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    Clinical Trial Results:
    Does progesterone prophylaxis to prevent preterm labour improve outcome? - a randomised double blind placebo controlled trial (OPPTIMUM)

    Summary
    EudraCT number
    		 2007-007950-77
    Trial protocol
    		 GB   SE  
    Global end of trial date
    31 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jul 2020
    First version publication date
    05 Jul 2020
    Other versions
    Summary report(s)
    		 Publication

    Trial information

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    Trial identification
    Sponsor protocol code
    OPPTIMUM
    Additional study identifiers
    ISRCTN number
    		 ISRCTN14568373
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ETHICS: 08/MREOO/6, UKCRN: 4496, MRC FUNDER: G0700452, Grant No: 84982 - 09/800/27 , MHRA CTA: 22931/0009/001-0001 revised by MHRA to 01384/0208/
    Sponsors
    Sponsor organisation name
    University of Edinburgh
    Sponsor organisation address
    47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Marise Bucukoglu, University of Edinburgh, marise.bucukoglu@ed.ac.uk
    Scientific contact
    Professor Jane Norman, University of Edinburgh, marise.bucukoglu@ed.ac.uk
    Sponsor organisation name
    NHS Lothian
    Sponsor organisation address
    47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Dr Heather Charles Head of Research Governance NHS Lothian, NHS Lothian, ACCORD@nhslothian.scot.nhs.uk
    Scientific contact
    Dr Heather Charles Head of Research Governance NHS Lothian, NHS Lothian, ACCORD@nhslothian.scot.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In women at high risk of preterm labour, does prophylactic vaginal natural progesterone, 200mg daily from 22 – 34 weeks gestation, compared to placebo:
    Protection of trial subjects
    We recruited pregnant women who were booked for their delivery at one of the hospitals participating in the study and who met the study eligibility criteria. Case notes of pregnant women were reviewed for the patient’s potential to participate and eligible patients were informed of the study at routine antenatal appointments or by the research midwife or another member of the hospital or research team by telephone or direct mailing of the participant invitation or the current patient information sheet. Women given information about the study were offered at least 24 hours to read the patient information sheet and invited to consider participation.
    Background therapy
    		 All women fulfilling the inclusion criteria and consented were tested for fetal fibrenectin (ffn). Those with a positive screening (fFN) test between 22+0 and 24+0 weeks, were eligible for randomisation. Additionally, those who have a previous spontaneous labour resulting in a preterm birth ≤ 34 weeks gestation (by any mode) or short cervix in index pregnancy, defined as cervical length ≤ 25mm were eligible for randomisation to progesterone or placebo even with a negative fFN test.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United Kingdom: 1221
    Worldwide total number of subjects
    1228
    EEA total number of subjects
    1228
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1228
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All eligible women will be invited to participate in this part of the study. The trial will be explained in detail to the patient and any questions they have will be answered. Those who complete the consent form will undergo fibronectin testing at 22+0 to 24+0weeks gestation.

    Pre-assignment
    Screening details
    		 Period 1: 5833 pregnant women were tested for fibronectin. 4605 were excluded from randomisation 1228 were randomised to either progesterone or matching placebo. Period 2: We assesed Neonatal outcomes 1176 babies of women randomised and who were willing. Period 3 We conducted 919 childhood assesments age 2 years of women randomised.

    Period 1
    Period 1 title
    Obstetric phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The IMP (progesterone) was supplied free of charge to all sites, directly by the manufacturer, Laboratories Besins International. Placebo capsules were identical to active treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Progesterone
    Arm description
    		 Utrogestan (Progesterone) 200mg soft capsules
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Progesterone
    Investigational medicinal product code
    PL16468/0001
    Other name
    Uterogestan
    Pharmaceutical forms
    Pessary
    Routes of administration
    Vaginal use
    Dosage and administration details
    Utrogestan (Progesterone) 200 mg soft capsules or placebo will be prescribed at Visit 2 to be inserted once daily vaginally at bedtime for up to 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo pessary
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pessary
    Routes of administration
    Vaginal use
    Dosage and administration details
    200mg Matching placebo dministered once daily

    Number of subjects in period 1
    		Progesterone Placebo
    Started
    618
    610
    Completed
    600
    597
    Not completed
    18
    13
         Consent withdrawn by subject
    12
    10
         Lost to follow-up
    6
    2
         Obstetric data missing
    -
    1
    Period 2
    Period 2 title
    Neonatal
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Progesterone
    Arm description
    		 Utrogestan (Progesterone) 200mg soft capsules
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Progesterone
    Investigational medicinal product code
    PL16468/0001
    Other name
    Uterogestan
    Pharmaceutical forms
    Pessary
    Routes of administration
    Vaginal use
    Dosage and administration details
    Utrogestan (Progesterone) 200 mg soft capsules or placebo will be prescribed at Visit 2 to be inserted once daily vaginally at bedtime for up to 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo pessary
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pessary
    Routes of administration
    Vaginal use
    Dosage and administration details
    200mg Matching placebo dministered once daily

    Number of subjects in period 2
    		Progesterone Placebo
    Started
    618
    610
    Completed
    589
    587
    Not completed
    29
    23
         Consent withdrawn by subject
    15
    18
         Lost to follow-up
    14
    5
    Period 3
    Period 3 title
    Paediatric
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Women were Blinded. Treatment was not unblinded throughout the follow up period

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Progesterone
    Arm description
    		 Utrogestan (Progesterone) 200mg soft capsules
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Progesterone
    Investigational medicinal product code
    PL16468/0001
    Other name
    Uterogestan
    Pharmaceutical forms
    Pessary
    Routes of administration
    Vaginal use
    Dosage and administration details
    Utrogestan (Progesterone) 200 mg soft capsules or placebo will be prescribed at Visit 2 to be inserted once daily vaginally at bedtime for up to 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo pessary
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pessary
    Routes of administration
    Vaginal use
    Dosage and administration details
    200mg Matching placebo dministered once daily

    Number of subjects in period 3
    		Progesterone Placebo
    Started
    618
    610
    Completed
    430
    439
    Not completed
    188
    171
         Consent withdrawn by subject
    47
    42
         Lost to follow-up
    141
    129

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Progesterone
    Reporting group description
    		 Utrogestan (Progesterone) 200mg soft capsules

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo pessary

    Reporting group values
    		 Progesterone Placebo Total
    Number of subjects
    		 618 610 1228
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.4 ( 5.7 ) 31.5 ( 5.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 618 610 1228
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Progesterone
    Reporting group description
    		 Utrogestan (Progesterone) 200mg soft capsules

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo pessary
    Reporting group title
    Progesterone
    Reporting group description
    		 Utrogestan (Progesterone) 200mg soft capsules

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo pessary
    Reporting group title
    Progesterone
    Reporting group description
    		 Utrogestan (Progesterone) 200mg soft capsules

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo pessary

    Primary: Fetal Death or delivery before 34 weeks’ gestation

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    End point title
    		 Fetal Death or delivery before 34 weeks’ gestation
    End point description
    End point type
    Primary
    End point timeframe
    Birth/ Delivery
    End point values
    		 Progesterone Placebo
    Number of subjects analysed
    618
    610
    Units: number
        number (not applicable)
    504
    489
    Statistical analysis title
    		 Death or delivery before 34 weeks’ gestation
    Comparison groups
    Progesterone v Placebo
    Number of subjects included in analysis
    1228
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [1] - Intention to treat

    Primary: Death, brain injury or severe chronic lung disease

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    End point title
    		 Death, brain injury or severe chronic lung disease
    End point description
    End point type
    Primary
    End point timeframe
    Neonatal period
    End point values
    		 Progesterone Placebo
    Number of subjects analysed
    589 [2]
    587 [3]
    Units: Number
        number (not applicable)
    46
    62
    Notes
    [2] - Nobs (Nmiss) 589 (27) No, n (%) 543 (92.2) Yes, n (%) 46 (7.8)
    [3] - Nobs, n 587 (23) NO, n (%) 525 (89.4) YES, n (%) 62 (10.6)
    Statistical analysis title
    		 Death or delivery before 34 weeks’ gestation
    Comparison groups
    Progesterone v Placebo
    Number of subjects included in analysis
    1176
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [4] - Intention to Treat

    Primary: Bayley-III cognitive composite score at 2 years

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    End point title
    		 Bayley-III cognitive composite score at 2 years
    End point description
    End point type
    Primary
    End point timeframe
    Age 2 years (adjusted)
    End point values
    		 Progesterone Placebo
    Number of subjects analysed
    410 [5]
    423 [6]
    Units: Number
        arithmetic mean (standard deviation)
    99.7 ( 14.7 )
    99.5 ( 15.0 )
    Notes
    [5] - Nobs (Nmiss) 410 (206) Mean (SD) 99.7 (14.7) Median (IQR) 100.0 (90.0–110.0)
    [6] - Nobs (Nmiss) 423 (187) Mean (SD) 99.5 (15.0) Median (IQR) 100.0 (90.0–105.0)
    Statistical analysis title
    		 Bayley-III cognitive composite score at 2 years
    Comparison groups
    Progesterone v Placebo
    Number of subjects included in analysis
    833
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.05
    Method
    		 Regression, Linear
    Confidence interval
    Notes
    [7] - Intention to treat

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Recorded from the time a participant is randomized to treatment until 30 days after stopping taking study drug (study observational visit) and until pregnancy outcome (28 days after delivery.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The Investigators were requested to review all documentation (e.g. hospital notes, laboratory and diagnostic reports) and record all relevant information in the patient notes, the eCRF only if the AE meets the criteria of serious was it reported to the Sponsors.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2008
    Ethics requested updates to docs in appoval letter
    21 Apr 2008
    Change sponsor
    22 Sep 2008
    Protocol redesigned layout to comply with NEW sponsor requirements
    03 Jun 2009
    Clarification of inclusion/exclusion criteria and items previously noted as TBC included.
    15 Oct 2009
    Correction of Typographical errors including the inclusion criteria which should have been aged16 as per previous ethics documentation. Removal of stratification Para 5.5
    07 Apr 2010
    Change in IMP excipient,
    01 Jun 2010
    Change to exclusion criteria and identifying patients
    12 Jul 2010
    To expand recruitment criteria (including fFN-ve women)
    24 Apr 2011
    Change exclusion,
    16 Feb 2012
    Background literature updated, Information on pilot studies removed Para 9.1 Sample size revised to 1250 Para 9.2.2 Deletion of formal plan for Health economic analysis (although collection of some economic data remains part of the study protocol)
    04 Oct 2013
    Revised Protocol V15_04 October 2013 to amend paras 7.2.7 Neonatal/Child Assessments (Section: ‘Child Assessment (at 2 years +/- 8 weeks)’

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29945711
    http://www.ncbi.nlm.nih.gov/pubmed/26921136
    http://www.ncbi.nlm.nih.gov/pubmed/22866909
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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