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Trial registered on ANZCTR


Registration number
ACTRN12617001455358
Ethics application status
Approved
Date submitted
1/06/2017
Date registered
13/10/2017
Date last updated
13/10/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing the appropriate dose and efficacy of bovine lactoferrin to correct iron deficiency anaemia in non pregnant women: 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 non pregnant women: A community-based randomized controlled trial in Mirpur, Dhaka
Secondary ID [1] 292097 0
None
Universal Trial Number (UTN)
Trial acronym
SHONJIBON 2 Part 1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Iron Deficiency Anemia 303518 0
Condition category
Condition code
Diet and Nutrition 302930 302930 0 0
Other diet and nutrition disorders
Blood 303412 303412 0 0
Anaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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 iii) standard oral iron supplements (60mg elemental iron). 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] 298239 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. 3 months). 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] 302322 0
The primary outcome will be the change in hemoglobin concentration from baseline to the end of the 12th week of treatment. Spot measurement of hemoglobin will be done at the site of primary screening using standard/validated hemocue device.
Timepoint [1] 302322 0
Baseline and 12 week assessment
Secondary outcome [1] 335489 0
Change in haemoglobin concentration from baseline to 4th, 8th and 12th week of treatment. Spot test of Hemoglobin will be done using standard validated hemocue machine.
Timepoint [1] 335489 0
Baseline, 4 week assessment, 8 week assessment, 12 week assessment
Secondary outcome [2] 337258 0
Change in serum ferritin concentration corrected with C-reactive protein (CRP) and Alpha 1 Glycoprotein (AGP) from baseline to 4th, 8th and 12th week of treatment. 5ml blood will be collected from each study participants. Serum ferritin will be measured using Chemiluminescence Immunoassay.
Timepoint [2] 337258 0
Baseline, 4 week assessment, 8 week assessment, 12 week assessment
Secondary outcome [3] 337259 0
Change in serum hepcidin concentration from baseline to 12th week of treatment. Hepcidin will be measured using ELISA methods.
Timepoint [3] 337259 0
at Baseline and 12 week assessment
Secondary outcome [4] 337260 0
Prevalence of anaemia-related symptoms (fatigue, pallor, dyspnoea, nail disorders, loss of appetite, deterioration in cognitive functions and skin disorders). This data will be collected during the scheduled follow-up interview of the study participants.
Timepoint [4] 337260 0
Baseline, 4 week assessment, 8 week assessment, 12 week assessment
Secondary outcome [5] 337261 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] 337261 0
Baseline, 4 week assessment, 8 week assessment, 12 week assessment
Secondary outcome [6] 337262 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] 337262 0
Continuously throughout the study period during the regular monitoring process.

Eligibility
Key inclusion criteria
• Age 18 through 49 years
• Non-lactating and non-pregnant
• Haemoglobin <120 g/L, & serum ferritin level <30 µg/L corrected with C-reactive protein (CRP) & a1-acid glycoprotein (AGP) (1, 40).
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 within 2 months of enrolment
• Reported 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
The estimated sample size is for a non-inferiority two-sample comparison of means for each dose of lactoferrin. The null hypothesis is that the degree of inferiority of the haemoglobin response after one month of oral bovine lactoferrin (L) to standard oral iron supplements (I), I-L, is greater than the margin M thus ruling out a degree of inferiority greater than the margin M.
Ho: I-L = M (L is more inferior to I than M)
Ha: I-L < M (L is less inferior to I than M)
Assumptions:
• Based on evidence from prior studies the response of iron compared to placebo is 10.0 g/L, and M, the largest clinically acceptable difference, is 2.5 g/L.
• Expected standard deviation = 0.80 (in each group)
• Power = 0.80
• Alpha = 0.025 (one-sided)
The estimated required sample size per group is 161, giving a total sample size of 483 for the 3 treatment groups.
Since 15% of subjects are expected to be lost to follow-up, the total sample size is adjusted to 556.
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 patients 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
1/11/2017
Actual
Date of last participant enrolment
Anticipated
28/02/2018
Actual
Date of last data collection
Anticipated
30/04/2018
Actual
Sample size
Target
556
Accrual to date
Final
Recruitment outside Australia
Country [1] 8945 0
Bangladesh
State/province [1] 8945 0
Dhaka

Funding & Sponsors
Funding source category [1] 296628 0
Government body
Name [1] 296628 0
Medical Research Council (MRC)
Country [1] 296628 0
United Kingdom
Funding source category [2] 296631 0
Charities/Societies/Foundations
Name [2] 296631 0
Saving Lives at Birth
Country [2] 296631 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] 295590 0
University
Name [1] 295590 0
University of Sydney
Address [1] 295590 0
Edward Ford Building (A27), Fisher Road, University of Sydney NSW 2006, Australia
Country [1] 295590 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297860 0
Institutional Review Board (IRB) of icddr,b
Ethics committee address [1] 297860 0
68, Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka 1212
Ethics committee country [1] 297860 0
Bangladesh
Date submitted for ethics approval [1] 297860 0
17/11/2015
Approval date [1] 297860 0
11/01/2016
Ethics approval number [1] 297860 0
PR-15116
Ethics committee name [2] 297863 0
Human Research Ethics Committee of The University of Sydney
Ethics committee address [2] 297863 0
Edward Ford Building (A27), Fisher Road, University of Sydney NSW 2006, Australia
Ethics committee country [2] 297863 0
Australia
Date submitted for ethics approval [2] 297863 0
21/01/2016
Approval date [2] 297863 0
07/07/2016
Ethics approval number [2] 297863 0
2016/148

Summary
Brief summary
Hypotheses:
• Oral bovine lactoferrin is at least as effective in correcting iron deficiency anaemia among non-pregnant women of reproductive age compared to standard iron supplements.

Objectives:
1. To determine the optimal dose of oral bovine lactoferrin for correction and prevention of iron deficiency anaemia in women of reproductive age.
2. To determine whether bovine lactoferrin is at least as effective as oral iron in treating iron deficiency anaemia among non-pregnant women of reproductive age.
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 non-inferiority randomized controlled trial (RCT), to compare different doses of oral bovine lactoferrin with standard oral iron supplements in non-pregnant anaemic women of reproductive age to determine the appropriate dose of bovine lactoferrin, and demonstrate it is safe and as effective as standard oral iron supplements in treating iron deficiency anaemia.

Outcome measures/variables:
The primary outcome will be the change in haemoglobin concentration from baseline to the end of the twelfth week of treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75294 0
Prof Michael J Dibley
Address 75294 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 75294 0
Australia
Phone 75294 0
+61293515203
Fax 75294 0
Email 75294 0
[email protected]
Contact person for public queries
Name 75295 0
Tanvir Mahmudul Huda
Address 75295 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 75295 0
Bangladesh
Phone 75295 0
+61412735284
Fax 75295 0
Email 75295 0
[email protected]
Contact person for scientific queries
Name 75296 0
Tanvir Mahmudul Huda
Address 75296 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 75296 0
Australia
Phone 75296 0
+61412735284
Fax 75296 0
Email 75296 0
[email protected]

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