Clinical Trials

MainTitle

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

This study is not yet open for participant recruitment. (see Contacts and Locations)

Verified April 2019 by Hospital Universitario 12 de Octubre

Sponsor
Hospital Universitario 12 de Octubre

Collaborator
University Hospital, Bordeaux
Institut National de la Santé Et de la Recherche Médicale, France
PENTA Foundation
Centre Hospitalier Cocody
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
Eduardo Mondlane University
Centro de Investigação em Saúde de Manhiça
Stichting Katholieke Universiteit
Barcelona Institute for Global Health
University of Lincoln
Makerere University
University Teaching Hospital, Lusaka, Zambia
University of Zimbabwe

Information provided by (Responsible Party)
Hospital Universitario 12 de Octubre
ClinicalTrials.gov Identifier
NCT03915366

First received: April 10, 2019
Last updated: April 11, 2019
Last Verified: April 2019
History of Changes
Purpose

Purpose

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

Condition Intervention Phase
Pneumonia
HIV/AIDS
Tuberculosis
Cytomegalovirus Infections

Drug : Valganciclovir Oral Solution [Valcyte]
Drug : Tuberculostatic Agents
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Empirical Treatment Against Cytomegalovirus and Tuberculosis in HIV-infected Infants With Severe Pneumonia: a Multicenter, Open-label Randomized Controlled Clinical Trial

Further study details as provided by Hospital Universitario 12 de Octubre:

Primary Outcome Measures

  • Mortality [ Time Frame: 1 year ]
    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.
Secondary Outcome Measures:
  • Days with oxygen therapy [ Time Frame: 60 days ]
    1. Duration of oxygen requirements (in days, from the first requirement until definitive withdrawal, being day 1 the first day of oxygen requirement).
  • Days of hospitalization [ Time Frame: 1 year ]
    2. Cumulative days of hospitalization from discharge to day +365 after enrollment
  • Serious Adverse Events [ Time Frame: 1 year ]
    Serious Adverse Events (SAEs), this is, grade 3 and 4 AEs.
  • Adverse Reactions [ Time Frame: 1 year ]
    Adverse Reactions (AR)
  • Notable Adverse Events [ Time Frame: 1 year ]
    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
  • Immune-reconstitution inflammatory syndrome [ Time Frame: 6 months ]
    Incidence of TB-related immune-reconstitution inflammatory syndrome (IRIS)
  • Baseline cytomegalovirus prevalence [ Time Frame: 30 days ]
    Baseline prevalence of CMV infection and CMV-attributable pneumonia (based in a CMV viral load threshold) in recruited HIV-infected infants with severe pneumonia
  • Baseline tuberculosis prevalence [ Time Frame: 60 days ]
    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
  • Tuberculosis incidence [ Time Frame: 1 year ]
    New confirmed and unconfirmed TB cases according to Graham criteria during 1-year of follow-up among patients without TB-T
  • Deaths attributable to tuberculosis [ Time Frame: 1 year ]
    Proportion of confirmed and unconfirmed TB, according to Graham criteria, in died children
  • CMV prevalence in died participants [ Time Frame: 1 year ]
    Proportion of CMV infection in died children
  • CMV Molecular response to treatment [ Time Frame: 1 year ]
    Reduction of quantitative CMV viral load in blood and saliva in infants treated with valganciclovir from enrollment to day +15
  • TB-lipoarabinomannan (LAM) sensitivity and specificity [ Time Frame: 1 year ]
    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)
  • Quality-adjusted life expectancy [ Time Frame: 1 year ]
    Economic evaluation for quality-adjusted life expectancy
  • Per-patient cost [ Time Frame: 1 year ]
    Economic evaluation of the treatments (per-patient cost)

Estimated Enrollment: 624
Study Start Date: January 1, 2020
Estimated Study Completion Date: January 31, 2024
Estimated Primary Completion Date: January 1, 2020 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
No Intervention: 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
Experimental: 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
Drug: Valganciclovir Oral Solution [Valcyte]

Treatment for CMV

Other Name: Treatment for CMV
Experimental: 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.
Drug: Tuberculostatic Agents

Treatment for tuberculosis

Other Name: Treatment for TB
Experimental: 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.
Drug: Valganciclovir Oral Solution [Valcyte]

Treatment for CMV

Other Name: Treatment for CMV
Drug: Tuberculostatic Agents

Treatment for tuberculosis

Other Name: Treatment for TB

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.

Eligibility

Eligibility

Ages Eligible for Study: up to 365 Days  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: No  

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
  4. Central cyanosis or saturation of O2 <90%
  5. Severe respiratory distress, e.g. grunting or very severe chest indrawing
  6. Signs of pneumonia with a general danger sign:
  7. Unable to drink or breastfeed
  8. Persisting vomiting
  9. Convulsions in the last 24 hours
  10. Lethargic or unconscious
  11. Stridor while calm
  12. Severe malnutrition
  13. HIV-confirmed infection (with at least one molecular method: DNA polymerase chain reaction (PCR) or RNA PCR/viral load).
  14. 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

    contacts and locations

    Contacts and Locations

    Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

    Please refer to this study by its ClinicalTrials.gov identifier: NCT03915366

    Contacts

    Contact:   Alfredo Tagarro, MD, PhD +34917792621 alfredo.tagarro@salud.madrid.org
    Contact:   Pablo Rojo, MD, PhD +34917792621 pablorojoconejo@aim.com

    Locations

    Côte D'Ivoire
    Programme PACCI. Centre Hospitalier Cocody.
    Abidjan, Côte D'Ivoire
    Contact: Raoul Moh
    France
    Université de Bourdeaux
    Bourdeaux, France
    INSERM
    Toulouse, France
    Italy
    PENTA Foundation
    Padova, Italy
    Malawi
    Malawi Liverpool Welcome Trust. Queen Elizabeth Central Hospital College of Medicine
    Blantyre, Malawi
    Contact: Pui Ying Iroh Tam
    Mozambique
    Cemtro de Investigaçao em Saúde da Manhiça
    Manhiça, Mozambique
    Contact: Nelson Tembe
    Hospital Central Maputo
    Maputo, Mozambique
    Contact: Christopher Buck
    Netherlands
    Stichting Katholieke Universiteit Radboudumc
    Nimega, Netherlands
    Spain
    Fundación para la Investigación Biomédica del Hospital 12 de Octubre
    Madrid, Spain, 28041
    Uganda
    Makerere University - Mulago Hospital
    Kampala, Uganda
    Contact: Victor Musiime
    United Kingdom
    University of Lincoln
    Lincoln, United Kingdom
    Zambia
    Lusaka Teaching Hospital
    Lusaka, Zambia
    Zimbabwe
    University of Zimbabwe Clinical Research Centre
    Harare, Zimbabwe
    Contact: Hilda A Mujuru

    Sponsors and Collaborators

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

    Investigators

    Study Chair: Cinta Moraleda, MD, PhD Fundación para la Investigación Biomédica del Hospital 12 de Octubre
    More Information

    More Information


    Responsible Party: Hospital Universitario 12 de Octubre  
    ClinicalTrials.gov Identifier: NCT03915366   History of Changes  
    Other Study ID Numbers: 19/096  
      2019-001749-42  
      EDCTP RIA2017MC-2013EMPIRICAL  
      U1111-1231-4736  
      PACTR201904797961340  
    Study First Received: April 10, 2019  
    Last Updated: April 11, 2019  
    Individual Participant Data    
    Plan to Share IPD: Yes  

    Studies a U.S. FDA-regulated Drug Product: No  
    Studies a U.S. FDA-regulated Device Product: No  
    Product Manufactured in and Exported from the U.S.: No  

    Additional relevant MeSH terms:
    Tuberculosis
    Cytomegalovirus Infections
    Pneumonia
    Valganciclovir
    Antitubercular Agents

    ClinicalTrials.gov processed this data on June 02, 2020
    This information is provided by ClinicalTrials.gov.