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Smith-Lemli-Opitz Syndrome and Cholic Acid

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03720990
Recruitment Status : Not yet recruiting
First Posted : October 26, 2018
Last Update Posted : March 25, 2020
University of Colorado, Denver
Children's Hospital Medical Center, Cincinnati
University of Pittsburgh
Information provided by (Responsible Party):
William Rizzo, MD, University of Nebraska

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).

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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
Estimated Study Start Date : May 1, 2020
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2020

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

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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

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.

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 identifier (NCT number): NCT03720990

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Contact: Ellen R Elias, MD 720-777-5401
Contact: Sara M Jones, RD 402-559-1747

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United States, Colorado
Colorado Children's Hospital
Aurora, Colorado, United States, 80045
Contact: Ellen R Elias, MD    720-777-5401   
Contact: Michelle Lowary, MS    (720) 777-8485   
United States, Nebraska
University of Nebraska Medical Center
Omaha, Nebraska, United States, 68198
Contact: Sara M Jones, RD    402-559-1747   
Contact: William B Rizzo, MD    402-559-2560   
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Contact: James E. Heubi, MD    513-636-4415   
Contact: Andre Hawkins, M.A.    (513) 636-4200   
United States, Pennsylvania
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
Contact: Gerard Vockley, MD    412-692-7746   
Contact: Danielle Black    412-692-3150   
Sponsors and Collaborators
University of Nebraska
University of Colorado, Denver
Children's Hospital Medical Center, Cincinnati
University of Pittsburgh
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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
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Responsible Party: William Rizzo, MD, Professor, University of Nebraska Identifier: NCT03720990    
Other Study ID Numbers: IRB#464-18-FB
First Posted: October 26, 2018    Key Record Dates
Last Update Posted: March 25, 2020
Last Verified: March 2020
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
Genetic Diseases, X-Linked
Smith-Lemli-Opitz Syndrome
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
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