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

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

Detailed Description
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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.

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

Conditions
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Pneumonia, HIV/AIDS, Tuberculosis, Cytomegalovirus Infections

Intervention / Treatment
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* Drug: Valganciclovir Oral Solution [Valcyte]
* Drug: Tuberculostatic Agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 28 days to 365 days of age 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. Current hospitalization due to pneumonia with criteria for parenteral antibiotics (1 or more criteria) Chest indrawing with HIV infection No improvement with oral treatment. 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 HIV-confirmed infection (with at least one molecular method: DNA polymerase chain reaction (PCR) or RNA PCR/viral load). Informed consent obtained Exclusion Criteria: Clinical TB (pulmonary or extrapulmonary) diagnosis, defined as the necessity of TB-T prescribed by a physician, at the moment of randomization Known bacteriologically confirmed TB case (at least one biological specimen positive by culture or Xpert MTB/RIF) at the moment of randomization Patient previously treated for TB or currently on treatment for TB 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) 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) Active malignancies Systemic immunosuppressive medications. Steroids will be considered to be immunosuppressing only if >2 mg/kg of prednisone or equivalent during >15 days 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 Less than 2.5 kg of weight 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 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

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 365 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard of Care (SoC)<br>Standard treatment for severe pneumonia and pneumonia in HIV-infected infants: Ceftriaxone 80 mg/k/day or Ampicillin plus Gentamicin ampicillin 50 mg/kg, or benzylpenicillin 50,000 unit/kg im/iv every six hours plus Gentamicin 7.5 mg/kg/im or iv once a day Cotrimoxazole trimethoprim (TMP) 8mg/kg/dose + sulfamethoxazole (SMX) 40mg/kg/dose three times daily Prednisolone 2mg/kg during 7 days, plus 1mg/kg other 7 days, plus 0.5 mg/kg for 7 days | |
| Experimental: Valganciclovir plus SoC<br>Treatment for cytomegalovirus (CMV) Valganciclovir (powder for suspension, 50 mg/mL) oral, 16 mg/kg/12 hours for 15 days, and Standard or Care as described in Control Group | Drug: Valganciclovir Oral Solution [Valcyte]<br>* Treatment for CMV<br>* Other names: Treatment for CMV;|
| Experimental: Tuberculosis Treatment plus SoC<br>Treatment for tuberculosis Fixed-dose dispersible tablet of rifampicin, isoniazid, pyrazinamide (75/50/150 mg) Fixed-dose dispersible tablet of rifampicin/isoniazid (75/50 mg) Ethambutol 100 mg dispersible tablet Plus Standard of Care described in the Control Group Doses of tuberculosis treatment: Isoniazid 10 mg/kg (range 7-15 mg/kg)/day; maximum dose 300 mg/day for 6 months. Rifampicin 15 mg/kg (range 10-20 mg/kg)/day; maximum dose 600 mg/day for 6 months. Pyrazinamide 35 mg/kg (range 30-40 mg/kg)/day for 2 months. Ethambutol 20 mg/kg (range 15-25 mg/kg)/day for 2 months. | Drug: Tuberculostatic Agents<br>* Treatment for tuberculosis<br>* Other names: Treatment for TB;|
| Experimental: Tuberculosis Treatment plus Valganciclovir plus SoC<br>Treatment for CMV and for tuberculosis. Fixed-dose dispersible tablet of rifampicin, isoniazid, pyrazinamide (75/50/150 mg) Fixed-dose dispersible tablet of rifampicin/isoniazid (75/50 mg) Ethambutol 100 mg dispersible tablet Valganciclovir (powder for suspension, 50 mg/mL) oral, 16 mg/kg/12 hours for 15 days, Plus Standard of Care described in the Control Group Doses of tuberculosis treatment: Isoniazid 10 mg/kg (range 7-15 mg/kg)/day; maximum dose 300 mg/day for 6 months. Rifampicin 15 mg/kg (range 10-20 mg/kg)/day; maximum dose 600 mg/day for 6 months. Pyrazinamide 35 mg/kg (range 30-40 mg/kg)/day for 2 months. Ethambutol 20 mg/kg (range 15-25 mg/kg)/day for 2 months. | Drug: Valganciclovir Oral Solution [Valcyte]<br>* Treatment for CMV<br>* Other names: Treatment for CMV;Drug: Tuberculostatic Agents<br>* Treatment for tuberculosis<br>* Other names: Treatment for TB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Days of hospitalization | 2. Cumulative days of hospitalization from discharge to day +365 after enrollment | 1 year | 
| Serious Adverse Events | Serious Adverse Events (SAEs), this is, grade 3 and 4 AEs. | 1 year | 
| Adverse Reactions | Adverse Reactions (AR) | 1 year | 
| 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 | 
| Immune-reconstitution inflammatory syndrome | Incidence of TB-related immune-reconstitution inflammatory syndrome (IRIS) | 6 months | 
| 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 | 
| 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 | 
| 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 | 
| Deaths attributable to tuberculosis | Proportion of confirmed and unconfirmed TB, according to Graham criteria, in died children | 1 year | 
| CMV prevalence in died participants | Proportion of CMV infection in died children | 1 year | 
| 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 | 
| 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 | 
| Quality-adjusted life expectancy | Economic evaluation for quality-adjusted life expectancy | 1 year | 
| Per-patient cost | Economic evaluation of the treatments (per-patient cost) | 1 year |