Empirical Treatment Against Cytomegalovirus and Tuberculosis in HIV-infected Infants With Severe Pneumonia

Tuberculosis Clinical Trial

— EMPIRICAL  

Official title:

Empirical Treatment Against Cytomegalovirus and Tuberculosis in HIV-infected Infants With Severe Pneumonia: a Multicenter, Open-label Randomized Controlled Clinical Trial

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
• 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
• 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

Related Conditions & MeSH terms

• Cytomegalovirus Infections
• HIV/AIDS
• Pneumonia
• Tuberculosis

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