo the study treatment.

You may not qualify if:

• A potential subject who meets any of the following criteria will be excluded from participation in this study:
• Previous exposure to any of the studied LRAs in the last year
• Acute or chronic co-infection with hepatitis B and/or C by the presence of hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA in blood.
• Co-medication with clinically significant interactions with LRA (see chapter 15.h for list)
• Comorbidities affected by LRA compounds, such as but not limited to: known Glucose-6-phospate-dehydrogenase (G6PD) deficiency with anaemia, untreated haemolysis of any cause or hereditary thrombophilia not currently treated by anticoagulation.
• Prolonged Qtc time \>480ms at screening, as measured by electrocardiogram (ECG).
• Patients of childbearing potential unless double contraceptive measures are taken. Non-childbearing is defined by one of the following criteria: amenorrhoea for ≥ 1 year, premature ovarian failure, assigned male at birth, or having undergone previous bilateral salpingo-oophorectomy, or hysterectomy
• Sexual active patients unwilling to abstain from sex unless willing to use condom protection during and until 1 week after administration of study medication.
• Active malignancy during the past year with the exception of basal carcinoma of the skin, stage 0 cervical carcinoma, Kaposi's sarcoma treated with ARTalone or other indolent malignancies.
• Registered allergies for any of the investigational medical products
• Any lab abnormalities at screening as listed below:
• Moderate kidney impairment, defined as eGFR \<50 mL/min
• Moderate hepatic impairment, defined as bilirubin \> 3 x upper limit of normal (ULN) or ALT \> 3x ULN
• Inadequate blood counts, defined as: Haemoglobin \<6.5 mmol/L (males) or \<6.0 mmol/L (females), absolute neutrophil count \<1000 cells/mm3, thrombocytes \<100 x109/L, international standardized ratio \>1.6, activated partial thromboplastin time \>40 seconds, serum sodium \<130 mmol/L, serum potassium \<3.0 mmol/L, serum phosphate \<0.5 mmol/L, serum calcium \<1.9 mmol/L, serum magnesium \<0.5 mmol/L.

Sponsors & Collaborators

• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Erasmus Medical Center: lead
• AIDSfonds: collaborator

Study Sites (3)

Erasmus Medical Centre

Rotterdam, South Holland, 3015 GD, Netherlands

Location

Amsterdam University Medical Center

Amsterdam, Netherlands

Location

University Medical Center Utrecht

Utrecht, Netherlands

Location

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome; Shock

Interventions

Panobinostat; Pyrimethamine; Tablets; Lenalidomide

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; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Dosage Forms; Pharmaceutical Preparations; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Piperidones; Piperidines; Isoindoles

Central Study Contacts

Casper Rokx, MD PhD

CONTACT

+31618069137; c.rokx@erasmusmc.nl

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: associate professor, internist and infectious diseases specialist

Model Details: Open label randomized controlled trial.

Study Record Dates

• First Submitted: January 26, 2024
• First Posted: February 5, 2024
• Study Start: April 1, 2024
• Primary Completion: May 1, 2025
• Study Completion: October 1, 2025
• Last Updated: February 5, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP, ANALYTIC CODE
• Time Frame: Data will be available after publication of primary results. Data will kept in storage for 15 years
• Access Criteria: Receiving facility has data privacy protection meeting EU GDPR standards

Locations

NL (3)