Idiopathic Infantile Hypercalcemia - Mild Form
Conditions
Keywords
CYP24A1, Nephrocalcinosis, Hypercalcemia, Hypercalcuria
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.
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.
Interventions
DRUGRifampin 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
Sponsors
Children's Hospital of Philadelphia
Canadian Institutes of Health Research (CIHR)
Cures Within Reach
The Hospital for Sick Children
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
6 Months to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Calcium | 40 weeks | Measured at baseline and every 2 months (8 weeks) |
| Change in Serum Parathyroid Hormone | 40 weeks | measured at baseline and every 2 months ( 8 weeks) |
| Change in Urinary calcium excretion | 40 weeks | Measured at baseline and every 2 months( 8 weeks) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nephrocalcinosis | 40 weeks | Renal ultrasound performed before and after treatment |
Countries
Canada
Contacts
Primary ContactYesmino Elia, MSc
Backup ContactMichelle Furman, BMSc
Outcome results
None listed