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.: PACTR202309763146420 Date of Approval: 28/09/2023
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Does probiotic treatment to newborns born with a low birth weight decrease the risk of severe disease in the year of life?
Official scientific title Probiotic treatment versus placebo to low birth weight neonates for prevention of mortality or undernutrition: two-arm multi-center superiority randomized controlled trial
Brief summary describing the background and objectives of the trial Background: To end all forms of malnutrition and stop preventable newborn deaths before 2030, established interventions are not sufficient. Hence, innovative, safe and acceptable evidence-based interventions must be developed. Preterm and LBW babies have a low gut microbiome diversity, a risk factor to develop severe disease. Probiotics are routine practice to prevent mortality in preterm and small for gestational age newborns in high income countries. Evidence shows that the impact could be even larger in low-income countries and can simultaneously address both mortality and undernutrition. Recently, the WHO stated that treatment with probiotics “may be considered” for children <32 weeks of gestational age or birth weight <1,5 kg but stressed the imminent need to study the effect of probiotics on mortality, morbidity, growth, and gut microbiome, given to newborns in resource limited settings. Objective: This trial aims to evaluate if the use of probiotics can reduce mortality and undernutrition among premature or LBW admitted and followed up from hospitals and health centers within three Rwandan districts catchment area. Methods: This randomized double-blinded placebo-controlled trial aims to recruit 1500 neonates from three referral Rwandan hospitals between February 2024 to May 2025. After proxy consent, inclusion of stable risk newborns (defined as LBW and/or preterm) will be made from days 0 to 7 after birth and randomized to receive probiotics or placebo or 4 weeks. Follow up visits to register neonatal outcome (mortality/morbidity/undernutrition/longitudinal growth/microbiome) will be performed at regular time points until 2 years of age. To study the effect of probiotics on the gut microbiome diversity, metagenomic sequencing of the 16SrRNA gene from rectal swabs will be collected during the study follow-up. Impact: The study could generate evidence for an intervention that is safe, easily administrable, where the need is highest.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) OPTIPRO
Disease(s) or condition(s) being studied Infections and Infestations,Neonatal Diseases,Nutritional, Metabolic, Endocrine
Sub-Disease(s) or condition(s) being studied sepsis
Purpose of the trial Prevention
Anticipated trial start date 01/02/2024
Actual trial start date
Anticipated date of last follow up 01/02/2027
Actual Last follow-up date
Anticipated target sample size (number of participants) 1500
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 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 Masking/blinding used Care giver/Provider,Outcome Assessors,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Probiotics once dose daily 4 weeks Probiotics comprised of three types of bacteria in one dose package. (Bifidobacterium infantis Bb-02 (DSM 33361) Bifidobacterium lactis (BB-12®), Streptococcus thermophilus (TH-4®) 750
Control Group Placebo once dose daily 4 weeks Placebo powder containing maltodextrin 750 Placebo
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
Inclusion criteria: Age 1-7 days old AND born at one of the study health facilities, AND a written informed consent by the mother, AND one or more of the following criteria (1, 2, or 3) 1. Low birth weight defined as birth weight 1000-2499 g as measured on the birth chart. 2. Preterm birth defined as gestational age at birth <37 weeks according to the birth chart. 3. Guardian agrees to complete the planned follow up visits 4. Permanent residents in the defined catchment area 5. Able to tolerate oral feeds Exclusion criteria 1. Infants admitted with severe diseases and in need of urgent medical intervention or referral due to the latter severity. 2. Infants with obvious congenital malformations 3. No information on birth weight or estimated gestational age 4. Infants who weigh more than 2500g on inclusion day when weighed by the study nurse. Participant discontinuation from interventional treatment criteria 1. Withdrawal of consent by the guardian during the entire continuation of the trial. Participants will be excluded from analysis, but will be followed up according to standard health management in addition to active and passive follow-up on side effects and adverse events also after withdrawal due to safety aspects of the individual. 2. Referral to another health facility beyond the reach of the study staff 3. Severe disease 4. At the discretion of the principal investigator 3.6.2.2 Participant discontinuation from further study follow-up in accordance to protocol 1. Withdrawal of consent by the mother or caregiver during the entire continuation of the trial. Study participants will be excluded from the analysis, but will be followed up according to standard health management in addition to active and passive follow-up on side effects and adverse effects 2. Loss to follow up 3. Participant will have moved out of the study catchment zone New born: 0 Day-1 Month 1 Day(s) 7 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 14/06/2023 Rwanda National Ethics Committee RNEC
Ethics Committee Address
Street address City Postal code Country
Ministry of Health, PO Box 84, Kigali Rwanda. Kigali PO Box 84 Rwanda
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Composite outcome of infant mortality (death <12 months of age) and hospitalisation for severe infection/septicemia before 6 months of age. This will be determined at the study visits where the death and episodes of severe infection/septicemia of the participant will be registered . 2,4,6,10,14 weeks. 6,9,12,15,18, 24 months
Secondary Outcome • Rates of undernutrition will be determined at follow up visits where weight, height and head circumference of the participant will be registered. Undernutrition is divided into different sub-groups based on anthropometry data, stunting (low height-for-age), underweight (low weight-for-age) and wasting (low weight-for-height). • Rates (%) of episodes of morbidities (in particular septicemia/severe infection) among participants receiving probiotics or placebo • Rates (%) of episodes of death before 24 months of age ● Feasibility of the intervention is defined by adherence to the prescribed intervention dietary supplement. Adherence is defined as ≤5 out of 28 daily doses missed and the proportion of patients adhering to the prescribed regimen will be determined [33]. ● Postnatal growth (g/kg/day increase) among groups receiving probiotics or placebo in the first 2 years of life. ● Growth monitored by length, weight and head circumference up to 24 months of age. ● Fecal Microbiome composition and diversity among groups receiving probiotics or placebo at 3, 6 and 12 months of age see primary outcome
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Ruhengeri Hospital Ruhengeri hospital Musanze Rwanda
Kibungo Referral hospital Kibungo Referral hospital Kibungo Rwanda
Kabutare Referral hospital Kabutare Referral hospital Butare Rwanda
FUNDING SOURCES
Name of source Street address City Postal code Country
Swedish Research Council Vetenskapsradet Box 1035 Stockholm 101 38 Sweden
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor University of Gothenburg BOX 100 Gothenburg 40530 Sweden University
COLLABORATORS
Name Street address City Postal code Country
University of Rwanda P.O. Box 4285, Kigali Kigali P.O. Box Rwanda
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator KRistina Elfving kristina.elfving@gu.se +4631786000 BOX 100 University of Gothenburg
City Postal code Country Position/Affiliation
Gothenburg 40530 Sweden researcher
Role Name Email Phone Street address
Principal Investigator Richard Kalisa kalichard@gmail.com +4631786000 POX BOx 4285
City Postal code Country Position/Affiliation
Kigali Rwanda senior lecturer
Role Name Email Phone Street address
Scientific Enquiries Kristina Elfving kristina.elfving@gu.se +4631786000 BOX 100 University of Gothenburg
City Postal code Country Position/Affiliation
Gothenburg Sweden researhcer
Role Name Email Phone Street address
Public Enquiries Richard Kalisa kalichard@gmail.com +4631786000 POX BOx 4285
City Postal code Country Position/Affiliation
Kigali Rwanda senior lecturer
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Individual participant data that underlie the results reported after deidentification making sure that none of the data could ever be traced back to the patient and its guardians/caretakers (text, tables, figures, and appendices) Statistical Analysis Plan 4 years Will be controlled and agreed upon by the principal investigators as well as data monitoring board after potential requests from other medical researchers working in the field.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
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