Metabolic SyndromePhase 4NCT01620684
Cortisol and Nutritional Sympathetic Responsiveness
A Phase 4 study testing metyrapone in people with Metabolic Syndrome and Obesity, run by Baker Heart Research Institute at 1 site in Australia.
Trial summary
This project will examine whether short-term (over a 12-hour period) pharmacological lowering of the stress hormone 'cortisol' improves the nervous system response to food intake in overweight or obese individuals who have metabolic syndrome. Read more about this study
- Who is it for?
- Ages 45 to 65 years
- Conditions the study is for
- Metabolic Syndrome, Obesity, Insulin Resistance
- What is being tested?
- metyrapone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 24 participants
- Where
- 1 siteAustralia
- Study dates
- Feb 2013to Dec 2014
- Phase
- Phase 4
- 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 45 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- un-medicated,
- overweight or obese subjects (12 men and 12 postmenopausal women),
- weight-stable,
- non-smoking,
- aged 45-65 years
- will be recruited on the basis of having > 3 MetS criteria as per the newly harmonized definition.
- elevated waist circumference will be defined as > 102 cm in men and > 88 cm in women.
- all subjects will also be insulin resistant (HOMA index > 2.5 and/or euglycaemic hyperinsulinemic clamp derived M/I value < 8 mg per kg fat free mass per minute per mU/L x 100).
Who cannot join
- adrenocortical insufficiency,
- pituitary dysfunction or tumour,
- sleep apnoea treated with CPAP,
- cardiovascular disease (previous MI, angina, stroke, heart failure, secondary hypertension),
- renal or hepatic disease (serum creatinine > 0.2 mmol/L; > 1 proteinuria on dipstick; alanine transferase > 2.5 times upper limit of normal, active liver disease) or
- diseases which may affect measured parameters (e.g. thyroid, Cushing's or Addison's diseases).
Trial locations and contacts
1 site in 1 country.
Australia1 site, 1 recruiting
- Recruiting
Heart Centre, Alfred Hospital
Prahran, Melbourne, Victoria, 3181
Nora E Straznicky, BPharm PhD MPH, 61 3 8532 1371, nora.straznicky@bakeridi.edu.au
Nora E Straznicky, PhD MPH
About this study
Official title: The Effects of Cortisol Blockade on Nutritional Sympathetic Nervous System Responsiveness in Overweight and Obese Subjects With Metabolic Syndrome
This project will examine whether short-term (over a 12-hour period) pharmacological lowering of the stress hormone 'cortisol' improves the nervous system response to food intake in overweight or obese individuals who have metabolic syndrome.
The investigators know from our previous research that overweight/obese persons who are insulin resistant, have a blunted sympathetic nervous response to carbohydrate ingestion. This means that they are less able to dissipate energy from caloric intake, which would favour the maintenance of the obese state. Cortisol adversely impacts on insulin action and transport into the brain and cortisol levels are often elevated in persons with central (abdominal) obesity.
Read more
A randomized, double-blind, placebo controlled, cross-over design will be used to compare the effects of overnight treatment with metyrapone (15 mg/kg at midnight and 15 mg/kg at 6 am) versus placebo on sympathetic nervous system activity in response to a standard 75-g oral sugar (glucose) tolerance test. A 2 week washout will separate treatments.
Metyrapone is a drug that reversibly inhibits the enzyme 11beta-hydroxylase, and therefore the production of cortisol. It is used clinically to test the activity of the adrenal gland (the key site of cortisol production) and the pituitary gland. The investigators anticipate that at the dosage used, it will lower blood cortisol concentration by 44 to 64% during the experimental morning.
The study protocol comprises two screening visits and two experimental mornings. Key procedures will include:
- Assessment of insulin action (sensitivity) using the gold standard 'clamp' method.
- Measurement of sympathetic nervous system activity by both biochemical methods (isotope dilution which provides a measure of the apparent rate of release of 'noradrenaline'-the key neurotransmitter in the sympathetic nervous system) and direct intra-neuronal nerve recordings from the peroneal nerve in the lower leg.
- Indirect calorimetry to assess resting metabolic rate and the response to sugar ingestion.
- DEXA scan to quantify fat and lean mass.
- Assessment of arterial elasticity and calf blood flow by non-invasive methods.
- A standard 75g oral sugar tolerance test.
The results will provide important new information regarding the role of cortisol on nervous system function in overweight/obese individuals.
Read the detailed description
Similarities between metabolic syndrome obesity and hypercortisolemic conditions such as Cushing's syndrome have raised interest in the pathogenic role of glucocorticoid excess in this clinical setting. Cortisol is a well known counter-regulator of insulin action and increased levels of serum cortisol have been linked to insulin resistance in many studies. Moreover, treatment with the synthetic glucocorticoid dexamethasone reduced central nervous system insulin uptake by 49% in dogs. We have previously identified in metabolic syndrome subjects, an inverse relationship between morning fasting cortisol levels and sympathetic neural responsiveness to oral glucose ingestion. This concurs with other evidence that cortisol and synthetic glucocorticoids have sympathoinhibitory effects.
This project will test the hypothesis that short-term lowering of plasma cortisol levels by overnight metyrapone treatment, will improve nutritional sympathetic nervous system responses to carbohydrate ingestion in obese insulin resistant subjects with metabolic syndrome.
- Conditions
- Metabolic Syndrome, Obesity, Insulin Resistance
- Being tested
- metyrapone, placebo
- Medical subject headings
- Metabolic Syndrome, Obesity, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
metyraponeDrug
Also called Metopirone (Novartis)
Overnight treatment (15 mg/kg at midnight and 15 mg/kg at 6 am)
placeboDrug
placebo capsules
| Study group | Role | What they receive |
|---|---|---|
| metyrapone | Active comparator | Overnight metyrapone treatment (total dose of 30 mg/kg) Receives: Drug: metyrapone |
| sugar pill | Placebo comparator | Overnight treatment with placebo capsules Receives: Drug: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Nutritional sympathetic nervous system responsiveness
Effects of acute overnight metyrapone treatment will be studied
Measured: 12-hours
Secondary outcomes (1)
insulin sensitivity
Acute effects of overnight metyrapone treatment will be studied
Measured: 12 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jun 2012 (estimated)
- Study startFeb 2013
- Primary completionDec 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metabolic SyndromeStudies of the same condition, open and under way.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Baker Heart Research Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Nora E. Straznicky, Baker Heart Research Institute
- Investigators
- Nora E Straznicky, PhD MPH, Principal investigator, Baker IDI Heart & Diabetes Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01620684
- Sponsor's protocol ID
- Metyrapone
- Other IDs
- Heart Foundation G11M5892
- Status last verified
- Sep 2014
- First submitted
- 12 Jun 2012
- Last updated
- 9 Sep 2014
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Sep 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Cortisol Blockade on Nutritional Sympathetic Nervous System Responsiveness in Overweight and Obese Subjects With Metabolic Syndrome
- ClinicalTrials.gov ID
- NCT01620684
- Acronym / sponsor ID
- Metyrapone
- Conditions
- Metabolic Syndrome, Obesity, Insulin Resistance
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- Baker Heart Research InstituteUniversity, hospital or other
- Study start
- Feb 2013
- Primary completion
- Dec 2014 (estimated)
- First posted
- 15 Jun 2012 (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.
This project will examine whether short-term (over a 12-hour period) pharmacological lowering of the stress hormone 'cortisol' improves the nervous system response to food intake in overweight or obese individuals who have metabolic syndrome.
The investigators know from our previous research that overweight/obese persons who are insulin resistant, have a blunted sympathetic nervous response to carbohydrate ingestion. This means that they are less able to dissipate energy from caloric intake, which would favour the maintenance of the obese state. Cortisol adversely impacts on insulin action and transport into the brain and cortisol levels are often elevated in persons with central (abdominal) obesity.
A randomized, double-blind, placebo controlled, cross-over design will be used to compare the effects of overnight treatment with metyrapone (15 mg/kg at midnight and 15 mg/kg at 6 am) versus placebo on sympathetic nervous system activity in response to a standard 75-g oral sugar (glucose) tolerance test. A 2 week washout will separate treatments.
Metyrapone is a drug that reversibly inhibits the enzyme 11beta-hydroxylase, and therefore the production of cortisol. It is used clinically to test the activity of the adrenal gland (the key site of cortisol production) and the pituitary gland. The investigators anticipate that at the dosage used, it will lower blood cortisol concentration by 44 to 64% during the experimental morning.
The study protocol comprises two screening visits and two experimental mornings. Key procedures will include:
- Assessment of insulin action (sensitivity) using the gold standard 'clamp' method.
- Measurement of sympathetic nervous system activity by both biochemical methods (isotope dilution which provides a measure of the apparent rate of release of 'noradrenaline'-the key neurotransmitter in the sympathetic nervous system) and direct intra-neuronal nerve recordings from the peroneal nerve in the lower leg.
- Indirect calorimetry to assess resting metabolic rate and the response to sugar ingestion.
- DEXA scan to quantify fat and lean mass.
- Assessment of arterial elasticity and calf blood flow by non-invasive methods.
- A standard 75g oral sugar tolerance test.
The results will provide important new information regarding the role of cortisol on nervous system function in overweight/obese individuals.
Detailed description
Similarities between metabolic syndrome obesity and hypercortisolemic conditions such as Cushing's syndrome have raised interest in the pathogenic role of glucocorticoid excess in this clinical setting. Cortisol is a well known counter-regulator of insulin action and increased levels of serum cortisol have been linked to insulin resistance in many studies. Moreover, treatment with the synthetic glucocorticoid dexamethasone reduced central nervous system insulin uptake by 49% in dogs. We have previously identified in metabolic syndrome subjects, an inverse relationship between morning fasting cortisol levels and sympathetic neural responsiveness to oral glucose ingestion. This concurs with other evidence that cortisol and synthetic glucocorticoids have sympathoinhibitory effects.
This project will test the hypothesis that short-term lowering of plasma cortisol levels by overnight metyrapone treatment, will improve nutritional sympathetic nervous system responses to carbohydrate ingestion in obese insulin resistant subjects with metabolic syndrome.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| metyrapone | Active comparator | Drug: metyraponeOvernight metyrapone treatment (total dose of 30 mg/kg) |
| sugar pill | Placebo comparator | Drug: placeboOvernight treatment with placebo capsules |
Who may qualify
- Ages
- 45 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- un-medicated,
- overweight or obese subjects (12 men and 12 postmenopausal women),
- weight-stable,
- non-smoking,
- aged 45-65 years
Key exclusion criteria (6 listed)
- adrenocortical insufficiency,
- pituitary dysfunction or tumour,
- sleep apnoea treated with CPAP,
- cardiovascular disease (previous MI, angina, stroke, heart failure, secondary hypertension),
- renal or hepatic disease (serum creatinine > 0.2 mmol/L; > 1 proteinuria on dipstick; alanine transferase > 2.5 times upper limit of normal, active liver disease) or
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 |
|---|---|---|
| metyraponeAlso: Metopirone (Novartis)Overnight treatment (15 mg/kg at midnight and 15 mg/kg at 6 am) | Drug | metyrapone |
| placeboplacebo capsules | Drug | sugar pill |
Primary outcome
Nutritional sympathetic nervous system responsiveness
Time frame: 12-hours
Effects of acute overnight metyrapone treatment will be studied
1 secondary outcome
insulin sensitivity
Time frame: 12 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Sep 2014.
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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.
Nora E Straznicky, PhD MPH principal investigator
Baker IDI Heart & Diabetes Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing metyrapone in people with Metabolic Syndrome and Obesity, run by Baker Heart Research Institute at 1 site in Australia.
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 8 inclusion and 6 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: status not confirmed, as of the sponsor's last update on 9 Sep 2014. 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 Australia. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Nora E Straznicky, PhD MPH (61 3 8532 1371, nora.straznicky@bakeridi.edu.au), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Nutritional sympathetic nervous system responsiveness (time frame: 12-hours). 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 9 Sep 2014.