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    Clinical Trial Results:
    A Non-Randomised, Open Label, Pilot Trial of Sirolimus Therapy for Segmental Overgrowth Due to PIK3CA Related Overgrowth

    Summary
    EudraCT number
    		 2014-000484-41
    Trial protocol
    		 GB  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Nov 2017
    First version publication date
    18 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PROMISE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cambridge University Hospital
    Sponsor organisation address
    Hills Road, Cambridge, United Kingdom,
    Public contact
    Carrie Bayliss, CCTU, 0044 01223348158, cctu@addenbrookes.nhs.uk
    Scientific contact
    Carrie Bayliss, CCTU, 0044 01223348158, cctu@addenbrookes.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
    Interim
    Date of interim/final analysis
    10 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 May 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate if sirolimus is effective at reducing overgrowth in PIK3CA-related overgrowth, and to quantify its efficacy. To measure the effect size of sirolimus therapy in reducing pathological overgrowth in PIK3CA related overgrowth to enable statistical power calculations for a future randomised controlled trial (RCT)
    Protection of trial subjects
    Prior to commencement and during the trial all subjects underwent safety assessments to ensure protection from harm. Subjects were assessed 6 months prior to the start of the trial at baseline and throughout the trial at every subject trial visit. Physician review and physical examination were performed along with safety blood tests, vitals taken and AE review, DXA scan, urine analysis as well as pregnancy test. Initial safety questionnaires were also undertaken prior to MRIs scans to exclude the presence of a pacemaker, defibrillator, aneurysm clips, orbital metal or recent surgical insertion of metal in the prior 6 weeks. Lose dosing of Sirolimus and levels monitored throughout the trial and dose adjustment were made where necessary along with monitoring any adverse effects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 11
    Worldwide total number of subjects
    11
    EEA total number of subjects
    11
    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)
    2
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 11 subjects were recruited from within the UK, with the first subject recruited February 16th 2016 and the last subject recruited October 21st 2016.

    Pre-assignment
    Screening details
    		 Subjects were identified with the inclusion criteria of having a confirmed PIK3CA mutation with measurable progressive growth between the ages of 3-65yrs and exclusion criteria of pregnancy and breastfeeding. All subjects who were enrolled in the trial had dxa scans and bloods

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Sirolimus
    Arm description
    		 Subjects who administered sirolimus drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Rapamune
    Pharmaceutical forms
    Coated tablet, Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Sirolimus was administered in tablet form for adults - 1mg daily Sirolimus solution was administered by children (17 years old and under) - 0.5 mg bd twice daily For participants aged 17 years old and under, the upper dosing limit was 1.5 mg total daily dose, and tablet therapy was administered where possible. Participants were advised to take sirolimus in the morning each day before breakfast and for children on twice daily dosing, again before the evening meal each day.

    Number of subjects in period 1
    		Sirolimus
    Started
    11
    Trial Initiation
    11
    Completed
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 11 11
    Age categorical
    Subjects enrolled were between 3 years old and 65 years old
    Units: Subjects
        Children (2-11 years)
    		 2 2
        Adolescents (12-17 years)
    		 4 4
        Adults (18-64 years)
    		 5 5
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 7 7
    Subject analysis sets

    Subject analysis set title
    UK subjects analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Results from 11 subjects from the UK trial on Sirolimus were analysed.

    Subject analysis sets values
    		 UK subjects analysis
    Number of subjects
    11
    Age categorical
    Subjects enrolled were between 3 years old and 65 years old
    Units: Subjects
        Children (2-11 years)
    2
        Adolescents (12-17 years)
    4
        Adults (18-64 years)
    5
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    4
        Male
    7

    End points

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    End points reporting groups
    Reporting group title
    Sirolimus
    Reporting group description
    		 Subjects who administered sirolimus drug.

    Subject analysis set title
    UK subjects analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Results from 11 subjects from the UK trial on Sirolimus were analysed.

    Primary: Primary endpoint - relative percentage tissue change

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    End point title
    		 Primary endpoint - relative percentage tissue change
    End point description
    Of the 11 enrolled, 8 subjects were evaluable for the primary end point as 1 subject was withdrawn and 2 subjects had diffuse disease making it not possible to calculate the primary endpoint of relative % tissue change.
    End point type
    Primary
    End point timeframe
    Baseline assessment (run-in) 6 months prior to treatment phase and post 6 months treatment phase.
    End point values
    		 Sirolimus UK subjects analysis
    Number of subjects analysed
    8 [1]
    8 [2]
    Units: change in relative % growth
        arithmetic mean (standard deviation)
    -3 ± 5.82
    -3 ± 5.82
    Notes
    [1] - Of the 11 enrolled, 8 subjects were evaluable for the primary end point as 1 subject was withdrawn a
    [2] - Of the 11 enrolled, 8 subjects were evaluable for the primary end point as 1 subject was withdrawn a
    Statistical analysis title
    		 Paired Student's t test - Relative % tissue change
    Statistical analysis description
    In subjects with established serial growth data, a measure of relative percent excess tissue volume at the affected site was taken at baseline (run-in 6 months prior) and following treatment phase of sirolimus to enable calculation of effect size. Paired student's t test was used to evaluate the relative % change in tissue growth during the run-in period and treatment phase.
    Comparison groups
    Sirolimus v UK subjects analysis
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.21 [4]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Percentage change from baseline
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 2.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.2
    Notes
    [3] - Of the 11 enrolled, 8 subjects were evaluable for the primary end point as 1 subject was withdrawn and 2 subjects had diffuse disease making it not possible to calculate the primary endpoint of relative % tissue change. The number of 16 patients reported, is just an artifact of Eudract not allowing a one-sample hypothesis test, and is double-counting each patient.
    [4] - Change in relative % growth between run-in and treatment phase (n=8) = -3.0% (95% CI -8.2, 2.2). The null hypothesis is a mean value of 0.

    Secondary: Secondary endpoints - Exploratory

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    End point title
    		 Secondary endpoints - Exploratory
    End point description
    Mean plasma sirolimus level = 3.1 ng/ml (95% CI 2.6, 3.1); Median plasma sirolimus level = 2.85 ng/ml; Correlation between mean sirolimus plasma level and tissue % change R=0.54, p=0.15; Mean daily sirolimus dose = 1.08 mg (95% CI 0.68, 1.48); Median daily sirolimus dose = 1mg QoL - No significant difference in scores from baseline to end of treatment phase. Adults WHO-QoL-Bref across all domains mean difference in physical health score = 6.5 (95% CI 1.7, 11.3) p=0.02, mean difference in psychological health score 1.3 (95% CI -10.2, 12.8), p=0.21 mean environmental score = 21 (95% CI =77.7, 35.2), p=0.07 PedsQL Parental report physical health mean difference 129.2 (95% CI=8.08, 266),p0.06, psychosocial health mean difference 129.2 (95% CI=-.77.7,35.2),p0.07 Hospitalisations - Run in phase = 2, treatment phase = 4, no significant difference, p=0.64 (odds ratio 0.39, 95% CI (0.06, 2.5) Surgical Interventions - Run-in = 2, treatment phase = 0, p=0.48 (1/[Odds ratio]=0, 95% CI (0,2.1
    End point type
    Secondary
    End point timeframe
    Sirolimus - treatment phase 6 months QoL - start of treatment phase and post treatment phase Hospitalisations - Run-in and treatment phase Surgical Interventions - Run-in and treatment phase
    End point values
    		 UK subjects analysis
    Number of subjects analysed
    11
    Units: siroliums levels/doses and other
        number (not applicable)
    11
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs during treatment phase: 5/11 (45%) of subjects had at least 1 AE (any grade) 3/11 (27% subjects had a grade 3 AE
    Adverse event reporting additional description
    Adverse event information collected during trial visits or when subject contacted study steam. Assessment by clinical examinations, monitoring and blood tests where needed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Overall Adverse Events
    Reporting group description
    		 11 subjects enrolled, 4 SAEs, 1 subject withdrawal (2 x SAEs) Overall: - 5/11 (45%) subjects had at least 1 AE (any grade) - 3/11 (27%) subjects had a grade 3 AE - No grade 4/5 AEs - 4 grade 3 AEs - 5 grade 2 AEs - 12 grade 1 AE

    Serious adverse events
    		 Overall Adverse Events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Skin and subcutaneous tissue disorders
    Epstein-Barr virus
    Additional description: EBV infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
    Additional description: Cellulitis of the foot (where overgrowth is)
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Overall Adverse Events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 8 (62.50%)
    Skin and subcutaneous tissue disorders
    Diarrhoea
    Additional description: Diarrhoaea and vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Temperature intolerance
    Additional description: Fever experienced
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
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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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