HealthyPhase 4NCT00851942
Determination of Method-specific Normal Cortisol and Adrenal Hormone Responses to the Short Synacthen Test
A Phase 4 study testing Synacthen (Tetracosactrin) in people with Healthy and Adrenal Insufficiency, run by Cardiff University at 1 site in United Kingdom.
Trial summary
Objectives: To establish valid serum total cortisol and salivary cut-offs for use with the short Synacthen test in patients with normal CBG concentrations. To investigate, using current assays, the effect of assay differences on the serum total cortisol cut-off. Read more about this study
- Who is it for?
- Ages 18 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy, Adrenal Insufficiency, Hypopituitarism
- What is being tested?
- Synacthen (Tetracosactrin)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 165 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Sep 2008to 31 Jan 2013
- 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 18 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Volunteers will be in self-proclaimed good health
- Volunteers will be free of illness on the day of testing
- Volunteers will not be taking drug therapy.
- Patients will be free of intercurrent illness on the day of testing
- Patients will have a confirmed diagnosis of hypoadrenalism or hypopituitarism
Who cannot join
- Is pregnant or lactating. Females of childbearing potential must have a negative pregnancy test before enrollment onto the study. Non-child bearing potential is defined as post-menopausal for at least 1 year, surgical sterilisation or hysterectomy at least three months before the start of the study,
- Is using corticosteroids,
- has any significant intercurrent disease,
- has a history of thyroid or other autoimmune disease,
- has a previous history of hypersensitivity to Synacthen®,
- has a previous history of asthma
- has a history of allergic disorder
- has any mental condition rendering the patient unable to understand the nature or possible consequences of the study, and/or evidence of an uncooperative attitude.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Clinical Research Facility, University Hospital of Wales
Cardiff, South Glamorgan, CF14 4XW
About this study
Objectives:
To establish valid serum total cortisol and salivary cut-offs for use with the short Synacthen test in patients with normal CBG concentrations.
Read more
To investigate, using current assays, the effect of assay differences on the serum total cortisol cut-off.
To explore the performance of these cut-offs in groups of patients with suspected adrenal insufficiency and high and low serum CBG concentration.
Methodology: An ACTH test (250 micrograms iv ACTH1-24) will be undertaken in healthy volunteers, women taking an oestrogen-containing oral contraceptive pill (OCP), patients with adrenal insufficiency and patients with low serum albumin. Serum cortisol in the samples collected from healthy volunteers will be measured using GC-MS, Advia Centaur (Siemens), Architect (Abbott), Modular Analytics E170 (Roche), Immulite 2000 (Siemens) and Access (Beckman) automated immunoassays. The estimated lower reference limit for the 30 min cortisol response to ACTH, defined as the 2.5th percentile of log-transformed concentrations, will be determined in this healthy population and used as a cut-off in the patient groups studied.
Read the detailed description
Synacthen® is a synthetic analogue of ACTH which has been used since the 1960s to assess adrenal sufficiency. It is now well established as a first line test to investigate diseases of the hypothalamo-pituitary-adrenal axis and to assess adrenal function in patients on long-term corticosteroid therapy. Briefly, cortisol is measured before and after injection of 250 micrograms of Synacthen®. In a normal individual serum cortisol will rise to concentrations greater than an arbitrary value (typically 550 nmol/l) 30 minutes after administration of Synacthen®.
In 2004 the All Wales Clinical Biochemistry Audit group surveyed protocols for performing and interpreting short Synacthen® tests. This identified wide differences in practice within Wales. As a result standards were drawn up for performance of the test. It was noted that there was considerable variability or bias between cortisol immunoassays and that the cortisol cut-off chosen for interpretation of the short Synacthen® test should be method dependent.
Clark et al., in 1998 reported cortisol cut-offs following Synacthen® using 4 well established commercially available cortisol immunoassays. This study demonstrated considerable differences between the cortisol immunoassays used in clinical laboratories at the time. It was also apparent that there were differences in gender-related responses to Synacthen® although there was no dependence on age. In the 8 years since publication of this study there have been advances in formulation of cortisol immunoassays as well as the instrumentation used to perform analyses. At the University Hospital of Wales cortisol is currently assayed using the Bayer Centaur automated immunoassay analyser. This assay was not available at the time of the study by Clark et al.,. The investigators' current short Synacthen® test cut-offs therefore rely on historical reference ranges which have become outdated. A re-evaluation of the cortisol cut-off is required to ensure that patients are not incorrectly classified.
It has been long been recognised that oestrogens (including ethinyloestradiol prescribed in combined oral contraceptive pills) increase total (but not free) serum cortisol levels. The degree of increase is related to the dose used and is thought to be due to an elevation in cortisol binding globulin (CBG). However, no comparisons of total serum cortisol in response to Synacthen® have been performed between women taking oestrogens and those who are not. Knowledge of the salivary cortisol response may also be useful in patients with decreased serum CBG concentrations e.g. severe nephrotic syndrome in whom the serum cortisol response may be misleading. The investigators therefore plan to measure salivary cortisol as part of the investigators' study protocol to assess the response of free cortisol.
17 Hydroxyprogesterone (17OHP) is an intermediate in the biosynthesis of cortisol. Deficiency of 21-hydroxylase enzyme activity leads to an increased concentration of 17OHP in the peripheral circulation. The short Synacthen® test can be used to assist in diagnosis of mild cases of congenital adrenal hyperplasia. Current reference ranges are taken from the literature.
- Conditions
- Healthy, Adrenal Insufficiency, Hypopituitarism
- Being tested
- Synacthen (Tetracosactrin)
- Keywords
- Volunteer, Hypoadrenalism, Hypopituitarism, Healthy volunteers
- Medical subject headings
- Adrenal Insufficiency, Hypopituitarism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Synacthen (Tetracosactrin)Drug
Also called Synacthen
IV injection of 250 micrograms of Synacthen in 1ml
| Study group | Role | What they receive |
|---|---|---|
| Synacthen 250 micrograms | Experimental | IV injection of 250 micrograms of Synacthen in 1m Receives: Drug: Synacthen (Tetracosactrin) |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary end-point of the study will be to establish method dependent cortisol cut offs for the normal response to Synacthen® using the 5th percentile.
Measured: Cortisol response at 30 minutes
Secondary outcomes (4)
Cortisol measurements by immunoassay will be compared with the GC-MS gold standard method for normal volunteers and patients with hypopituitarism and hypoadrenalism.
Measured: Cortisol response at 30 minutes
Synacthen® responses in women taking ethinyloestradiol-containing contraceptive pills will be compared with those who are not.
Measured: Cortisol response at 30 minutes
We will establish cut offs for the salivary cortisol response to Synacthen® in normal volunteers using the 5th percentile.
Measured: Cortisol response at 30 minutes
We will establish a 17OHP cut off in response to Synacthen® in normal female volunteers using the 5th percentile.
Measured: 17OHP response at 60 minutes
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2009 (estimated)
- Study startSep 2008
- Primary completion28 Jul 2012
- Study completion31 Jan 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies 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
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 165 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cardiff University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Aled Rees, MB BCh, PhD, Principal investigator, Cardiff University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00851942
- Sponsor's protocol ID
- SPON 431-07
- Status last verified
- Aug 2020
- First submitted
- 25 Feb 2009
- Last updated
- 12 Aug 2020
- Results posted
- No
- Data monitoring committee
- No
Publications
Owen LJ, Adaway JE, Davies S, Neale S, El-Farhan N, Ducroq D, Evans C, Rees DA, MacKenzie F, Keevil BG. Development of a rapid assay for the analysis of serum cortisol and its implementation into a routine service laboratory. Ann Clin Biochem. 2013 Jul;50(Pt 4):345-52. doi: 10.1177/0004563212473448. Epub 2013 Jun 12.
PubMed 23761380
Study at a glance
From the registry record, last updated by the sponsor on 12 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Determination of Method-specific Normal Cortisol and Adrenal Hormone Responses to the Short Synacthen Test
- ClinicalTrials.gov ID
- NCT00851942
- Acronym / sponsor ID
- SPON 431-07
- Conditions
- Healthy, Adrenal Insufficiency, Hypopituitarism
- Keywords
- Volunteer, Hypoadrenalism, Hypopituitarism, Healthy volunteers
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 165 participants (actual)
- Lead sponsor
- Cardiff UniversityUniversity, hospital or other
- Study start
- Sep 2008
- Primary completion
- 28 Jul 2012 (actual)
- Study completion
- 31 Jan 2013 (actual)
- First posted
- 26 Feb 2009 (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.
Objectives:
To establish valid serum total cortisol and salivary cut-offs for use with the short Synacthen test in patients with normal CBG concentrations.
To investigate, using current assays, the effect of assay differences on the serum total cortisol cut-off.
To explore the performance of these cut-offs in groups of patients with suspected adrenal insufficiency and high and low serum CBG concentration.
Methodology: An ACTH test (250 micrograms iv ACTH1-24) will be undertaken in healthy volunteers, women taking an oestrogen-containing oral contraceptive pill (OCP), patients with adrenal insufficiency and patients with low serum albumin. Serum cortisol in the samples collected from healthy volunteers will be measured using GC-MS, Advia Centaur (Siemens), Architect (Abbott), Modular Analytics E170 (Roche), Immulite 2000 (Siemens) and Access (Beckman) automated immunoassays. The estimated lower reference limit for the 30 min cortisol response to ACTH, defined as the 2.5th percentile of log-transformed concentrations, will be determined in this healthy population and used as a cut-off in the patient groups studied.
Detailed description
Synacthen® is a synthetic analogue of ACTH which has been used since the 1960s to assess adrenal sufficiency. It is now well established as a first line test to investigate diseases of the hypothalamo-pituitary-adrenal axis and to assess adrenal function in patients on long-term corticosteroid therapy. Briefly, cortisol is measured before and after injection of 250 micrograms of Synacthen®. In a normal individual serum cortisol will rise to concentrations greater than an arbitrary value (typically 550 nmol/l) 30 minutes after administration of Synacthen®.
In 2004 the All Wales Clinical Biochemistry Audit group surveyed protocols for performing and interpreting short Synacthen® tests. This identified wide differences in practice within Wales. As a result standards were drawn up for performance of the test. It was noted that there was considerable variability or bias between cortisol immunoassays and that the cortisol cut-off chosen for interpretation of the short Synacthen® test should be method dependent.
Clark et al., in 1998 reported cortisol cut-offs following Synacthen® using 4 well established commercially available cortisol immunoassays. This study demonstrated considerable differences between the cortisol immunoassays used in clinical laboratories at the time. It was also apparent that there were differences in gender-related responses to Synacthen® although there was no dependence on age. In the 8 years since publication of this study there have been advances in formulation of cortisol immunoassays as well as the instrumentation used to perform analyses. At the University Hospital of Wales cortisol is currently assayed using the Bayer Centaur automated immunoassay analyser. This assay was not available at the time of the study by Clark et al.,. The investigators' current short Synacthen® test cut-offs therefore rely on historical reference ranges which have become outdated. A re-evaluation of the cortisol cut-off is required to ensure that patients are not incorrectly classified.
It has been long been recognised that oestrogens (including ethinyloestradiol prescribed in combined oral contraceptive pills) increase total (but not free) serum cortisol levels. The degree of increase is related to the dose used and is thought to be due to an elevation in cortisol binding globulin (CBG). However, no comparisons of total serum cortisol in response to Synacthen® have been performed between women taking oestrogens and those who are not. Knowledge of the salivary cortisol response may also be useful in patients with decreased serum CBG concentrations e.g. severe nephrotic syndrome in whom the serum cortisol response may be misleading. The investigators therefore plan to measure salivary cortisol as part of the investigators' study protocol to assess the response of free cortisol.
17 Hydroxyprogesterone (17OHP) is an intermediate in the biosynthesis of cortisol. Deficiency of 21-hydroxylase enzyme activity leads to an increased concentration of 17OHP in the peripheral circulation. The short Synacthen® test can be used to assist in diagnosis of mild cases of congenital adrenal hyperplasia. Current reference ranges are taken from the literature.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Synacthen 250 micrograms | Experimental | Drug: Synacthen (Tetracosactrin)IV injection of 250 micrograms of Synacthen in 1m |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Volunteers will be in self-proclaimed good health
- Volunteers will be free of illness on the day of testing
- Volunteers will not be taking drug therapy.
- Patients will be free of intercurrent illness on the day of testing
- Patients will have a confirmed diagnosis of hypoadrenalism or hypopituitarism
Key exclusion criteria (8 listed)
- Is pregnant or lactating. Females of childbearing potential must have a negative pregnancy test before enrollment onto the study. Non-child bearing potential is defined as post-menopausal for at least 1 year, surgical sterilisation or hysterectomy at least three months before the start of the study,
- Is using corticosteroids,
- has any significant intercurrent disease,
- has a history of thyroid or other autoimmune disease,
- has a previous history of hypersensitivity to Synacthen®,
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 |
|---|---|---|
| Synacthen (Tetracosactrin)Also: SynacthenIV injection of 250 micrograms of Synacthen in 1ml | Drug | Synacthen 250 micrograms |
Primary outcome
The primary end-point of the study will be to establish method dependent cortisol cut offs for the normal response to Synacthen® using the 5th percentile.
Time frame: Cortisol response at 30 minutes
4 secondary outcomes
Cortisol measurements by immunoassay will be compared with the GC-MS gold standard method for normal volunteers and patients with hypopituitarism and hypoadrenalism.
Time frame: Cortisol response at 30 minutes
Synacthen® responses in women taking ethinyloestradiol-containing contraceptive pills will be compared with those who are not.
Time frame: Cortisol response at 30 minutes
We will establish cut offs for the salivary cortisol response to Synacthen® in normal volunteers using the 5th percentile.
Time frame: Cortisol response at 30 minutes
We will establish a 17OHP cut off in response to Synacthen® in normal female volunteers using the 5th percentile.
Time frame: 17OHP response at 60 minutes
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 12 Aug 2020.
- Derived from this study: PubMed 23761380Owen LJ, Adaway JE, Davies S, Neale S, El-Farhan N, Ducroq D, Evans C, Rees DA, MacKenzie F, Keevil BG. Development of a rapid assay for the analysis of serum cortisol and its implementation into a routine service laboratory. Ann Clin Biochem. 2013 Jul;50(Pt 4):345-52. doi: 10.1177/0004563212473448. Epub 2013 Jun 12.
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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.
Aled Rees, MB BCh, PhD principal investigator
Cardiff University
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 Synacthen (Tetracosactrin) in people with Healthy and Adrenal Insufficiency, run by Cardiff University at 1 site in United Kingdom.
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 5 inclusion and 8 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 12 Aug 2020. 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 United Kingdom. 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.
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?
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?
The primary end-point of the study will be to establish method dependent cortisol cut offs for the normal response to Synacthen® using the 5th percentile. (time frame: Cortisol response at 30 minutes). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00851942, which also lists 1 linked publication.
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 12 Aug 2020; AzTrials last refreshed its copy on 26 Oct 2026.