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.: PACTR201712002827168 Date of Approval: 30/11/2017
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Transfer of healthy gut flora for restoration of intestinal microbiota via enema (THRIVE) for severe acute malnutrition
Official scientific 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
Brief summary describing the background and objectives of the trial Globally, approximately 19 million children under the age of five are affected by severe acute malnutrition (SAM) annually. This patient group is vulnerable. SAM in early life is not only associated with an increased risk of mortality during childhood but also a number of non-communicable diseases through childhood and later life including persistent stunting, immune dysfunction, and neurocognitive deficits. There is emerging evidence that perturbations in the gut microbiota are causally related to malnutrition. Building on these basic science insights, this pilot translational study aims to examine the capacity of microbiota transfer therapy (MTT) to correct dysbiosis associated with SAM and improve nutritional recovery. This single-center, randomized, open-label trial will compare the safety and efficacy of microbial transfer therapy (MTT) delivered by enema in participants 18-60 months of age with stable SAM not responsive to 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 enema: 10mL/kg (maximum 150mL) 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). Stool samples will be collected at enrollment and through days 3, 7, 21 and 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.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) THRIVE
Disease(s) or condition(s) being studied Nutritional, Metabolic, Endocrine,Severe acute malnutrition
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/02/2018
Actual trial start date
Anticipated date of last follow up 01/02/2019
Actual Last follow-up date
Anticipated target sample size (number of participants) 20
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
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
Parallel: different groups receive different interventions at same time during study Randomised Simple randomisation using 1:1 ratio according to a pre-determined block randomization procedure to the treatment or control arm. Central randomisation by phone. Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Microbiota Transfer Therapy 10mL/kg (maximum 150mL) Once The investigational agent consists of screened-donor gastrointestinal microbiota prepared for MTT. MTT will be administered using frozen screened-donor liquid stool (the investigational agent) in the form of enemas 10mL/kg (maximum 60mL) of donor gastrointestinal microbiota material will be infused. 10
Control Group Standard of care N/A N/A Standard of care treatment for severe acute malnutrition as prescribed by local and national Department of Health Guidelines 10 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Age 18 to 60 months. 2. Stable SAM defined as: a. A WHZ of less than ¿3 according to the 2006 WHO Growth Standards or a mid-upper-arm circumference of less than 115 mm b. No medical complications present c. 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. d. Participant is in the rehabilitation phase of treatment for SAM 3. No bilateral pitting pedal edema or generalized anasarca. 4. HIV negative. 5. Optimal WHO treatment for SAM: o Completed course of antibiotics as part of standard therapy for SAM within the last 3 months. o Deworming in the last 3 months. o Micronutrient supplementation (Vitamin A, zinc and iron) as recommended by local guidelines o Nutritional rehabilitation as recommended by local guidelines 6. Written informed consent obtained by parent or caregiver. 1. Evidence of current complicated SAM defined as any of the following: a. Admitted to acute care ward as inpatient b. Signs of acute infection. c. One or more WHO Integrated Management of Childhood Illness danger signs.(2) d. Failure to pass appetite test. e. 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 or malignancy undergoing active chemotherapy. f. Bilateral pitting pedal edema or generalized anasarca 2. Ongoing antibiotic use for indication other than SAM (e.g. infection, HIV prophylaxis). 3. Congenital malformations, syndromic conditions and metabolic abnormalities (inborn errors of metabolism) that may adversely affect growth. 4. Kwashiorkor or marsmic-kwashiorkor. 5. Bilateral pitting edema Grade 2. 6. Contraindications to enema: a. Anorectal malformations b. Rectal prolapse c. Hirschsprungs disease d. Other contraindication to enema. 7. Primary immune deficiencies 8. Neutropenia 9. Persistent and chronic diarrhea (>7 days of loose or water stools). 10. Dysentery 11. Intestinal abnormalities including malformations, Hirschsprungs disease and short bowel syndrome 18 Month(s) 60 Month(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
No 04/12/2017 Department of Paediatrics and Child Health, University of Cape Town
Ethics Committee Address
Street address City Postal code Country
Red Cross War Memorial Children's Hospital Rondebosch 7700 Rondebosch 7700 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Safety: Number of participants with an SAE grade 2 or above up 56 days
Secondary Outcome Nutritional: Proportion of participants with nutritional recovery. Defined as weight for height z-score (WHZ) ¿ -2, MUAC ¿ 115 mm. 56 days
Secondary Outcome Clinical: Resolution of signs and symptoms of SAM. Clinical signs include diarrhea (¿ 3 loose stools in the last 24 hours), vomiting, fever (axillary temperature > 38.5¿C), cough, tachypnea (average of two measures; defined as respiratory rate of > 40 breaths per minute for children 18-60 months of age). 56 days
Secondary Outcome Microbiological: 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. 3, 7, 21 and 56 days
Secondary Outcome Translational: Assess the capacity for MTT to normalize biomarkers correlated with disease status and mortality in SAM. Stool biomarkers include Myeloperoxidase and Aplha-1-Antitrypsin. Serological biomarkers include CRP, serum calprotectin (S100 A8/9), endotoxin assay (Hek-Blue) and leptin. 56 days
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Department of Paediatrics and Child Health, University of Cape Town Red Cross War Memorial Children's Hospital Rondebosch 7700 Rondebosch 7700 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Bill and Melinda Gates Foundation 500 Fifth Avenue North Seattle WA 98109 United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor OpenBiome 200 INNER BELT ROAD SOMERVILLE 02143 United States of America Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
Dr Shrish Budree 200 INNER BELT ROAD SOMERVILLE 02143 United States of America
Dr Majdi Osman 200 INNER BELT ROAD SOMERVILLE 02143 United States of America
Prof Heather Zar Department of Paediatrics and Child Health, University of Cape Town, Red Cross Children's Hospital Klipfontein Road Rondebosch South Africa
Prof Mark Division of Medical Microbiology 5th Floor, Falmouth Building UCT Medical School Anzio Road Cape Town South Africa
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Majdi Osman majdi@openbiome.org 8573138664 200 INNER BELT ROAD
City Postal code Country Position/Affiliation
Somerville 02143 United States of America
Role Name Email Phone Street address
Public Enquiries Majdi Osman majdi@openbiome.org 8573138664 200 INNER BELT ROAD
City Postal code Country Position/Affiliation
SOMERVILLE United States of America
Role Name Email Phone Street address
Scientific Enquiries Majdi Osman majdi@openbiome.org 8573138664 200 INNER BELT ROAD
City Postal code Country Position/Affiliation
SOMERVILLE 02143 United States of America
REPORTING
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