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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK112955 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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This study evaluates the efficacy of rifampin in the treatment of hypercalcemia and/or hypercalciuria in participants with at least one inactivating mutation of the CYP24A1 gene. Eligible subjects will receive rifampin for a total of 16 weeks during this study.
Idiopathic infantile hypercalcemia (IIH; omim 143880) is a genetic disorder of mineral metabolism characterized by severe hypercalcemia and/or hypercalciuria, suppressed serum levels of parathyroid hormone (PTH) and elevated levels of the active vitamin D metabolite, 1,25(OH)2D. Biallelic inactivating 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 repurpose rifampin as an agent to induce over-expression of CYP3A4 and CYP3A5, enzymes that are expressed in the liver and intestine. When these enzymes are induced, the increased enzyme activity provides an alternative catabolic pathway for inactivation of vitamin D metabolites. The purpose of this study is to obtain support for an open label, escalating dose study to assess the effect, safety, and tolerability of once daily oral rifampin in participants with IIH due to inactivating mutations in CYP24A1.
In this study, Investigators will recruit 60 patients with at least one inactivating mutation of CYP24A1. Participants will be observed for 8-weeks before a 16-week treatment phase of rifampin and 8 further weeks of observation. In addition to following the effect of treatment on calcium homeostasis, Investigators will also study the pharmacokinetics of rifampin in this condition and the effect on intestinal calcium absorption.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| All Subjects | Experimental | SingleArm: Escalating doses of rifampin (5 and 10 mg/kg/day) (SingleArm) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rifampin | Drug | Rifampin 5 mg/kg (max 300 mg) daily for 8 weeks, followed by rifampin 10 mg/kg (max 600 mg) daily for 8 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Serum albumin-adjusted calcium | Measured at baseline and every 4 weeks | up to 32 weeks |
| Serum parathyroid hormone | Measured at baseline and every 4 weeks | up to 32 weeks |
| Urinary calcium excretion | Measured at baseline and every 4 weeks | up to 32 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Intestinal calcium absorption | Measured using stable calcium isotopes five times during the study | baseline, 8, 16, 24 and 32 weeks post-dose |
| Nephrocalcinosis | Renal ultrasound performed before and after treatment |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Michael A Levine, MD | Contact | 267-426-3907 | levinem@chop.edu | |
| Vashisht Arshanapally | Contact | 267-426-7482 | arshanapav@chop.edu |
| Name | Affiliation | Role |
|---|---|---|
| Michael A Levine, MD | Children'sHospital of Philadelphia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital of Philadelphia | Recruiting | Philadelphia | Pennsylvania | 19104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28324001 | Background | Hawkes CP, Li D, Hakonarson H, Meyers KE, Thummel KE, Levine MA. CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations. J Clin Endocrinol Metab. 2017 May 1;102(5):1440-1446. doi: 10.1210/jc.2016-4048. | |
| 22112808 | Background | Dauber A, Nguyen TT, Sochett E, Cole DE, Horst R, Abrams SA, Carpenter TO, Hirschhorn JN. Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia. J Clin Endocrinol Metab. 2012 Feb;97(2):E268-74. doi: 10.1210/jc.2011-1972. Epub 2011 Nov 23. |
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| Baseline and week 32 |
| Rifampin pharmacokinetics | Measured three times during the study | 8, 16 and 24 weeks post-dose |
| 21675912 | Background | Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U, Misselwitz J, Klaus G, Kuwertz-Broking E, Fehrenbach H, Wingen AM, Guran T, Hoenderop JG, Bindels RJ, Prosser DE, Jones G, Konrad M. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011 Aug 4;365(5):410-21. doi: 10.1056/NEJMoa1103864. Epub 2011 Jun 15. |
| ID | Term |
|---|---|
| D030342 | Genetic Diseases, Inborn |
| C562581 | Hypercalcemia, Idiopathic, of Infancy |
| C563373 | Hypercalciuric Hypercalcemia |
| D053565 | Hypercalciuria |
| D006934 | Hypercalcemia |
| D009397 | Nephrocalcinosis |
| ID | Term |
|---|---|
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D020924 | Urological Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D002128 | Calcium Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D014883 | Water-Electrolyte Imbalance |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002114 | Calcinosis |
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| ID | Term |
|---|---|
| D012293 | Rifampin |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
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