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| ID | Type | Description | Link |
|---|---|---|---|
| 15-HG-0120 | Other Identifier | National Institutes of Health |
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Background:
- 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.
Objectives:
- 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.
Eligibility:
- 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).
Design:
The primary study objective is to determine the likely size of sirolimus treatment effect. The patient population will include male and female subjects, aged greater than or equal to 3 years and less than or equal to 65 years of age with segmental overgrowth identified to have clinical and molecular findings of somatic PIK3CA gene mutation. The planned study size will be ten patients seen at the NIHCC. An additional 20 patients will be contributed by two other centers, who will be responsible for the conduct of the proposed research at their site, but the study procedures and dosing schedule will be identical to enable pooling of results for statistical analyses. The study design will be a nonrandomized, open label, phase II pilot study of sirolimus treatment. As patients have highly variable clinical presentations, and there are no established evidence-based methodologies for measuring serial changes in growth, the aim of this pilot study is to establish the optimal methodology for evaluating changes in growth to inform the design of a future randomized controlled trial, in addition to determining treatment effect size, and evaluating safety and toxicity of low dose sirolimus. Overall desired outcome will be reduced size of affected body part, and measures will include: reduction in affected tissue (fibroadipose or bone) size by clinical exam measurement and by radiological studies (MRI area measurements and/or DXA study measurements of fat).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with PIK3CA gene mutation treated with Sirolimus | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus | Drug | Low dose sirolimus will be given in daily dosing to achieve trough levels of 2-6 ng/ ml. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA | 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)]. | Run-in (0-26 weeks), treatment (26-52 weeks) |
| Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by MRI Scan | 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)]. | Run-in (0-26 weeks), treatment (26-52 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Sirolimus Doses to Achieve the Target Plasma Concentration | To establish optimal sirolimus dosing algorithms for a future RCT. | Between 6 months and 12 months |
| Additional Measure of Efficacy: Quality of Life Assessment |
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INCLUSION CRITERIA:
Age: greater than or equal to 3 years to less than or equal to 65 years
Male or Female
Confirmed PIK3CA somatic mutation
Measurably progressive overgrowth, in current progression or with clinical history of overgrowth progression
Adequate Bone Marrow Function Defined as:
Adequate Renal Function Defined as:
A serum creatinine based on age as follows:
OR a creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2
Adequate Liver Function Defined As:
Fasting LDL Cholesterol:
EXCLUSION CRITERIA:
The participant may not enter the study if ANY of the following apply:
We propose to restrict participation in this study to those with sufficient English language skills to complete the quality of life measures we will employ among all three study sites, as many of the specific quality of life measures we are employing at the NIH only are not available in other languages.
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| Name | Affiliation | Role |
|---|---|---|
| Kim M Keppler-Noreuil, M.D. | National Human Genome Research Institute (NHGRI) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22729222 | Background | Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, O'Rahilly S, Savage DB, Wakelam MJ, Barroso I, Biesecker LG, Semple RK. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet. 2012 Jun 24;44(8):928-33. doi: 10.1038/ng.2332. | |
| 25557259 |
| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by DXA | 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)]. | The anatomy of 23 patients permitted DXA analysis of affected versus unaffected tissue. | Posted | Mean | Standard Deviation | mean percentage change in tissue volume | Run-in (0-26 weeks), treatment (26-52 weeks) |
|
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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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Blood and lymphatic disorders | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
Phenotypic heterogeneity; post hoc subanalyses and QoL assessments had small sample sizes; overestimation of AEs; interruption of treatment due to intercurrent AEs; asymmetric overgrowth not included in primary outcome analysis
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Kim Keppler-Noreuil | Children's National Medical Center | 2024766287 | kkepplerno@childrensnational.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 4, 2018 | Sep 5, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006130 | Growth Disorders |
| D000013 | Congenital Abnormalities |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| D020123 | Sirolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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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).
| baseline (0 months) and end of treatment (12 months) |
| Number of Hospitalizations and Surgical Interventions | Tracked number of hospitalizations and surgical interventions occurring over the course of the run-in and treatment period. | Run-in (0-26 weeks) and treatment (27-52 weeks) |
| Background |
| Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, Sapp JC, Alomari A, Ezaki M, Dobyns W, Biesecker LG. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015 Feb;167A(2):287-95. doi: 10.1002/ajmg.a.36836. Epub 2014 Dec 31. |
| 24782230 | Background | Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, Parker VE, Blumhorst C, Darling T, Tosi LL, Huson SM, Whitehouse RW, Jakkula E, Grant I, Balasubramanian M, Chandler KE, Fraser JL, Gucev Z, Crow YJ, Brennan LM, Clark R, Sellars EA, Pena LD, Krishnamurty V, Shuen A, Braverman N, Cunningham ML, Sutton VR, Tasic V, Graham JM Jr, Geer J Jr, Henderson A, Semple RK, Biesecker LG. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014 Jul;164A(7):1713-33. doi: 10.1002/ajmg.a.36552. Epub 2014 Apr 29. |
| 30270358 | Result | Parker VER, Keppler-Noreuil KM, Faivre L, Luu M, Oden NL, De Silva L, Sapp JC, Andrews K, Bardou M, Chen KY, Darling TN, Gautier E, Goldspiel BR, Hadj-Rabia S, Harris J, Kounidas G, Kumar P, Lindhurst MJ, Loffroy R, Martin L, Phan A, Rother KI, Widemann BC, Wolters PL, Coubes C, Pinson L, Willems M, Vincent-Delorme C; PROMISE Working Group; Vabres P, Semple RK, Biesecker LG. Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum. Genet Med. 2019 May;21(5):1189-1198. doi: 10.1038/s41436-018-0297-9. Epub 2018 Oct 1. |
| years |
|
| Age, Customized | Count of Participants | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
Affected sites were defined by clinical observation. |
| OG001 | Unaffected Tissue | Unaffected sites showed no overgrowth, nor evidence of skin or vascular abnormalities. |
|
|
| Primary | Percent Change in Unaffected and Affected Fibrofatty Tissue Measured by MRI Scan | 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)]. | 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). | Posted | Mean | Standard Deviation | percentage of tissue volume change | Run-in (0-26 weeks), treatment (26-52 weeks) |
|
|
|
| Secondary | Mean Sirolimus Doses to Achieve the Target Plasma Concentration | To establish optimal sirolimus dosing algorithms for a future RCT. | All patients were analyzed to determine at which dose the patient would reach the target plasma concentration. | Posted | Mean | 95% Confidence Interval | mg/day | Between 6 months and 12 months |
|
|
|
| Secondary | Additional Measure of Efficacy: Quality of Life Assessment | 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). | 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. | Posted | Mean | 95% Confidence Interval | mean change in quality of life score | baseline (0 months) and end of treatment (12 months) |
|
|
|
| Secondary | Number of Hospitalizations and Surgical Interventions | Tracked number of hospitalizations and surgical interventions occurring over the course of the run-in and treatment period. | Posted | Number | number of events | Run-in (0-26 weeks) and treatment (27-52 weeks) |
|
|
|
| 0 |
| 39 |
| 12 |
| 39 |
| 31 |
| 39 |
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
|
| Neutropenic fever | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
|
| Constipation aggravated | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Appendicitis | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
| Cellulitis | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
| Epstein Barr Virus | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
| Pelvic infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
| Viral meningitis | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
| Over-medication | Injury, poisoning and procedural complications | CTCAE (4.0) | Systematic Assessment |
|
| Sirolimus hypersensitivity syndrome | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Hemarthrosis | Vascular disorders | CTCAE (4.0) | Systematic Assessment |
|
| Pulmonary embolus | Vascular disorders | CTCAE (4.0) | Systematic Assessment |
|
| Gastrointestinal disorders | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Infections and infestations | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
|
| Injury, poisoning, and procedural complications | Injury, poisoning and procedural complications | CTCAE (4.0) | Systematic Assessment |
|
| Metabolism and nutrition disorders | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
|
| Musculoskeletal and connective tissue disorders | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Nervous system disorders | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
|
| Renal and urinary disorders | Renal and urinary disorders | CTCAE (4.0) | Systematic Assessment |
|
| Respiratory, thoracic and mediastinal disorders | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
|
| Skin and subcutaneous disorders | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Systematic Assessment |
|
| Vascular disorders | Vascular disorders | CTCAE (4.0) | Systematic Assessment |
|
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|
|
| Adults (physical health) |
|
|
| Adults (psychological health) |
|
|
| Adults (social relationships) |
|
|
| Adults (environment) |
|
|
| Title | Measurements |
|---|---|
|
| Treatment period : Surgical interventions |
|