Ignite Creation Date:
2026-03-26 @ 3:16 PM
Ignite Modification Date:
2026-03-31 @ 12:17 AM
Study NCT ID:
NCT07379203
Status:
NOT_YET_RECRUITING
Last Update Posted:
2026-01-30
First Post:
2026-01-22
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
ValgaNciclovIR for CMV Viraemia in AdvaNced HIV diseAse
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2026-03-25'}, 'conditionBrowseModule': {'meshes': [{'id': 'D003586', 'term': 'Cytomegalovirus Infections'}], 'ancestors': [{'id': 'D006566', 'term': 'Herpesviridae Infections'}, {'id': 'D004266', 'term': 'DNA Virus Infections'}, {'id': 'D014777', 'term': 'Virus Diseases'}, {'id': 'D007239', 'term': 'Infections'}]}, 'interventionBrowseModule': {'meshes': [{'id': 'D000077562', 'term': 'Valganciclovir'}], 'ancestors': [{'id': 'D015774', 'term': 'Ganciclovir'}, {'id': 'D000212', 'term': 'Acyclovir'}, {'id': 'D006147', 'term': 'Guanine'}, {'id': 'D007042', 'term': 'Hypoxanthines'}, {'id': 'D011688', 'term': 'Purinones'}, {'id': 'D011687', 'term': 'Purines'}, {'id': 'D006574', 'term': 'Heterocyclic Compounds, 2-Ring'}, {'id': 'D000072471', 'term': 'Heterocyclic Compounds, Fused-Ring'}, {'id': 'D006571', 'term': 'Heterocyclic Compounds'}]}}, 'protocolSection': {'designModule': {'phases': ['PHASE2'], 'studyType': 'INTERVENTIONAL', 'designInfo': {'allocation': 'RANDOMIZED', 'maskingInfo': {'masking': 'QUADRUPLE', 'whoMasked': ['PARTICIPANT', 'CARE_PROVIDER', 'INVESTIGATOR', 'OUTCOMES_ASSESSOR']}, 'primaryPurpose': 'TREATMENT', 'interventionModel': 'PARALLEL'}, 'enrollmentInfo': {'type': 'ESTIMATED', 'count': 130}}, 'statusModule': {'overallStatus': 'NOT_YET_RECRUITING', 'startDateStruct': {'date': '2026-02-01', 'type': 'ESTIMATED'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2026-01', 'completionDateStruct': {'date': '2027-06-30', 'type': 'ESTIMATED'}, 'lastUpdateSubmitDate': '2026-01-22', 'studyFirstSubmitDate': '2026-01-22', 'studyFirstSubmitQcDate': '2026-01-22', 'lastUpdatePostDateStruct': {'date': '2026-01-30', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2026-01-30', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2027-02-28', 'type': 'ESTIMATED'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Adverse events of special interest plus re-hospitalisation or death up to week 8', 'timeFrame': '8 weeks post randomisation', 'description': "Adverse Events of Special Interest• Absolute neutrophil count \\< 0.4 X109/L\n\n* Haemoglobin \\< 7 g/dL\n* Platelets \\< 50 X109/L\n* Creatinine increases to \\> 1.5X participant's baseline\n* ALT \\> 5X ULN"}]}, 'oversightModule': {'isUsExport': False, 'oversightHasDmc': True, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['Cytomegalovirus', 'Advanced HIV disease', 'valganciclovir'], 'conditions': ['Cytomegalovirus (CMV) Infection']}, 'descriptionModule': {'briefSummary': 'The goal of this clinical trial is to learn if valganciclovir works to treat cytomegalovirus (CMV) infection in people with advanced HIV disease. It will also look at the safety of valganciclovir and how the body handles the drug.\n\nThe main questions this study aims to answer are:\n\nDoes valganciclovir safely lower the amount of CMV virus in the blood of people with advanced HIV disease?\n\nWhat medical problems or side effects do participants have when taking valganciclovir?\n\nResearchers will compare valganciclovir to a placebo (a look-alike tablet that does not contain any active drug) to see if valganciclovir works better than no treatment for CMV.\n\nWho can take part\n\nAdults and adolescents (15 years and older) who:\n\nAre living with HIV\n\nHave a CD4 count of 100 or less (meaning their immune system is very weak)\n\nHave CMV detected in their blood\n\nPeople who are pregnant, breastfeeding, very unwell, or have certain blood or kidney problems cannot take part.\n\nWhat will happen in the study\n\nParticipants will:\n\nBe randomly assigned (like flipping a coin) to take either valganciclovir 900 mg or a placebo once a day for 4 weeks\n\nContinue to receive standard medical care for HIV and any other infections\n\nBe followed for 12 weeks after starting the study treatment\n\nDuring this time, participants will:\n\nHave blood tests to check CMV, HIV, and general health\n\nHave regular medical check-ups (daily in hospital, then at weeks 1, 2, 3, 4, 8, and 12)\n\nBe monitored closely for side effects, such as low blood counts or kidney problems\n\nWhy this study is important\n\nEven though HIV treatment is widely available, many people still come to hospital with advanced HIV disease. In this group, about one in five people die despite starting antiretroviral therapy (ART). Reactivation of CMV is very common in these patients and has been linked to a higher risk of death.\n\nValganciclovir is a medicine that stops CMV from multiplying. If it proves to be safe and effective in this study, it could become part of routine care to help reduce deaths in people with advanced HIV disease.\n\nStudy design\n\nType: Phase 2b, double-blind, randomised, placebo-controlled trial\n\nSites: Helen Joseph Hospital (South Africa) and Mulago National Referral Hospital (Uganda)\n\nNumber of participants: 150 (130 in the main trial, 20 in a smaller sub-study)\n\nDuration: Each participant will be followed for 12 weeks; total study duration about 2 years\n\nPossible risks and benefits\n\nRisks: Valganciclovir can cause low white blood cells, anaemia, or low platelets. These effects will be checked for regularly, and treatment will be stopped if unsafe levels are found.\n\nBenefits: The study may or may not directly benefit participants. However, it could provide important information that helps improve care for people with advanced HIV disease in the future.\n\nOversight and safety\n\nThe study is being conducted by researchers in Uganda, South Africa, the UK, and the USA, and follows international Good Clinical Practice (GCP) guidelines.\n\nAn independent Data Safety and Monitoring Committee (DSMC) will regularly review safety information to protect participants.', 'detailedDescription': "Scientific Background and Rationale\n\nDespite the widespread availability of antiretroviral therapy (ART), approximately 30 percent of adults with HIV continue to present to care with AHD, defined as a CD4 count \\< 200 cells/μL or a World Health Organization (WHO) stage 3 or 4 disease. In sub-Saharan Africa, mortality among hospitalised adults with AHD remains unacceptably high, typically exceeding 20 percent within weeks of admission. There is an urgent need for interventions that reduce early mortality in this extremely vulnerable population.\n\nCytomegalovirus is a ubiquitous herpesvirus that remains latent after primary infection but can reactivate when immunity is impaired. In individuals with AHD, CMV reactivation is common: up to 50 percent of those with CD4 counts \\< 100 cells/μL have detectable CMV DNA in plasma. CMV viraemia, even without end-organ disease, is associated with increased risk of death and opportunistic infections. However, no guidelines currently recommend antiviral therapy for CMV viraemia in this setting. International HIV guidelines emphasise early ART initiation, yet early mortality remains high irrespective of ART timing.\n\nValganciclovir, the oral prodrug of ganciclovir, is widely available, affordable, and effective against CMV. It has a well-characterised safety profile, though it can cause dose-related bone-marrow suppression. Observational and mechanistic studies suggest that CMV may contribute directly and indirectly to immune dysfunction, inflammation, and mortality among people with advanced HIV disease. If pre-emptive suppression of CMV replication reduces viraemia and improves outcomes, it could represent a feasible strategy to lower mortality in low-resource settings.\n\nThe NIRVANA trial will therefore assess whether valganciclovir is a safe and effective therapy for CMV viraemia in AHD. Pharmacokinetic data in this population are scarce; this study will also describe drug exposure and relationships with viral suppression and toxicity. The findings will inform the design of a larger Phase 3 trial powered to evaluate survival benefit.\n\nStudy Objectives and Hypothesis\n\nPrimary Objective:\n\nTo determine whether valganciclovir safely reduces CMV viral load compared with placebo among hospitalised adults with advanced HIV disease and CMV viraemia.\n\nSecondary Objectives:\n\nTo assess the effect of valganciclovir on all-cause mortality and re-hospitalisation up to 12 weeks.\n\nTo characterise the pharmacokinetics of valganciclovir in this population. To evaluate tolerability and adverse-event rates. To explore immune responses, including cytokine profiles and interferon-gamma release to CMV antigen.\n\nTo describe HIV viral suppression at week 12 stratified by ART status. To examine emergence of ganciclovir resistance mutations at week 4.\n\nHypothesis:\n\nValganciclovir 900 mg once daily for 4 weeks, started at hospital admission, will significantly reduce CMV viral load compared with placebo and will be a safe therapeutic option for AHD-associated CMV viraemia.\n\nStudy Design\n\nThis is a multicentre, double-blind, parallel-group, randomised, placebo-controlled Phase 2b trial with a nested open-label pharmacokinetic sub-study. Participants meeting eligibility criteria will be randomised 1:1 to receive valganciclovir or placebo, stratified by site and baseline CMV viral load (\\> 1000 IU/mL). Randomisation will be implemented through a central, web-based REDCap system using computer-generated blocks to maintain allocation concealment. Study tablets for both arms are identical in appearance, packaging, and dosing schedule. Participants and all site staff involved in patient management and outcome assessment will remain blinded to allocation.\n\nAn additional non-randomised sub-study of 20 participants receiving valganciclovir will provide intensive pharmacokinetic sampling before the main randomised trial begins.\n\nThe study duration per participant is 12 weeks, including 4 weeks of study treatment and 8 weeks of post-treatment follow-up. The overall trial is expected to last approximately 24 months.\n\nIntervention and Comparator\n\nExperimental Arm:\n\nValganciclovir 900 mg once daily, taken orally for 28 days, beginning on the day of randomisation. Participants with creatinine clearance 40-60 mL/min will receive 450 mg daily.\n\nControl Arm:\n\nMatching placebo tablets, identical in size, colour, and packaging, administered once daily for 28 days.\n\nAll participants will continue to receive \\*\\*standard of care (SOC)\\*\\* for advanced HIV disease according to national or local guidelines, which may include:\n\nDiagnosis and treatment of opportunistic infections Antiretroviral therapy (ART) initiation or re-initiation Tuberculosis preventive therapy Cotrimoxazole prophylaxis Cryptococcal antigen screening and pre-emptive antifungal therapy if positive\n\nART initiation will follow WHO and national recommendations, typically within 2-3 weeks of hospital admission, except for participants with cryptococcal or tuberculous meningitis, who will defer ART for 4-8 weeks.\n\nStudy Population and Setting\n\nStudy Sites:\n\nHelen Joseph Hospital, Johannesburg, South Africa Mulago National Referral Hospital, Kampala, Uganda\n\nTarget Population:\n\nHospitalised adults and adolescents (≥ 15 years) with advanced HIV disease and detectable CMV viraemia.\n\nInclusion Criteria:\n\nAge ≥ 15 years Confirmed HIV infection CD4 count ≤ 100 cells/µL Plasma CMV viral load \\> 500 IU/mL Ability to provide informed consent (or via legal surrogate if incapacitated)\n\nExclusion Criteria:\n\nClinical suspicion or diagnosis of CMV end-organ disease (including CMV retinitis) Pregnancy or breastfeeding Haematologic contraindications (absolute neutrophil count \\< 1.0 × 10⁹/L, haemoglobin \\< 8 g/dL, platelets \\< 100 × 10⁹/L) Estimated creatinine clearance \\< 40 mL/min or alanine aminotransferase \\> 3× upper limit of normal Current high-dose acyclovir use or concurrent myelosuppressive therapy (e.g., amphotericin B deoxycholate, linezolid) Allergy or prior adverse reaction to valganciclovir Inability to swallow tablets or expected inability to complete follow-up Moribund condition likely to result in death within 48 hours\n\nStudy Procedures and Follow-up\n\nScreening and Consent:\n\nAll hospital admissions will be screened for HIV and CD4 count per routine care. Eligible individuals with AHD will be approached for study participation. Informed consent will be obtained in the participant's preferred language. For those lacking decision-making capacity, proxy consent from a legally authorised representative will be permitted, with re-consent sought if the participant regains capacity.\n\nBaseline Assessments:\n\nDemographics, clinical history, physical examination, ART status, concomitant medications, and baseline laboratory tests (haematology, renal and liver function, HIV viral load, CD4 count, CMV viral load) will be recorded in electronic case-report forms (eCRFs).\n\nRandomisation and Treatment:\n\nEligible participants will be randomised via REDCap to one of the two treatment arms. Study medication will be dispensed within 24 hours of randomisation, and dosing will be supervised by nursing or study staff during hospitalisation.\n\nFollow-up Visits:\n\nParticipants will be followed daily while in hospital, then weekly to week 4, and at weeks 8 and 12 post-randomisation. At each visit, clinical status, medication adherence, vital signs, and laboratory parameters will be reviewed. CMV viral load will be measured at baseline, days 14 and 28, and weeks 8 and 12. Blood counts, creatinine, and liver enzymes will be checked at multiple time points.\n\nSafety Monitoring:\n\nAdverse events of special interest (AESIs) include severe neutropenia, anaemia, thrombocytopenia, renal dysfunction, and hepatotoxicity. Participants experiencing grade ≥ 3 events will be promptly evaluated; study medication will be discontinued if no alternative cause is identified.\n\nPharmacokinetic (PK) Sampling:\n\nSparse PK samples will be collected at 2-3 hours post-dose on days 4, 7, 14, and 28 from all randomised participants. Intensive PK sampling will be performed in the sub-study cohort. Plasma samples will be analysed at the Infectious Diseases Institute laboratory in Uganda.\n\nImmunology Sub-study:\n\nBlood samples at baseline and selected follow-up points will be used for cytokine and interferon-gamma analyses to characterise immune response to CMV antigen.\n\nWithdrawal and Replacement Participants discontinuing study drug will continue scheduled follow-up unless consent is withdrawn. Data collected prior to withdrawal will be retained; participants withdrawing before 4 weeks may be replaced.\n\nOutcome Measures\n\nPrimary Outcome:\n\nComposite of safety events (adverse events of special interest, re-hospitalisation, or death) up to 8 weeks after randomisation.\n\nSecondary Outcomes:\n\nSafety: same composite endpoint up to 12 weeks. Hospital length of stay post-randomisation. Serious adverse events through week 12. Mortality: survival time and all-cause mortality at 4 and 12 weeks.\n\nEfficacy:\n\nMedian reduction in CMV viral load (log₁₀ IU/mL) from baseline to day 28 and week 12.\n\nProportion of participants with undetectable CMV viral load at weeks 2, 4, 8, and 12.\n\nTolerability: proportion of participants discontinuing study medication early. Resistance: presence of UL97 kinase or UL54 DNA polymerase gene mutations at week 4.\n\nHIV treatment response: proportion achieving HIV RNA \\< 50 copies/mL at 12 weeks.\n\nPharmacokinetic parameters of valganciclovir. Immunologic markers of cytokine response.\n\nStatistical Considerations\n\nThe study is powered to detect a 20 percent difference in the primary efficacy endpoint-median reduction in CMV viral load-between treatment arms with 90 percent power and a two-sided α of 0.05. Allowing for attrition, 130 randomised participants (65 per arm) will be enrolled.\n\nAnalyses will follow the intention-to-treat principle. Primary efficacy comparisons will use the geometric mean ratio of log₁₀ CMV viral load with 95 percent confidence intervals. Safety analyses will summarise adverse events by frequency and grade with absolute risk differences between arms. Missing data will be addressed using multiple imputation when appropriate. PK data will be analysed using both non-compartmental and mixed-effects modelling to explore exposure-response relationships.\n\nSafety Monitoring and Reporting\n\nAll adverse events, serious adverse events (SAEs), and AESIs will be recorded in eCRFs. SAEs deemed related to study intervention and unexpected for the patient population will be reported promptly to the relevant institutional review boards (IRBs) and national regulatory authorities according to local requirements.\n\nAn independent Data Safety and Monitoring Committee (DSMC) will review unblinded safety and efficacy data periodically. The DSMC will include independent clinicians from Uganda and South Africa, the trial statistician, and a chairperson. Recommendations from the DSMC will guide the Trial Management Group on continuation or modification of the study.\n\nData Management\n\nData will be collected electronically using a secure REDCap platform with built-in range and consistency checks. Paper worksheets may be used temporarily if electronic capture is unavailable. The Clinical HIV Research Unit in Johannesburg will maintain the de-identified database on a secure server with restricted access. Quality-control procedures include regular data audits, query resolution, and compliance with Good Clinical Data Management Practice. Participant confidentiality will be preserved using coded identifiers; no personally identifying data will leave the site.\n\nEthical and Regulatory Oversight\n\nThe trial will be conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice (GCP), and all applicable national and institutional regulations. Ethical approval will be obtained from the University of the Witwatersrand Human Research Ethics Committee, the Uganda National Council for Science and Technology, and the London School of Hygiene and Tropical Medicine Research Ethics Committee.\n\nWritten informed consent will be obtained from all participants or their authorised representatives. Consent procedures will be conducted in participants' preferred languages, with accommodations for literacy and comprehension. All participants will be informed that participation is voluntary and that withdrawal will not affect their medical care.\n\nParticipant confidentiality will be maintained through coded data, secure storage, and controlled access. Clinical information will be released only to authorised entities such as the sponsor, IRBs, and regulatory authorities for monitoring and auditing purposes.\n\nStudy Governance\n\nThe Wits Health Consortium serves as the trial sponsor. Principal Investigators include Dr Mohammed Rassool (South Africa) and Dr Laura Nsangi (Uganda), with oversight by an international team of co-investigators from the London School of Hygiene and Tropical Medicine, the Infectious Diseases Institute (Uganda), St George's University of London, and the University of Minnesota.\n\nA Trial Management Group (TMG) composed of investigators and the study statistician will meet regularly to monitor trial progress, review data, and approve protocol amendments and publications. An independent Trial Advisory Committee (TAC) of senior external academics will review progress approximately every six months and advise the TMG.\n\nAll investigators have completed Human Subjects Protection Training and have declared no conflicts of interest. Personnel are indemnified by their employing institutions. Funding is provided by the United Kingdom Medical Research Council.\n\nExpected Impact\n\nThe NIRVANA trial addresses a major gap in the management of advanced HIV disease in resource-limited settings. CMV viraemia is common and strongly associated with early mortality, yet there is no evidence-based therapeutic strategy to address it. By establishing whether valganciclovir safely reduces CMV viral load and by defining its pharmacokinetics and tolerability in this population, NIRVANA will provide the essential foundation for a definitive Phase 3 trial powered to detect mortality benefit.\n\nIf successful, the findings could lead to a low-cost, implementable intervention to reduce deaths among people with advanced HIV disease worldwide."}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['CHILD', 'ADULT', 'OLDER_ADULT'], 'minimumAge': '15 Years', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\nConfirmed HIV infection CD4 count ≤100 cells/mm³ Expected to survive at least 48 hours CMV viral load \\>500 international units (IU) / mL in blood. Provision of informed consent\n\nExclusion Criteria:\n\nConfirmed or high level of clinical suspicion for CMV end organ disease as determined by the treating team CMV retinitis confirmed by retinal phography Pregnancy or breastfeeding Contraindication to valganciclovir (absolute neutrophil count \\< 1.0 X109/L, haemoglobin \\< 8 g/dL, platelets \\< 100 X109/L) Allergy or prior adverse reaction to valganciclovir Expected to be unable to complete follow up Moribund - treating team considers patient is likely to die within next 48 hours Estimated creatinine clearance \\< 40 mL/min ALT \\> 3X ULN Receipt of high dose acyclovir as standard of care Unable to swallow whole tablets Concurrent administration of highly myelosuppressive drug, e.g. amphotericin B deoxycolate and linezolid\n\n\\-'}, 'identificationModule': {'nctId': 'NCT07379203', 'acronym': 'NIRVANA', 'briefTitle': 'ValgaNciclovIR for CMV Viraemia in AdvaNced HIV diseAse', 'organization': {'class': 'OTHER', 'fullName': 'Wits Health Consortium (Pty) Ltd'}, 'officialTitle': 'A Phase 2b Randomised Placebo Controlled Trial of Valganciclovir for Cytomegalovirus Viraemia in Adults and Adolescents With Advanced HIV Disease', 'orgStudyIdInfo': {'id': 'NIRVANA'}}, 'armsInterventionsModule': {'armGroups': [{'type': 'EXPERIMENTAL', 'label': 'Valganciclovir', 'description': 'Valganciclovir 900mg daily for 28 days', 'interventionNames': ['Drug: Valganciclovir']}, {'type': 'PLACEBO_COMPARATOR', 'label': 'Arm B', 'interventionNames': ['Drug: Placebo']}], 'interventions': [{'name': 'Valganciclovir', 'type': 'DRUG', 'description': 'Valganciclovir', 'armGroupLabels': ['Valganciclovir']}, {'name': 'Placebo', 'type': 'DRUG', 'description': 'Placebo', 'armGroupLabels': ['Arm B']}]}, 'ipdSharingStatementModule': {'infoTypes': ['STUDY_PROTOCOL', 'SAP', 'ICF', 'CSR', 'ANALYTIC_CODE'], 'timeFrame': 'August 2027 to July 2030', 'ipdSharing': 'YES', 'description': 'All', 'accessCriteria': 'Reputable researchers'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Wits Health Consortium (Pty) Ltd', 'class': 'OTHER'}, 'collaborators': [{'name': 'Infectious Diseases Institute, Uganda', 'class': 'OTHER'}, {'name': 'London School of Hygiene and Tropical Medicine', 'class': 'OTHER'}, {'name': "St George's, University of London", 'class': 'OTHER'}], 'responsibleParty': {'type': 'SPONSOR'}}}}