Smith-Lemli-Opitz Syndrome and Cholic Acid

Smith-Lemli-Opitz Syndrome: A Pilot Study of Cholic Acid Supplementation

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 plasma cholesterol and reduction in harmful cholesterol precursors. SLOS participants will be treated with dietary cholic acid for 8 weeks and plasma cholesterol and cholesterol precursor metabolites will be measured.

Study Overview

• Status: Completed
• Conditions: Smith-Lemli-Opitz Syndrome
• Intervention / Treatment: Drug: Cholic Acid

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 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 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 plasma 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 plasma 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 plasma cholesterol ≤125 mg/dl 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 Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Colorado Children's Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 plasma cholesterol ≤125 mg/dL 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.

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: 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 Names: Cholbam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma Cholesterol	Plasma cholesterol will be measured. Response to cholic acid treatment will consist of an increase in plasma cholesterol.	8 weeks

Collaborators and Investigators

• Sponsor: University of Nebraska
• Collaborators: University of Colorado, Denver; University of Pittsburgh; Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: William B Rizzo, MD, University of Nebraska; Study Chair: Ellen R Elias, MD, University of Colorado - Colorado Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2021
• Primary Completion (Actual): August 30, 2022
• Study Completion (Actual): September 30, 2023

Study Registration Dates

• First Submitted: October 24, 2018
• First Submitted That Met QC Criteria: October 24, 2018
• First Posted (Actual): October 26, 2018

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: 7-Dehydrocholesterol reductase deficiency
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Stomatognathic Diseases; Mouth Diseases; Bone Diseases; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Dyslipidemias; Mouth Abnormalities; Stomatognathic System Abnormalities; Jaw Abnormalities; Jaw Diseases; Maxillofacial Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Abnormalities, Multiple; Lipid Metabolism, Inborn Errors; Bone Diseases, Developmental; Steroid Metabolism, Inborn Errors; Penile Diseases; Craniofacial Dysostosis; Dysostoses; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Syndrome; Cleft Palate; Hypospadias; Genetic Diseases, X-Linked; Smith-Lemli-Opitz Syndrome; Hypertelorism; Gastrointestinal Agents; Cholic Acids
• Other Study ID Numbers: 0464-18-FB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All data will be de-identified and submitted to the Database of Genotypes and Phenotypes (dbGAP), according to NIH regulations.
• IPD Sharing Time Frame: Data will be available one year after completion of the study. Data will be available indefinitely.
• IPD Sharing Access Criteria: Data will be made available to everyone.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

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.: Yes