Back to resultsSirolimus for the Treatment of Hyperinsulinism
Primary Purpose
Hyperinsulinism
Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Sirolimus
Sponsored by
About this trial
This is an interventional treatment trial for Hyperinsulinism
Eligibility Criteria
Inclusion Criteria:
- Males or females age ≥14 days to 12 months.
- Confirmed diagnosis of hyperinsulinism.
- Mutation analysis results demonstrating bi-allelic mutations in either ABCC8 or KCNJ11.
Failure to respond to maximal dose of diazoxide (15 mg/kg/day), if diazoxide is indicated.
- Unable to wean intravenous dextrose after at least 3 days of diazoxide therapy and/or
- Persistent hypoglycemia after at least 3 days of diazoxide therapy
- High glucose infusion rate requirement (greater or equal to 10 mg/kg/min).
- Parental/guardian permission (informed consent).
Exclusion Criteria:
- Infants with suspected or confirmed focal hyperinsulinism who are candidates for surgical resection
- Current therapy with diazoxide. Subjects may be eligible for participation 48 hrs after discontinuation of diazoxide.
Laboratory abnormalities that indicate clinically significant hematologic, hepatobiliary, or renal disease:
- AST/SGOT > 2.5 times the upper limit of normal
- ALT/SGPT > 2.5 times the upper limit of normal
- Total bilirubin > 2.5 times the upper limit of normal
- Hemoglobin < 9 gm/dL
- White blood cell count < 3,000/ mm3
- Platelet count < 100,000/mm3
- Creatinine > 2.5 times the upper limit of normal
- Evidence of active infection.
- Evidence of cardiac or respiratory failure.
- Known immune deficiency.
- Preterm (< 37 week gestation at birth).
- Treatment with immunosuppressants.
Treatment with any drug known to interact significantly with sirolimus (strong inducers and strong inhibitors of CYP3A4 and P-gp with risk category D and X) including:
Cyclosporine, clozapine, conivaptan, crizotinib, dabrafenib, dipyrone, boceprevir, echinacea, efavirenz, enzalutamide, fluconazole, fosphenytoin, fusidic acid, idelalisib, leflunomide, lomitapide, mifepristone, mitotane, natalizumab, nelfinavir, phenytoin, pimecrolimus, pimozide, posaconazole, roflumilast, St Johns Wort, stiripentol, tacrolimus, telaprevir, tofacitinib, rifampin, rifabutin, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin
Any investigational drug use within 5 half-lives of the drug prior to initiation of therapy.
Subjects who had participated in other investigational drug studies will be eligible to participate after 5 half-lives from the last dose of the investigational agent and have recovered from acute investigational agent associated toxicity
- History of surgical procedure within 8 weeks of enrollment.
- Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
Sites / Locations
- The Children's Hospital of Philadelphia
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Sirolimus
Arm Description
All enrolled subjects will receive Sirolimus 1 mg/m2/day twice a day for 6 weeks.
Outcomes
Primary Outcome Measures
Number of children off intravenous dextrose support
Secondary Outcome Measures
Change in number hypoglycemic episodes per child per day
Plasma insulin levels during fasting
Number of participants with Adverse Events
Full Information
NCT ID
NCT02524639
First Posted
August 12, 2015
Last Updated
June 12, 2018
Sponsor
Children's Hospital of Philadelphia
1. Study Identification
Unique Protocol Identification Number
NCT02524639
Brief Title
Sirolimus for the Treatment of Hyperinsulinism
Official Title
Pilot Study of the Efficacy and Safety of Sirolimus in the Treatment of Congenital Hyperinsulinism.
Study Type
Interventional
2. Study Status
Record Verification Date
May 2018
Overall Recruitment Status
Withdrawn
Why Stopped
Due to strict inclusion and exclusion criteria no subjects were enrolled
Study Start Date
August 12, 2015 (Anticipated)
Primary Completion Date
May 29, 2018 (Actual)
Study Completion Date
May 29, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Children's Hospital of Philadelphia
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this pilot study is to generate data to assess feasibility of study design/procedures and for formal sample size estimation for a larger multicenter study of the efficacy and safety of sirolimus in infants with medically-unresponsive congenital hyperinsulinism (HI) due to inactivating mutations of adenosine triphosphate-sensitive potassium (KATP) channels.
Detailed Description
Treatment options for children with diffuse adenosine triphosphate-sensitive potassium (KATP) channel hyperinsulinism (KATPHI) are limited and most of them require a near-total pancreatectomy to control the hypoglycemia. However, at least 40% of these children continue to have persistent hypoglycemia after surgery and their long-term outcomes are complicated by the development of diabetes.
There is evidence that suggests that mammalian target of rapamycin (mTOR) inhibitors are useful in controlling the hypoglycemia in hyperinsulinemic hypoglycemia. But before adapting this as standard therapy for children with hyperinsulinism, a carefully controlled study of the efficacy and safety of sirolimus for hyperinsulinism is clearly needed.
Sirolimus is an mTOR inhibitor, which is FDA-approved for the prophylaxis of organ rejection in patients age 13 years and older receiving kidney transplantation. This is an open label pilot study to assess the effect, safety and tolerability of sirolimus in infants with diazoxide-unresponsive HI due to mutations in the genes encoding the KATP channels. Subjects will be treated with sirolimus for 6 weeks.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyperinsulinism
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sirolimus
Arm Type
Experimental
Arm Description
All enrolled subjects will receive Sirolimus 1 mg/m2/day twice a day for 6 weeks.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamune
Intervention Description
Subjects will receive 1 mg/m2/day orally for 6 weeks. Maintenance dose will be titrated up or down by 0.25-0.5 mg/m2/day every 4 days. Serum concentration will be checked on day 4 after initial therapy and 4 days after any dose adjustment. Levels will be checked at lease once a week during the duration of the study. Target serum concentration range is 5-10 ng/mL.
Primary Outcome Measure Information:
Title
Number of children off intravenous dextrose support
Time Frame
6 weeks
Secondary Outcome Measure Information:
Title
Change in number hypoglycemic episodes per child per day
Time Frame
6 weeks
Title
Plasma insulin levels during fasting
Time Frame
8 hours
Title
Number of participants with Adverse Events
Time Frame
6 weeks
10. Eligibility
Sex
All
Maximum Age & Unit of Time
12 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Males or females age ≥14 days to 12 months.
Confirmed diagnosis of hyperinsulinism.
Mutation analysis results demonstrating bi-allelic mutations in either ABCC8 or KCNJ11.
Failure to respond to maximal dose of diazoxide (15 mg/kg/day), if diazoxide is indicated.
Unable to wean intravenous dextrose after at least 3 days of diazoxide therapy and/or
Persistent hypoglycemia after at least 3 days of diazoxide therapy
High glucose infusion rate requirement (greater or equal to 10 mg/kg/min).
Parental/guardian permission (informed consent).
Exclusion Criteria:
Infants with suspected or confirmed focal hyperinsulinism who are candidates for surgical resection
Current therapy with diazoxide. Subjects may be eligible for participation 48 hrs after discontinuation of diazoxide.
Laboratory abnormalities that indicate clinically significant hematologic, hepatobiliary, or renal disease:
AST/SGOT > 2.5 times the upper limit of normal
ALT/SGPT > 2.5 times the upper limit of normal
Total bilirubin > 2.5 times the upper limit of normal
Hemoglobin < 9 gm/dL
White blood cell count < 3,000/ mm3
Platelet count < 100,000/mm3
Creatinine > 2.5 times the upper limit of normal
Evidence of active infection.
Evidence of cardiac or respiratory failure.
Known immune deficiency.
Preterm (< 37 week gestation at birth).
Treatment with immunosuppressants.
Treatment with any drug known to interact significantly with sirolimus (strong inducers and strong inhibitors of CYP3A4 and P-gp with risk category D and X) including:
Cyclosporine, clozapine, conivaptan, crizotinib, dabrafenib, dipyrone, boceprevir, echinacea, efavirenz, enzalutamide, fluconazole, fosphenytoin, fusidic acid, idelalisib, leflunomide, lomitapide, mifepristone, mitotane, natalizumab, nelfinavir, phenytoin, pimecrolimus, pimozide, posaconazole, roflumilast, St Johns Wort, stiripentol, tacrolimus, telaprevir, tofacitinib, rifampin, rifabutin, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin
Any investigational drug use within 5 half-lives of the drug prior to initiation of therapy.
Subjects who had participated in other investigational drug studies will be eligible to participate after 5 half-lives from the last dose of the investigational agent and have recovered from acute investigational agent associated toxicity
History of surgical procedure within 8 weeks of enrollment.
Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Diva De Leon, MD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Sirolimus for the Treatment of Hyperinsulinism
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