Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001577707
Ethics application status
Approved
Date submitted
21/11/2022
Date registered
20/12/2022
Date last updated
20/12/2022
Date data sharing statement initially provided
20/12/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Folate trial for recurrent miscarriage
Scientific title
The effectiveness of 5-methyltetrahydrofolate versus folic acid prenatal multivitamins in couples with a history of recurrent pregnancy loss: A randomised-controlled feasibility trial
Secondary ID [1] 308115 0
Nil known
Universal Trial Number (UTN)
U1111-1283-5932
Trial acronym
FRM- Folate trial for recurrent miscarriage
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recurrent Miscarriage 327822 0
Condition category
Condition code
Reproductive Health and Childbirth 324898 324898 0 0
Abortion
Reproductive Health and Childbirth 324899 324899 0 0
Fertility including in vitro fertilisation
Reproductive Health and Childbirth 324900 324900 0 0
Fetal medicine and complications of pregnancy
Reproductive Health and Childbirth 324901 324901 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
5-methyltetrahydrofolate (5-MTHF) based prenatal multivitamin (intervention - Arm 1)
Dose: 5-MTHF 2,500mcg per day
5-methyltetrahydrofolate (5-MTHF) is the biologically active form of folate. It does not build up like folic acid and can be utilised without being converted to the form required to support DNA integrity.
Participants will be required to take one dose (3 capsules) of their allocated prenatal multivitamin per day. They will also be provided to avoid folic acid fortified foods.
They will be asked to receive regular blood testing including: Methylenetetrahydrofolate reductase (MTHFR) polymorphism, Vitamin B12, methylmalonic acid (MMA), red cell folate, serum folate, homocysteine. The initial baseline blood test will be completed immediately upon recruitment ie: first 2 weeks, another blood test will be taken following 2 reproductive cycles. Participants who fall pregnant will receive a blood test each trimester of pregnancy for the duration of the trial.
Provider - the PhD candidate is a naturopath with 12 years experience and therefore within her scope of practice to dispense the prenatal multivitamins.
Delivery - Intervention will be sent every 3 months via mail with internet based meetings every 6 weeks
Participants will be recruited Australia wide
There will be a rolling recruitment period from January 16, 2023 to March 30, 2023. Participants recruited into the study will immediately commence on the prenatal multivitamin and continue until the trial period is completed, December 30, 2023. Participants will be therefore be participating in the trial for a minimum of 9 months, maximum 12 months, depending on their recruitment date.
An internet based meeting will be conducted with the PhD Candidate who is a naturopath, every 6 weeks for approximately 30 minutes per participant. The purpose of this meeting will be to document and understand:
1. How the participant experiencing any tolerability issues with their intervention.
2. Does the participant need any support around folic acid avoidance diet
3. Are there any adherance issues - If more than 20% of supplement doses are missed then the participant will be ask to explain why they are unable to meet the requirements of the trial and if they are unable to improve fidelity they will be eliminated from the trial.
4. Have there been any adverse events
5. Is the participant experiencing any distress due to the protocols
6. Reproductive status ie: any hormonal issues, pregnancies to report
Intervention code [1] 324569 0
Prevention
Comparator / control treatment
Folic acid based prenatal multivitamin.
Dose: 2,500mcg
Participants will be required to take one dose (3 capsules) of their allocated prenatal multivitamin per day. They will also be provided to avoid folic acid fortified foods.
Provider - the PhD candidate is a naturopath and therefore within her scope of practice to dispense the prenatal multivitamins.
There will be a rolling recruitment for this trial commencing January 16, 2023 until March 30 2023. Upon recruitment, participants will commence the multivitamin and continue until the completion of the study or until they withdraw. This will be a minimum of 9 months or maximum 12 months period of time or until study completion (December 30, 2023)
Delivery - via mail with internet based meetings every 6 weeks.
An internet based meeting will be conducted with the PhD Candidate who is a naturopath, every 6 weeks for approximately 30 minutes per participant. The purpose of this meeting will be to document and understand:
1. How the participant experiencing any tolerability issues with their intervention.
2. Does the participant need any support around folic acid avoidance diet
3. Are there any adherance issues - If more than 20% of supplement doses are missed then the participant will be ask to explain why they are unable to meet the requirements of the trial and if they are unable to improve fidelity they will be eliminated from the trial.
4. Have there been any adverse events
5. Is the participant experiencing any distress due to the protocols
6. Reproductive status ie: any hormonal issues, pregnancies to report
Participants will be recruited Australia wide
Participants will be participating in the trial for a minimum of 9 months, maximum 12 months (study completion December 30, 2023)
Control group
Active

Outcomes
Primary outcome [1] 332705 0
Feasibility determined by an audit of participant adherence to their allocated treatment, which will be assessed using participant self-report.
Timepoint [1] 332705 0
At 9 months after randomisation
Secondary outcome [1] 414421 0
Acceptability of the proposed study protocol to participants and potential participants determined by assessing the number of eligible individuals who enquire about study involvement according to study recruitment logs.
Timepoint [1] 414421 0
At 9 months after randomisation
Secondary outcome [2] 414423 0
Implementation – Participant adherence to data collection requirements (ie. whether or not assessments were completed within two weeks of the required timepoints) assessed by audit of study database.


Timepoint [2] 414423 0
assessed at week 2, 4, 12, 18, at 9 months post-randomisation
Secondary outcome [3] 414424 0
Number of researcher hours requred to manage the trial assessed by study-specific diary kept by researchers.
Timepoint [3] 414424 0
At 9 months post randomisation
Secondary outcome [4] 414425 0
Investigate the 'folate for miscarriage trial' study participants behaviours and attitudes towards taking 5-MTHF vs folic acid via a post study survey of trial participants created specifically for this study.
Timepoint [4] 414425 0
At 12 months post randomisation
Secondary outcome [5] 414426 0
Levels of Unmetabolised folic acid, serum folate, red cell folate, Vitamin B 12, homocysteine and MTHFR polymorphisms assessed using blood samples.
Timepoint [5] 414426 0
At baseline: ie: first two week of the trial, 8 weeks post-randomisation, 3 months post randomisation and once only during second and third trimesters (if pregnant)
Secondary outcome [6] 416614 0
Side effects associated with the dose of 5-MTHF or folic acid assessed via research/participant regular update meetings
Timepoint [6] 416614 0
Identified at time points: week 2, 8, 14 and every 6 weeks thereafter until conclusion of study (December 30, 2023)
Secondary outcome [7] 416790 0
Acceptability - Conversion rate of participants who enquire about the study assessed assessed by audit of participants that enquire vs those that are recruited.
Timepoint [7] 416790 0
After completion of rolling recruitment phase (end March 2023)
Secondary outcome [8] 416792 0
Acceptability - Proportion of participants who accept randomisation assessed by audit of study database.
Timepoint [8] 416792 0
9 months post randomisation
Secondary outcome [9] 416793 0
Acceptability - Proportion of participants who withdraw from the study assessed by audit of study database.
Timepoint [9] 416793 0
9 months post randomisation
Secondary outcome [10] 416794 0
Acceptability - Proportion of participants who complete the study assessed by audit of study database.
Timepoint [10] 416794 0
9 months post randomisation
Secondary outcome [11] 416803 0
Implementation - Adherence to the dietary requirement of avoiding folic acid fortified foods using 24-hour and 7-day recall of diet assessed by diet diary at check in meetings.
Timepoint [11] 416803 0
Assessed at 6, 8, 12 and every 6 weeks thereafter until study conclusion (December 30, 2023).
Secondary outcome [12] 416804 0
Implementation - Adherence to the abstinence of trying to conceive for 2 reproductive cycles following the introduction of the multivitamin via meeting update data collected throughout the trial.
Timepoint [12] 416804 0
Assessed at 4, 6, 8 and every 6 weeks thereafter until conclusion of study (December 30, 2023).
Secondary outcome [13] 416805 0
Implementation - Study participants perceptions of the support provided through online meetings assessed by post event survey of study participants.
Timepoint [13] 416805 0
9 months post randomisation
Secondary outcome [14] 416808 0
Implementation - Practicalities and adherence by participant and Dr for the confirmation processes. Rate of consenting participants and their practitioners that
completed the confirmation sheets within two weeks of the requirements assessed by audit of study database.
Timepoint [14] 416808 0
9 months post randomisation
Secondary outcome [15] 416809 0
Resources required by researchers. Financial, capital, and perishable resources required to run the trial via a researcher study diary
Timepoint [15] 416809 0
9 months post randomisation
Secondary outcome [16] 416810 0
Practicality and effectiveness of recruitment methods including screening and eligibility processes. The dollar cost per participant for recruitment including the most cost-effective method used for recruitment via audit of recruitment strategy and execution.
Timepoint [16] 416810 0
9 months post randomisation
Secondary outcome [17] 416811 0
Recruitment rates per week/month, recruitment and screening/eligibility process evaluation via audit of recruitment strategy and execution.
Timepoint [17] 416811 0
9 months post randomisation
Secondary outcome [18] 416812 0
Effectiveness and practicality of the participant and researcher blinding process. Participants self-reported perception of whether they had been allocated the trial or control product assessed by post event survey of study participants
Timepoint [18] 416812 0
9 months post randomisation
Secondary outcome [19] 416813 0
Practicalities, ease of use of the online booking system and meeting scheduling system. Participant perceptions of the online booking system including ease of use, errors, failures in booking procedures assessed via post event survey of study participants.
Timepoint [19] 416813 0
9 month post randomisation
Secondary outcome [20] 416814 0
Rate of errors associated with booking procedures using the online booking system assessed by audit of study database.
Timepoint [20] 416814 0
9 months randomisation
Secondary outcome [21] 416815 0
Practicalities associated with clinicians adherence to the study protocol assessed by audit of study database.
Timepoint [21] 416815 0
9 month post randomisation
Secondary outcome [22] 416817 0
Confirmation of recurrent pregnancy loss assessed via researcher/participant meetings.
Timepoint [22] 416817 0
Assessed at 4, 6, 8 and every 6 weeks thereafter until conclusion of study (December 30, 2023)
Secondary outcome [23] 416818 0
Confirmation of viable pregnancy scan at 18-22 weeks gestation assessed via Dr confirmation of a 'viable pregnancy' scan.
Timepoint [23] 416818 0
Assessed between 18-22 weeks of gestation
Secondary outcome [24] 416819 0
Participant retention overall and between the groups
- Rate of participant retention amongst the allocation groups, and reasons for study withdrawal assessed by audit of study database.
Timepoint [24] 416819 0
9 months post randomisation
Secondary outcome [25] 416820 0
Practicalities of data collection processes including time to data completion assessed by post event participant survey.
Timepoint [25] 416820 0
9 months post randomisation
Secondary outcome [26] 416821 0
Protocol changes required to achieve objectives assessed via audit of study database.
Timepoint [26] 416821 0
9 months post randomisation
Secondary outcome [27] 416822 0
Treatment effects/outcome expectations . Time to pregnancy versus expected time to pregnancy in the intervention group (2-4 reproductive
cycles post the abstinence period) assessed by audit of study database.

Timepoint [27] 416822 0
9 month post randomisation
Secondary outcome [28] 416823 0
Research team challenges in conducting the study assessed via researcher diary


Timepoint [28] 416823 0
9 months post randomisation

Eligibility
Key inclusion criteria
1. Women aged 20-49 years of age with two or more pregnancy losses before 22 weeks and their reproductive partners
2. Ability to speak and understand English sufficiently to comprehend the purpose and risks of the study and to provide consent
3. Ability to attend a pathology centre for specimen collection
4. Ability to not take concomitant medications, vitamins, food containing folic acid
Minimum age
20 Years
Maximum age
49 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant or lactating women
2. Couples who are currently undergoing assisted reproductive technologies
3. Men and women taking folate antagonist medication (phenytoin, valproic acid, valproate sodium, carbamazepine, methotrexate, trimethoprim hydrochloride, trimethoprim sulphate, trimethoprim, aminopterin sodium, phenobarbital, phenobarbital sodium, primidone, divalproex)
4. Individuals with a known sensitivity to any ingredients in the products
5. History or presence of psychiatric disorders (including depression and severe anxiety), autoimmune disease, and cancer
6. History of gynaecological and/or genetic problems– antiphospholipid syndrome, blocked fallopian tubes, Pelvic inflammatory disease, Primary ovarian insufficiency, endometriosis, Uterine fibroids, Factor V Leiden

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is concealed.
Central randomisation by computer within the REDCap software programme
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation
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
As this is a pilot study a sample of 30 women in each arm has been selected based on a previous study (Kelsey M. Cochrane et al., 2020). Partners will be included (30 women and men in each arm) 120 participants in total.
This pilot study will help to inform sample size calculations for the future study.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
16/01/2023
Actual
Date of last participant enrolment
Anticipated
31/03/2023
Actual
Date of last data collection
Anticipated
30/04/2024
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 312370 0
University
Name [1] 312370 0
University of Technology Sydney
Country [1] 312370 0
Australia
Funding source category [2] 312771 0
Commercial sector/Industry
Name [2] 312771 0
Aprofol AG
Country [2] 312771 0
Switzerland
Funding source category [3] 312772 0
Commercial sector/Industry
Name [3] 312772 0
Balchem Corporation
Country [3] 312772 0
United States of America
Funding source category [4] 312826 0
Other
Name [4] 312826 0
Go Fund me
Country [4] 312826 0
Australia
Primary sponsor type
University
Name
University of Technology Sydney
Address
Dr Amie Steel
University of Technology Sydney
School of Public Health
Faculty of Health
P.O Box 123, Broadway NSW 2007
Country
Australia
Secondary sponsor category [1] 313936 0
None
Name [1] 313936 0
Address [1] 313936 0
Country [1] 313936 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311730 0
UTS HREC
Ethics committee address [1] 311730 0
Ethics committee country [1] 311730 0
Australia
Date submitted for ethics approval [1] 311730 0
16/05/2022
Approval date [1] 311730 0
20/10/2022
Ethics approval number [1] 311730 0
ETH22-7218.

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122162 0
Dr Amie Steel
Address 122162 0
Senior Research Fellow
School of Public Health
Faculty of Health
Level 7
235 Jones Street,
Ultimo NSW 2007
Country 122162 0
Australia
Phone 122162 0
+61 418786186
Fax 122162 0
Email 122162 0
amie.steel@uts.edu.au
Contact person for public queries
Name 122163 0
Amie Steel
Address 122163 0
Senior Research Fellow
School of Public Health
Faculty of Health
University of Technology Sydney
Level 7,
235 Jones Street, Ultimo NSW 2007
Country 122163 0
Australia
Phone 122163 0
+61 418786186
Fax 122163 0
Email 122163 0
amie.steel@uts.edu.au
Contact person for scientific queries
Name 122164 0
Amie Steel
Address 122164 0
Senior Research Fellow
School of Public Health
Faculty of Health
University of Technology Sydney
Level 7,
235 Jones Street, Ultimo NSW 2007
Country 122164 0
Australia
Phone 122164 0
+61 418786186
Fax 122164 0
Email 122164 0
amie.steel@uts.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
individual participant data underlying published results only
When will data be available (start and end dates)?
Immediately following publication
Data will be available for 2 years after publication
Available to whom?
only researchers who provide a methodologically sound proposal
Available for what types of analyses?
only to achieve the aims in the approved proposal
How or where can data be obtained?
access subject to approvals by Principal Investigator - amie.steel@uts.edu.au


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.