Clinical Trial to Evaluate the Effects of Letermovir Prophylaxis on T-cell Immune Activation in Participants With Treated HIV-1 Infection (PROACTIV)

October 1, 2024 updated by: University College, London

Pilot, Randomized, Open-Label, Non-Active Comparator Controlled Clinical Trial to Evaluate the Effects of Letermovir Prophylaxis on T-cell Immune Activation in Participants With Treated HIV-1 Infection

People living with HIV (PLWH), even with an undetectable viral load (VL) on antiretroviral treatment (ART), develop health conditions, such as heart disease, diabetes, various cancers, and conditions that can affect the brain, more commonly than the general population.

These conditions occur earlier in PLWH compared to HIV negative individuals with similar lifestyles. Ongoing inflammation in the body despite antiretroviral therapy is thought to be contributing to the development of these conditions that can affect healthy ageing in PLWH.

Cytomegalovirus (CMV) is a very common infection in PLWH and is an important driver of inflammation in the body that can affect the function of the immune immune cells in the body (defense system) causing unwanted activation and damage of the gut making it more leaky. A drug with potent activity against CMV called valganciclovir has previously shown to reduce this potentially damaging inflammation in the body.

In this study, the investigators want to investigate if a new drug called Letermovir, in combination with HIV treatment, will prevent CMV from replicating (multiplying), and thereby reduce inflammation in the body. Letermovir has received approval to prevent CMV from multiplying in patients receiving bone marrow transplants. It has been shown to have a more favourable side-effect profile compared to other available drugs and is predicted to interact little with anti-HIV drugs.

The aim of this study is to find out if the letermovir is safe and effective in reducing CMV related immune activation and inflammation PLWH. These findings will be used to help us design larger studies to identify individuals who would benefit most from this treatment to prevent the development of health conditions that can affect their quality of life.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

36

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Is HIV-1 antibody positive with a plasma HIV-1 RNA ≤50 copies/mL for greater than 12 months
  • ≥50 years of age of any gender
  • Females of childbearing potential who agree to avoid pregnancy for the duration of the trial and follow methods of contraception as detailed in section 7.1
  • Has a nadir CD4 of ≤200 cells/mm3 prior to screening
  • Has been on antiretroviral therapy for ≥ 6 months
  • Has documented CMV IgG seropositivity within one year of trial screening
  • Has an undetectable (≤168 international units/mL) CMV Deoxyribonucleic acid (DNA) within 14 days prior to randomisation
  • Laboratory parameters are not clinically significant as determined by the investigator
  • The participant (or legally acceptable representative, if applicable) has provided written informed consent for the trial and Future Biomedical Research

Exclusion Criteria:

  • Is HIV-1 antibody positive with a plasma HIV-1 RNA ≤50 copies/mL for greater than 12 months
  • ≥50 years of age of any gender
  • Females of childbearing potential who agree to avoid pregnancy for the duration of the trial and follow methods of contraception as detailed in section 7.1
  • Has a nadir CD4 of ≤200 cells/mm3 prior to screening
  • Has been on antiretroviral therapy for ≥ 6 months
  • Has documented CMV IgG seropositivity within one year of trial screening
  • Has an undetectable (≤168 international units/mL) CMV Deoxyribonucleic acid (DNA) within 14 days prior to randomisation
  • Laboratory parameters are not clinically significant as determined by the investigator
  • The participant (or legally acceptable representative, if applicable) has provided written informed consent for the trial and Future Biomedical Research

Main Exclusion criteria:

  • Has a history of ulcerative colitis or Crohn's disease or active colitis within 6 months prior to randomisation
  • Has a history of CMV end-organ disease within 6 months prior to randomisation
  • Has significant hypersensitivity or other contraindication to any of the components of the trial drug as described in the SmPC
  • Has a detectable HCV RNA or hepatitis B surface antigen (HBsAg) within 90 days prior to randomisation
  • Has a history of malignancy ≤5 years prior to signing informed consent
  • Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through 90 days after the last dose of trial therapy
  • Has received within 7 days prior to screening any of the following: ganciclovir; valganciclovir; foscarnet; acyclovir (≥ 3200 mg PO per day or ≥25 mg/kg IV per day); valaciclovir (≥3000 mg PO per day) or famciclovir (≥1500 mg PO per day).
  • Has used systemic immunosuppressive therapy or immune modulators within 30 days prior to treatment in this trial or is anticipated to need them during the trial

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Letermovir
Letermovir 480mg PO once daily
Drug: Letermovir
Letermovir 480mg PO once daily
No Intervention: Standard of Care
Standard of care - No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in activation in global CD8 T cells in response to letermovir.
Time Frame: Baseline, weeks 4, 8, 12, 16 and 24

To assess the effect of CMV replication inhibition with letermovir on activated (HLADR+CD38+) CD8 T cell percentage using flow cytometry analysis at specified time frames.

Measurement: Measured by flow cytometric analysis.
Baseline, weeks 4, 8, 12, 16 and 24

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quantitative analysis of T cell subsets/detailed phenotypic profile will be performed as part of the exploratory analysis
Time Frame: Baseline, weeks 12 and 24
Quantitative analysis of T cell subsets/detailed phenotypic profile will be performed as part of the exploratory analysis
Baseline, weeks 12 and 24
Characterization of NK profile and function in response to Letermovir
Time Frame: Baseline, weeks 4, 8, 12, 16 and 24

To assess the effect of CMV replication inhibition with letermovir on NK cell phenotype and cytokine production (IFN-g/TNF) via flow cytometry.

Measurement: Measured by flow cytometric analysis.
Baseline, weeks 4, 8, 12, 16 and 24
High resolution characterization of cells that fall between the innate and adaptive responses
Time Frame: Baseline, weeks 12 and 24

To assess the effect of CMV replication inhibition with letermovir on NK-like cells (CD56+CD3+) at specified time points.

Measurement: Measured by flow cytometric analysis.
Baseline, weeks 12 and 24
Determine the extent of CMV and HIV replication in the gut of HIV-positive individuals and how impacted by intervention
Time Frame: Baseline, weeks 12 and 24
To assess CMV DNA and HIV RNA in gut biopsies and the effect of intervention. Measurement: Measured by quantitative PCR analysis and in situ hybridisation.
Baseline, weeks 12 and 24
Assessment of integrity of the intestinal barrier and how impacted by intervention
Time Frame: Baseline, weeks 12 and 24

To assess the influence of CMV replication inhibition with letermovir on intestinal barrier integrity in gut biopsies.

Measurement: Measured by immunohistochemistry of biopsy samples for zonula occludens-1 (ZO-1).
Baseline, weeks 12 and 24
Assessment of markers of systemic inflammation and how impacted by intervention
Time Frame: Baseline, weeks 4, 8, 12, 16 and 24

To assess the influence of CMV replication inhibition with letermovir on inflammatory cytokines/chemokines (IL-1, IL-6, IP10, TNF-a), sTNFRII, microbial products/activation (LPS, sCD14, CRP), intestinal damage marker (iFABP), vascular dysfunction markers (sICAM-1, sVCAM-1) in the blood of people with HIV.

Measurement: Measured by ELISA.
Baseline, weeks 4, 8, 12, 16 and 24

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Higher resolution analysis of specific responses to peptide level and how impacted by intervention
Time Frame: Baseline, weeks 4, 8, 12, 16 and 24

To assess the influence of letermovir on CMV and HIV-specific T cell responses to peptide stimulation via multiparameter intracellular cytokine staining. Expression of cytokines, such as IFN-γ, TNF and IL-2, and activation markers will be measured via flow cytometry in conjunction with established phenotypic and memory markers.

Measurement: Measured by flow cytometric analysis
Baseline, weeks 4, 8, 12, 16 and 24
Standard molecular analyses of proviral and HIV transcript quantitation, both surrogate markers of persistent infection
Time Frame: Baseline, weeks 4, 8, 12, 16 and 24
To assess the influence of CMV replication inhibition with letermovir on HIV DNA and Cell-associated RNA Measure: Measured by quantitative real-time PCR and droplet digital PCR (ddPCR).
Baseline, weeks 4, 8, 12, 16 and 24

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University College, London

Collaborators

Royal Free Hospital NHS Foundation Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

October 1, 2024

Primary Completion (Estimated)

March 1, 2026

Study Completion (Estimated)

March 1, 2026

Study Registration Dates

First Submitted

August 14, 2024

First Submitted That Met QC Criteria

October 1, 2024

First Posted (Actual)

October 4, 2024

Study Record Updates

Last Update Posted (Actual)

October 4, 2024

Last Update Submitted That Met QC Criteria

October 1, 2024

Last Verified

October 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 125096
  • 2020-000288-22 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on HIV

Clinical Trials on Letermovir

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Sri Lanka

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe