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The Influence of Different Hydrocortisone Replacement Doses on the Partitioning and Flexibility of Ectopic Lipids in Patients With Corticotropic Hypopituitarism (Hydrocort)

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ClinicalTrials.gov Identifier: NCT02360046
Recruitment Status : Terminated
First Posted : February 10, 2015
Last Update Posted : October 9, 2018
Sponsor:
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

Brief Summary:
This study aims at assessing the effect of today's standard of hydrocortisone dosage versus previous hydrocortisone dosage on flexibility and partitioning of ectopic lipid depots (IMCL and IHCL) after a standardised fat load followed by a short-term aerobic exercise in patients with corticotropic pituitary insufficiency.

Condition or disease Intervention/treatment Phase
Hypopituitarism Hydrocortisone Lipids Fatty Acids, Nonesterified Insulin Sensitivity Drug: Hydrocortisone Drug: Placebo Not Applicable

Detailed Description:

Background

The investigators and others have shown that long-term hydrocortisone replacement therapy at higher doses of hydrocortisone replacement therapy at higher doses of hydrocortisone replacement (as previously recommended) is associated with higher mortality. The pathophysiology for the association of hydrocortisone-replacement dose and mortality remains unclear. A possible underlying mechanism is nonalcoholic fatty liver disease which is more prevalent in patients with hypopituitarism. Patients with non-alcoholic fatty liver disease are at a higher risk for overall-mortality.

It remains to be established whether the insulin resistance, associated with increased intrahepatocellular lipids and increased intramusculoskeletal lipids, is implicated in the pathophysiology of these epidemiological findings.

Interestingly, it has been shown that a reduction of hydrocortisone replacement dose from 20-30mg/d to 10-15mg/d resulted in a loss of body fat and a significant decrease of plasma total cholesterol and triglyceride concentration. The effect of IMCL and IHCL is so far unknown.

Patients with hypopituitarism with hydrocortisone replacement therapy provide a unique disease model to study the short-term effects of previously recommended dose (higher dose) of hydrocortisone versus lower dose of HC replacement therapy on ectopic lipids (IMCL; IHCL) lipids, as well as on subcutaneous and visceral fat mass and on parameters of insulin resistance. Combining MRI and MR-spectroscopy techniques, different fat mass (subcutaneous and visceral) and ectopic lipids can be repeatedly and non-invasively assessed.

Objective

To investigate the impact of today's standard of hydrocortisone dosage (lower) versus previous (higher) hydrocortisone dosage on flexibility and partitioning of ectopic lipid depots after a standardised fat load followed by a short-term aerobic exercise in patients with corticotropic pituitary insufficiency.

Methods

Ectopic lipids are measured by MR-spectroscopy, separate assessment of visceral and subcutaneous fat mass will be performed by MR-imaging, standardized exercise capacity test using spiroergometry. Short-time exercise consists of 2h aerobic cycling at 50% VO2max. Laboratory analysis include lipid profile, free fatty acids, HOMA-Index, hormones.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: The Influence of Different Hydrocortisone Replacement Doses on the Partitioning and Flexibility of Ectopic Lipids (Intrahepatocellular IHCL and Intramyocellular IMCL) in Patients With Corticotropic Hypopituitarism, a Randomised Placebo-controlled Double-blind Trial
Study Start Date : January 2015
Actual Primary Completion Date : December 2016
Actual Study Completion Date : December 2016


Arm Intervention/treatment
Higher hydrocortisone dose
Established hydrocortisone replacement therapy plus 10mg of hydrocortisone
Drug: Hydrocortisone
Established Hydrocortisone replacement therapy plus Hydrocortisone (10mg/day)

Lower hydrocortisone dose
Established hydrocortisone replacement therapy plus placebo
Drug: Placebo
Established Hydrocortisone replacement therapy plus Placebo (0mg Hydrocortisone)




Primary Outcome Measures :
  1. Change from baseline in flexibility of Intramyocellular Lipids (IMCL) Measured in mmol/L [ Time Frame: 3 months ]
    Measured in mmol/L

  2. Change from baseline in flexibility of Intrahepatocellular Lipids (IHCL) Measured in mmol/L [ Time Frame: 3 months ]
    Measured in mmol/L


Secondary Outcome Measures :
  1. Free Fatty Acids (FFA) availability during exercise before and after additional hydrocortisone/placebo Measured in mmol/L [ Time Frame: At baseline, 3 months ]
    Measured in mmol/L

  2. Flexibility of ectopic fat stores, defined as difference between intramyocellular/intrahepatocellular lipid concentration before and after exercise, and their possible relation to insulin sensitivity before and after additional hydrocortisone/placebo [ Time Frame: At baseline, 3 months ]
  3. Free Fatty Acids (FFA) availability during exercise and the possible relation to insulin sensitivity before and after additional hydrocortisone/placebo Measured in mmol/L [ Time Frame: At baseline, 3 months ]
    Measured in mmol/L

  4. Effect of exercise on insulin at baseline [ Time Frame: At baseline ]
  5. Effect of exercise on insulin at 3 months [ Time Frame: 3 months ]
  6. Effect of exercise on catecholamines at baseline [ Time Frame: At baseline ]
  7. Effect of exercise on catecholamines at 3 months [ Time Frame: 3 months ]
  8. Effect of exercise on growth hormone at baseline [ Time Frame: At baseline ]
  9. Effect of exercise on growth hormone at 3 months [ Time Frame: 3 months ]
  10. Effect of exercise on cortisol at baseline [ Time Frame: At baseline ]
  11. Effect of exercise on cortisol at 3 months [ Time Frame: 3 months ]
  12. Effect of exercise on lactate at baseline [ Time Frame: At baseline ]
  13. Effect of exercise on lactate at 3 months [ Time Frame: 3 months ]
  14. Effect of exercise on glucose at baseline [ Time Frame: At baseline ]
  15. Effect of exercise on glucose at 3 months [ Time Frame: 3 months ]
  16. Effect of exercise on inflammatory markers at baseline [ Time Frame: At baseline ]
  17. Effect of exercise on inflammatory markers at 3 months [ Time Frame: 3 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent
  • Male and female patients
  • Corticotropic pituitary insufficiency
  • Capable to exercise during 120 minutes on a bicycle
  • Normal ECG during ergometry

Exclusion Criteria

  • Concomitant medication with NSAID, anticoagulants, digoxin, salbutamol, anticonvulsants, cholinesterase inhibitor, pancuronium
  • Abnormal liver, renal or thyroid function, heart failure
  • Hemophilia
  • Diabetes mellitus
  • Severe dyslipidemia
  • Active neoplasia
  • Women who are pregnant or breast feeding
  • Intention to become pregnant during the course of the study
  • Lack of safe contraception
  • Known or suspected non-compliance
  • Drug or alcohol abuse
  • Inability to follow the procedures of the study
  • Participation in another study with investigational drug within the 30 days preceding and during the study
  • Previous enrolment into current study
  • Enrolment of the investigator, his/her family members, employees and other dependent persons
  • Inability to exercise
  • Contraindications to exposure to a 3 T magnetic field
  • Major depression, psychosis, claustrophobia

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): NCT02360046


Locations
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Switzerland
Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Berne
Berne, Switzerland, 3010
Sponsors and Collaborators
University Hospital Inselspital, Berne
Investigators
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Principal Investigator: Emanuel Christ, MD, PhD Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Bern
Principal Investigator: Chris Boesch, MD, PhD AMSM; Division of Radiology, University Hopsital of Bern, Inselspital

Publications:
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Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT02360046     History of Changes
Other Study ID Numbers: 211/14
2014 DR 4137 ( Other Identifier: Swissmedic )
First Posted: February 10, 2015    Key Record Dates
Last Update Posted: October 9, 2018
Last Verified: October 2018
Additional relevant MeSH terms:
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Hypopituitarism
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Endocrine System Diseases
Anti-Inflammatory Agents