Clinical trial NCT03915366: Empirical Treatment Against Cytomegalovirus and Tuberculosis in HIV-infected Infants With Severe Pneumonia
Official title: Empirical Treatment Against Cytomegalovirus and Tuberculosis in HIV-infected Infants With Severe Pneumonia: a Multicenter, Open-label Randomized Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Pneumonia
HIV/AIDS
Tuberculosis
Cytomegalovirus Infections
Lead sponsor: Hospital Universitario 12 de Octubre
Sponsor class: OTHER
Collaborators: name: University Hospital, Bordeaux
name: Institut National de la Santé Et de la Recherche Médicale, France
name: PENTA Foundation
name: Centre Hospitalier Cocody
name: Malawi-Liverpool-Wellcome Trust Clinical Research Programme
name: Eduardo Mondlane University
name: Centro de Investigação em Saúde de Manhiça
name: Stichting Katholieke Universiteit
name: Barcelona Institute for Global Health
name: University of Lincoln
name: Makerere University
name: University Teaching Hospital, Lusaka, Zambia
name: University of Zimbabwe
name: Kamuzu Central Hospital
name: Servicio Madrileño de Salud, Madrid, Spain
First posted: 2019-04-16
Enrollment: 563
Sex: ALL
Minimum age (years): 28
Maximum age (years): 365
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: This trial will evaluate whether empirical treatment against cytomegalovirus and tuberculosis improves survival of HIV-infected infants with severe pneumonia.

Detailed description: Pneumonia is the main cause of death in Human Immunodeficiency Virus (HIV)-infected children. A significant number of undiagnosed or poorly treated HIV-infected children present to health services with severe pneumonia. World Health Organization (WHO) guidelines to treat severe pneumonia in HIV-infected infants include empirical treatment against common bacteria plus Pneumocystis jirovecii. Although this approach has contributed to reducing overall case fatality rates, mortality in this particularly vulnerable group remains unacceptably high. Autopsy studies in Africa have shown that cytomegalovirus (CMV) infection and tuberculosis (TB) are important underdiagnosed and undertreated causes of deaths. Our objective is to evaluate whether empirical treatment against cytomegalovirus and tuberculosis improves survival of HIV-infected infants with severe pneumonia. A randomized factorial clinical trial will be conducted in six sub-Saharan African countries to evaluate the safety and efficacy of empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants aged 28 days to 365 days admitted to hospital with severe pneumonia. The primary outcome is mortality. All HIV-infected infants will receive standard of care (SoC) pneumonia treatment, including antibiotics, cotrimoxazole, and prednisolone. A group of patients will receive SoC, another group will receive valganciclovir plus SoC, another group will receive tuberculosis treatment plus SoC, and another group will receive valganciclovir, tuberculosis treatment, and SoC.

Eligibility criteria: Inclusion Criteria:

1. Age 28 days to 365 days of age
2. Pneumonia defined as chest indrawing or fast breathing for age, for infants 28 to 60 days of age ≥60 breaths per minute and for infants 61 to 365 days of age, ≥50 breaths per minute.
3. Current hospitalization due to pneumonia with criteria for parenteral antibiotics (1 or more criteria)

   1. Chest indrawing with HIV infection
   2. No improvement with oral treatment.
   3. One or more danger signs according to WHO 5,44,45

      * Central cyanosis or saturation of O2 \<90%
      * Severe respiratory distress, e.g. grunting or very severe chest indrawing
      * Signs of pneumonia with a general danger sign:
      * Unable to drink or breastfeed
      * Persisting vomiting
      * Convulsions in the last 24 hours
      * Lethargic or unconscious
      * Stridor while calm
      * Severe malnutrition
4. HIV-confirmed infection (with at least one molecular method: DNA polymerase chain reaction (PCR) or RNA PCR/viral load).
5. Informed consent obtained

Exclusion Criteria:

1. Clinical TB (pulmonary or extrapulmonary) diagnosis, defined as the necessity of TB-T prescribed by a physician, at the moment of randomization
2. Known bacteriologically confirmed TB case (at least one biological specimen positive by culture or Xpert MTB/RIF) at the moment of randomization
3. Patient previously treated for TB or currently on treatment for TB
4. Documented evidence of close TB exposure (household contact of a patient with documented TB during the lifetime of the child, or currently receiving TB-T)
5. Pure wheezers defined as a clear clinical improvement after a bronchodilator test (give a challenge of rapid-acting inhaled bronchodilator for up to three times 15-20 minutes apart. Count the breaths and look for chest indrawing again, and then re-classify)
6. Active malignancies
7. Systemic immunosuppressive medications. Steroids will be considered to be immunosuppressing only if \>2 mg/kg of prednisone or equivalent during \>15 days
8. Evidence of condition other than HIV and pneumonia which precludes, to the judgment of the clinical researcher, enrollment in this trial due to risk for the patient. In case of doubt, the Trial Management Team will be contacted to assess eligibility
9. Less than 2.5 kg of weight
10. Hb \<6 g/dL in the screening blood test or in a test done in the last 48 hours. Transfusion is permitted to achieve \>6 g/dL if the patient's state allows it. In case a transfusion is administered, the patient can be enrolled
11. Neutropenia \<500 /mm3 in the screening blood test or in a test done in the last 48 hours. Repeating the test is allowed to check eligibility

Primary outcomes:
measure: Mortality
timeFrame: 1 year
Secondary outcomes:
measure: Days with oxygen therapy
timeFrame: 60 days
measure: Days of hospitalization
timeFrame: 1 year
measure: Serious Adverse Events
timeFrame: 1 year
measure: Adverse Reactions
timeFrame: 1 year
measure: Notable Adverse Events
timeFrame: 1 year
measure: Immune-reconstitution inflammatory syndrome
timeFrame: 6 months
measure: Baseline cytomegalovirus prevalence
timeFrame: 30 days
measure: Baseline tuberculosis prevalence
timeFrame: 60 days
measure: Tuberculosis incidence
timeFrame: 1 year
measure: Deaths attributable to tuberculosis
timeFrame: 1 year
measure: CMV prevalence in died participants
timeFrame: 1 year
measure: CMV Molecular response to treatment
timeFrame: 1 year
measure: TB-lipoarabinomannan (LAM) sensitivity and specificity
timeFrame: 1 year
measure: Quality-adjusted life expectancy
timeFrame: 1 year
measure: Per-patient cost
timeFrame: 1 year
Other outcomes:
Locations:
city: Abidjan
country: Côte D'Ivoire
facility: Programme PACCI. Centre Hospitalier Cocody.
city: Bourdeaux
country: France
facility: Université de Bourdeaux
city: Toulouse
country: France
facility: INSERM
city: Padova
country: Italy
facility: PENTA Foundation
city: Blantyre
country: Malawi
facility: Malawi Liverpool Welcome Trust. Queen Elizabeth Central Hospital College of Medicine
city: Manhiça
country: Mozambique
facility: Cemtro de Investigaçao em Saúde da Manhiça
city: Maputo
country: Mozambique
facility: Hospital Central Maputo
city: Nimega
country: Netherlands
facility: Stichting Katholieke Universiteit Radboudumc
city: Madrid
country: Spain
facility: Fundación para la Investigación Biomédica del Hospital 12 de Octubre
city: Kampala
country: Uganda
facility: Makerere University - Mulago Hospital
city: Lincoln
country: United Kingdom
facility: University of Lincoln
city: Lusaka
country: Zambia
facility: Lusaka Teaching Hospital
city: Harare
country: Zimbabwe
facility: University of Zimbabwe Clinical Research Centre
Study officials:
affiliation: Fundación para la Investigación Biomédica del Hospital 12 de Octubre
name: Cinta Moraleda, MD, PhD
role: STUDY_CHAIR
References:
citation: Rojo P, Moraleda C, Tagarro A, Dominguez-Rodriguez S, Castillo LM, Tato LMP, Lopez AS, Manukyan L, Marcy O, Leroy V, Nardone A, Burger D, Bassat Q, Bates M, Moh R, Iroh Tam PY, Mvalo T, Magallhaes J, Buck WC, Sacarlal J, Musiime V, Chabala C, Mujuru HA. Empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants with severe pneumonia: study protocol for a multicenter, open-label randomized controlled clinical trial. Trials. 2022 Jun 27;23(1):531. doi: 10.1186/s13063-022-06203-1.