Effect of Cortisol on Physical Exertion in Patients With Primary Adrenal Failure

November 29, 2013 updated by: Haukeland University Hospital

Effect of Cortisol on Physical Exertion in Patients With Primary Adrenal

The conventional glucocorticoid replacement therapy in primary adrenal insufficiency- Addison's disease,renders the cortisol levels unphysiological, which may cause symptoms and long-term complications. Many patients take stress-doses that are extra doses of hydrocortisone or cortisone acetate before or during stressful physical or psychological events. However, the effect of such dosing has not been tested in scientific studies. In this double blind cross-over designed pilot trial we aim to test the effect of an extra dose of cortisol on physical activity and hormone levels.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Addison's disease occurs when more than 90% of the adrenal cortex is destroyed. Cortisol levels in serum vary throughout the day. In addition to the daily need, cortisol increases in response to all forms of stress including intercurrent illness. The Addison patient must in such situations increase replacement doses 2 to 3-fold. While it is broad agreement on this procedure based on clinical experience and empirical data, it is controversial as to whether there is a need to increase the dose by less stressful events and tasks, such as average to vigorous physical activity and mental stress. In any event, many patients report that they benefit from stress doses not only in order to increase performance, but also to reduce post-exertion fatigue.

Using a combination of oxygen uptake measurements under controlled exercise and assay of hormones and metabolites, we aim to test whether extra doses of hydrocortisone can increase physical capacity and reduce post-exertion fatigue. Each patient perform two tests, one with and one without hydrocortisone in randomised order. The controls perform one test. The patients will be assigned a participation number and randomised to any of two treatment sequences (A-B or B-A) by pharmacy. All exercise tests will be performed 3-5 hours after intake of morning medication, after an overnight fast (water permitted). Patients will be instructed to avoid caffeinated food and drink, alcohol, strenuous exercise and starvation for at least 24h before each exercise session. Patients will be instructed to avoid smoking, brush teeth one hour before exercise testing.

One hour before each test, subjects drink one teaspoon of water per kilogram body weight to provide adequate hydration. Stress-dose or placebo will be taken 60 min before start. Also at this time, an indwelling line will be placed in the forearm of each subject that blood and saliva can be drawn before, directly after exercise, then 15 or 30 min after termination of exercise. Patients fill out the questionnaire about quality of life after each exercise.

Patient's daily glycemic profile will be followed up by continuous glucose monitoring systems for 24 hours before, during and for 24 hours after exercise. Patients will be educated in using the sensor and calibration with blood glucose self-measurements three to four times per day. Calibration of the sensor will be performed according to the protocol established. At the completion of the measuring period, the system will be returned, and the data will be downloaded to determine glucose patterns. This device will be applied to the abdomen of each subject, 24 h before each exercise session, calibrated as recommended (before operation and 2-3 additional times/day, 6 h apart over the 24 h of the study) and removed 24 h after the exercise session.

The patient's movements will be followed for 24 hour by Actigraph after each test. The test is repeated after 1 week with the opposite treatment option.

Ten adult patients (18-70 years) with verified Addison's disease will be invited to participate in the study. From a list of patients (consecutive out-patients or a patient registry) unselected patients should be invited to participate. Five age and sex matched healthy controls will be included to assess normal metabolic and endocrine responses to physical activity.

The investigator will keep a log of all patients that have been invited to participate in the study. If a screened patient does not fulfil the inclusion criteria, the reason will be documented on a screening log. Eligible patients who fulfil all of the inclusion criteria and none of the exclusion criteria will be randomised. Randomization will be performed by the hospital pharmacies at each study site. When a subject is randomized, he or she must always be assigned to the lowest available randomization number. The patients will be randomised in blocks of two to secure even patient number in each treatment sequence.

The patient will have to give written informed consent. The patients should not take grapefruit juice, liquorice and do not be on a special diet the last two weeks before or during the study period. Patients will be instructed to avoid caffeinated food and drink, alcohol, strenuous exercise and starvation for at least 24 h before each exercise session. Patients will be instructed to avoid smoking at least one hour before each exercise session.

Withdrawal criteria/Adverse Events. The patient is free to withdraw at any time. If a patient is having major difficulties managing the exercise the investigator will consider withdrawal. In the best interest of the patient, the investigator and the sponsor can decide to withdraw the patient from the study. If a patient develops conditions meeting the exclusion criteria, the patient will be withdrawn from the study. In case of serious adverse events the patient may be withdrawn from the study.

Any adverse event will be registered and reported to the Norwegian Medicines Agency. Any serious adverse events will be reported within 15 days, and in case of lethal or life threatening events immediately. The patients will report any problems or discomfort during or after examination in the patient log or diary, any need for extra doses during the study day after exercise with glucocorticoids will also be documented there. In addition, we ask them to contact the study group directly in case of problems between visits. The study documentation and research date will be stored 15 years after the termination of the study.

Statistical considerations This is a pilot study to evaluate the effect stress-dosing of cortisol on physical capacity. The results will be used for statistical calculations of effect size for a larger trial. The variation of the various efficacy parameters in this group of patients is not well known.

Study Type

Interventional

Enrollment (Anticipated)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Norway
      • Bergen, Norway, 5021
        • Haukeland Universitetessykehus, Department of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • patients with Addison's disease

Exclusion Criteria:

  • Type 1 diabetes
  • malignant disease
  • pregnant women
  • cardiac disease
  • lung disease
  • neuromuscular diseases
  • pharmacological treatment with glucocorticoids or drugs that interfere with cortisol metabolism (anti-epileptics, rifampicin, St Johns wart, oral estrogens, antidepressives).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Treatment B is placebo (2 placebo tablets).
Active Comparator: Hydrocortisone
Treatment A is 10 mg hydrocortisone (2 tablets Cortef, 5 mg each),Stress-dose will be taken per os one time 2 tablets 10 mg of Cortef 60 min before start of exercise. Cortef tablets 5 mg produced by Pharmacia and Upjohn . One day.
Drug: Hydrocortisone
Cortef 5 mg tablets per os, 2x5 mg, one day, one time
Other Names:
  • Cortef

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
O2 uptake
Time Frame: 2 days
O2 uptake as V O2 90%.
2 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
post- exercise hypoglycemic events
Time Frame: 4 days
blood glucose below ≤ 3.1 mmol ⁄ L
4 days
glycemic variability
Time Frame: 6 days
glycemic variability monitored by continuous glucose monitoring system
6 days
hormone response to exercise
Time Frame: 2 days
  • Plasma norepinephrine, epinephrine, salivary alfa amylase
  • Glucose, insulin, C-peptide, and lactate, glucagon
  • Growth hormone and insulin like growth factor
  • Free fatty acids
2 days
Blood pressure
Time Frame: 2 days
vascular action
2 days
Subjective health status
Time Frame: 2 days
Self administration by questionnaires
2 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Haukeland University Hospital

Investigators

  • Study Director: Eystein Husebye, Professor, Haukeland University Hospital
  • Principal Investigator: Katerina Simunkova, MUDr. PhD, Haukeland University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2013

Primary Completion (Anticipated)

January 1, 2014

Study Completion (Anticipated)

March 1, 2014

Study Registration Dates

First Submitted

April 23, 2013

First Submitted That Met QC Criteria

May 2, 2013

First Posted (Estimate)

May 7, 2013

Study Record Updates

Last Update Posted (Estimate)

December 2, 2013

Last Update Submitted That Met QC Criteria

November 29, 2013

Last Verified

November 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2012/2216
  • 2012-005117-40 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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