Clinical Trial Results:
A Non-Randomised, Open Label, Pilot Trial of Sirolimus Therapy for Segmental Overgrowth Due to PIK3CA Related Overgrowth
Summary
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EudraCT number |
2014-000484-41 |
Trial protocol |
GB |
Global end of trial date |
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Nov 2017
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First version publication date |
18 Nov 2017
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Other versions |
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 |
PROMISE
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Cambridge University Hospital
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Sponsor organisation address |
Hills Road, Cambridge, United Kingdom,
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Public contact |
Carrie Bayliss, CCTU, 0044 01223348158, cctu@addenbrookes.nhs.uk
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Scientific contact |
Carrie Bayliss, CCTU, 0044 01223348158, cctu@addenbrookes.nhs.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 |
Interim
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Date of interim/final analysis |
10 Oct 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 May 2017
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Global end of trial reached? |
No
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General information about the trial
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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)
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Jul 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
United Kingdom: 11
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Worldwide total number of subjects |
11
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EEA total number of subjects |
11
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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) |
2
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Adolescents (12-17 years) |
4
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Adults (18-64 years) |
5
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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 |
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
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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
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Period 1 title |
Baseline (overall period)
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Is this the baseline period? |
Yes | ||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||
Arms
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Arm title
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Sirolimus | ||||||||
Arm description |
Subjects who administered sirolimus drug. | ||||||||
Arm type |
Experimental | ||||||||
Investigational medicinal product name |
Sirolimus
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Investigational medicinal product code |
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Other name |
Rapamune
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Pharmaceutical forms |
Coated tablet, Concentrate for oral solution
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Routes of administration |
Oral use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
UK subjects analysis
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Results from 11 subjects from the UK trial on Sirolimus were analysed.
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End points reporting groups
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Reporting group title |
Sirolimus
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Reporting group description |
Subjects who administered sirolimus drug. | ||
Subject analysis set title |
UK subjects analysis
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Results from 11 subjects from the UK trial on Sirolimus were analysed.
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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.
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End point type |
Primary
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End point timeframe |
Baseline assessment (run-in) 6 months prior to treatment phase and post 6 months treatment phase.
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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 |
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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.
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Comparison groups |
Sirolimus v UK subjects analysis
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Number of subjects included in analysis |
16
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||
P-value |
= 0.21 [4] | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Percentage change from baseline | ||||||||||||
Point estimate |
-3
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-8.2 | ||||||||||||
upper limit |
2.2 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.2
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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. |
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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
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End point type |
Secondary
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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
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No statistical analyses for this end point |
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Adverse events information
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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
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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.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Overall Adverse Events
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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 | ||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
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 |