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Smith-Lemli-Opitz Syndrome and Cholic Acid

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ClinicalTrials.gov Identifier: NCT03720990
Recruitment Status : Recruiting
First Posted : October 26, 2018
Last Update Posted : May 3, 2021
Sponsor:
Collaborators:
University of Colorado, Denver
Children's Hospital Medical Center, Cincinnati
University of Pittsburgh
Information provided by (Responsible Party):
William Rizzo, MD, University of Nebraska

Study Description
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Brief Summary:
The purpose of this study is to determine whether dietary cholic acid therapy benefits people with Smith-Lemli-Opitz syndrome (SLOS) by leading to an increase in serum cholesterol and reduction in harmful cholesterol precursors. SLOS participants will be treated with dietary cholic acid for 8 weeks and serum cholesterol and cholesterol precursor metabolites will be measured.

Condition or disease Intervention/treatment Phase
Smith-Lemli-Opitz Syndrome Drug: Cholic Acid Phase 1 Phase 2

Detailed Description:

People with SLOS have a deficiency of the 7-dehydrocholesterol reductase enzyme that makes cholesterol. Consequently, they exhibit deficient cholesterol levels and increased cholesterol precursor lipids, which are thought to be toxic. Cholesterol itself normally regulates the cholesterol synthesis pathway in the body and under conditions of low serum cholesterol seen in SLOS, more of the toxic cholesterol precursors are made. Since cholesterol is also necessary for production of bile acids in the liver, which help digest dietary cholesterol from the intestine, it is likely that low cholesterol levels in SLOS impairs bile acids from being made, which in turn prevents dietary cholesterol from being absorbed properly and contributes to the cholesterol deficiency seen in SLOS. Raising serum cholesterol in SLOS people by improving its absorption from the diet is expected to decrease the potentially toxic cholesterol precursor lipids, and both changes would be theoretically beneficial for SLOS people.

The objective of this study is to determine whether treatment with cholic acid (a major bile acid made in the body that improves fat absorption) will increase dietary absorption of cholesterol, reverse serum cholesterol deficiency, and reduce harmful cholesterol precursor lipids. These changes would be favorable for SLOS people. To accomplish this objective, SLOS participants will be given dietary cholic acid (brand name Cholbam, manufactured by Retrophin) for 8 weeks and serum cholesterol and its precursor lipids will be measured before and while taking the drug.

SLOS participants who are between 2 years and 25 years of age and are taking supplemental dietary cholesterol for at least 3 months will be enrolled. Participants must be clinically stable and able to travel to a study site. No change in supplemental dietary cholesterol intake will be allowed during the study, and dietary records will be obtained throughout the study.

To qualify for cholic acid therapy, participants must have two measurements of serum cholesterol ≤100 mg/dl within one month before starting cholic acid. Participants will be treated with cholic acid for 8 weeks and will have blood specimens drawn at baseline (day 0), 4-weeks, 8-weeks and 12 weeks (4 weeks after stopping cholic acid therapy).

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Smith-Lemli-Opitz Syndrome: A Pilot Study of Cholic Acid Supplementation
Actual Study Start Date : March 27, 2021
Estimated Primary Completion Date : August 31, 2021
Estimated Study Completion Date : November 30, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cholic acid
Participants will be treated with cholic acid 10 mg/kg body weight.
 Drug: Cholic Acid
Participants will be treated with cholic acid for 8 weeks
Other Name: Cholbam


Outcome Measures
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Primary Outcome Measures :
  1. Change in Serum Cholesterol and Cholesterol Metabolites [ Time Frame: From enrollment to end of 8 weeks on cholic acid treatment ]
    Serum cholesterol will be measured along with 7-dehydrocholesterol, 8-dehydrocholesterol and oxysterols. Response to cholic acid treatment will consist of an increase in serum cholesterol and/or decrease in 7-dehydrocholesterol, 8-dehydrocholesterol and oxysterols.


Eligibility Criteria
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Ages Eligible for Study:   2 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ages 2-25 years.
  • Participants (or their parents/legally-authorized representative) must provide signed informed consent.
  • Assent must be obtained from those participants ages 7-17 years who are intellectually capable of understanding this study.
  • Diagnosis of SLOS based on clinical features and biochemical + genetic confirmation.
  • Participants are capable of traveling to the STAIR study site.
  • Fasting serum cholesterol ≤125 mg/dL on at least 2 specimens, each obtained at least 2 weeks apart during the Qualification Phase must be established before starting cholic acid therapy.
  • Clinically stable at the time of enrollment
  • Participants must be on a constant dietary cholesterol intake for at least 3-months prior to treatment with cholic acid.
  • Participants must agree to make no changes in cholesterol supplementation during the STAIR study.
  • SLOS participants who are taking antioxidants will be included. Participants must agree to make no changes in the antioxidant dose during this study.
  • For females of childbearing age (who have begun menstruating), a negative pregnancy test must be documented at the start of the study (week 0/ baseline) and at the end of cholic acid administration (week 8).

Exclusion Criteria:

  • Participants are unable to provide signed informed consent and/or verbal assent.
  • Participants have an unstable clinical condition that would prevent completion of the study. Medically unstable participants would include those with severe liver disease, complex birth defects such as severe heart disease or renal dysplasia, those with severe respiratory compromise requiring tracheostomy, or those who are not likely to survive longer than 1 year.
  • Participants are taking drugs, nutraceuticals, probiotics or other compounds that are known or suspected to affect sterol metabolism.
  • Participants have transaminase elevations (>3-fold above the reference range) at baseline.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03720990


Contacts
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Contact: Ellen R Elias, MD 720-777-5401 Ellen.elias@childrenscolorado.org
Contact: Sara M Jones, RD 402-559-1747 SaraM.Jones@unmc.edu

Locations
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United States, Colorado
Colorado Children's Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Ellen R Elias, MD    720-777-5401    Ellen.elias@childrenscolorado.org   
Contact: Michelle Lowary, MS    (720) 777-8485    michelle.lowary@childrenscolorado.org   
United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Sara M Jones, RD    402-559-1747    SaraM.Jones@unmc.edu   
Contact: William B Rizzo, MD    402-559-2560    wrizzo@unmc.edu   
Sponsors and Collaborators
University of Nebraska
University of Colorado, Denver
Children's Hospital Medical Center, Cincinnati
University of Pittsburgh
Investigators
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Study Chair: Ellen R Elias, MD University of Colorado - Colorado Children's Hospital
Principal Investigator: William B Rizzo, MD University of Nebraska
More Information
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Responsible Party: William Rizzo, MD, Professor, University of Nebraska
ClinicalTrials.gov Identifier: NCT03720990    
Other Study ID Numbers: IRB#464-18-FB
First Posted: October 26, 2018    Key Record Dates
Last Update Posted: May 3, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All data will be de-identified and submitted to the Database of Genotypes and Phenotypes (dbGAP), according to NIH regulations.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Data will be available one year after completion of the study. Data will be available indefinitely.
Access Criteria: Data will be made available to everyone.

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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.: Yes
Keywords provided by William Rizzo, MD, University of Nebraska:
7-Dehydrocholesterol reductase deficiency
Additional relevant MeSH terms:
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Cleft Palate
Hypertelorism
Hypospadias
Genetic Diseases, X-Linked
Smith-Lemli-Opitz Syndrome
Syndrome
Disease
Pathologic Processes
Jaw Abnormalities
Jaw Diseases
Musculoskeletal Diseases
Maxillofacial Abnormalities
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Stomatognathic Diseases
 Mouth Abnormalities
Mouth Diseases
Stomatognathic System Abnormalities
Congenital Abnormalities
Craniofacial Dysostosis
Dysostoses
Bone Diseases, Developmental
Bone Diseases
Penile Diseases
Urogenital Abnormalities
Genetic Diseases, Inborn
Abnormalities, Multiple
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Steroid Metabolism, Inborn Errors