Mendelian Reverse Cholesterol Transport Study

Brief Title

Mendelian Reverse Cholesterol Transport Study

Official Title

A Validation Study Evaluating the Use of 3H-Cholesterol Bound to Albumin as a Method to Assess Reverse Cholesterol Transport in Subjects With Monogenic Diseases Affecting HDL Metabolism

Brief Summary

      The purpose of this study is to investigate the use of radiolabeled particulate cholesterol
      administered intravenously in association with albumin, as a method to study reverse
      cholesterol transport (RCT) in people carrying mutations in genes known to affect high
      density lipoprotein (HDL) metabolism by analyzing changes in the tracer activity in total
      plasma, lipoproteins fractions and feces.
    

Detailed Description

      The study will use 3H-cholesterol bound to albumin (particulate cholesterol) to assess the
      ability of HDL to transport cholesterol from the periphery to the liver to be eliminated.
      This process is called reverse cholesterol transport (RCT) and is one of the main mechanisms
      by which HDL protect against atherosclerotic cardiovascular disease. Mutations in some of the
      genes affecting HDL metabolism, may results in changes in RCT. The validation of a method
      assessing RCT is important for the development of new drugs which affect RCT and may result
      in useful treatments for atherosclerosis.

      Subjects carrying mutations in genes known to affect HDL metabolism and healthy controls will
      be enrolled in the study. Changes in the tracer activity in total plasma, lipoproteins
      fractions and feces will be analyzed following the intravenous administration of radiolabeled
      particulate cholesterol.
    


Study Type

Interventional


Primary Outcome

determination of 3H cholesterol in plasma and lipoproteins

Secondary Outcome

 determination of 3H cholesterol and its metabolites in red blood cells over time

Condition

Cholesterol, HDL

Intervention

3H-cholesterol bound to albumin

Study Arms / Comparison Groups

 3H-cholesterol
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

30

Start Date

October 2012

Completion Date

May 2021

Primary Completion Date

May 2021

Eligibility Criteria

        Inclusion Criteria:

          1. Men and women between the ages of 18 and 75

          2. Subjects must be:

               1. Carriers of functional mutations of genes encoding proteins affecting HDL
                  metabolism;

               2. Healthy control subjects with HDL cholesterol levels within the normal range of
                  the lab where screening tests are run, or at the discretion of the investigator,
                  and matched for gender, race, age (± 5 years) to the patients.

          3. Negative screening pregnancy test if female of child bearing potential (females of
             child-bearing potential must be following a medically accepted form of contraception)

          4. Subjects must be able to comprehend and willing to provide a signed IRB approved
             Informed Consent Form.

          5. Subjects must be willing and able to comply with all study-related procedures.

        Exclusion Criteria:

          1. Known cardiovascular disease, including coronary disease, cerebrovascular disease, or
             peripheral vascular disease (control subjects only)

          2. History of diabetes mellitus or fasting glucose > 126 mg/dL at the screening visit
             (control subjects only).

          3. Any current, unstable endocrine disease as assessed by collection of medical history
             during screening. Subjects with rare Mendelian disorders with thyroid disease that is
             well controlled by stable treatment may be considered for enrollment at the discretion
             of the principal investigator

          4. History of previous malignancy, other than basal cell or squamous cell carcinoma of
             the skin, from which the patient has been disease free for less than 5 years as
             assessed by collection of medical history during screening

          5. Current diagnosis of anemia as assessed by collection of medical history during
             screening or hemoglobin less than 10 g/dL as evaluated during safety lab at screening

          6. History of kidney disease or chronic renal insufficiency, as defined as estimated
             glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 in control subjects and patients
             with other disorders of HDL metabolism and eGFR < 30 ml/min/1.73m2 in subjects with
             Lecithin-Cholesterol Acyltransferase (LCAT) deficiency.

          7. Any active rheumatologic, pulmonary, or dermatologic disease or inflammatory condition
             as assessed by collection of medical history during screening, and judged by the
             investigator to be a major condition.

          8. Sustained uncontrolled hypertension (Systolic >160 mm Hg and/or Diastolic BP >100
             mmHg) at screening. Blood pressure may be re-tested twice after initial assessment in
             the supine position at five minute intervals (for a total of 3 blood pressure
             assessments). The pressure elevation is considered sustained if either the systolic or
             the diastolic pressure values are outside the stated limits for all three assessments

          9. Use of warfarin, or any known coagulopathy and /or elevated prothrombin time/partial
             thromboplastin time (PT/PTT) >1.5 x upper limit of normal (ULN)

         10. Self-reported history of human immunodeficiency virus (HIV) positive

         11. History of previous organ transplantation, as assessed by collection of medical
             history during screening

         12. Clinical evidence of liver disease or liver injury as indicated by abnormal liver
             function tests such as alanine transaminase (ALT) or aspartate transaminase (AST) >
             1.5x ULN, or self-reported history of positive Hepatitis B or Hepatitis C test result

         13. Any surgical procedure that occurred within the previous 3 months of the screening
             visit, as assessed by collection of medical history during screening, and judged by
             the investigator to be a major procedure.

         14. History of drug abuse (< 1 year), as assessed by collection of medical history during
             screening procedures

         15. Regular abuse of alcoholic beverages (> 2 drinks/day), as assessed by collection of
             medical history during screening procedures

         16. Self-reported participation in an investigational drug study within 6 weeks prior to
             the screening visit

         17. Serious or unstable medical or psychological conditions that, in the opinion of the
             investigator, would compromise the subject's safety or successful participation in the
             study will be excluded.

         18. Use of lipid lowering drugs expected to affect RCT (e.g. fibrates) within the 6 weeks
             prior to dosing or during the study, as assessed by collection of medical history
             during screening and concomitant medication checks at each study visit. Use of statins
             (stable dose for at least 30 days) is permitted.

         19. Male subjects who plan to conceive a child within 3 months of the conclusion of the
             study.

         20. Women who are pregnant or lactating or who are planning to become pregnant
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Marina Cuchel, MD, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01782027

Organization ID

815075


Responsible Party

Sponsor

Study Sponsor

University of Pennsylvania


Study Sponsor

Marina Cuchel, MD, PhD, Principal Investigator, University of Pennsylvania


Verification Date

January 2021