Clinical Trial Results:
First trimester progesterone therapy in women with a history of unexplained recurrent miscarriages: A randomised, double-blind, placebo-controlled, multi-centre trial [The PROMISE (PROgesterone in recurrent MIScarriagE) Trial] Funded by NIHR-HTA(UK) 08/38/01 for £1.2million
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Summary
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EudraCT number |
2009-011208-42 |
Trial protocol |
NL GB |
Global end of trial date |
01 Sep 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Mar 2020
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First version publication date |
25 Mar 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
HTA083801
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Additional study identifiers
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ISRCTN number |
ISRCTN92644181 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Imperial College London
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Sponsor organisation address |
South Kensington Campus, London, United Kingdom, SW7 2AZ
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Public contact |
Dr Rajendra Rai, Imperial College London, r.rai@imperial.ac.uk
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Scientific contact |
Dr Rajendra Rai, Imperial College London, r.rai@imperial.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Sep 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Sep 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Sep 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
PRINCIPAL OBJECTIVE: To test the hypothesis that in women with unexplained recurrent miscarriages, progesterone (2 x 200mg pessaries, twice daily), started as soon as possible after a positive pregnancy test (and no later than 6 weeks gestation) and continued to 12 weeks of gestation, compared to placebo, increases live births beyond 24 completed weeks of pregnancy by at least 10%.
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Protection of trial subjects |
None
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 May 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 170
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Country: Number of subjects enrolled |
United Kingdom: 666
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Worldwide total number of subjects |
836
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EEA total number of subjects |
836
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
836
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 836 participants were randomized, exceeding the planned target of 790 participants, from 45 active centers (36 in the UK and nine in the Netherlands) over 41 months. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 1568 participants were screened for eligibility and consented to take part in the PROMISE trial. Of these, 732 participants were excluded from randomization, the most common reasons being that they did not conceive naturally within 1 year or due to withdraw from the study. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Progresteron | |||||||||||||||||||||
Arm description |
Participants received progesterone at a dose of 400 mg (that is, two capsules of Utrogestan® 200 mg) taken vaginally twice daily (every morning and every evening) for the duration of treatment. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Progesterone
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Investigational medicinal product code |
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Other name |
UTROGESTAN
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Pharmaceutical forms |
Capsule
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Routes of administration |
Vaginal use
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Dosage and administration details |
Micronised progesterone at a dose of 400 mg (that is, two capsules of Utrogestan® 200 mg) taken vaginally twice daily (every morning and every evening) for the duration of treatment.
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Participants received placebo treatment | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Vaginal use
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Dosage and administration details |
Two capsules of placebo capsules were taken vaginally twice daily (every morning and every evening) for the duration of treatment. Placebo capsules were composed of sunflower oil, soybean lecithin, gelatin, glycerol, titanium dioxide and purified water, encapsulated in the same form as the progesterone capsules, and identical in color, shape, and weight.
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Baseline characteristics reporting groups
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Reporting group title |
Progresteron
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Reporting group description |
Participants received progesterone at a dose of 400 mg (that is, two capsules of Utrogestan® 200 mg) taken vaginally twice daily (every morning and every evening) for the duration of treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received placebo treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Progresteron
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Reporting group description |
Participants received progesterone at a dose of 400 mg (that is, two capsules of Utrogestan® 200 mg) taken vaginally twice daily (every morning and every evening) for the duration of treatment. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants received placebo treatment | ||
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End point title |
Number of the live birth after at least 24 weeks of gestation compared to the total birth | |||||||||
End point description |
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End point type |
Primary
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End point timeframe |
12 months
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Statistical analysis title |
Live birth after at least 24 weeks of gestation | |||||||||
Statistical analysis description |
Analyses based on the intention-to-treat principle.
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Comparison groups |
Progresteron v Placebo
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Number of subjects included in analysis |
826
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.45 | |||||||||
Method |
RR | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
1.04
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.94 | |||||||||
upper limit |
1.15 | |||||||||
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End point title |
Clinical pregnancy at 6–8 weeks | |||||||||
End point description |
The presence of a gestational sac) at 6–8 weeks.
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End point type |
Secondary
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End point timeframe |
12 months
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Statistical analysis title |
Clinical pregnancy at 6–8 weeks | |||||||||
Comparison groups |
Progresteron v Placebo
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Number of subjects included in analysis |
826
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Analysis specification |
Post-hoc
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Analysis type |
superiority | |||||||||
P-value |
= 0.16 | |||||||||
Method |
RR | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
1.05
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.98 | |||||||||
upper limit |
1.12 | |||||||||
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End point title |
Ongoing pregnancy at 12 weeks | |||||||||
End point description |
The presence of a fetal heartbeat at 12 weeks.
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End point type |
Secondary
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End point timeframe |
12 months
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Statistical analysis title |
Ongoing pregnancy at 12 weeks | |||||||||
Comparison groups |
Progresteron v Placebo
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Number of subjects included in analysis |
826
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.47 | |||||||||
Method |
RR | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
1.04
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.94 | |||||||||
upper limit |
1.14 | |||||||||
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End point title |
Number of Miscarriage | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 months
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Statistical analysis title |
Miscarriage | |||||||||
Comparison groups |
Progresteron v Placebo
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Number of subjects included in analysis |
826
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.7 | |||||||||
Method |
RR | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
0.96
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.79 | |||||||||
upper limit |
1.17 | |||||||||
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End point title |
Number of Neonatal survival to 28 days | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
12 months
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Statistical analysis title |
Neonatal survival to 28 days | |||||||||
Comparison groups |
Progresteron v Placebo
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Number of subjects included in analysis |
530
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
= 0.32 | |||||||||
Method |
RR | |||||||||
Parameter type |
Risk ratio (RR) | |||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.99 | |||||||||
upper limit |
1 | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
12 months
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
Progresteron
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Reporting group description |
Participants received progesterone at a dose of 400 mg (that is, two capsules of Utrogestan® 200 mg) taken vaginally twice daily (every morning and every evening) for the duration of treatment. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received placebo treatment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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02 Dec 2010 |
Adding new recruitment sites |
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10 Jan 2011 |
Adding new recruitment sites |
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23 Mar 2011 |
Change wording |
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06 Apr 2011 |
Adding new recruitment sites |
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20 Apr 2011 |
Adding new recruitment sites |
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20 Apr 2011 |
Wishaw General Hospital is going to be a PIC Patient Identification Centre only. Staffing issues make it difficult to function as a full research site. |
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03 May 2011 |
Pregnancy and delivery of trial drug - new wording. Some research centers have participants who live far away from the clinic, so returning solely to collect the study treatment is difficult for these individuals and may prevent them from taking part in the trial. The option of delivery directly from the trial pharmacy to their home address would make it possible for them to take part. |
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17 Jun 2011 |
Adding new recruitment sites |
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11 Aug 2011 |
Adding new recruitment sites |
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04 Feb 2013 |
Adding new recruitment sites |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/27225013 |
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