RICHH: Rifampin in CYP24A1-related Hypercalcemia and Hypercalciuria

Sponsor

Children's Hospital of Philadelphia (Other)

Overall Status

Recruiting

CT.gov ID

NCT03301038

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Enrollment

Location

Arm

149.4

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Infantile Hypercalcaemia - Severe Form Genetic Disease Hypercalcemia, Idiopathic, of Infancy Hypercalciuric Hypercalcemia Idiopathic Infantile Hypercalcemia - Mild Form Hypercalciuria	Drug: Rifampin	Phase 2

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 18 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 Design

Study Type:

Interventional

Anticipated Enrollment :

18 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 19, 2018

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All Subjects	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: Rifadin Rifampicin

Arm

Intervention/Treatment

Experimental: All Subjects

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:

Rifadin

Rifampicin

Outcome Measures

Primary Outcome Measures

Serum albumin-adjusted calcium [up to 32 weeks]
Measured at baseline and every 4 weeks
Serum parathyroid hormone [up to 32 weeks]
Measured at baseline and every 4 weeks
Urinary calcium excretion [up to 32 weeks]
Measured at baseline and every 4 weeks

Secondary Outcome Measures

Intestinal calcium absorption [baseline, 8, 16, 24 and 32 weeks post-dose]
Measured using stable calcium isotopes five times during the study
Nephrocalcinosis [Baseline and week 32]
Renal ultrasound performed before and after treatment
Rifampin pharmacokinetics [8, 16 and 24 weeks post-dose]
Measured three times during the study

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Months to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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