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Effects and Interactions of Liquorice and Grapefruit on Glucocorticoid Replacement Therapy in Addison's Disease

This study has been completed.
Sponsor:
Information provided by:
Haukeland University Hospital
ClinicalTrials.gov Identifier:
NCT01271296
First received: December 22, 2010
Last updated: January 13, 2011
Last verified: December 2010
  Purpose

Addison's disease is a rare disease, wherein the adrenals can not produce sufficient steroid hormones (cortisol and aldosterone). Patients with Addison's disease report impaired subjective health status, and they have increased all-cause mortality. Conventional therapy is by oral replacement of glucocorticoid and mineralocorticoid hormones, but this strategy imperfectly mimic the diurnal cortisol variations, and render the patients both over- and under-treated. Anecdotally, some patients with adrenal insufficiency may benefit from the use of various nutritional compounds. We hypothesised that liquorice and grapefruit altered the metabolism and absorption of cortisone acetate.


Condition Intervention
Addison Disease
Dietary Supplement: Liquorice
Dietary Supplement: Grapefruit Juice

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Supportive Care
Official Title: Use of Liquorice and Grapefruit in Patients With Addison's Disease

Resource links provided by NLM:


Further study details as provided by Haukeland University Hospital:

Primary Outcome Measures:
  • AUC Serum Cortisol - Levels of cortisol in serum during the first 2.6 hours after oral administration of cortisone acetate. [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    The area under the curve (AUC) of cortisol is calculated based on serum time-series sampling (every 20 minutes for 2.6 h after oral administration of cortisone acetate). The AUCs obtained during liquorice and grapefruit juice intakes are compared to the baseline assessment (without these nutritional compounds). All other pharmacokinetic properties (primary and secondary outcome measures) are compared analogously.


Secondary Outcome Measures:
  • Serum Cortisol levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments

  • Serum Cortisone levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments

  • Saliva Cortisol levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments

  • Saliva Cortisone levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments

  • Time of maximum concentration of serum Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Based on time-series sampling at each of the three assessments

  • Time of maximum concentration of serum Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Based on time-series sampling at each of the three assessments

  • Time of maximum concentration of Saliva Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Based on time-series sampling at each of the three assessments

  • Time of maximum concentration of Saliva Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Based on time-series sampling at each of the three assessments

  • Half life of serum cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Based on time-series sampling at each of the three assessments

  • Half life of serum cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Based on time-series sampling at each of the three assessments

  • Urinary aTHF/THF-ratio [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

    Measured in 24h urine obtained at the three assessments.

    aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol


  • AUC Serum Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Similar to primary outcome Serum AUC Cortisol

  • Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

    24-hour urine collected on each of the three assessments

    aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone, 6OHF = 6beta-hydroxycortisol


  • Urinary ratio (aTHF+THF)/THE [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

    Assessed in 24h urine obtained at the three assessments (baseline, after liquorice and after grapefruit juice). It is an index of 5-reductase activity.

    24-hour urine collected on each of the three assessments

    aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone


  • Urinary Ratio Cortisol/6beta-OH-Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

    Assess the enzymatic activity of CYP3A4 by the index urinary cortisol/6beta-oh cortisol ratio obtained at the three assessments (baseline, after liquorice and after grapefruit juice.

    6OHF = 6beta-hydroxycortisol


  • Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

    24-hour urine collected on each of the three assessments

    24-hour urine collected on each of the three assessments

    aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone, 6OHF = 6beta-hydroxycortisol


  • AUC Saliva cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Similar to primary outcome Saliva AUC Cortisol, but for cortisone.

  • AUC Serum Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Similar to primary outcome Serum AUC Cortisol, but for cortisone.

  • AUC Saliva Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]
    Similar to AUC Serum Cortisol, but measurements are on saliva.


Enrollment: 17
Study Start Date: April 2008
Study Completion Date: January 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Liquorice
Liquorice eq to 150 mg glycyrrhizinic acid. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion.
Dietary Supplement: Liquorice
24 gram liquorice eq. to 150 mg glycyrrhizinic acid, taken orally, for three days.
Active Comparator: Grapefruit juice
200 ml pink grapefruit juice three times a day. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion.
Dietary Supplement: Grapefruit Juice
200 ml pink grapefruit juice three times a day, taken orally, for three days.
No Intervention: Baseline
Baseline assessment without intake of liquorice or grapefruit juice

Detailed Description:

In the present study, cortisone acetate absorption and metabolism are assessed in subjects with Addison's disease on three occasions. On the first occasion, the subjects are on their regular diet, but avoid ingestion of grapefruit and liquorice. At the end of the baseline assessment the order of the nutritional compounds (liquorice-grapefruit juice or grapefruit juice-liquorice) to be investigated in the next two assessments are randomised.

On the two next occasions, the absorption and metabolism of cortisone acetate is studied when study subjects consume liquorice and grapefruit juice. Between the use of grapefruit and liquorice there is a wash out period of at least 3 weeks.

For studies on liquorice effects, the subjects ingest 24-gram liquorice per day (equivalent of 150-mg glycyrrhizinic acid per day). For studies on grapefruit juice effects, subjects drink 200-ml grapefruit juice three times a day for three days. They maintain their regular medication and usual diet.

Time-series of cortisol and cortisone are obtained in serum and saliva samples on the third day of liquorice/grapefruit juice use. 24-hour urine is also collected.

Measurements of cortisol and metabolites in serum and saliva are used to calculate pharmacokinetical parameters. The measurements from samples obtained when using the investigated nutritional compounds are compared to the baseline assessment in each subject. Metabolites in 24-hour urine are compared similarly to investigate changes in urinary excretion, and to estimate the activity of enzymes involved in the metabolism of cortisol (5alfa-reductase, 5beta-reductase, cytochrome P450 3A4 system, 11-beta hydroxysteroid dehydrogenase).

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Verified diagnosis of adrenal insufficiency (Addison's disease)
  • Stable cortisone acetate replacement therapy
  • Written informed consent

Exclusion Criteria:

  • Malignant disease
  • Pharmacological treatment with other glucocorticoids
  • Pregnancy
  • Current minor disease (ie the flu)
  • Major disease or accident requiring hospitalization the last three months
  • Use of grapefruit juice or liquorice the last two weeks before study start
  • Blood pressure above 150mmHg systolic or 90 mmHg diastolic.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01271296

Locations
Norway
Haukeland University Hospital, Helse-Bergen HF
Bergen, Norway, 5020
Sponsors and Collaborators
Haukeland University Hospital
Investigators
Principal Investigator: Paal Methlie, MD University of Bergen. Helse-Bergen HF
Principal Investigator: Kristian Løvås, MD, PhD University of Bergen. Helse-Bergen HF.
Principal Investigator: Eystein S Husebye, Prof, MD University of Bergen. Helse-Bergen HF.
Principal Investigator: Ernst A Lien, Prof. MD. University of Bergen
  More Information

No publications provided

Responsible Party: Lars Birger Nesje, Head of Department of Medicine, Haukeland University Hospital, Helse-Bergen HF, Haukeland University Hospital
ClinicalTrials.gov Identifier: NCT01271296     History of Changes
Other Study ID Numbers: 3.2007.2620 (REK), 17775 (NSD), 07/5829 (SHdir), 3.2007.2620
Study First Received: December 22, 2010
Last Updated: January 13, 2011
Health Authority: Norway:National Committee for Medical and Health Research Ethics
Norway: Norwegian Social Science Data Services (NSD)
Norway: Directorate for Health and Social Affairs (SHdir)

Keywords provided by Haukeland University Hospital:
Addison Disease
Pharmacokinetics
Hormone Replacement Therapy
cortisone acetate
Quality of Life

Additional relevant MeSH terms:
Addison Disease
Adrenal Insufficiency
Adrenal Gland Diseases
Autoimmune Diseases
Endocrine System Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on November 20, 2014