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Trial record 76 of 102 for:    Valcyte

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

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ClinicalTrials.gov Identifier: NCT03915366
Recruitment Status : Not yet recruiting
First Posted : April 15, 2019
Last Update Posted : April 15, 2019
Sponsor:
Collaborators:
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

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

Condition or disease Intervention/treatment Phase
Pneumonia HIV/AIDS Tuberculosis Cytomegalovirus Infections Drug: Valganciclovir Oral Solution [Valcyte] Drug: Tuberculostatic Agents Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 624 participants
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
Estimated Study Start Date : January 1, 2020
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : January 31, 2024


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. 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 :
  1. 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).

  2. Days of hospitalization [ Time Frame: 1 year ]
    2. Cumulative days of hospitalization from discharge to day +365 after enrollment

  3. Serious Adverse Events [ Time Frame: 1 year ]
    Serious Adverse Events (SAEs), this is, grade 3 and 4 AEs.

  4. Adverse Reactions [ Time Frame: 1 year ]
    Adverse Reactions (AR)

  5. 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

  6. Immune-reconstitution inflammatory syndrome [ Time Frame: 6 months ]
    Incidence of TB-related immune-reconstitution inflammatory syndrome (IRIS)

  7. 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

  8. 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

  9. 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

  10. Deaths attributable to tuberculosis [ Time Frame: 1 year ]
    Proportion of confirmed and unconfirmed TB, according to Graham criteria, in died children

  11. CMV prevalence in died participants [ Time Frame: 1 year ]
    Proportion of CMV infection in died children

  12. 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

  13. 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)

  14. Quality-adjusted life expectancy [ Time Frame: 1 year ]
    Economic evaluation for quality-adjusted life expectancy

  15. Per-patient cost [ Time Frame: 1 year ]
    Economic evaluation of the treatments (per-patient cost)



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 365 Days   (Child)
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

      • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03915366


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

Locations
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Côte D'Ivoire
Programme PACCI. Centre Hospitalier Cocody. Not yet recruiting
Abidjan, Côte D'Ivoire
Contact: Raoul Moh         
France
Université de Bourdeaux Active, not recruiting
Bourdeaux, France
INSERM Active, not recruiting
Toulouse, France
Italy
PENTA Foundation Active, not recruiting
Padova, Italy
Malawi
Malawi Liverpool Welcome Trust. Queen Elizabeth Central Hospital College of Medicine Not yet recruiting
Blantyre, Malawi
Contact: Pui Ying Iroh Tam         
Mozambique
Cemtro de Investigaçao em Saúde da Manhiça Not yet recruiting
Manhiça, Mozambique
Contact: Nelson Tembe         
Hospital Central Maputo Not yet recruiting
Maputo, Mozambique
Contact: Christopher Buck         
Netherlands
Stichting Katholieke Universiteit Radboudumc Active, not recruiting
Nimega, Netherlands
Spain
Fundación para la Investigación Biomédica del Hospital 12 de Octubre Active, not recruiting
Madrid, Spain, 28041
Uganda
Makerere University - Mulago Hospital Not yet recruiting
Kampala, Uganda
Contact: Victor Musiime         
United Kingdom
University of Lincoln Active, not recruiting
Lincoln, United Kingdom
Zambia
Lusaka Teaching Hospital
Lusaka, Zambia
Zimbabwe
University of Zimbabwe Clinical Research Centre Not yet recruiting
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
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Study Chair: Cinta Moraleda, MD, PhD Fundación para la Investigación Biomédica del Hospital 12 de Octubre

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Responsible Party: Hospital Universitario 12 de Octubre
ClinicalTrials.gov Identifier: NCT03915366     History of Changes
Other Study ID Numbers: 19/096
2019-001749-42 ( EudraCT Number )
EDCTP RIA2017MC-2013EMPIRICAL ( Other Grant/Funding Number: EDCTP )
U1111-1231-4736 ( Other Identifier: Universal Trial Number )
PACTR201904797961340 ( Other Identifier: Pan African Clinical Trial Registry )
First Posted: April 15, 2019    Key Record Dates
Last Update Posted: April 15, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
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.

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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:
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Valganciclovir
Tuberculosis
Cytomegalovirus Infections
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Antitubercular Agents
Antiviral Agents
Anti-Infective Agents
Anti-Bacterial Agents