Trial Outcomes & Findings for Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation (NCT NCT02428296)
NCT ID: NCT02428296
Last Updated: 2020-02-05
Results Overview
The primary outcome measures will use quantitative DXA scan of the affected and unaffected body part (s) to demonstrate negative change in fibrofatty, muscular, and/or bony overgrowth. Absolute volumes of affected and unaffected tissue at week 0 (designated X), week 26 (designated Y), and week 52 (designated Z), were compared by taking the difference between the mean value obtained during the run-in period and the mean value obtained during the treatment period. Tissue volume changes (week 0-26 and week 26-52) were designated "DELTA," and the percent change "% Change." Percent change for the untreated period was \[100(Y-X/X)\], and for the treated period \[100(Z-Y/Y)\].
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
39 participants
Primary outcome timeframe
Run-in (0-26 weeks), treatment (26-52 weeks)
Results posted on
2020-02-05
Participant Flow
Participant milestones
| Measure |
PIK3CA-Related Overgrowth Spectrum Patients
Participants were assessed for sirolimus efficacy at week 0 (before the run-in phase), week 26 (after the run-in phase and before treatment), and at week 52 (after 26 weeks of treatment).
Pharmacokinetic data for sirolimus for children and adults with renal transplants informed dosing algorithms. A target sirolimus plasma concentration of 2-6ng/ml was selected based on in vitro preclinical studies off-label clinical experience, and with the aim of minimizing AEs.
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|---|---|
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Overall Study
STARTED
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39
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Overall Study
Treated
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39
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Overall Study
COMPLETED
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30
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Overall Study
NOT COMPLETED
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9
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Reasons for withdrawal
| Measure |
PIK3CA-Related Overgrowth Spectrum Patients
Participants were assessed for sirolimus efficacy at week 0 (before the run-in phase), week 26 (after the run-in phase and before treatment), and at week 52 (after 26 weeks of treatment).
Pharmacokinetic data for sirolimus for children and adults with renal transplants informed dosing algorithms. A target sirolimus plasma concentration of 2-6ng/ml was selected based on in vitro preclinical studies off-label clinical experience, and with the aim of minimizing AEs.
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|---|---|
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Overall Study
Adverse Event
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7
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Overall Study
Withdrawal by Subject
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2
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Baseline Characteristics
Race and Ethnicity were not collected from any participant.
Baseline characteristics by cohort
| Measure |
PIK3CA-Related Overgrowth Spectrum Patients
n=39 Participants
Participants were assessed for sirolimus efficacy at week 0 (before the run-in phase), week 26 (after the run-in phase and before treatment), and at week 52 (after 26 weeks of treatment).
Pharmacokinetic data for sirolimus for children and adults with renal transplants informed dosing algorithms. A target sirolimus plasma concentration of 2-6ng/ml was selected based on in vitro preclinical studies off-label clinical experience, and with the aim of minimizing AEs.
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|---|---|
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Age, Continuous
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16.6 years
n=39 Participants
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Age, Customized
Age · 3-16 years
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23 Participants
n=39 Participants
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Age, Customized
Age · 17-48 years
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16 Participants
n=39 Participants
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Sex: Female, Male
Female
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17 Participants
n=39 Participants
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Sex: Female, Male
Male
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22 Participants
n=39 Participants
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Region of Enrollment
United States
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13 Participants
n=39 Participants
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Region of Enrollment
France
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15 Participants
n=39 Participants
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Region of Enrollment
United Kingdom
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11 Participants
n=39 Participants
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PRIMARY outcome
Timeframe: Run-in (0-26 weeks), treatment (26-52 weeks)Population: The anatomy of 23 patients permitted DXA analysis of affected versus unaffected tissue.
The primary outcome measures will use quantitative DXA scan of the affected and unaffected body part (s) to demonstrate negative change in fibrofatty, muscular, and/or bony overgrowth. Absolute volumes of affected and unaffected tissue at week 0 (designated X), week 26 (designated Y), and week 52 (designated Z), were compared by taking the difference between the mean value obtained during the run-in period and the mean value obtained during the treatment period. Tissue volume changes (week 0-26 and week 26-52) were designated "DELTA," and the percent change "% Change." Percent change for the untreated period was \[100(Y-X/X)\], and for the treated period \[100(Z-Y/Y)\].
Outcome measures
| Measure |
Affected Tissue
n=23 Participants
Affected sites were defined by clinical observation.
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Unaffected Tissue
n=23 Participants
Unaffected sites showed no overgrowth, nor evidence of skin or vascular abnormalities.
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|---|---|---|
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Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA
Run-in period
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7.9 mean percentage change in tissue volume
Standard Deviation 12.8
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4.8 mean percentage change in tissue volume
Standard Deviation 9.7
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Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA
Treatment period
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0.71 mean percentage change in tissue volume
Standard Deviation 10.2
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6.5 mean percentage change in tissue volume
Standard Deviation 12.3
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Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA
Change in mean percentage change of tissue volume
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-7.2 mean percentage change in tissue volume
Standard Deviation 16.0
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1.7 mean percentage change in tissue volume
Standard Deviation 11.5
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PRIMARY outcome
Timeframe: Run-in (0-26 weeks), treatment (26-52 weeks)Population: Ten MRI series were analyzed. Only six of ten MRI series that were eligible for analysis included both affected and unaffected sites (the remaining only measured affected tissue).
The outcome was measured as a percent change in tissue volume between the treatment period and run-in period. For volume calculation, IDEAL fat (Dixon sequence) images were visualized using volumetric software (SliceOmatic, TomoVision, Magog, Canada). Morphology segmentation was performed through computation of watershed gradients. Tissues (fat, muscle, bone, and blood vessel) were manually defined and software was used to generate a surrogate of tissue volume using five slices, with manual adjustments where required. Absolute volumes of affected and unaffected tissue at week 0 (designated X), week 26 (designated Y), and week 52 (designated Z), were compared. Tissue volume changes (week 0-26 and week 26-52) were designated "DELTA," and the percent change "% Change." Percent change for the untreated period was \[100(Y-X/X)\], and for the treated period \[100(Z-Y/Y)\].
Outcome measures
| Measure |
Affected Tissue
n=10 Participants
Affected sites were defined by clinical observation.
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Unaffected Tissue
n=6 Participants
Unaffected sites showed no overgrowth, nor evidence of skin or vascular abnormalities.
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|---|---|---|
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Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by MRI Scan
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-3.7 percentage of tissue volume change
Standard Deviation 12.3
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0 percentage of tissue volume change
Standard Deviation 16.7
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SECONDARY outcome
Timeframe: Between 6 months and 12 monthsPopulation: All patients were analyzed to determine at which dose the patient would reach the target plasma concentration.
To establish optimal sirolimus dosing algorithms for a future RCT.
Outcome measures
| Measure |
Affected Tissue
n=39 Participants
Affected sites were defined by clinical observation.
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Unaffected Tissue
Unaffected sites showed no overgrowth, nor evidence of skin or vascular abnormalities.
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|---|---|---|
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Mean Sirolimus Doses to Achieve the Target Plasma Concentration
Adults
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1.2 mg/day
Interval 1.1 to 1.3
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—
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Mean Sirolimus Doses to Achieve the Target Plasma Concentration
Children
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1.16 mg/day
Interval 1.0 to 1.3
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—
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SECONDARY outcome
Timeframe: baseline (0 months) and end of treatment (12 months)Population: Children (N=15) and parents of children (N=19) were administered quality of life questionnaires. Adult subjects (N=9) were also administered quality of life questionnaires, but the scores were reported as individual domain mean scores; health total mean scores were not reported. Total score data for adults was not analyzed or reported.
The World Health Organization Quality of Life-BREF (WHOQOL-BREF) assessment measures four domains related to quality of life (physical health, psychological, social relationships, and environment) and produces both individual domain scores (0-100) a total score on a 0-100 scale (high scores indicate a better quality of life). This measure was used to assess quality of life of parents on behalf of their children, and adult subjects. The Pediatric Quality of Life (PedsQL) assessment is scored on a 0-100 scale (high scores indicate a better health related quality of life). This measure was used to assess quality of life of children. The outcomes are reported as a change in quality of life based on the change in scores from these assessments between baseline (time 0 months) and end of treatment (time 12 months).
Outcome measures
| Measure |
Affected Tissue
n=43 Participants
Affected sites were defined by clinical observation.
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Unaffected Tissue
Unaffected sites showed no overgrowth, nor evidence of skin or vascular abnormalities.
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Additional Measure of Efficacy: Quality of Life Assessment
Children (total health)
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-1.7 mean change in quality of life score
Interval -5.0 to 8.8
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—
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Additional Measure of Efficacy: Quality of Life Assessment
Parents (total health)
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4.9 mean change in quality of life score
Interval -0.7 to 10.4
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—
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Additional Measure of Efficacy: Quality of Life Assessment
Adults (physical health)
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0.25 mean change in quality of life score
Interval -8.9 to 9.4
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—
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Additional Measure of Efficacy: Quality of Life Assessment
Adults (psychological health)
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-1.25 mean change in quality of life score
Interval -7.3 to 4.8
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—
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Additional Measure of Efficacy: Quality of Life Assessment
Adults (social relationships)
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6.3 mean change in quality of life score
Interval -1.8 to 14.3
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—
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Additional Measure of Efficacy: Quality of Life Assessment
Adults (environment)
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-7.3 mean change in quality of life score
Interval -32.5 to 17.7
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—
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SECONDARY outcome
Timeframe: Run-in (0-26 weeks) and treatment (27-52 weeks)Tracked number of hospitalizations and surgical interventions occurring over the course of the run-in and treatment period.
Outcome measures
| Measure |
Affected Tissue
n=39 Participants
Affected sites were defined by clinical observation.
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Unaffected Tissue
Unaffected sites showed no overgrowth, nor evidence of skin or vascular abnormalities.
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Number of Hospitalizations and Surgical Interventions
Run-in period : Hospitalizations
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5 number of events
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—
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Number of Hospitalizations and Surgical Interventions
Run-in period : Surgical interventions
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2 number of events
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—
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Number of Hospitalizations and Surgical Interventions
Treatment period : Hospitalizations
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9 number of events
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—
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Number of Hospitalizations and Surgical Interventions
Treatment period : Surgical interventions
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0 number of events
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—
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Adverse Events
PIK3CA-Related Overgrowth Spectrum Patients
Serious events: 12 serious events
Other events: 31 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
PIK3CA-Related Overgrowth Spectrum Patients
n=39 participants at risk
Participants were assessed for sirolimus efficacy at week 0 (before the run-in phase), week 26 (after the run-in phase and before treatment), and at week 52 (after 26 weeks of treatment).
Pharmacokinetic data for sirolimus for children and adults with renal transplants informed dosing algorithms. A target sirolimus plasma concentration of 2-6ng/ml was selected based on in vitro preclinical studies off-label clinical experience, and with the aim of minimizing AEs.
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|---|---|
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Musculoskeletal and connective tissue disorders
Sirolimus hypersensitivity syndrome
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Vascular disorders
Hemarthrosis
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Vascular disorders
Pulmonary embolus
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Respiratory, thoracic and mediastinal disorders
Pneumonia
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Respiratory, thoracic and mediastinal disorders
Pneumonitis
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Blood and lymphatic system disorders
Neutropenia
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Blood and lymphatic system disorders
Anemia
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2.6%
1/39 • Number of events 2 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Blood and lymphatic system disorders
Neutropenic fever
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Gastrointestinal disorders
Constipation aggravated
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Infections and infestations
Appendicitis
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Infections and infestations
Cellulitis
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2.6%
1/39 • Number of events 6 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Infections and infestations
Epstein Barr Virus
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Infections and infestations
Pelvic infection
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Infections and infestations
Viral meningitis
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Injury, poisoning and procedural complications
Over-medication
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Other adverse events
| Measure |
PIK3CA-Related Overgrowth Spectrum Patients
n=39 participants at risk
Participants were assessed for sirolimus efficacy at week 0 (before the run-in phase), week 26 (after the run-in phase and before treatment), and at week 52 (after 26 weeks of treatment).
Pharmacokinetic data for sirolimus for children and adults with renal transplants informed dosing algorithms. A target sirolimus plasma concentration of 2-6ng/ml was selected based on in vitro preclinical studies off-label clinical experience, and with the aim of minimizing AEs.
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|---|---|
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Blood and lymphatic system disorders
Blood and lymphatic disorders
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20.5%
8/39 • Number of events 8 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Gastrointestinal disorders
Gastrointestinal disorders
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5.1%
2/39 • Number of events 2 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
|
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Infections and infestations
Infections and infestations
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41.0%
16/39 • Number of events 21 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
|
|
Renal and urinary disorders
Renal and urinary disorders
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2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
|
5.1%
2/39 • Number of events 2 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
|
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Skin and subcutaneous tissue disorders
Skin and subcutaneous disorders
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5.1%
2/39 • Number of events 2 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
|
|
Vascular disorders
Vascular disorders
|
7.7%
3/39 • Number of events 3 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
|
|
Injury, poisoning and procedural complications
Injury, poisoning, and procedural complications
|
2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
|
|
Metabolism and nutrition disorders
Metabolism and nutrition disorders
|
7.7%
3/39 • Number of events 3 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
|
2.6%
1/39 • Number of events 1 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
|
|
Nervous system disorders
Nervous system disorders
|
5.1%
2/39 • Number of events 2 • 12 months
Adverse event definitions are consistent with the clinicaltrials.gov definitions. AEs were identified by laboratory testing, clinical examination, or self-report. Severity was graded with the CTCAE (version 4.0). All AEs and SAEs possibly, probably, or definitely related to sirolimus were reviewed by an international committee.
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Additional Information
Dr. Kim Keppler-Noreuil
Children's National Medical Center
Phone: 2024766287
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place