Rifampin in CYP24A1-related Hypercalcemia and Hypercalciuria

Genetic Disease Clinical Trial

— RICHH  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03301038
• Other study ID #: 16-013429
• Secondary ID: R01DK112955
• Status: Recruiting
• Phase: Phase 2
• Start date: July 25, 2018
• Est. completion date: December 2030

Study information

• Verified date: October 2023
• Source: Children's Hospital of Philadelphia
• Contact: Michael A Levine, MD
• Phone: 267-426-3907
• Email: levinem[@]chop.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 30 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 2030
• Est. primary completion date: December 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Genetic Disease
• Genetic Diseases, Inborn
• Hypercalcemia
• Hypercalcemia, Idiopathic, of Infancy
• Hypercalciuria
• Hypercalciuric Hypercalcemia
• Idiopathic Infantile Hypercalcaemia - Severe Form
• Idiopathic Infantile Hypercalcemia - Mild Form
• Infant, Newborn, Diseases
• Metabolism, Inborn Errors

Intervention

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.

Locations

Country	Name	City	State
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Children's Hospital of Philadelphia	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum albumin-adjusted calcium	Measured at baseline and every 4 weeks	up to 32 weeks
Primary	Serum parathyroid hormone	Measured at baseline and every 4 weeks	up to 32 weeks
Primary	Urinary calcium excretion	Measured at baseline and every 4 weeks	up to 32 weeks
Secondary	Intestinal calcium absorption	Measured using stable calcium isotopes five times during the study	baseline, 8, 16, 24 and 32 weeks post-dose
Secondary	Nephrocalcinosis	Renal ultrasound performed before and after treatment	Baseline and week 32
Secondary	Rifampin pharmacokinetics	Measured three times during the study	8, 16 and 24 weeks post-dose