Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001016325
Ethics application status
Approved
Date submitted
9/07/2017
Date registered
14/07/2017
Date last updated
24/10/2019
Date data sharing statement initially provided
27/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Pregnancy outcomes when adding a progesterone pessary dose amongst women who are receiving frozen embryo transfer with hormone replacement therapy, compared with placebo.
Scientific title
Prospective randomised trial of change of progesterone dosage in HRT FETs with low serum progesterone concentrations after 2 days of progesterone pessary treatment
Secondary ID [1] 292392 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infertility 303957 0
Condition category
Condition code
Reproductive Health and Childbirth 303312 303312 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised to receive either an extra progesterone 400mg pessary or a placebo pessary for 12 weeks. For patients on a twice daily dose this study pessary will be used at midday. Those on a thrice daily dose will use the extra study pessary in the late evening. This aims to leave unchanged the timing of initial active pessaries for patients where a placebo pessary is added, so that there is no change to the background dosing. We do not intend to monitor compliance of participants with the allocated intervention. Participation will be viewed on an ‘intention to treat’ analysis.
Intervention code [1] 298565 0
Treatment: Drugs
Comparator / control treatment
Treatment arm: progesterone pessary 400mg dose daily for 12 weeks
Control arm: placebo pessary daily for 12 weeks
Control group
Placebo

Outcomes
Primary outcome [1] 302697 0
Live birth rate
Timepoint [1] 302697 0
At time of birth
Secondary outcome [1] 336772 0
Clinical pregnancy levels at 16 days of treatment. This will be measured by serum hCG level.
Timepoint [1] 336772 0
Day 16 of treatment
Secondary outcome [2] 336773 0
Serum progesterone levels at Day 2 and Day 16 of treatment
Timepoint [2] 336773 0
Day 2 and Day 16 of treatment

Eligibility
Key inclusion criteria
1. Is a female receiving single embryo FET with HRT at Monash IVF
2. Is between the age of 18 and 45 years
3. Has provided informed consent
4. Speaks sufficient English to provide informed consent
5. Has been prescribed an initial progesterone pessary dose of 400mg bd or tds and is obtaining these pessaries from Slade pharmacy
6. Low serum progesterone levels at Day 2 of progesterone treatment (<50nmol/L)
Minimum age
18 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Already completed an HRT FET cycle in this study
• Planned double embryo transfer.

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)
2 sets of sealed envelopes will be held by trial coordinator. The envelopes will be opened consecutively as each new patientis enrolled in the study (ie provides consent and then has Day 2 progesterone <50 nmol/L). Trial coordinator will then communicate the assignment (green vs orange) to the patient and pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Consecutive randomisation (as above).
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
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size – this has been calculated based on Monash IVF data (live birth rate if P4<50 nmol/L of 11.3% vs 26.4% if >50nmonl/L). For power of 80 and alpha of 0.05, requires 152 patients in each group.

For comparison of proportions Chi square testing will be used. Continuous variables will be compared using Mann Whitney U testing. Repeated measures ANOVA or linear mixed modelling will be used for comparison of repeated measures.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
1/01/2019
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
304
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 8504 0
Monash IVF - Clayton - Clayton
Recruitment hospital [2] 8505 0
Epworth Richmond - Richmond
Recruitment hospital [3] 8506 0
Western Day Surgery - St Albans
Recruitment postcode(s) [1] 16599 0
3021 - St Albans
Recruitment postcode(s) [2] 16598 0
3121 - Richmond
Recruitment postcode(s) [3] 16597 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 296947 0
Commercial sector/Industry
Name [1] 296947 0
Monash IVF Pty Ltd
Country [1] 296947 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Monash IVF Pty Ltd
Address
Epworth Hospital Richmond, Level 7, 89 Bridge Road, Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 295951 0
None
Name [1] 295951 0
N/A
Address [1] 295951 0
N/A
Country [1] 295951 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298152 0
Monash Health
Ethics committee address [1] 298152 0
246 Clayton Road
Clayton
VIC 3168
Ethics committee country [1] 298152 0
Australia
Date submitted for ethics approval [1] 298152 0
23/03/2017
Approval date [1] 298152 0
22/02/2019
Ethics approval number [1] 298152 0

Summary
Brief summary
FETs using HRT stimulation occur with no corpus luteum. This means endometrial growth, maturation and maintenance is entirely dependent on the effect of HRT for at least the first 2-5 weeks post-transfer. By 10 weeks post-transfer the placenta is producing adequate hormone to support the endometrium. Although intramuscular progesterone treatment is popular in North America, in Australia and Europe vaginal preparations are preferred.
Natural and HRT FET cycles have been compared and show equivalent live birth rates on meta-analysis. The local experience at Monash IVF is different, with a significantly lower live birth rate for HRT compared to natural FETs (14.5% vs 22.4% - OR 0.59 (0.55-0.62)) for all comers. This difference is maintained when 20 potential confounding factors are allowed for using logistic regression (patient age; number of embryos transferred, embryo maturity etc) with an adjusted odds ratio of 0.55 (0.48-0.64).
A recent publication from Yovich (2015) showed a significantly higher live birth rate in women undergoing HRT FETs, where the mid-luteal phase serum progesterone was >50 nmol/L. Review of the Monash IVF dataset investigating serum progesterone concentrations after 14-18 days of treatment in HRT FETs confirmed a significantly higher live birth rate (26.4% vs 11.3%). A shortcoming of measuring progesterone both at mid-luteal and Day 14-18, is that the opportunity to change management and improve outcome has potentially already passed.
A further retrospective review of Monash IVF HRT FET cycles investigating progesterone dosage, Day 14-18 serum progesterone and live birth rates, suggested that dose frequency may be as important of actual dosage.
This study aims to investigate “at risk” women with low serum progesterone (<50 nmol/L), but measure this after 2 days of treatment and then assess the effect of adding an extra dose of progesterone each day upon the live birth rate.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76154 0
A/Prof Martin Healey
Address 76154 0
Monash IVF Pty Ltd, 7/89 Bridge Rd, Richmond VIC 3121
Country 76154 0
Australia
Phone 76154 0
+6139429 9188
Fax 76154 0
Email 76154 0
kathandmutt@bipond.com
Contact person for public queries
Name 76155 0
Ms Samantha Ter
Address 76155 0
Monash IVF Pty Ltd, 7/89 Bridge Rd, Richmond VIC 3121
Country 76155 0
Australia
Phone 76155 0
+61394208245
Fax 76155 0
Email 76155 0
samantha.ter@monashivf.com
Contact person for scientific queries
Name 76156 0
Dr Surabhi Basnayake
Address 76156 0
Monash Health
246 Clayton Road
Clayton
VIC 3168
Country 76156 0
Australia
Phone 76156 0
+61395946666
Fax 76156 0
Email 76156 0
surabhi.basnayake@monashhealth.org

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


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.