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Trial registered on ANZCTR


Registration number
ACTRN12617001634369
Ethics application status
Approved
Date submitted
17/08/2017
Date registered
15/12/2017
Date last updated
15/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing the appropriate dose and efficacy of bovine lactoferrin to correct iron deficiency anaemia in pregnancy: A community-based randomized controlled trial in Mirpur, Dhaka
Scientific title
Assessing the appropriate dose and efficacy of bovine lactoferrin to correct iron deficiency anaemia in pregnancy: A community-based randomized controlled trial in Mirpur, Dhaka
Secondary ID [1] 292404 0
None
Universal Trial Number (UTN)
Trial acronym
SHONJIBON 2 Part 2
Linked study record
This trial will be conducted after completion of SHONJIBON 2 Part 1 trial titled" Assessing the appropriate dose and efficacy of bovine lactoferrin to correct iron deficiency anaemia in non pregnant women: A community-based randomized controlled trial in Mirpur, Dhaka". We have applied for registration of SHONJIBON 2 Part 1 trial in ANZCTR and the process of trial registry is ongoing.
The ANZCTR Trial ID for the Part 1 is ACTRN12617001455358

Health condition
Health condition(s) or problem(s) studied:
Iron Deficiency Anemia 304079 0
Condition category
Condition code
Diet and Nutrition 303413 303413 0 0
Other diet and nutrition disorders
Blood 303414 303414 0 0
Anaemia
Reproductive Health and Childbirth 303415 303415 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
We will conduct a parallel, double-blind, individually randomized, controlled trial of i) oral bovine lactoferrin (200mg or 400mg [as identified in the preceding 'Part 1' trial to find the effective dose for anemia correction]) compared to ii) standard oral iron supplements in anaemic pregnant women (haemoglobin <120 g/L & serum ferritin <30 µg/L) to assess impact on haemoglobin & iron status. The intervention (each capsule once daily) will be started as soon as pregnancy is detected and will be continued throughout pregnancy till delivery. Study personnel (field implementer and study physicians) will have monthly contacts with the enrolled women for monitoring compliance to intervention.
In the part 1 trial , we will conduct a non-inferiority, double blind, individually randomized controlled trial in non-pregnant women of reproductive age with iron deficiency anaemia (haemoglobin <120 g/L & serum ferritin <30 µg/L) to assess the haemoglobin and iron status in response to i) 200mg oral bovine lactoferrin, ii) 400mg of oral bovine lactoferrin and iii) standard oral iron supplements (60mg elemental iron). The aim of Part 1 trial is to find out the effective dose of bovine Lactoferrin (200 mg or 400mg) for anaemia correction compared to standard iron supplementation. The intervention (each capsule once daily) will be continued for 3 months. Study personnel (field implementer and study physicians) will have monthly contacts with the enrolled women for monitoring compliance to intervention.
Intervention code [1] 298699 0
Treatment: Other
Comparator / control treatment
Daily oral 60mg iron sulphate + placebo
Both comparators will be administered for the same duration as the intervention (i.e. throughout pregnancy). The placebo will contain sucrose -01.059mg, lactose-61.758mg, maize starch-92.18mg, heavy kaolin-2.467mg, povidone (5 30)-59.358mg, purified talc-52.622mg.
Control group
Active

Outcomes
Primary outcome [1] 302882 0
The primary outcome will be the change in haemoglobin concentration from baseline to 24 weeks, and 34th weeks of gestation. Spot test of Hemoglobin will be done using standard validated hemocue machine.
Timepoint [1] 302882 0
Baseline assessment, 24 week of gestation, 34 week of gestation
Secondary outcome [1] 337303 0
Change in serum ferritin concentration adjusted with CRP & AGP from baseline to 24th and 34th week of gestation. 5ml blood will be collected from each study participants. Serum ferritin will be measured using Chemiluminescence Immunoassay.
Timepoint [1] 337303 0
Baseline assessment, 24 week of gestation, 34 week of gestation
Secondary outcome [2] 337304 0
Change in serum hepcidin from baseline to 24th & 34th week of gestation. Hepcidin will be measured using ELISA methods.
Timepoint [2] 337304 0
Baseline assessment, 24 weeks gestation and 34 weeks of gestation
Secondary outcome [3] 337306 0
Change in serum IL6 concentrations wil be measured using ELISA technniques at baseline to 24th & 34th week of gestation
Timepoint [3] 337306 0
Baseline assessment, 24 week of gestation, 34 week of gestation
Secondary outcome [4] 337307 0
Prevalence of anaemia-related symptoms (fatigue, pallor, dyspnoea, nail disorders, loss of appetite, deterioration in cognitive functions and skin disorders) at each visit. This data will be collected during the scheduled follow-up interview of the study participants.
Timepoint [4] 337307 0
Baseline assessment, 24 week of gestation, 34 week of gestation, Birth assessment
Secondary outcome [5] 337308 0
Percentage of women reporting side effects including abdominal pain, nausea, vomiting, regurgitation, diarrhoea and constipation during the treatment. This data will be collected during the scheduled follow-up interview of the study participants.
Timepoint [5] 337308 0
Baseline assessment, 24 week of gestation, 34 week of gestation, Birth assessment
Secondary outcome [6] 337309 0
Number of women who discontinued the study because of side effects of the trial treatment. This information will be available from the regular monitoring data throughout study period.
Timepoint [6] 337309 0
Continuously throughout the study period during the regular monitoring process.
Secondary outcome [7] 337983 0
Mean changes in SF12 health survey summary indicators - Physical Component Summary (PCS) and Mental Component Summary (MCS) from baseline to 34 weeks of gestation. This information will assess the change in quality of life of the participants at the beginning till towards the end of pregnancy.
Timepoint [7] 337983 0
Baseline and 34 week of gestation
Secondary outcome [8] 337984 0
Weight of newborn at birth. This information will help measure the rate of low birthweght and preterm births among the enrolled pregnant women.
Timepoint [8] 337984 0
at delivery
Secondary outcome [9] 338320 0
Gestational weeks at delivery. This information will help measure the rate of preterm births among the enrolled pregnant women.
Timepoint [9] 338320 0
at delivery
Secondary outcome [10] 338321 0
Adherence to treatment will be assessed at 24 and 34 weeks of gestation by using structured questionnaire designed specifically for the study.
Timepoint [10] 338321 0
24 and 34 weeks of gestation

Eligibility
Key inclusion criteria
• Pregnant women (18 years or older upto 49 years) identified at <12 weeks of gestation (i.e. in their first trimester)
• Low haemoglobin <110 g/L to >70 g/L & serum ferritin <30 µg/L adjusted with CRP & AGP
Minimum age
18 Years
Maximum age
49 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
• Cases of severe anemia with haemoglobin <70 g/L will be excluded and referred to Shaheed Suhrawardy Medical College Hospital, which is the nearest tertiary level hospital for treatment
• Other iron supplements taken in the one month preceding enrolment
• Recent blood transfusion
• Women who are currently ill with fever
• History of chronic non-communicable diseases or history of TB
• Women intending to move from study area before the end of the study
• Ascertained allergy to milk proteins or to iron products

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
i) Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation), and ii) Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Estimated sample size is for a parallel two group superiority designed trial that will compare mean haemoglobin from each treatment group. The null hypothesis is that the haemoglobin response after one month of oral bovine lactoferrin (ML) is the same as with standard oral iron supplements (MI).
Ho: ML = MI
Ha: ML != MI (the means are not equal)
Assumptions:
• ML = 12.25 after 4 weeks of treatment
• MI = 12.00 after 4 weeks of treatment
• Expected standard deviation in each group = 0.85 (This is higher than part 1 because of increased variability of haemoglobin in pregnancy)
• Power = 0.90
• Alpha = 0.050 (two-sided)
The estimated required sample size per group is 243, giving a total estimated sample size of 486.
Since 20% of subjects are expected to be lost to follow-up, the total sample size is adjusted to 608.
This sample size would have 80% power to detect a difference in mean birthweight between the two treatment groups of 102g assuming a two sided alpha of 0.05, and standard deviation for birthweight in both groups of 400g.
This sample size would also have 80% power to detect a 41% relative difference in prevalence of low birth weight (25.0% in iron and 14.85% in lactoferrin treatment group) assuming a two sided alpha of 0.05. It would also have 80% power to detect a 56% relative difference in prevalence of preterm delivery (13.5% in iron and 6.0% in lactoferrin treatment group) assuming a two sided alpha of 0.05.
Calculation based on 'SSI': module to estimate sample size for RCTs in Stata version 14.

Analysis Plan
Participants who will receive at least one dose of supplement and at least one post-baseline efficacy assessment during the double-blind part will be included in the analysis. All analysis will be conducted at individual level. We will analyze participants categorized by the treatment group to which they will be allocated on an intention-to-treat (ITT) basis. The last day of follow up will be considered as outcome status for study participants who may be lost to follow-up without having the outcome of interest. To obtain the overall across-dose-range treatment (Lactoferrin and IFA supplements) effects, the average differences between log-dose slopes for percent changes from baseline in iron status and inflammatory biomarkers will be obtained in separate analyses (ANOVA) for all arms of part one. For safety analyses, descriptive statistics will be included for all parameters and an analysis of variance model (ANOVA) will be used for between-group (treatment arms) and within group (anaemic and mild anaemic) comparisons. For subgroup analyses, we will use Cox proportional hazard models (for mortality outcome), and other generalized linear mixed models (for preterm and low birth-weight outcomes) that will incorporate each of the major covariates. Statistical significance will be considered at p<0·05. Models will be able to evaluate the impact of the interventions by testing for interactions over time in all intervention groups. Analysis will be conducted to identify covariates that influence the response to interventions (based on household wealth, maternal education, or income).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
18/03/2018
Actual
Date of last participant enrolment
Anticipated
21/09/2018
Actual
Date of last data collection
Anticipated
31/03/2019
Actual
Sample size
Target
608
Accrual to date
Final
Recruitment outside Australia
Country [1] 9088 0
Bangladesh
State/province [1] 9088 0
Dhaka

Funding & Sponsors
Funding source category [1] 296956 0
Government body
Name [1] 296956 0
Medical Research Council (MRC)
Country [1] 296956 0
United Kingdom
Funding source category [2] 297098 0
Charities/Societies/Foundations
Name [2] 297098 0
Saving Lives at Birth
Country [2] 297098 0
United States of America
Primary sponsor type
Other
Name
International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)
Address
68, Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka, 1212
Country
Bangladesh
Secondary sponsor category [1] 295960 0
University
Name [1] 295960 0
University of Sydney
Address [1] 295960 0
Edward Ford Building (A27), Fisher Road, University of Sydney NSW 2006, Australia
Country [1] 295960 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298160 0
Institutional Review Board (IRB) of icddr,b
Ethics committee address [1] 298160 0
68, Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka 1212
Ethics committee country [1] 298160 0
Bangladesh
Date submitted for ethics approval [1] 298160 0
17/11/2015
Approval date [1] 298160 0
11/01/2016
Ethics approval number [1] 298160 0
PR-15116
Ethics committee name [2] 298275 0
Human Research Ethics Committee of The University of Sydney
Ethics committee address [2] 298275 0
Edward Ford Building (A27), Fisher Road, University of Sydney NSW 2006, Australia
Ethics committee country [2] 298275 0
Australia
Date submitted for ethics approval [2] 298275 0
21/01/2016
Approval date [2] 298275 0
07/07/2016
Ethics approval number [2] 298275 0
2016/148

Summary
Brief summary
Hypotheses:
• Oral bovine lactoferrin is more efficacious in correcting iron deficiency anaemia among pregnant women recruited in the first trimester compared to standard iron supplements.

Objectives:
1. To determine whether bovine lactoferrin is at least as effective as oral iron in treating iron deficiency anaemia among pregnant women of reproductive age.
2. To compare effectiveness of standard oral iron supplements and oral bovine lactoferrin in improving birthweight and reducing low birth weight and preterm births
3. To compare the side-effects of oral iron supplements and bovine lactoferrin
4. To compare the adherence of oral iron supplements and bovine lactoferrin

Methods:
We will conduct a parallel two-arm, double-blind, randomized controlled trial (RCT) in pregnant women, to compare the impact of supplementation with oral bovine lactoferrin and standard oral iron supplements on maternal iron status, and secondarily on low birth weight and preterm birth.

Outcome measures/variables:
The primary outcome will be the change in haemoglobin concentration from enrollment in the first trimester to third trimester (34 weeks) of pregnancy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76186 0
Prof Michael J Dibley
Address 76186 0
Professor in Global Public Health Nutrition
Sydney School of Public Health
Sydney Medical School
Edward Ford Building (A27), Fisher Road,
University of Sydney NSW 2006,
Australia
Country 76186 0
Australia
Phone 76186 0
+61293515203
Fax 76186 0
Email 76186 0
[email protected]
Contact person for public queries
Name 76187 0
Tanvir Mahmudul Huda
Address 76187 0
Research Associate and PhD Candidate
Sydney School of Public Health
Sydney Medical School
Edward Ford Building (A27), Fisher Road,
University of Sydney NSW 2006,
Australia

and
Project Coordinator
Maternal and Child Health Division (MCHD)
International Centre for Diarrhoeal Disease Research, Bangladeh (icddr,b)
68, Shaheed Tajudddin Ahmed Sarani
Mohakhali, Dhaka 1212
Country 76187 0
Australia
Phone 76187 0
+61412735284
Fax 76187 0
Email 76187 0
[email protected]
Contact person for scientific queries
Name 76188 0
Tanvir Mahmudul Huda
Address 76188 0
Research Associate and PhD Candidate
Sydney School of Public Health
Sydney Medical School
Edward Ford Building (A27), Fisher Road,
University of Sydney NSW 2006,
Australia

and
Project Coordinator
Maternal and Child Health Division (MCHD)
International Centre for Diarrhoeal Disease Research, Bangladeh (icddr,b)
68, Shaheed Tajudddin Ahmed Sarani
Mohakhali, Dhaka 1212
Country 76188 0
Australia
Phone 76188 0
+61412735284
Fax 76188 0
Email 76188 0
[email protected]

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