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

NCT ID: NCT03915366

Last Updated: 2025-09-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 563 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-03-01
• Study Completion Date: 2025-01-31

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.

Conditions

Pneumonia; HIV/AIDS; Tuberculosis; Cytomegalovirus Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard of Care (SoC)

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Valganciclovir plus SoC

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

Group Type: EXPERIMENTAL

Valganciclovir Oral Solution [Valcyte]

Intervention Type: DRUG

Treatment for CMV

Tuberculosis Treatment plus SoC

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.

Group Type: EXPERIMENTAL

Tuberculostatic Agents

Intervention Type: DRUG

Treatment for tuberculosis

Tuberculosis Treatment plus Valganciclovir plus SoC

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.

Group Type: EXPERIMENTAL

Valganciclovir Oral Solution [Valcyte]

Intervention Type: DRUG

Treatment for CMV

Tuberculostatic Agents

Intervention Type: DRUG

Treatment for tuberculosis

Interventions

Valganciclovir Oral Solution [Valcyte]

Treatment for CMV

Intervention Type: DRUG

Tuberculostatic Agents

Treatment for tuberculosis

Intervention Type: DRUG

Other Intervention Names

Treatment for CMV; Treatment for TB

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

• Minimum Eligible Age: 28 Days
• Maximum Eligible Age: 365 Days
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Bordeaux

OTHER

Sponsor Role: collaborator

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role: collaborator

PENTA Foundation

NETWORK

Sponsor Role: collaborator

Centre Hospitalier Cocody

UNKNOWN

Sponsor Role: collaborator

Malawi-Liverpool-Wellcome Trust Clinical Research Programme

OTHER

Sponsor Role: collaborator

Eduardo Mondlane University

OTHER

Sponsor Role: collaborator

Centro de Investigação em Saúde de Manhiça

OTHER

Sponsor Role: collaborator

Stichting Katholieke Universiteit

OTHER

Sponsor Role: collaborator

Barcelona Institute for Global Health

OTHER

Sponsor Role: collaborator

University of Lincoln

OTHER

Sponsor Role: collaborator

Makerere University

OTHER

Sponsor Role: collaborator

University Teaching Hospital, Lusaka, Zambia

OTHER

Sponsor Role: collaborator

University of Zimbabwe

OTHER

Sponsor Role: collaborator

Kamuzu Central Hospital

OTHER

Sponsor Role: collaborator

Servicio Madrileño de Salud, Madrid, Spain

OTHER

Sponsor Role: collaborator

Hospital Universitario 12 de Octubre

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Cinta Moraleda, MD, PhD

Role: STUDY_CHAIR

Fundación para la Investigación Biomédica del Hospital 12 de Octubre

Locations

Programme PACCI. Centre Hospitalier Cocody.

Abidjan, , Côte d’Ivoire

Université de Bourdeaux

Bourdeaux, , France

INSERM

Toulouse, , France

PENTA Foundation

Padua, , Italy

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

Blantyre, , Malawi

Cemtro de Investigaçao em Saúde da Manhiça

Manhiça, , Mozambique

Hospital Central Maputo

Maputo, , Mozambique

Stichting Katholieke Universiteit Radboudumc

Nijmegen, , Netherlands

Fundación para la Investigación Biomédica del Hospital 12 de Octubre

Madrid, , Spain

Makerere University - Mulago Hospital

Kampala, , Uganda

University of Lincoln

Lincoln, , United Kingdom

Lusaka Teaching Hospital

Lusaka, , Zambia

University of Zimbabwe Clinical Research Centre

Harare, , Zimbabwe

Countries

Côte d’Ivoire; France; Italy; Malawi; Mozambique; Netherlands; Spain; Uganda; United Kingdom; Zambia; Zimbabwe

References

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.

Reference Type: DERIVED

PMID: 40307889 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36724434 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35761406 (View on PubMed)

Other Identifiers

2019-001749-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EDCTP RIA2017MC-2013EMPIRICAL

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

U1111-1231-4736

Identifier Type: OTHER

Identifier Source: secondary_id

PACTR201904797961340

Identifier Type: OTHER

Identifier Source: secondary_id

19/096

Identifier Type: -

Identifier Source: org_study_id