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Sirolimus for the Treatment of Hyperinsulinism

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02524639
Recruitment Status : Withdrawn (Due to strict inclusion and exclusion criteria no subjects were enrolled)
First Posted : August 17, 2015
Last Update Posted : June 13, 2018
Information provided by (Responsible Party):
Diva De Leon, Children's Hospital of Philadelphia

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.

Condition or disease Intervention/treatment Phase
Hyperinsulinism Drug: Sirolimus Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study of the Efficacy and Safety of Sirolimus in the Treatment of Congenital Hyperinsulinism.
Estimated Study Start Date : August 12, 2015
Actual Primary Completion Date : May 29, 2018
Actual Study Completion Date : May 29, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Sirolimus

Arm Intervention/treatment
Experimental: Sirolimus
All enrolled subjects will receive Sirolimus 1 mg/m2/day twice a day for 6 weeks.
Drug: Sirolimus
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.
Other Name: Rapamune

Primary Outcome Measures :
  1. Number of children off intravenous dextrose support [ Time Frame: 6 weeks ]

Secondary Outcome Measures :
  1. Change in number hypoglycemic episodes per child per day [ Time Frame: 6 weeks ]
  2. Plasma insulin levels during fasting [ Time Frame: 8 hours ]
  3. Number of participants with Adverse Events [ Time Frame: 6 weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 12 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Males or females age ≥14 days to 12 months.
  2. Confirmed diagnosis of hyperinsulinism.
  3. Mutation analysis results demonstrating bi-allelic mutations in either ABCC8 or KCNJ11.
  4. Failure to respond to maximal dose of diazoxide (15 mg/kg/day), if diazoxide is indicated.

    1. Unable to wean intravenous dextrose after at least 3 days of diazoxide therapy and/or
    2. Persistent hypoglycemia after at least 3 days of diazoxide therapy
  5. High glucose infusion rate requirement (greater or equal to 10 mg/kg/min).
  6. Parental/guardian permission (informed consent).

Exclusion Criteria:

  1. Infants with suspected or confirmed focal hyperinsulinism who are candidates for surgical resection
  2. Current therapy with diazoxide. Subjects may be eligible for participation 48 hrs after discontinuation of diazoxide.
  3. Laboratory abnormalities that indicate clinically significant hematologic, hepatobiliary, or renal disease:

    1. AST/SGOT > 2.5 times the upper limit of normal
    2. ALT/SGPT > 2.5 times the upper limit of normal
    3. Total bilirubin > 2.5 times the upper limit of normal
    4. Hemoglobin < 9 gm/dL
    5. White blood cell count < 3,000/ mm3
    6. Platelet count < 100,000/mm3
    7. Creatinine > 2.5 times the upper limit of normal
  4. Evidence of active infection.
  5. Evidence of cardiac or respiratory failure.
  6. Known immune deficiency.
  7. Preterm (< 37 week gestation at birth).
  8. Treatment with immunosuppressants.
  9. 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

  10. 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

  11. History of surgical procedure within 8 weeks of enrollment.
  12. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.

Information from the National Library of Medicine

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 identifier (NCT number): NCT02524639

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United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Children's Hospital of Philadelphia
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Principal Investigator: Diva De Leon, MD Children's Hospital of Philadelphia

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Responsible Party: Diva De Leon, Study Principal Investigator, Children's Hospital of Philadelphia Identifier: NCT02524639     History of Changes
Other Study ID Numbers: 15-011973
First Posted: August 17, 2015    Key Record Dates
Last Update Posted: June 13, 2018
Last Verified: May 2018
Additional relevant MeSH terms:
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Glucose Metabolism Disorders
Metabolic Diseases
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs