Addison DiseaseNCT01271296
Effects and Interactions of Liquorice and Grapefruit on Glucocorticoid Replacement Therapy in Addison's Disease
A study testing Liquorice and Grapefruit Juice in people with Addison Disease, run by Haukeland University Hospital at 1 site in Norway.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Addison Disease
- What is being tested?
- Liquorice and Grapefruit Juice
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteNorway
- Study dates
- Apr 2008to Jan 2009
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Verified diagnosis of adrenal insufficiency (Addison's disease)
- Stable cortisone acetate replacement therapy
- Written informed consent
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Use of Liquorice and Grapefruit in Patients With Addison's Disease
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.
Read the 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).
- Conditions
- Addison Disease
- Being tested
- Liquorice, Grapefruit Juice
- Keywords
- Addison Disease, Pharmacokinetics, Hormone Replacement Therapy, cortisone acetate, Quality of Life
- Medical subject headings
- Addison Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LiquoriceDietary supplement
24 gram liquorice eq. to 150 mg glycyrrhizinic acid, taken orally, for three days.
Grapefruit JuiceDietary supplement
200 ml pink grapefruit juice three times a day, taken orally, for three days.
| Study group | Role | What they receive |
|---|---|---|
| Liquorice | Active comparator | Liquorice eq to 150 mg glycyrrhizinic acid. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion. Receives: Dietary Supplement: Liquorice |
| Grapefruit juice | Active comparator | 200 ml pink grapefruit juice three times a day. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion. Receives: Dietary Supplement: Grapefruit Juice |
| Baseline | No intervention | Baseline assessment without intake of liquorice or grapefruit juice |
What is being measured
The primary outcome is the main question the study is designed to answer.
AUC Serum Cortisol - Levels of cortisol in serum during the first 2.6 hours after oral administration of cortisone acetate.
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.
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Secondary outcomes (19)
Serum Cortisol levels at the end of time-series sampling (t=160min)
At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Serum Cortisone levels at the end of time-series sampling (t=160min)
At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Saliva Cortisol levels at the end of time-series sampling (t=160min)
At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Saliva Cortisone levels at the end of time-series sampling (t=160min)
At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Time of maximum concentration of serum Cortisol
Based on time-series sampling at each of the three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Time of maximum concentration of serum Cortisone
Based on time-series sampling at each of the three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Time of maximum concentration of Saliva Cortisol
Based on time-series sampling at each of the three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Time of maximum concentration of Saliva Cortisone
Based on time-series sampling at each of the three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Half life of serum cortisol
Based on time-series sampling at each of the three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Half life of serum cortisone
Based on time-series sampling at each of the three assessments
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Urinary aTHF/THF-ratio
Measured in 24h urine obtained at the three assessments.
aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
AUC Serum Cortisone
Similar to primary outcome Serum AUC Cortisol
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE)
24-hour urine collected on each of the three assessments
aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol, THE = tetrahydrocortisone, 6OHF = 6beta-hydroxycortisol
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Urinary ratio (aTHF+THF)/THE
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
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Urinary Ratio Cortisol/6beta-OH-Cortisol
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
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE)
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
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
AUC Saliva cortisone
Similar to primary outcome Saliva AUC Cortisol, but for cortisone.
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
AUC Serum Cortisone
Similar to primary outcome Serum AUC Cortisol, but for cortisone.
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
AUC Saliva Cortisol
Similar to AUC Serum Cortisol, but measurements are on saliva.
Measured: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jan 2011 (estimated)
- Study startApr 2008
- Primary completionJan 2009
- Study completionJan 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Addison DiseaseStudies of the same condition, open and under way.
- More trials run by Haukeland University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Haukeland University Hospital
- Sponsor type
- University, hospital or other
- Investigators
- Paal Methlie, MD, Principal investigator, University of Bergen. Helse-Bergen HFKristian Løvås, MD, PhD, Principal investigator, University of Bergen. Helse-Bergen HF.Eystein S Husebye, Prof, MD, Principal investigator, University of Bergen. Helse-Bergen HF.Ernst A Lien, Prof. MD., Principal investigator, University of Bergen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01271296
- Sponsor's protocol ID
- 3.2007.2620 (REK)
- Other IDs
- 17775 (NSD), 07/5829 (SHdir), 3.2007.2620
- Status last verified
- Dec 2010
- First submitted
- 22 Dec 2010
- Last updated
- 17 Jan 2011
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Jan 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Use of Liquorice and Grapefruit in Patients With Addison's Disease
- ClinicalTrials.gov ID
- NCT01271296
- Acronym / sponsor ID
- 3.2007.2620 (REK)
- Conditions
- Addison Disease
- Keywords
- Addison Disease, Pharmacokinetics, Hormone Replacement Therapy, cortisone acetate, Quality of Life
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Haukeland University HospitalUniversity, hospital or other
- Study start
- Apr 2008
- Primary completion
- Jan 2009 (actual)
- Study completion
- Jan 2009 (actual)
- First posted
- 6 Jan 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Liquorice | Active comparator | Dietary Supplement: LiquoriceLiquorice eq to 150 mg glycyrrhizinic acid. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion. |
| Grapefruit juice | Active comparator | Dietary Supplement: Grapefruit Juice200 ml pink grapefruit juice three times a day. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion. |
| Baseline | No intervention | –Baseline assessment without intake of liquorice or grapefruit juice |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Verified diagnosis of adrenal insufficiency (Addison's disease)
- Stable cortisone acetate replacement therapy
- Written informed consent
Key exclusion criteria (7 listed)
- Malignant disease
- Pharmacological treatment with other glucocorticoids
- Pregnancy
- Current minor disease (ie the flu)
- Major disease or accident requiring hospitalization the last three months
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Liquorice24 gram liquorice eq. to 150 mg glycyrrhizinic acid, taken orally, for three days. | Dietary supplement | Liquorice |
| Grapefruit Juice200 ml pink grapefruit juice three times a day, taken orally, for three days. | Dietary supplement | Grapefruit juice |
Primary outcome
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.
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.
19 secondary outcomes
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jan 2011.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paal Methlie, MD principal investigator
University of Bergen. Helse-Bergen HF
Kristian Løvås, MD, PhD principal investigator
University of Bergen. Helse-Bergen HF.
Eystein S Husebye, Prof, MD principal investigator
University of Bergen. Helse-Bergen HF.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Liquorice and Grapefruit Juice in people with Addison Disease, run by Haukeland University Hospital at 1 site in Norway.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Jan 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jan 2011.