A Study to Evaluate the Anti-inflammatory Effects of Letermovir (Prevymis) in Adults With Human Immunodeficiency Virus (HIV)-1 and Asymptomatic Cytomegalovirus (CMV) Who Are on Suppressive Antiretroviral Therapy, Plus Its Effect on Chronic Inflammation, HIV Persistence and Other Clinical Outcomes.

NCT04840199 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: A538338597
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 15

Brief Summary

This was an open-label, controlled study, conducted at US sites to evaluate the anti-inflammatory effectiveness of the study drug letermovir in adults with HIV and asymptomatic cytomegalovirus (CMV) who were on antiretroviral therapy (ART)-mediated suppression. Participants were randomly assigned to receive either letermovir once daily or no anti-CMV treatment, for 48 weeks. The primary hypothesis of this study was that letermovir would cause a greater reduction in plasma soluble receptor for tumor necrosis factor type II (sTNFRII) levels than no anti-CMV treatment at weeks 46/48.

Conditions

HIV Infections; Cytomegalovirus; CMV

Outcome Measures

Primary Outcomes (1)

• Change (Absolute) in sTNFRII

  The absolute change in sTNFRII from Baseline (average of study entry and treatment initiation visits) to Week 46/48 (average of Week 46 and Week 48), or the latest result in the treatment phase. Linear regression was used to estimate the mean change. The covariates were study arm and the gender and CD4 stratification factors.

  Measured at Baseline and Weeks 46 and 48

Secondary Outcomes (7)

• Occurrence of Grade ≥3 AEs or Confirmed HIV-1 Virologic Failure

  Measured from study entry through Week 48

• Rate of Change in Odds of Oral CMV DNA Detection

  Measured at Baseline and Weeks 8, 46, 48, 52 and 60

• Rate of Change in Odds of Genital CMV DNA Detection

  Measured at Baseline and Weeks 8, 46, 48, 52 and 60

• Rate of Change in Odds of Rectal CMV DNA Detection

  Measured at Baseline and Weeks 8, 48 and 60

• Rate of Change in Odds of Plasma CMV DNA Detection

  Measured at Baseline and Weeks 8, 46, 48, 52 and 60

Study Arms (2)

Letermovir

EXPERIMENTAL

Participants randomized to letermovir for 48 weeks followed by 12 weeks off letermovir

Drug: Letermovir Oral Tablet

No anti-CMV treatment

NO INTERVENTION

Participants randomized to no study intervention for 60 weeks

Interventions

Letermovir Oral Tablet DRUG

480 mg administered orally once daily with or without food

Also known as: Prevymis

Letermovir

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
• NOTE: The term "licensed" refers to a US FDA-approved kit, which is required for all IND studies.
• WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. More information on this criterion can be found in the protocol.
• Currently on continuous combination ART (antiretroviral therapy) for ≥48 weeks prior to study entry. This is defined as continuous ART for the 48-week period prior to study entry with no ART interruption longer than 7 consecutive days.
• Screening plasma HIV-1 RNA \<40 copies/mL within 90 days prior to study entry using a FDA-approved assay with a quantification limit of 40 copies/mL or lower performed by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent.
• HIV-1 RNA level \<40 copies/mL for at least 48 weeks prior to study entry performed by any US laboratory that has a CLIA certification or its equivalent.
• NOTE: Single determinations that are between the assay quantification limit and 500 copies/mL (i.e., "blips") are allowed as long as the preceding and subsequent determinations are below the level of quantification. The screening value may serve as the subsequent undetectable value following a blip.
• CD4⁺/CD8⁺ cell count obtained within 90 days prior to study entry at any US laboratory that has a CLIA certification or its equivalent.
• Positive CMV IgG serology, at any time prior to study entry using a FDA-approved assay at any US laboratory that has a CLIA certification or its equivalent.
• NOTE: If a prior positive CMV IgG serology test is confirmed in the medical record, a repeat CMV IgG test is not required at screening.
• The following laboratory values obtained within 90 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent:
• Hemoglobin \>9.0 g/dL
• Platelet count \>75,000/mm³
• Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and alkaline phosphatase ≤3 x ULN (upper limit of normal)
• Total bilirubin ≤2.5 x ULN

You may not qualify if:

• Change in the ART regimen within 12 weeks prior to study entry or intended modification of ART during the study.
• NOTE: Modifications in the dosage or frequency (i.e. twice a day \[bid\] to once a day \[qd\]) of individual antiretroviral (ARV) drugs during the 12 weeks prior to study entry are permitted. In addition, the change in formulation (e.g. from standard formulation to fixed-dose combination) is allowed within 12 weeks prior to study entry. A within class single drug substitution (e.g. switch from atazanavir to darunavir, or tenofovir disoproxil fumarate to tenofovir alafenamide) is allowed within 12 weeks prior to study entry. A switch to any other nucleoside reverse transcriptase inhibitor (NRTI) from abacavir (or vice versa) is not permissible. No other changes in ART within the 12 weeks prior to study entry are permitted.
• Use of any of the following ARV drugs in current regimen: efavirenz, nevirapine, etravirine, lopinavir/ritonavir, and once-daily dosing of raltegravir (bid dosing of raltegravir is acceptable).
• Two or more HIV-1 RNA determinations \>200 copies/mL within 48 weeks prior to study entry.
• Any febrile illness (\>101°F) within 30 days prior to study entry.
• Use of drugs with anti-CMV activity within 90 days prior to study entry, with the exception of standard dose valacyclovir and acyclovir. See the protocol for more information.
• Immunosuppressive or immunomodulatory drug use, with the exception of topical, inhaled, and intranasal corticosteroids within 90 days prior to study entry. See the protocol for more information.
• Concomitant use of prohibited medications. See the protocol for more information.
• Persons who are breastfeeding, pregnant or planning to become pregnant during the study.
• Participating in a study where co-enrollment is not allowed.
• Receipt of any vaccination within 14 days prior to study entry.
• History of cardiomyopathy or congenital heart disease or evidence of advanced conduction system disease including second degree heart block Mobitz type II, third degree heart block, AV dissociation or ECG findings that may be suggestive of predisposition to arrhythmia (i.e. delta wave).
• Known allergy/sensitivity or any hypersensitivity to components of the study drug or its formulation.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Acute or serious illness requiring systemic treatment and/or hospitalization within 90 days prior to study entry.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (15)

UCSD Antiviral Research Center CRS (Site 701)

San Diego, California, 92103, United States

Location

UCSF HIV/AIDS CRS (Site 801)

San Francisco, California, 94110, United States

Location

University of Colorado Hospital CRS

Aurora, Colorado, 80045, United States

Location

Northwestern University CRS

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital CRS (MGH CRS)

Boston, Massachusetts, 02114, United States

Location

Washington University Therapeutics (WT) CRS

St Louis, Missouri, 63110, United States

Location

Weill Cornell Chelsea CRS (7804)

New York, New York, 10010, United States

Location

Weill Cornell Uptown CRS (7803)

New York, New York, 10065, United States

Location

University of Rochester Adult HIV Therapeutic Strategies Network CRS

Rochester, New York, 14642, United States

Location

Cincinnati Clinical Research Site

Cincinnati, Ohio, 45267, United States

Location

Case Clinical Research Site

Cleveland, Ohio, 44106, United States

Location

Penn Therapeutics, CRS

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh CRS

Pittsburgh, Pennsylvania, 15213, United States

Location

Vanderbilt Therapeutics (VT) CRS

Nashville, Tennessee, 37204, United States

Location

University of Washington Positive Research CRS

Seattle, Washington, 98104-9929, United States

Location

Related Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

HIV Infections

Interventions

letermovir

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

Limitations include the open-label design and the premature study closure leading to a small sample size and differential time in the treatment phase between the two arms.

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company

ACTGCT.gov@fstrf.org

(301) 628-3348

Study Officials

• Peter Hunt, MD

  University of California, San Francisco, HIV/AIDS CRS

  STUDY CHAIR

• Sara Gianella, MD

  University of California, San Diego, AntiViral Research Center CRS

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 7, 2021
• First Posted: April 9, 2021
• Study Start: April 19, 2022
• Primary Completion: November 30, 2023
• Study Completion: November 30, 2023
• Last Updated: March 4, 2025
• Results First Posted: March 4, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
• Access Criteria: * With whom? * Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group. * For what types of analyses? * To achieve aims in the proposal approved by the AIDS Clinical Trials Group. * By what mechanism with data be made available? * Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://submit.mis.s-3.net/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

Locations

US (15)