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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT03915366
Other study ID # 19/096
Secondary ID 2019-001749-42ED
Status Active, not recruiting
Phase Phase 2/Phase 3
First received
Last updated
Start date March 1, 2020
Est. completion date July 31, 2025

Study information

Verified date February 2024
Source Hospital Universitario 12 de Octubre
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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


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.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 563
Est. completion date July 31, 2025
Est. primary completion date January 31, 2025
Accepts healthy volunteers No
Gender All
Age group 28 Days to 365 Days
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Valganciclovir Oral Solution [Valcyte]
Treatment for CMV
Tuberculostatic Agents
Treatment for tuberculosis

Locations

Country Name City State
Côte D'Ivoire Programme PACCI. Centre Hospitalier Cocody. Abidjan
France Université de Bourdeaux Bourdeaux
France INSERM Toulouse
Italy PENTA Foundation Padova
Malawi Malawi Liverpool Welcome Trust. Queen Elizabeth Central Hospital College of Medicine Blantyre
Mozambique Cemtro de Investigaçao em Saúde da Manhiça Manhiça
Mozambique Hospital Central Maputo Maputo
Netherlands Stichting Katholieke Universiteit Radboudumc Nimega
Spain Fundación para la Investigación Biomédica del Hospital 12 de Octubre Madrid
Uganda Makerere University - Mulago Hospital Kampala
United Kingdom University of Lincoln Lincoln
Zambia Lusaka Teaching Hospital Lusaka
Zimbabwe University of Zimbabwe Clinical Research Centre Harare

Sponsors (16)

Lead Sponsor Collaborator
Hospital Universitario 12 de Octubre Barcelona Institute for Global Health, Centre Hospitalier Cocody, Centro de Investigação em Saúde de Manhiça, Eduardo Mondlane University, Institut National de la Santé Et de la Recherche Médicale, France, Kamuzu Central Hospital, Makerere University, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, PENTA Foundation, Servicio Madrileño de Salud, Madrid, Spain, Stichting Katholieke Universiteit, University Hospital, Bordeaux, University of Lincoln, University of Zimbabwe, University Teaching Hospital, Lusaka, Zambia

Countries where clinical trial is conducted

Côte D'Ivoire,  France,  Italy,  Malawi,  Mozambique,  Netherlands,  Spain,  Uganda,  United Kingdom,  Zambia,  Zimbabwe, 

Outcome

Type Measure Description Time frame Safety issue
Primary Mortality The primary endpoint of the study is all-cause mortality, focusing on the short term (up to 15-days) and long-term (up to 1-year) mortality. Mortality will be calculated using all-cause mortality after the admission over all the trial time. 1 year
Secondary Days with oxygen therapy 1. Duration of oxygen requirements (in days, from the first requirement until definitive withdrawal, being day 1 the first day of oxygen requirement). 60 days
Secondary Days of hospitalization 2. Cumulative days of hospitalization from discharge to day +365 after enrollment 1 year
Secondary Serious Adverse Events Serious Adverse Events (SAEs), this is, grade 3 and 4 AEs. 1 year
Secondary Adverse Reactions Adverse Reactions (AR) 1 year
Secondary Notable Adverse Events Adverse events (AEs) requiring stop of investigational medical product (IMP), all AEs relevant for risk/benefit ratio, including infections, liver toxicity, neurological and optic toxicity, renal, hematological and any AE grade 1, 2, 3 or 4 that the investigator estimates to be relevant 1 year
Secondary Immune-reconstitution inflammatory syndrome Incidence of TB-related immune-reconstitution inflammatory syndrome (IRIS) 6 months
Secondary Baseline cytomegalovirus prevalence Baseline prevalence of CMV infection and CMV-attributable pneumonia (based in a CMV viral load threshold) in recruited HIV-infected infants with severe pneumonia 30 days
Secondary Baseline tuberculosis prevalence Baseline prevalence of microbiological confirmed and unconfirmed TB (according to Graham criteria, Updated Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children 2015) in recruited HIV-infected patients with severe pneumonia 60 days
Secondary Tuberculosis incidence New confirmed and unconfirmed TB cases according to Graham criteria during 1-year of follow-up among patients without TB-T 1 year
Secondary Deaths attributable to tuberculosis Proportion of confirmed and unconfirmed TB, according to Graham criteria, in died children 1 year
Secondary CMV prevalence in died participants Proportion of CMV infection in died children 1 year
Secondary CMV Molecular response to treatment Reduction of quantitative CMV viral load in blood and saliva in infants treated with valganciclovir from enrollment to day +15 1 year
Secondary TB-lipoarabinomannan (LAM) sensitivity and specificity To assess the diagnostic accuracy (sensitivity and specificity) of TB-LAM for the diagnosis of confirmed TB (reference: positive Xpert Mycobacterium tuberculosis (MTB)/RIF Ultra in feces and/or NPA) 1 year
Secondary Quality-adjusted life expectancy Economic evaluation for quality-adjusted life expectancy 1 year
Secondary Per-patient cost Economic evaluation of the treatments (per-patient cost) 1 year
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