Rifampin in CYP24A1-related Hypercalcemia and Hypercalciuria (RICHH)

Rifampin to Reduce Elevated Levels of Blood and Urine Calcium in Patients With Inactivating Mutations in the CYP24A1 Gene

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.

Study Overview

• Status: Recruiting
• Conditions: Genetic Disease; Hypercalciuria; Idiopathic Infantile Hypercalcemia - Mild Form; Idiopathic Infantile Hypercalcaemia - Severe Form; Hypercalcemia, Idiopathic, of Infancy; Hypercalciuric Hypercalcemia
• Intervention / Treatment: Drug: Rifampin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael A Levine, MD; Phone Number: 267-426-3907; Email: levinem@chop.edu
• Study Contact Backup: Name: Vashisht Arshanapally; Phone Number: 267-426-7482; Email: arshanapav@chop.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Principal Investigator: Michael A Levine, MD
      • Contact: Michael A Levine, MD; Phone Number: 267-426-3907; Email: levinem@chop.edu
      • Contact: Sara Pinney, MD; Phone Number: 215-590-3174; Email: PINNEYS@chop.edu
      • Sub-Investigator: Sara Pinney, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 61 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males or females age 6 months to 65 years.
• at least one mutations of CYP24A1
• Serum and/or urinary calcium above the normal reference range for age
• Serum PTH concentration <20 pg/ml
• Elevated or normal serum concentration of 1,25-dihydroxyvitamin D3.

Exclusion Criteria:

• Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
• Allergy to rifampin or related medications
• Current therapies with medications that have significant drug-drug interactions with rifampin, defined as a medication considered to interact with CYP3A4 or CYP3A5 and either induce or inhibit expression or function of these P450 enzymes. By "drug-drug" interactions we are looking for medications that will affect metabolism or action of rifampin as exclusionary, not medications that will be affected by rifampin.
• Pregnancy or breastfeeding
• Laboratory abnormalities that indicate clinically significant hepatic, or renal disease:
• Aspartate Aminotransferase (AST/SGOT) > 2.0 times the upper limit of normal Alanine aminotransferase (ALT/SGPT) > 2.0 times the upper limit of normal Total bilirubin > 2.0 times the upper limit of normal Creatinine > 2.0 times the upper limit of normal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: All Subjects; SingleArm: Escalating doses of rifampin (5 and 10 mg/kg/day) (SingleArm)	Drug: Rifampin; Rifampin 5 mg/kg (max 300 mg) daily for 8 weeks, followed by rifampin 10 mg/kg (max 600 mg) daily for 8 weeks.; Other Names: Rifampicin; Rifadin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	Baseline and week 32
Rifampin pharmacokinetics	Measured three times during the study	8, 16 and 24 weeks post-dose

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Michael A Levine, MD, Children'sHospital of Philadelphia

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2018
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: September 1, 2017
• First Submitted That Met QC Criteria: September 29, 2017
• First Posted (Actual): October 4, 2017

Study Record Updates

• Last Update Posted (Actual): July 28, 2025
• Last Update Submitted That Met QC Criteria: July 23, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: hypercalciuria; nephrocalcinosis; CYP24A1; hypercalcemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Urological Manifestations; Water-Electrolyte Imbalance; Calcium Metabolism Disorders; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Infant, Newborn, Diseases; Hypercalciuria; Hypercalcemia; Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; Antibiotics, Antitubercular; Antitubercular Agents; Leprostatic Agents; 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; Rifampin
• Other Study ID Numbers: 16-013429; R01DK112955 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No