Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation
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|ClinicalTrials.gov Identifier: NCT02428296|
Recruitment Status : Completed
First Posted : April 28, 2015
Results First Posted : January 27, 2020
Last Update Posted : February 5, 2020
- PIK3CA-related overgrowth spectrum (PROS) is caused by changes in the PIK3CA gene. This gene makes a protein that communicates with other proteins in the body to cause cells to grow. Alterations in PIK3CA change the chemical signals in the body and cause overgrowth in fatty, vascular and other tissues. Sirolimus is a drug that reduces the signals sent by one of the proteins in this chemical signaling pathway. Researchers want to learn whether the drug sirolimus can reduce or stabilize some of the overgrowth that patients with PROS experience.
- To measure how the overgrowth of patients with PROS changes over time and whether taking a drug called sirolimus can reduce or stabilize a person s overgrowth.
- People ages 3 to 65 years old with a confirmed mutation or alteration of the PIK3CA gene in the person s affected tissues (a somatic mutation).
- Participants will be screened with medical history and genetic counseling.
- First 6 months: Participants will have their overgrowth monitored.
- Next 6 months: Participants will take sirolimus once or twice a day.
- Participants will have to visit the clinic several times, and stay in the area for 4 to 5 days each time.
- Participants will have a one month-long visit to the clinic.
- During clinic visits, participants will have:
- Blood and urine tests.
- Photographs of their physical features.
- Scans, including an MRI and DEXA, and possibly x-rays and CT scans.
- For the MRI and CT scans, participants will lie in a machine that takes pictures of their body.
- The DEXA involves a small amount of radiation.
- They may have:
- Non-invasive heart function tests.
- Lung function tests.
- Participants will have several blood and urine tests between visits.
- Participants will complete surveys and keep a diary of their treatment and side effects.
- Participants may visit other health specialists or undergo other tests based on side effects.
- One month after stopping the study drug, participants will have 1 clinic visit.
|Condition or disease||Intervention/treatment||Phase|
|PIK3CA-Related Overgrowth Spectrum (PROS) Growth Disorder Genetics||Drug: Sirolimus||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||39 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Nonrandomized Open Label Pilot Study of Sirolimus Therapy for Segmental Overgrowth Caused by Somatic PI3K Activation|
|Study Start Date :||April 23, 2015|
|Actual Primary Completion Date :||February 14, 2018|
|Actual Study Completion Date :||February 14, 2018|
Experimental: Patients with PIK3CA gene mutation treated with Sirolimus
This is a single-arm, non-randomized, open-label study for the treatment of segmental overgrowth disorders (somatic PIK3CA gene mutation) with Sirolimus in thirty-nine patients.
Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml.
- Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA [ Time Frame: Run-in (0-26 weeks), treatment (26-52 weeks) ]
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)].
- Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by MRI Scan [ Time Frame: Run-in (0-26 weeks), treatment (26-52 weeks) ]
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)].
- Mean Sirolimus Doses to Achieve the Target Plasma Concentration [ Time Frame: Between 6 months and 12 months ]To establish optimal sirolimus dosing algorithms for a future RCT.
- Additional Measure of Efficacy: Quality of Life Assessment [ Time Frame: baseline (0 months) and end of treatment (12 months) ]
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).
- Number of Hospitalizations and Surgical Interventions [ Time Frame: 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02428296
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Kim M Keppler-Noreuil, M.D.||National Human Genome Research Institute (NHGRI)|