Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR201904797961340 Date of Approval: 09/04/2019
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants with severe pneumonia: a multicenter, open-label randomized controlled clinical trial
Official scientific title Empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants with severe pneumonia: a multicenter, open-label randomized controlled clinical trial
Brief summary describing the background and objectives of the trial Pneumonia is the main cause of death in HIV-infected children. A significant number of undiagnosed or poorly treated HIV-infected children present to health services with severe pneumonia. 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 infection and tuberculosis 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 1 month-12 month admitted to hospital with severe pneumonia. Study end-point is mortality. HIV-infected infants will receive standard of care (SoC) pneumonia treatment including antibiotics, cotrimoxazole, and prednisolone.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) EMPIRICAL
Disease(s) or condition(s) being studied Infections and Infestations,Paediatrics,Respiratory
Sub-Disease(s) or condition(s) being studied Cytomegalovirus pneumonia,HIV/AIDS,Tuberculosis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/02/2020
Actual trial start date 01/02/2020
Anticipated date of last follow up 31/01/2025
Actual Last follow-up date
Anticipated target sample size (number of participants) 624
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
U111112314736 Unique Trial Number
201900174942 EudraCT
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously Randomised Simple randomization using a randomization table created by a computer software program Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Standard of Care 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 Antibiotics: 5 days. Cotrimoxazole trimethoprim: 21 days. Prednisolone: 21 days. Standard treatment for severe pneumonia in HIV-infected children includes broad-spectrum antibiotics for bacteria and cotrimoxazole plus prednisolone for P. jirovecii. 156 Active-Treatment of Control Group
Experimental Group TBT plus Standard of Care 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 Plus Standard of Care described in the Control Group Isoniazid, 6 months Rifampicin, 6 months Pyrazinamide, 2 months Ethambutol, 2 months Plus Standard of Care described in the Control Group Empirical treatment with drugs against 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 156
Experimental Group Valganciclovir plus Standard of Care 16 mg/kg/12 hours Plus Standard or Care described in Control Group 15 days Valganciclovir (powder for suspension, 50 mg/mL) oral, 16 mg/kg/12 hours for 15 days Plus Standard or Care described in Control Group 156
Experimental Group TBT plus Valganciclovir plus SoC 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 Valganciclovir (powder for suspension, 50 mg/mL) oral, 16 mg/kg/12 hours for 15 days Plus Standard of Care described in the Control GroupPlus Standard or Care described in Control Group Isoniazid, 6 months Rifampicin, 6 months Pyrazinamide, 2 months Ethambutol, 2 months Valganciclovir, 15 days Plus Standard of Care described in the Control Group Empirical treatment with drugs against tuberculosis and against CMV: 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 or Care described in Control Group 156
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
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) a) Chest indrawing with HIV infection b) No improvement with oral treatment. c) One or more danger signs according to WHO - 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 PCR or RNA PCR/viral load). 5. Informed consent obtained 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 Infant: 1 Month-23 Month 28 Day(s) 365 Day(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 13/03/2019 CEIm Hospital 12 de Octubre
Ethics Committee Address
Street address City Postal code Country
Avenida de Cordoba Madrid 28041 Spain
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Mortality 15 days and 1 year
Secondary Outcome Duration of oxygen requirements (in days, from the first requirement until definitive withdrawal, being day 1 the first day of oxygen requirement). Discharge
Secondary Outcome Cumulative days of hospitalization from discharge to day +365 after enrollment 1 year
Secondary Outcome Serious Adverse Events (SAEs), this is, grade 3 and 4 AEs, Adverse Reactions, Adverse Events requiring stop of IMP, IRIS. 1 year
Secondary Outcome Prevalence of CMV infection 15 days
Secondary Outcome Baseline prevalence of Tuberculosis 60 days
Secondary Outcome Incidence of Tuberculosis 1 year
Secondary Outcome Proportion of CMV and Tuberculosis in died children 365
Secondary Outcome Reduction of quantitative CMV viral load in blood and saliva in infants treated with valganciclovir from enrollment to day +15 15 days
Secondary Outcome To assess the diagnostic accuracy of TB-LAM for the diagnosis of confirmed TB (reference: positive Xpert MTB/RIF Ultra in feces and/or NPA). 60 days
Secondary Outcome Quality-adjusted life expectancy and per-patient cost 365
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Hospital Central de Maputo 1653 Avenida Eduardo Mondlane Maputo 1164 Mozambique
Manhica Research Center Bairro Cambeve, Rua 12, Distrito da Manhica Manhica 1929 Mozambique
Malawi Liverpool Welcome Trust Queen Elizabeth Central Hospital College of Medicine Blantyre 30096 Malawi
University Teaching Hospital NATIONALIST ROAD Lusaka Zambia
University of Zimbabwe Clinical Research Centre 630 Churchill Avenue Harare Zimbabwe
Mulago Hospital Lower Mulago Hill Road Kampala Uganda
Centre Hospitalier Cocody Boulevard de lUniversite Abidjan Cote Divoire
FUNDING SOURCES
Name of source Street address City Postal code Country
EDCTP Anna van Saksenlaan 51 Le Hague 2593 Netherlands
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Servicio Madrileno de Salud Fundacion para la Investigacion Biomedica Hospital Universitario 12 de Octubre Avenida de Cordoba Madrid 28041 Spain Hospital
COLLABORATORS
Name Street address City Postal code Country
Cinta Moraleda Fundacion 12 Octubre Madrid 28041 Spain
Sara Dominguez Fundacion 12 Octubre Madrid 28041 Spain
Olivier Marcy Bourdeaux University Bourdeaux France
Valeriane Leroy INSERM Bourdeaux France
Laura Mangiarini PENTA Foundation Padova Italy
Alessandra Nardone PENTA Foundation Padova Italy
Raoul Moh Programme PACCI Abidjan Cote Divoire
Pui Ying Iroh Tam Malawi Wellcome Trust Blantyre Malawi
Christopher Buck Hospital Central Maputo Maputo Mozambique
Nelson Tembe CISM Manhica Mozambique
Victor Musiime Makerere University Kampala Uganda
Chishala Chabala Lusaka Teaching Hospital Lusaka Zambia
Hilda Mujuru University of Zimbabwe Harare Zimbabwe
Matthew Bates University of Lincoln Lincoln United Kingdom
David Burger Stichting Katholieke Universiteit Radboudumc Nimega Netherlands
Lola Madrid Fundacion 12 de Octubre Madrid Spain
Tisungane Mvalo Kamuzu Central Hospital Lilongwe Malawi
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Pablo Rojo pablorojoconejo@aim.com +34615513222 Avenida de Cordoba
City Postal code Country Position/Affiliation
Madrid 28041 Spain Researcher Fundacion Hospital 12 Octubre
Role Name Email Phone Street address
Public Enquiries Lilit Manukyan lilit.empirical@gmail.com +34622420559 Avenida de Cordoba
City Postal code Country Position/Affiliation
Madrid 28041 Spain Fundacion 12 de Octubre
Role Name Email Phone Street address
Scientific Enquiries Alfredo Tagarro alfredotagarro@gmail.com +34606194888 Avenida de Cordoba
City Postal code Country Position/Affiliation
Madrid 28041 Spain Fundacion 12 de Octubre
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes After principal results, addressing primary and secondary objectives will be published. A final repository will be chosen for anonymized data sharing, and transparency after the trial is closed, according to the funder (EDCTP) rules and recommendations, unless national laws impede it. Informed Consent Form,Statistical Analysis Plan,Study Protocol Within 12 months of the completion of the study. The repository will be public-available by concrete permission of the CTU. Those interested in having the database or any of its subsets should provide concrete research proposal that may be accepted under citation condition.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
www.empiricalEDCTP.eu No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 Scientific Coordinator of EMPIRICAL Project Cinta Moraleda, Avenida de Cordoba , Madrid, 28041, Spain
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 Data Scientist Sara Dominguez, Avenida de Cordoba , Madrid, 28041, Spain
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 Safety Coordinator Luis Prieto, Avenida de Cordoba, Madrid, 28041, Spain
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 TB Speed Coordinator Olivier Marcy, Bourdeaux University, Bourdeaux, , France
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 Pharmacoeconomics Valeriane Leroy, INSERM, Bourdeaux, , France
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 Ethics Coordination Laura Mangiarini, PENTA Foundation, Padova, , Italy
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 Ethics Coordination Alessandra Nardone, PENTA Foundation, Padova, , Italy
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 PI Cote D'Ivoire Raoul Moh, Programme PACCI, Abidjan, , Cote Divoire
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 PI Malawi Pui Ying Iroh Tam, Malawi Wellcome Trust, Blantyre, , Malawi
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 PI Maputo Christopher Buck, Hospital Central Maputo, Maputo, , Mozambique
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 PI Manhica Nelson, Tembe, Manhica, , Mozambique
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 PI Uganda Victor Musiime, Makerere University, Kampala, , Uganda
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 PI Zambia Chishala Chabala, Lusaka Teaching Hospital, Lusaka, , Zambia
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 PI Zimbabwe Hilda Mujuru , University of Zimbabwe, Harare, , Zimbabwe
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 Laboratory Responsible Matthew Bates, University of Lincoln, Lincoln, , United Kingdom
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 correction Cinta Moraleda, Avenida de Cordoba , Madrid, 28041, Spain Cinta Moraleda, Fundacion 12 Octubre, Madrid, 28041, Spain
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 correction Sara Dominguez, Avenida de Cordoba , Madrid, 28041, Spain Sara Dominguez, Fundacion 12 Octubre, Madrid, 28041, Spain
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 09/04/2019 correction Luis Prieto, Avenida de Cordoba, Madrid, 28041, Spain Luis Prieto, Fundacion 12 Octubre, Madrid, 28041, Spain
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD-Sharing time frame 09/04/2019 as required by WHO 1 year after completion of the study. Within 12 months of the completion of the study.
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD URL 09/04/2019 The website will be available soon www.empirical.org
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Public title 09/04/2019 edit EMPIRICAL Empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants with severe pneumonia: a multicenter, open-label randomized controlled clinical trial
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 10/04/2019 forgot David Burger, Stichting Katholieke Universiteit Radboudumc , Nimega, , Netherlands
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 10/04/2019 mistake Nelson, Tembe, Manhica, , Mozambique Nelson Tembe, CISM, Manhica, , Mozambique
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD URL 10/04/2019 mistake www.empirical.org www.empiricalEDCTP.eu
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Anticipated trial start date 18/02/2022 Delay in approvals 01 Jan 2020 01 Feb 2020
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Actual trial start date 18/02/2022 Delay in approvals 01 Feb 2020
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Anticipated date of last follow up 18/02/2022 Covid-19 pandemics. A no-cost extension has been granted by EDCTP 01 Jan 2023 31 Jan 2025
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 18/02/2022 enrolment ongoing Not yet recruiting Recruiting
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 19/02/2022 No longer working in the project Luis Prieto, Fundacion 12 Octubre, Madrid, 28041, Spain
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 19/02/2022 New collaborator Tisungan Mvalo, Kamuzu Central Hospital, Lilongwe, , Malawi
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 19/02/2022 typo Tisungan Mvalo, Kamuzu Central Hospital, Lilongwe, , Malawi Tisungane Mvalo, Kamuzu Central Hospital, Lilongwe, , Malawi
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 19/02/2022 New collaborator Tisungan Mvalo, Kamuzu Central Hospital, Lilongwe, , Malawi Tisungane Mvalo, Kamuzu Central Hospital, Lilongwe, , Malawi
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 19/02/2022 new collaborator Tisungan Mvalo, Kamuzu Central Hospital, Lilongwe, , Malawi Lola Madrid, Fundacion 12 de Octubre, Madrid, , Spain
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 19/02/2022 new collaborator Tisungane Mvalo, Kamuzu Central Hospital, Lilongwe, , Malawi