A Phase 2b Randomised Placebo Controlled Trial of Valganciclovir for Cytomegalovirus Viraemia in Adults and Adolescents With Advanced HIV Disease
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 130
- 主要终点
- Adverse events of special interest plus re-hospitalisation or death up to week 8
研究概览
简要总结
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.
The main questions this study aims to answer are:
Does valganciclovir safely lower the amount of CMV virus in the blood of people with advanced HIV disease?
What medical problems or side effects do participants have when taking valganciclovir?
Researchers 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.
Who can take part
Adults and adolescents (15 years and older) who:
Are living with HIV
Have a CD4 count of 100 or less (meaning their immune system is very weak)
Have CMV detected in their blood
People who are pregnant, breastfeeding, very unwell, or have certain blood or kidney problems cannot take part.
What will happen in the study
Participants will:
Be randomly assigned (like flipping a coin) to take either valganciclovir 900 mg or a placebo once a day for 4 weeks
Continue to receive standard medical care for HIV and any other infections
Be followed for 12 weeks after starting the study treatment
During this time, participants will:
Have blood tests to check CMV, HIV, and general health
Have regular medical check-ups (daily in hospital, then at weeks 1, 2, 3, 4, 8, and 12)
Be monitored closely for side effects, such as low blood counts or kidney problems
Why this study is important
Even 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.
Valganciclovir 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.
Study design
Type: Phase 2b, double-blind, randomised, placebo-controlled trial
Sites: Helen Joseph Hospital (South Africa) and Mulago National Referral Hospital (Uganda)
Number of participants: 150 (130 in the main trial, 20 in a smaller sub-study)
Duration: Each participant will be followed for 12 weeks; total study duration about 2 years
Possible risks and benefits
Risks: 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.
Benefits: 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.
Oversight and safety
The study is being conducted by researchers in Uganda, South Africa, the UK, and the USA, and follows international Good Clinical Practice (GCP) guidelines.
An independent Data Safety and Monitoring Committee (DSMC) will regularly review safety information to protect participants.
详细描述
Scientific Background and Rationale
Despite 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.
Cytomegalovirus 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.
Valganciclovir, 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.
The 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 15 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed 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
排除标准
- •Confirmed 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
研究组 & 干预措施
Valganciclovir
Valganciclovir 900mg daily for 28 days
干预措施: Valganciclovir (Drug)
Arm B
干预措施: Placebo (Drug)
结局指标
主要结局
Adverse events of special interest plus re-hospitalisation or death up to week 8
时间窗: 8 weeks post randomisation
Adverse Events of Special Interest• Absolute neutrophil count \< 0.4 X109/L * Haemoglobin \< 7 g/dL * Platelets \< 50 X109/L * Creatinine increases to \> 1.5X participant's baseline * ALT \> 5X ULN
次要结局
未报告次要终点