Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000397910
Ethics application status
Approved
Date submitted
19/02/2020
Date registered
23/03/2020
Date last updated
23/03/2020
Date data sharing statement initially provided
23/03/2020
Date results information initially provided
23/03/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Metformin and vitamin B12 deficiency in patients with gestational diabetes mellitus.
Scientific title
To determine an association between metformin use in gestational diabetes mellitus and 
vitamin B12 deficiency 

Secondary ID [1] 300487 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gestational diabetes mellitus 316161 0
Vitamin B12 deficiency in pregnancy 316162 0
Impact of vitamin B12 deficiency on the pregnancy outcome.   316163 0
Condition category
Condition code
Metabolic and Endocrine 314458 314458 0 0
Other metabolic disorders
Reproductive Health and Childbirth 314679 314679 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Pregnant women with gestational diabetes underwent measurements of total vitamin B12 levels and holotranscobalamin levels (HoloTC) as a marker of functional vitamin B12 status [1]. In addition, all women underwent measurements of folate, FBC with MCV and MCH as per current standard of care in gestational diabetes clinics. The vitamin B12 levels was measured at the first visit to the gestational diabetes clinic, after 30 weeks of pregnancy and additionally after 4­-6 weeks of treatment with metformin.
Study participants were assigned to their study treatments (diet, insulin, metformin or metformin and insulin) and their clinical progress was monitored as per standard medical care. The data collection from studied participants will start from their first visit to the gestational diabetes clinic until 7 days post-partum.
For the purpose of the analysis patients will be split based on their treatment regimen into the following groups: 1. Treated with metformin <1000 mg 2. Treated with metformin 1000mg-2000 mg 3. Treated with diet and lifestyle changes (control group) 4. Treated with insulin 5. Treated with metformin and insulin
We will assess the outcome of pregnancies in patients with vitamin B12 deficiency, which we will determine based on the following information from medical records: 1. Gestational age at delivery 2. Duration of metformin treatment – to elucidate the average duration of metformin treatment leading to the vitamin B12 deficiency 3. Impact of vitamin B12 status on control of GDM – to assess whether deficiency/ insufficiency of vitamin B12 levels was associated with poorer control of GDM 4. Birth weight of neonate 5. Rates of pregnancy complications for: A Gestational hypertension B. Pre¬eclampsia C. Antenatal haemorrhage D. Pre­term labour E. Pre­term rupture of membranes

1. Nexo, E. and E. Hoffmann-Lucke, Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr, 2011. 94(1): p. 359S-365S.
Intervention code [1] 316796 0
Not applicable
Comparator / control treatment
Women treated with diet and lifestyle changes (control group).
Control group
Active

Outcomes
Primary outcome [1] 322814 0
The principle study outcome was the difference in vitamin B12 level, in comparison with baseline, as measured by the serum assay, following 4 different treatment interventions for the gestational diabetes mellitus (GDM) (such as dietary modification, treatment with metformin, metformin and insulin and insulin alone).
Timepoint [1] 322814 0
The vitamin B12 levels will be measured at the first visit to the gestational diabetes clinic, after 30 weeks of pregnancy and additionally after 4­-6 weeks of treatment with metformin.
The primary timepoint will be the last measurement of vitamin B12 levels during the pregnancy of GDM women as outlined by the standard of clinical care .
Primary outcome [2] 322815 0
The primary study outcome is the effect of vitamin B12 status on composite obstetric outcome with the rates of pregnancy complications: a Gestational hypertension b. Pre­eclampsia c. Antenatal haemorrhage d. Pre­term labour e. Pre­term rupture of membranes as identified from patients medical records.
Timepoint [2] 322815 0
The assessment will occur at the time of childbirth.
Primary outcome [3] 323281 0
The primary composite study outcome is the effect of vitamin B12 status on composite neonatal outcome including a. Neonatal birth weight b. Neonatal admission c. Still birth d. Shoulder dystocia. as identified from patients medical records.
Timepoint [3] 323281 0
The assessment will occur at the time of childbirth.
Secondary outcome [1] 379880 0
To identify the composite predictors of gestational diabetes treatment as identified from patients' medical records.
Timepoint [1] 379880 0
The assessment will occur at the time of childbirth.

Eligibility
Key inclusion criteria
1. Gestational diabetes mellitus diagnosed on oral glucose tolerance test.
2. Patient at Sutherland Hospital and St George Gestational Diabetes Clinic.
3. Valid consent
Minimum age
18 Years
Maximum age
50 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior diagnosis of diabetes (T1DM or T2DM)
2. Diagnosis of pernicious anaemia
3. Treatment with proton pump inhibitors or H2 receptor antagonists

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Both
Statistical methods / analysis
Data analysis plan As outlined by the recent report, vitamin B12 insuffciency among pregnant women was common in all trimesters across the world affecting up to 30 % of patients even in nonvegetarian populations[1].
Based on the expected changes in Vitamin B12 level in metformin treated pregnant patients, we anticipate that up to 37% of pregnant patients may become diagnosed with vitamin B12 deficiency by 36 weeks of gestation[2]. Therefore we need to recruit a minimum 110 study subjects, 55 subjects in the metformin taking GDM group and 55 subjects in the diet or insulin treated GDM group. It is therefore anticipated that 120 patients will take part in this study. We have estimated that a study with a sample size of 110 individuals has an 80% chance to detect the effect of metformin use on vitamin B12 level in GDM patients at the significance level of 5%.
The analysis plan will have several steps:
1) Determine baseline characteristics of study participants including their baseline vitamin B12 status.
2) Determine the individual (within­ subject) change of parameters (FBC, MCV, MCH, folate levels, holotranscobalamin levels, total vitamin B12) after 30 weeks of pregnancy as well as after 4­-6 weeks of metformin treatment in comparison with their baseline values.
3) Analysis and comparison of the pattern of change amongst the two different intervention groups (patients treated with diet or insulin in comparison with people treated with metformin).
We will analyze the data using SAS statistical software. We will examine if there is a difference in total vitamin B12 and holotranscobalamin levels between GDM patients who are treated with metformin and those GDM patients who are treated with diet and lifestyle changes as well as with insulin. We will also investigate changes in vitamin B12 and holotranscobalamin levels in relation to BMI, age, duration of metformin treatment, use of multivitamins, alcohol intake and folate levels. The results from this study will highlight groups of women with gestational diabetes that are at a higher risk of vitamin B12 deficiency and therefore requiring monitoring of their vitamin B12 status.

1. Sukumar, N., et al., Prevalence of vitamin B-12 insufficiency during pregnancy and its effect on offspring birth weight: a systematic review and meta-analysis. Am J Clin Nutr, 2016. 103(5): p. 1232-51.
2. Gatford, K.L., et al., Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment. Diabetes Obes Metab, 2013. 15(7): p. 660-7.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
1/01/2016
Date of last participant enrolment
Anticipated
Actual
30/06/2019
Date of last data collection
Anticipated
30/06/2020
Actual
Sample size
Target
120
Accrual to date
Final
120
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 15833 0
The Sutherland Hospital - Caringbah
Recruitment postcode(s) [1] 29278 0
2229 - Caringbah

Funding & Sponsors
Funding source category [1] 304906 0
Self funded/Unfunded
Name [1] 304906 0
Country [1] 304906 0
Primary sponsor type
Hospital
Name
Sutherland Hospital
Address
Sutherland Hospital  Mailing Address: The Kingsway, Caringbah NSW 2229, Australia 
Country
Australia
Secondary sponsor category [1] 305248 0
None
Name [1] 305248 0
Address [1] 305248 0
Country [1] 305248 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305315 0
South Eastern Sydney Local Health District Human Research Ethics Committee,
Ethics committee address [1] 305315 0
Prince of Wales Hospital
G71 East Wing , Edmund Blacket Building,
Randwick NSW 2031, Australia
Ethics committee country [1] 305315 0
Australia
Date submitted for ethics approval [1] 305315 0
10/08/2017
Approval date [1] 305315 0
10/10/2017
Ethics approval number [1] 305315 0

Summary
Brief summary
Several studies have shown that vitamin B12 status during pregnancy is of major importance to health of mother and her offspring. As vitamin B12 deficiency poses risks to both the expectant mother and foetus it is vital for pregnant women, who are at risk of vitamin B12 deficiency, to undergo appropriate monitoring and to have adequate vitamin B12 supplementation.
We hypothesized that the metformin use for treatment of gestational diabetes will increase the risk for the development of vitamin B12 deficiency.
Study participants were assigned to their study treatments (diet, insulin, metformin or metformin and insulin) according to the required standard of care during their pregnancies. Pregnant women underwent measurements of total vitamin B12 levels and holotranscobalamin levels, folate, FBC with MCV and MCH. The vitamin B12 levels were measured at the first visit to the gestational diabetes clinic, after 30 weeks of pregnancy and additionally after 4­-6 weeks of treatment with metformin. The present study will additionally examine the antenatal and postnatal outcomes of pregnancies in patients with vitamin B12 deficiency, which we will determine based on the information from patients’ medical records.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 99966 0
Dr Malgorzata Brzozowska
Address 99966 0
Sutherland Hospital, Caringbah NSW, 2229
Country 99966 0
Australia
Phone 99966 0
+61295407111
Fax 99966 0
Email 99966 0
[email protected]
Contact person for public queries
Name 99967 0
Dr Malgorzata Brzozowska
Address 99967 0
Sutherland Hospital, Caringbah New South Wales, 2229
Country 99967 0
Australia
Phone 99967 0
+61295407111
Fax 99967 0
Email 99967 0
[email protected]
Contact person for scientific queries
Name 99968 0
Dr Malgorzata Brzozowska
Address 99968 0
Sutherland Hospital, Caringbah, NSW 2229
Country 99968 0
Australia
Phone 99968 0
+61295407111
Fax 99968 0
Email 99968 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
Current Study Results
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Conference abstractNo Predictors of response to treatment and effects of... [More Details]
Conference posterNo

Update to Study Results
Doc. No.TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
836Conference abstractYes Predictors of response to treatment and effects of... [More Details]
837Conference posterYes Brzozowska MM; Puvanendran A; Bliuc D; Zuschmann A... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbasePredictors for pharmacological therapy and perinatal outcomes with metformin treatment in women with gestational diabetes.2023https://dx.doi.org/10.3389/fendo.2023.1119134
N.B. These documents automatically identified may not have been verified by the study sponsor.