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

NCT03915366 | Completed Phase 2 DMC

• 5 other identifiers: 19/0962019-001749-42EDCTP RIA2017MC-2013EMPIRICALU1111-1231-4736PACTR201904797961340
• Study Type: interventional
• Target: 563
• Locations: 11 countries
• Sites: 13

Brief Summary

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

Conditions

Pneumonia; HIV/AIDS; Tuberculosis; Cytomegalovirus Infections

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• Days with oxygen therapy

  60 days

• Days of hospitalization

  1 year

• Serious Adverse Events

  1 year

• Adverse Reactions

  1 year

• Notable Adverse Events

  1 year

Study Arms (4)

Standard of Care (SoC)

NO INTERVENTION

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

Valganciclovir plus SoC

EXPERIMENTAL

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]

Tuberculosis Treatment plus SoC

EXPERIMENTAL

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

Tuberculosis Treatment plus Valganciclovir plus SoC

EXPERIMENTAL

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]; Drug: Tuberculostatic Agents

Interventions

Valganciclovir Oral Solution [Valcyte] DRUG

Treatment for CMV

Also known as: Treatment for CMV

Tuberculosis Treatment plus Valganciclovir plus SoC; Valganciclovir plus SoC

Tuberculostatic Agents DRUG

Treatment for tuberculosis

Also known as: Treatment for TB

Tuberculosis Treatment plus SoC; Tuberculosis Treatment plus Valganciclovir plus SoC

Eligibility Criteria

• Age: 28 Days - 365 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (13)

Programme PACCI. Centre Hospitalier Cocody.

Abidjan, Côte d’Ivoire

Location

Université de Bourdeaux

Bourdeaux, France

Location

INSERM

Toulouse, France

Location

PENTA Foundation

Padua, Italy

Location

Malawi Liverpool Welcome Trust. Queen Elizabeth Central Hospital College of Medicine

Blantyre, Malawi

Location

Cemtro de Investigaçao em Saúde da Manhiça

Manhiça, Mozambique

Location

Hospital Central Maputo

Maputo, Mozambique

Location

Stichting Katholieke Universiteit Radboudumc

Nijmegen, Netherlands

Location

Fundación para la Investigación Biomédica del Hospital 12 de Octubre

Madrid, 28041, Spain

Location

Makerere University - Mulago Hospital

Kampala, Uganda

Location

University of Lincoln

Lincoln, United Kingdom

Location

Lusaka Teaching Hospital

Lusaka, Zambia

Location

University of Zimbabwe Clinical Research Centre

Harare, Zimbabwe

Location

Related Publications (3)

• Dominguez-Rodriguez S, Lora D, Tagarro A, Moraleda C, Ballesteros A, Madrid L, Manukyan L, Marcy O, Leroy V, Nardone A, Burger D, Bassat Q, Bates M, Moh R, Tam PI, Mvalo T, Magallhaes J, Buck WC, Sacarlal J, Mussime V, Chabala C, Mujuru HA, Rojo P; EMPIRICAL group. Statistical analysis plan for the "empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants with severe pneumonia" clinical trial. Trials. 2025 Apr 30;26(1):144. doi: 10.1186/s13063-025-08841-7.

  PMID: 40307889 DERIVED

• Jacobs TG, Mumbiro V, Chitsamatanga M, Namuziya N, Passanduca A, Dominguez-Rodriguez S, Tagarro A, Nathoo KJ, Nduna B, Ballesteros A, Madrid L, Mujuru HA, Chabala C, Buck WC, Rojo P, Burger DM, Moraleda C, Colbers A; EMPIRICAL Clinical Trial Group; EMPIRICAL Clinical Trial Group. Brief Report: Suboptimal Lopinavir Exposure in Infants on Rifampicin Treatment Receiving Double-dosed or Semisuperboosted Lopinavir/Ritonavir: Time for a Change. J Acquir Immune Defic Syndr. 2023 May 1;93(1):42-46. doi: 10.1097/QAI.0000000000003168. Epub 2023 Apr 1.

  PMID: 36724434 DERIVED

• 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.

  PMID: 35761406 DERIVED

MeSH Terms

Conditions

Pneumonia; Acquired Immunodeficiency Syndrome; Tuberculosis; Cytomegalovirus Infections

Interventions

Valganciclovir; Therapeutics; Antitubercular Agents

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Lung Diseases; Respiratory Tract Diseases; HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Herpesviridae Infections; DNA Virus Infections

Intervention Hierarchy (Ancestors)

Ganciclovir; Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Anti-Bacterial Agents; Anti-Infective Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Cinta Moraleda, MD, PhD

  Fundación para la Investigación Biomédica del Hospital 12 de Octubre

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2019
• First Posted: April 16, 2019
• Study Start: March 1, 2020
• Primary Completion: January 31, 2025
• Study Completion: January 31, 2025
• Last Updated: September 19, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Time Frame: Within 12 months of the completion of the study.
• Access Criteria: The repository will be public-available by concrete permission of the Clinical Trial Unit. Those interested in having the database or any of its subsets should provide concrete research proposal that may be accepted under citation condition.

Locations

ZI (1); ZA (1); FR (2); CÔ (1); MO (2); UG (1); GB (1); NL (1); MA (1); ES (1); IT (1)