Optimizing reversal of HIV latency with combination therapy (pyrimethamine, lenalidomide, panobinostat)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

7 Jul 2024 → 30 Apr 2026

Decision date (initial)

2024-05-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-511192-15-00

ClinicalTrials.gov

NCT06240520

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Safety, Efficacy

To longitudinally assess dual latency-reversing agent combination treatments on HIV reservoir reactivation and tolerability in people with HIV.

Secondary objectives 1

1. 1. To longitudinally assess LRA monotherapy on HIV reservoir reactivation, their synergy in LRA combinations, and their tolerability in people with HIV. 2. To assess the effect of the investigational drugs on the HIV reservoir. 3. To assess the immune activity and anti-HIV immune responses. 4. To evaluate the pharmacokinetics of the investigational drugs. 5. To assess the correlation of ex vivo LRA responses on in vivo latency reversal. 6. To assess the correlation of clinical variables with latency reversal and tolerability of the investigational drugs. 7. To evaluate the induction of low-level viremia following exposure to the investigational drugs. 8. To evaluate the presence of counterfactuals and their correlation with participation in HIV cure studies

Conditions and MedDRA coding

HIV-1

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. • 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.

Exclusion criteria 1

1. • 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, def ined as eGFR <50 mL/min. In PLWH on dolutegravir- or bictegravir-based ART regimens, cystatin C-based eGFR can be used, as creatinine-based eGFR is underestimat ed due to drug interf erence with tubular creatinine excretion which leads to eGFR underestimation. • 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The fold change in cell-associated HIV-RNA at time points 6 and 24 hours as compared to baseline (time point 0 hour)
2. The number and severity of clinical and biochemical adverse events considered by the investigator to be related to any of the investigational drugs.

Secondary endpoints 8

1. 1. The fold change in cell-associated HIV-RNA on LRA monotherapy components compared to combination LRA treatments.
2. 2. The change in the HIV reservoir size and genetic composition from baseline to the end of the study.
3. 3. The level of immune activation, and phenotype and functionality of the cellular immunity as compared from baseline to end of treatment.
4. 4. The plasma concentrations of the investigational drugs during treatment.
5. 5. Correlations of ex vivo and in-vivo cell associated HIV-RNA responses to the investigational drugs.
6. 6. The association between clinical variables and the primary endpoints.
7. 7. The number and frequency of measurable (above limit of detection or above limit of quantitation) plasma HIV-RNA during treatment.
8. 8. Number of upward and downward counterfactuals

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Sponsor organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

Casper Rokx

Public contact point

Organisation

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Contact name

Casper Rokx

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications