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Transfer of Healthy Gut Flora for Restoration of Intestinal Microbiota Via Enema for Severe Acute Malnutrition (THRIVE)

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ClinicalTrials.gov Identifier: NCT03087097
Recruitment Status : Recruiting
First Posted : March 22, 2017
Last Update Posted : July 19, 2019
Sponsor:
Collaborator:
University of Cape Town
Information provided by (Responsible Party):
Microbiome Health Research Institute

Brief Summary:

This single-center, randomized, open-label trial will compare the safety and efficacy of MTT delivered by rectal catheter enema in participants 12-60 months of age with stable SAM not responsive to at least 8 weeks of standard therapy. Participants must meet inclusion criteria, no exclusion criteria prior to randomization. Participants will then be randomized in a 1:1 ratio at each site to 1 of 2 treatment groups:

  • MTT by rectal catheter enema: 10mL/kg (maximum 150mL, +/- 5ml) of healthy donor human intestinal microbiota will be infused.
  • Standard of care treatment for SAM as prescribed by local and national Department of Health Guidelines Participants will be evaluated through 56 days (±5) after randomization for primary outcomes (safety) as well as secondary outcomes (nutritional, clinical and microbiological response). See definition under endpoints/outcome measures above.

Participant blood and urine samples will be collected at enrollment and day 56. Participant stool samples will be collected at enrollment and through days 3, 7, 21 and 56. A caregiver stool sample will be collected at enrollment and day 56. Samples will be used for microbiome determination and other exploratory microbiological endpoints. An aliquot of donor stool will also be stored for microbiome determination and other exploratory microbiological endpoints and assessment of newly acquired infectious agents.


Condition or disease Intervention/treatment Phase
Severe Acute Malnutrition Biological: Fecal Microbiota Transplantation Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Transfer of Healthy Gut Flora for Restoration of Intestinal Microbiota Via Enema (THRIVE) for Severe Acute Malnutrition: A Pilot Study Evaluating Microbial Engraftment, Safety and Nutritional Outcomes
Actual Study Start Date : January 14, 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Fecal Microbiota Transplant
FMT by enema: 10mL/kg (maximum 150mL) of donor fecal material will be infused.
Biological: Fecal Microbiota Transplantation
Fecal microbiota delivered by rectal catheter enema in participants 12-60 months of age with stable SAM not responsive to at least 8 weeks of standard therapy.

No Intervention: Standard of Care
Standard of care treatment for SAM as prescribed by local and national Department of Health Guidelines



Primary Outcome Measures :
  1. SAEs [ Time Frame: 56 days ]
    Proportion of participants with a severe adverse event (SAE) grade 2 or above (according to NIH grading)


Secondary Outcome Measures :
  1. Nutritional recovery: [ Time Frame: 56 days ]
    Proportion of participants with nutritional recovery at day 56 after randomization. Defined as weight for height z-score (WHZ) ≥ -2 or MUAC ≥ 125 mm. In cases where there is a significant discrepancy between the weight and MUAC the participants weight will be used as the definitive measure.

  2. Clinical: [ Time Frame: 56 days ]
    Presence of signs and symptoms or complications of SAM at day 56. Clinical signs include fever (axillary temperature > 38.5⁰C), tachypnea (average of two measures; defined as respiratory rate of > 40 breaths per minute for children 12-60 months of age). Symptoms include diarrhea (≥ 3 loose stools in the last 24 hours), vomiting, and cough.

  3. Microbiological: [ Time Frame: 56 Days ]
    Assess engraftment of donor microbial communities in recipients through taxonomic characterization of donor and recipient microbiota pre- and post-MTT using both 16S rRNA and metagenomic techniques.

  4. Translational: [ Time Frame: 56 Days ]
    Assess the capacity for MTT to normalize biomarkers correlated with disease status and mortality in SAM. Stool biomarkers include Myeloperoxidase, Alpha-1-Antitrypsin, fecal calprotectin and neopterin. Serological biomarkers include CRP, endotoxin assay (Hek-Blue), IGF1, Ferritin and leptin.



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Ages Eligible for Study:   12 Months to 60 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Participant Inclusion Criteria

Participants eligible to participate in this study must meet the following inclusion criteria:

  1. Age 12 to 60 months.
  2. History of SAM defined as a WHZ less than -3 according to the WHO 2006 standards or a MUAC less than 115mm.
  3. Previous SAM with failure to respond nutritionally, defined as:

    a. A WHZ of less than −2 according to the 2006 World Health Organization (WHO) Growth Standards or a mid-upper-arm circumference of less than 125 mm i. No medical complications present ii. Participant is sufficiently alert and successfully passes the appetite test which involves consumption of breastmilk or a ready to use therapeutic food (RUTF) under supervision.

    iii. Participant is in the rehabilitation phase of treatment for SAM

  4. No bilateral pitting pedal edema or generalized anasarca.
  5. HIV negative.
  6. Received at least 8 weeks of optimal WHO treatment for SAM:

    • Micronutrient supplementation (Vitamin A, zinc and iron) as recommended by local guidelines
    • Nutritional rehabilitation as recommended by local guidelines
  7. Have not taken antibiotics in the past seven days.
  8. Written informed consent obtained by parent or caregiver.

Most children with a diagnosis of SAM tend to present at a young age, either during or shortly after weaning onto solid feeds. A large proportion of patients are diagnosed at approximately 12months of age. Due to this, the age inclusion criteria has been amended from 18months on the original protocol, to 12months. Since these patients will be clinically stable and in the rehabilitation phase of SAM, we do not anticipate any additional patient risks by performing an MTT in this younger age group. In addition, previous studies have safely treated children as young as 3 months with MTT (1,2)

Participant Exclusion Criteria

Participants will not be able to participate if they meet any of the following exclusion criteria:

  1. Evidence of current complicated SAM defined as any of the following:

    1. Admitted to acute care ward as inpatient
    2. Signs of acute infection.
    3. One or more WHO Integrated Management of Childhood Illness danger signs.(3)
    4. Failure to pass appetite test.
    5. Presence of known comorbid diseases such as pulmonary Tuberculosis, cystic fibrosis, type I diabetes mellitus, intestinal malabsorptive syndromes, chronic lung disease, chronic liver disease, chronic renal disease, chronic neurological diseases (e.g. cerebral palsy) or malignancy undergoing active chemotherapy.
    6. Bilateral pitting pedal edema or generalized anasarca
  2. Have taken antibiotics in the past seven days.
  3. Congenital malformations, syndromic conditions (fetal alcohol syndrome) and metabolic abnormalities (inborn errors of metabolism) that may adversely affect growth.
  4. Presence of bilateral pitting edema.
  5. Contraindications to rectal catheter enema:

    1. Anorectal malformations
    2. Rectal prolapse
    3. Hirschsprungs disease
    4. Other contraindication to enema.
  6. Primary immune deficiencies
  7. Acute, persistent or chronic diarrhea.
  8. Dysentery
  9. Intestinal abnormalities including malformations, Hirschsprungs disease and short bowel syndrome
  10. Any condition that the physician investigators deems unsafe, including other conditions or medications that the investigator determines puts the participant at greater risk from MTT

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): NCT03087097


Contacts
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Contact: Susie Corl, MPH, CIP, CCRP, CHRC 617-575-2201 ext 799 scorl@openbiome.org
Contact: Mary Njenga 617-575-2201 ext 717 mnjenga@openbiome.org

Locations
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South Africa
University of Cape Town Recruiting
Cape Town, South Africa
Contact: Sandhia Padayachee, MD       sandhia.padayachee@uct.ac.za   
Principal Investigator: Heather Zar, MD         
Sponsors and Collaborators
Microbiome Health Research Institute
University of Cape Town
Investigators
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Principal Investigator: Majdi A Osman, MD MPH Microbiome Health Research Institute
Principal Investigator: Shrish Budree, MD MBChB DCH FCPeds Microbiome Health Research Institute

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Responsible Party: Microbiome Health Research Institute
ClinicalTrials.gov Identifier: NCT03087097     History of Changes
Other Study ID Numbers: THRIVE001
First Posted: March 22, 2017    Key Record Dates
Last Update Posted: July 19, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Microbiome Health Research Institute:
SAM

Additional relevant MeSH terms:
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Malnutrition
Severe Acute Malnutrition
Nutrition Disorders