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The Antibiotic Rifampin to Reduce High Levels of Blood and Urine Calcium in IIH

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ClinicalTrials.gov Identifier: NCT03384121
Recruitment Status : Recruiting
First Posted : December 27, 2017
Last Update Posted : December 27, 2017
Sponsor:
Collaborators:
Children's Hospital of Philadelphia
Canadian Institutes of Health Research (CIHR)
Cures Within Reach
Information provided by (Responsible Party):
Etienne Sochett, The Hospital for Sick Children

Brief Summary:
Idiopathic infantile hypercalcemia(IIH) is a rare,genetic disorder of mineral metabolism. Biallelic loss of functions mutations of CYP24A1, the gene encoding the 24-hydroxylase enzyme that represents the principal pathway for inactivation of vitamin D metabolites, cause the most common and severe form of IIH.Investigators have preliminary data supporting a novel therapeutic approach to suggest rifampin as an investigational drug to induce over-expression of CYP3A4, an important enzyme that provides an alternate catabolic pathway for inactivation of vitamin D metabolites. In this study, investigators will recruit 5 patients with biallelic inactivating mutations of CYP24A1. Participants will be followed prospectively for a total 6-11 months. This will include 2 months of observation, 2 months of receiving the starting dose of rifampin, followed by 2 month washout phase. Efficacy of the starting dose of rifampin will be determined prior to proceeding only in non responders to the escalation dose of rifampin 10mg/kg/day.

Condition or disease Intervention/treatment Phase
Idiopathic Infantile Hypercalcemia - Mild Form Drug: Rifampin 150 mg, 300 mg capsules and 25 mg/mL oral suspension Phase 1

Detailed Description:

Idiopathic infantile hypercalcemia(IIH) is a rare,genetic disorder of mineral metabolism characterized by severe hypercalcemia and/or hypercalciuria, suppressed serum levels of parathyroid hormone (PTH), elevated levels of the active vitamin D metabolite, 1,25(OH)2D, and nephrocalcinosis. Biallelic loss of functions mutations of CYP24A1, the gene encoding the 24-hydroxylase enzyme that represents the principal pathway for inactivation of vitamin D metabolites, cause the most common and severe form of IIH.

Investigators have preliminary data supporting a novel therapeutic approach to suggest rifampin as an investigational drug to induce over-expression of CYP3A4, an important P450 microsomal enzyme that is expressed in the liver and intestine. When CYP3A4 is induced, the increased enzyme activity provides an alternative catabolic pathway for inactivation of vitamin D metabolites. The purpose of this study is to obtain results and support for an open label, escalating dose study to assess the effect, safety, and tolerability of once daily oral rifampin for two months in participants with IIH due to inactivating mutations in CYP24A1.

In this study, Investigators will recruit 5 patients with biallelic inactivating mutations of CYP24A1. Participants will be followed prospectively for a total 6-11 months. This will include 2 months of observation, 2 months of receiving the starting dose of rifampin, followed by 2 month washout phase. Efficacy of the starting dose of rifampin will be determined prior to proceeding only in non responders to the escalation dose of rifampin 10mg/kg/day. In addition to determining if this treatment is efficacious in reducing elevated serum and urinary calcium in patients, it will be determined if there is a dose effect of rifampin. As well, detailed measurements of vitamin D metabolites will determine if rifampin reduces hypercalcemia through increased CYP3A4 activity.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is a phase 1 pilot study whereby all participants start the study at a starting dose 5mg/kg/day (at study visit 2) for two months, and those that do not respond to 5mg/kg/day, otherwise known as non-responders, will receive a higher dose of 10 mg/kg/day (at study visit 4) for another two months. Recruited patients will be followed prospectively for a total of 6-11 months. This will include 2 months of observation, 2 months of receiving the starting dose of rifampin of 5mg/kg/day with a maximum dose of 600mg/day followed by a 2 month washout phase. The efficacy of the starting dose of rifampin will be determined prior to proceeding only in non-responders to the higher dose of 10 mg/kg/day with a maximum dose of 600 mg/day.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Rifampin to Reduce Elevated Levels of Blood and Urine Calcium in Patients With Idiopathic Infantile Hypercalcemia
Estimated Study Start Date : December 2017
Estimated Primary Completion Date : June 30, 2019
Estimated Study Completion Date : June 30, 2019


Arm Intervention/treatment
Experimental: Rifampin
All subjects
Drug: Rifampin 150 mg, 300 mg capsules and 25 mg/mL oral suspension
Starting Dose (V2): 5 mg/kg/day (max 600mg/day) orally for 2 months followed by a 2 month washout period V4: After washout period, only Non-responders will escalate dose to 10 mg/kg/day (max 600mg/day) orally for 2 months
Other Name: Rifadin, Rofact, Rifampicin



Primary Outcome Measures :
  1. Change in Serum Calcium [ Time Frame: 40 weeks ]
    Measured at baseline and every 2 months (8 weeks)

  2. Change in Serum Parathyroid Hormone [ Time Frame: 40 weeks ]
    measured at baseline and every 2 months ( 8 weeks)

  3. Change in Urinary calcium excretion [ Time Frame: 40 weeks ]
    Measured at baseline and every 2 months( 8 weeks)


Secondary Outcome Measures :
  1. Nephrocalcinosis [ Time Frame: 40 weeks ]
    Renal ultrasound performed before and after treatment



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Ages Eligible for Study:   6 Months to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • all patients between 6 months- 17 years of age with the clinical phenotype of idiopathic infantile hypercalcemia
  • Biochemical evidence of this disorder: Serum calcium>upper limit of the reference age for range; high, 1,25 (OH)D; reduced PTH, reduced 24,25(OH)2D, and suppresses 24,1,25 (OH)2D, normal serum creatinine, AST, and ALT with or without
  • biallelic inactivating mutations of CYP24A1
  • mutations in newly published genes which are shown during the course of the study to cause an inappropriate increase in 1,25 (OH)2D

Exclusion Criteria:

  • Allergy to rifampin or related medications
  • Pregnancy or breastfeeding
  • Significant cardiac, hepatic, or endocrine comorbidities
  • Taking any medications/foods known to interact with CYP3A4 or 1,25 (OH)D
  • Parents or guardians or subjects who in the opinion of the Investigator may be non compliant with study schedules or procedures
  • Other comorbidities considered unsuitable by the investigator, including TB

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 ClinicalTrials.gov identifier (NCT number): NCT03384121


Contacts
Contact: Yesmino Elia, MSc 416-813-7654 ext 201518 yesmino.elia@sickkids.ca
Contact: Michelle Furman, BMSc 416-813-7654 ext 228985 michelle.furman@sickkids.ca

Locations
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Etienne Sochett, MD    416-813-6218    etienne.sochett@sickkids.ca   
Contact: Yesmino Elia, Msc.    416-813-7654 ext 1518    yesmino.elia@sickkids.ca   
Principal Investigator: Etienne Sochett, MD         
Sponsors and Collaborators
The Hospital for Sick Children
Children's Hospital of Philadelphia
Canadian Institutes of Health Research (CIHR)
Cures Within Reach
Investigators
Principal Investigator: Etienne Sochett, MD The Hospital for Sick Children

Publications:

Responsible Party: Etienne Sochett, Staff Endocrinologist, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT03384121     History of Changes
Other Study ID Numbers: 1000057141
First Posted: December 27, 2017    Key Record Dates
Last Update Posted: December 27, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Etienne Sochett, The Hospital for Sick Children:
CYP24A1
Nephrocalcinosis
Hypercalcemia
Hypercalcuria

Additional relevant MeSH terms:
Hypercalcemia
Calcium Metabolism Disorders
Metabolic Diseases
Water-Electrolyte Imbalance
Rifampin
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers