Clinical trial NCT01271296: Effects and Interactions of Liquorice and Grapefruit on Glucocorticoid Replacement Therapy in Addison's Disease
Official title: Use of Liquorice and Grapefruit in Patients With Addison's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Addison Disease
Keywords: Addison Disease
Pharmacokinetics
Hormone Replacement Therapy
cortisone acetate
Quality of Life
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
First posted: 2011-01-06
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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 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.

Primary outcomes:
measure: AUC Serum Cortisol - Levels of cortisol in serum during the first 2.6 hours after oral administration of cortisone acetate.
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Secondary outcomes:
measure: Serum Cortisol levels at the end of time-series sampling (t=160min)
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Serum Cortisone levels at the end of time-series sampling (t=160min)
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Saliva Cortisol levels at the end of time-series sampling (t=160min)
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Saliva Cortisone levels at the end of time-series sampling (t=160min)
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Time of maximum concentration of serum Cortisol
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Time of maximum concentration of serum Cortisone
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Time of maximum concentration of Saliva Cortisol
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Time of maximum concentration of Saliva Cortisone
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Half life of serum cortisol
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Half life of serum cortisone
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Urinary aTHF/THF-ratio
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: AUC Serum Cortisone
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE)
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Urinary ratio (aTHF+THF)/THE
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Urinary Ratio Cortisol/6beta-OH-Cortisol
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE)
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: AUC Saliva cortisone
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: AUC Serum Cortisone
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
measure: AUC Saliva Cortisol
timeFrame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Other outcomes:
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital, Helse-Bergen HF
Study officials:
affiliation: University of Bergen. Helse-Bergen HF
name: Paal Methlie, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Bergen. Helse-Bergen HF.
name: Kristian Løvås, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Bergen. Helse-Bergen HF.
name: Eystein S Husebye, Prof, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Bergen
name: Ernst A Lien, Prof. MD.
role: PRINCIPAL_INVESTIGATOR
References: