<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03301038</url>
  </required_header>
  <id_info>
    <org_study_id>16-013429</org_study_id>
    <secondary_id>R01DK112955</secondary_id>
    <nct_id>NCT03301038</nct_id>
  </id_info>
  <brief_title>Rifampin in CYP24A1-related Hypercalcemia and Hypercalciuria</brief_title>
  <acronym>RICHH</acronym>
  <official_title>Rifampin to Reduce Elevated Levels of Blood and Urine Calcium in Patients With Inactivating Mutations in the CYP24A1 Gene</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital of Philadelphia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's Hospital of Philadelphia</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates the efficacy of rifampin in the treatment of hypercalcemia and/or&#xD;
      hypercalciuria in participants with at least one inactivating mutation of the CYP24A1 gene.&#xD;
      Eligible subjects will receive rifampin for a total of 16 weeks during this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Idiopathic infantile hypercalcemia (IIH; omim 143880) is a genetic disorder of mineral&#xD;
      metabolism characterized by severe hypercalcemia and/or hypercalciuria, suppressed serum&#xD;
      levels of parathyroid hormone (PTH) and elevated levels of the active vitamin D metabolite,&#xD;
      1,25(OH)2D. Biallelic inactivating mutations of CYP24A1, the gene encoding the 24-hydroxylase&#xD;
      enzyme that represents the principal pathway for inactivation of vitamin D metabolites, cause&#xD;
      the most common and severe form of IIH.&#xD;
&#xD;
      Investigators have preliminary data supporting a novel therapeutic approach to repurpose&#xD;
      rifampin as an agent to induce over-expression of CYP3A4 and CYP3A5, enzymes that are&#xD;
      expressed in the liver and intestine. When these enzymes are induced, the increased enzyme&#xD;
      activity provides an alternative catabolic pathway for inactivation of vitamin D metabolites.&#xD;
      The purpose of this study is to obtain support for an open label, escalating dose study to&#xD;
      assess the effect, safety, and tolerability of once daily oral rifampin in participants with&#xD;
      IIH due to inactivating mutations in CYP24A1.&#xD;
&#xD;
      In this study, Investigators will recruit 18 patients with at least one inactivating mutation&#xD;
      of CYP24A1. Participants will be observed for 8-weeks before a 16-week treatment phase of&#xD;
      rifampin and 8 further weeks of observation. In addition to following the effect of treatment&#xD;
      on calcium homeostasis, Investigators will also study the pharmacokinetics of rifampin in&#xD;
      this condition and the effect on intestinal calcium absorption.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 25, 2018</start_date>
  <completion_date type="Anticipated">December 2030</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Serum albumin-adjusted calcium</measure>
    <time_frame>up to 32 weeks</time_frame>
    <description>Measured at baseline and every 4 weeks</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum parathyroid hormone</measure>
    <time_frame>up to 32 weeks</time_frame>
    <description>Measured at baseline and every 4 weeks</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Urinary calcium excretion</measure>
    <time_frame>up to 32 weeks</time_frame>
    <description>Measured at baseline and every 4 weeks</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Intestinal calcium absorption</measure>
    <time_frame>baseline, 8, 16, 24 and 32 weeks post-dose</time_frame>
    <description>Measured using stable calcium isotopes five times during the study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nephrocalcinosis</measure>
    <time_frame>Baseline and week 32</time_frame>
    <description>Renal ultrasound performed before and after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rifampin pharmacokinetics</measure>
    <time_frame>8, 16 and 24 weeks post-dose</time_frame>
    <description>Measured three times during the study</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Idiopathic Infantile Hypercalcaemia - Severe Form</condition>
  <condition>Genetic Disease</condition>
  <condition>Hypercalcemia, Idiopathic, of Infancy</condition>
  <condition>Hypercalciuric Hypercalcemia</condition>
  <condition>Idiopathic Infantile Hypercalcemia - Mild Form</condition>
  <condition>Hypercalciuria</condition>
  <arm_group>
    <arm_group_label>All Subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>SingleArm: Escalating doses of rifampin (5 and 10 mg/kg/day) (SingleArm)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifampin</intervention_name>
    <description>Rifampin 5 mg/kg (max 300 mg) daily for 8 weeks, followed by rifampin 10 mg/kg (max 600 mg) daily for 8 weeks.</description>
    <arm_group_label>All Subjects</arm_group_label>
    <other_name>Rifadin</other_name>
    <other_name>Rifampicin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males or females age 6 months to 65 years.&#xD;
&#xD;
          -  at least one mutations of CYP24A1&#xD;
&#xD;
          -  Serum and/or urinary calcium above the normal reference range for age&#xD;
&#xD;
          -  Serum PTH concentration &lt;20 pg/ml&#xD;
&#xD;
          -  Elevated or normal serum concentration of 1,25-dihydroxyvitamin D3.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Parents/guardians or subjects who, in the opinion of the Investigator, may be&#xD;
             non-compliant with study schedules or procedures.&#xD;
&#xD;
          -  Allergy to rifampin or related medications&#xD;
&#xD;
          -  Current therapies with medications that have significant drug-drug interactions with&#xD;
             rifampin, defined as a medication considered to interact with CYP3A4 or CYP3A5 and&#xD;
             either induce or inhibit expression or function of these P450 enzymes. By &quot;drug-drug&quot;&#xD;
             interactions we are looking for medications that will affect metabolism or action of&#xD;
             rifampin as exclusionary, not medications that will be affected by rifampin.&#xD;
&#xD;
          -  Pregnancy or breastfeeding&#xD;
&#xD;
          -  Laboratory abnormalities that indicate clinically significant hepatic, or renal&#xD;
             disease:&#xD;
&#xD;
        Aspartate Aminotransferase (AST/SGOT) &gt; 2.0 times the upper limit of normal Alanine&#xD;
        aminotransferase (ALT/SGPT) &gt; 2.0 times the upper limit of normal Total bilirubin &gt; 2.0&#xD;
        times the upper limit of normal Creatinine &gt; 2.0 times the upper limit of normal&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael A Levine, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children'sHospital of Philadelphia</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Michael A Levine, MD</last_name>
    <phone>267-426-3907</phone>
    <email>levinem@chop.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Vashisht Arshanapally</last_name>
    <phone>267-426-7482</phone>
    <email>arshanapav@chop.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael A Levine, MD</last_name>
      <phone>267-426-3907</phone>
      <email>levinem@chop.edu</email>
    </contact>
    <contact_backup>
      <last_name>Sara Pinney, MD</last_name>
      <phone>215-590-3174</phone>
      <email>PINNEYS@chop.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Sara Pinney, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Michael A Levine, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <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.</citation>
    <PMID>28324001</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22112808</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>21675912</PMID>
  </reference>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>September 1, 2017</study_first_submitted>
  <study_first_submitted_qc>September 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 4, 2017</study_first_posted>
  <last_update_submitted>October 27, 2022</last_update_submitted>
  <last_update_submitted_qc>October 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 31, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>hypercalcemia</keyword>
  <keyword>nephrocalcinosis</keyword>
  <keyword>CYP24A1</keyword>
  <keyword>hypercalciuria</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Genetic Diseases, Inborn</mesh_term>
    <mesh_term>Infant, Newborn, Diseases</mesh_term>
    <mesh_term>Metabolism, Inborn Errors</mesh_term>
    <mesh_term>Hypercalcemia</mesh_term>
    <mesh_term>Hypercalciuria</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rifampin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03301038
org study id: 16-013429
secondary id: R01DK112955
nct id: NCT03301038
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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 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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Serum albumin-adjusted calcium
time frame: up to 32 weeks
description: Measured at baseline and every 4 weeks
measure: Serum parathyroid hormone
time frame: up to 32 weeks
description: Measured at baseline and every 4 weeks
measure: Urinary calcium excretion
time frame: up to 32 weeks
description: Measured at baseline and every 4 weeks
measure: Intestinal calcium absorption
time frame: baseline, 8, 16, 24 and 32 weeks post-dose
description: Measured using stable calcium isotopes five times during the study
measure: Nephrocalcinosis
time frame: Baseline and week 32
description: Renal ultrasound performed before and after treatment
measure: Rifampin pharmacokinetics
time frame: 8, 16 and 24 weeks post-dose
description: Measured three times during the study
arm group label: All Subjects
arm group type: Experimental
description: SingleArm: Escalating doses of rifampin (5 and 10 mg/kg/day) (SingleArm)
intervention type: Drug
intervention name: Rifampin
description: Rifampin 5 mg/kg (max 300 mg) daily for 8 weeks, followed by rifampin 10 mg/kg (max 600 mg) daily for 8 weeks.
arm group label: All Subjects
other name: Rifadin
other name: Rifampicin
criteria: 
gender: All
minimum age: 6 Months
maximum age: 65 Years
healthy volunteers: No
last name: Michael A Levine, MD
role: Principal Investigator
affiliation: Children'sHospital of Philadelphia
last name: Michael A Levine, MD
phone: 267-426-3907
email: levinem@chop.edu
last name: Vashisht Arshanapally
phone: 267-426-7482
email: arshanapav@chop.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: United States
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.
PMID: 28324001
citation: 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.
PMID: 22112808
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.
PMID: 21675912
responsible party type: Sponsor
mesh term: Genetic Diseases, Inborn
mesh term: Infant, Newborn, Diseases
mesh term: Metabolism, Inborn Errors
mesh term: Hypercalcemia
mesh term: Hypercalciuria
mesh term: Rifampin
sharing ipd: No