ANZCTR - Registration

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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]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Infertility

Condition category

Condition code

Reproductive Health and Childbirth

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]

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]

Live birth rate

Timepoint [1]

At time of birth

Secondary outcome [1]

Clinical pregnancy levels at 16 days of treatment. This will be measured by serum hCG level.

Timepoint [1]

Day 16 of treatment

Secondary outcome [2]

Serum progesterone levels at Day 2 and Day 16 of treatment

Timepoint [2]

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]

Monash IVF - Clayton - Clayton

Recruitment hospital [2]

Epworth Richmond - Richmond

Recruitment hospital [3]

Western Day Surgery - St Albans

Recruitment postcode(s) [1]

3168 - Clayton

Recruitment postcode(s) [2]

3121 - Richmond

Recruitment postcode(s) [3]

3021 - St Albans

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Monash IVF Pty Ltd

Address [1]

Epworth Hospital Richmond, Level 7, 89 Bridge Road, Richmond VIC 3121

Country [1]

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]

None

Name [1]

N/A

Address [1]

N/A

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health

Ethics committee address [1]

246 Clayton Road
Clayton
VIC 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

23/03/2017

Approval date [1]

22/02/2019

Ethics approval number [1]

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

A/Prof Martin Healey

Address

Monash IVF Pty Ltd, 7/89 Bridge Rd, Richmond VIC 3121

Country

Australia

Phone

+6139429 9188

Fax

kathandmutt@bipond.com

Contact person for public queries

Name

Samantha Ter

Address

Monash IVF Pty Ltd, 7/89 Bridge Rd, Richmond VIC 3121

Country

Australia

Phone

+61394208245

Fax

samantha.ter@monashivf.com

Contact person for scientific queries

Name

Surabhi Basnayake

Address

Monash Health
246 Clayton Road
Clayton
VIC 3168

Country

Australia

Phone

+61395946666

Fax

surabhi.basnayake@monashhealth.org

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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.

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