Adrenal InsufficiencyPhase 4NCT03752190
Comparison of Intramuscular and Intravenous ACTH Stimulation Test in Normal Volunteers
A Phase 4 study testing Cosyntropin in people with Adrenal Insufficiency, run by Johns Hopkins University.
Trial summary
Cosyntropin (synthetic ACTH) stimulation test is considered the optimal test for diagnosis of primary and long-standing secondary adrenal insufficiency. The standard cosyntropin stimulation test is performed by administering 250 µg cosyntropin intravenously. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Adrenal Insufficiency
- What is being tested?
- Cosyntropin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Jul 2019to 31 Dec 2020
- 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 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Healthy volunteers
Who cannot join
- Know history of pituitary or adrenal disease. Current or recent use of glucocorticoids, and use of oral estrogen, pregnancy
About this study
Cosyntropin (synthetic ACTH) stimulation test is considered the optimal test for diagnosis of primary and long-standing secondary adrenal insufficiency.
The standard cosyntropin stimulation test is performed by administering 250 µg cosyntropin intravenously. Serum cortisol is measured before, and at 30 and 60 minutes after the bolus injection. Peak cortisol levels below 500 nmol/L (18.1 µg/dL) at 30 or 60 minutes after cosyntropin administration indicate adrenal insufficiency per recent guidelines, without specification of how the cosyntropin is administered (intravenously or intramuscularly). However, the peak stimulated cortisol cutoff value is based on old, fluorometric or radio-immunological methods that are known to detect significant amounts of glucocorticoids other than cortisol. For this reason, peak cortisol levels, as determined by older assays, may set higher thresholds than what might be considered necessary using a newer, more specific assay.
Read more
The widely-used old Elecsys® Cortisol Immunoassay from Roche Diagnostics (Cortisol I) is now replaced worldwide (including Johns Hopkins Hospital) by a new Elecsys® Cortisol assay from Roche Diagnostics (Cortisol II). The new Cortisol II assay employs a monoclonal as opposed to a polyclonal capturing antibody, which was used in the old Cortisol I assay. This results in greater specificity for cortisol. The new Cortisol II assay was shown to have strong correlation with cortisol levels measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) which is considered the gold standard for cortisol measurement.
Previous studies addressing the cortisol cutoff levels for the diagnosis of adrenal insufficiency with different cortisol assays have been heterogeneous in terms of the dose and route of administration of cosyntropin used, and the wide variety of subjects being tested including healthy subjects that are occasionally on oral estrogen therapy and patients with adrenal insufficiency.
Many clinical centers use intramuscular cosyntropin injections given its convenience, and as mentioned earlier, many institutions are now using the new Roche Cortisol II assay.
Investigators will conduct a study looking at healthy subjects to establish the expected range of peak cosyntropin-stimulated cortisol levels with two different cosyntropin administration modalities. The goal of this study is to compare intravenous (IV) and intramuscular (IM) administration, and to generate a normal range of post-cosyntropin serum cortisol measure with the new assay.
The two aims of the study are: (1) Compare the cortisol values at baseline, 30 minutes and 60 minutes after IV and IM cosyntropin stimulation testing in the same subjects. (2) Generate assay-specific normal ACTH stimulation test results
Read the detailed description
Investigators will conduct a study looking at healthy subjects to establish the expected range of peak cosyntropin-stimulated cortisol levels in normal healthy subjects with two different cosyntropin administration modalities. The goal of this study is to compare intravenous (IV) and intramuscular (IM) administration, and to generate a normal range of post-cosyntropin serum cortisol measure with the new assay.
The two aims of the study are: (1) Compare the cortisol values at baseline, 30 minutes and 60 minutes after IV and IM cosyntropin stimulation testing in the same subjects. (2) Study the values obtained using the new Roche Cortisol II assay and establish a new reference range for cosyntropin-stimulated cortisol levels in healthy subjects for both cosyntropin administration modalities.
The widely-used old Elecsys® Cortisol Immunoassay from Roche Diagnostics (Cortisol I) is now being replaced worldwide by a new Elecsys® Cortisol assay from Roche Diagnostics (Cortisol II). The new Cortisol II assay is also a competitive immunoassay, but employs a monoclonal as opposed to a polyclonal capturing antibody, which was used in the old Cortisol I assay. This results in greater specificity for cortisol with less interference from other endogenous or exogenous glucocorticoids. The new Cortisol II assay was shown to have strong correlation with cortisol levels measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) which is considered the gold standard for cortisol measurement. It has been shown in earlier studies that Cortisol II assay generates cortisol values that are approximately 20-30% lower than the older Cortisol I immunoassay with proposed new cortisol cutoff for the diagnosis of adrenal insufficiency between 350-375 nmol/L (12.7-13.6 µg/dL).
This is a prospective study on healthy subjects. Investigators will perform two cosyntropin stimulation tests on participants on two separate visits, one using intravenous and another one using intramuscular cosyntropin (250 µg). Investigators will allow a minimum of one week and a maximum of 2 months between the two tests.
Blood samples for each of the two tests will be drawn at baseline, before cosyntropin administration, then at 30 minutes and 60 minutes after cosyntropin administration from indwelling catheter. A maximum of 5 ml of blood will be drawn at each time point. Serum will be separated, and samples will be stored at - 80o C after collection until analyzed.
All of the blood samples will be tested to measure cortisol levels using the new Roche Cortisol II assay. The Cortisol assay kits will be provided from Roche Diagnostics.
Overall study duration will be 18 months. There will be two study visits. Investigators will allow a minimum of one week and a maximum of 2 months between the two visits.
The study will include 40 healthy subjects between the ages of 18 and 65. Investigators will exclude subjects with known hypothalamic-pituitary adrenal axis or other endocrine disease, glucocorticoid use (chronic, current, or within 3 months), pregnancy or oral estrogen use. Women will be studied during the same menstrual cycle phase for each of the 2 tests. Participants will be recruited by word of mouth and adds placed within the medical school campus. Participants will provide written informed consent.
Study Statistics
- Primary outcome variable.
- Comparison between peak cosyntropin-stimulated cortisol levels measured using IV and IM cosyntropin administration in the same subjects
- Establishing new reference range for expected peak cosyntropin-stimulated cortisol levels using the new Cortisol II assay for both cosyntropin administration modalities.
- Secondary outcome variables.
- Statistical plan including sample size justification and interim data analysis.
To test the hypothesis that the cortisol levels after IM administration of cosyntropin is slightly lower than IV administration, the investigator assume that 1) proportional analytical variability (constant CV) for both methods; 2) a difference > 50% of analytical variability is clinically meaningful (i.e., an effect size of 0.5). A sample size of 30 subjects will provide 85% power at a significance level of 5% using one-sided paired t-test. When the two time point data are analyzed together, the power will be higher.
For correlation estimation, the sample size of 30 produces a two-sided 95% confidence interval with a width < 0.153, assuming the sample correlation is >0.900.
With the proposed 40 healthy subjects, the distance of the reference range (defined as 95 percentile of the reference population) from the upper-bound of the estimated 95% confidence interval will be < 22%.
- Conditions
- Adrenal Insufficiency
- Being tested
- Cosyntropin
- Medical subject headings
- Adrenal Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CosyntropinDrug
intramuscular and intravenous administration
| Study group | Role | What they receive |
|---|---|---|
| Intravenous and intramuscular administration | Experimental | Subjects will receive intravenous and intramuscular ACTH on different days Receives: Drug: Cosyntropin |
What is being measured
The primary outcome is the main question the study is designed to answer.
peak serum cortisol
We will obtain peak serum cortisol level in nmol/L form each participant and determine the average
Measured: 60 minutes
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Nov 2018
- Study startJul 2019 (estimated)
- Primary completion30 Sep 2020 (estimated)
- Study completion31 Dec 2020 (estimated)
Why it stopped: Change in personnel leading to inability to conduct study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Adrenal InsufficiencyStudies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe 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 4
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03752190
- Sponsor's protocol ID
- IRB00193457
- Status last verified
- May 2019
- First submitted
- 21 Nov 2018
- Last updated
- 10 May 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 May 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Intramuscular and Intravenous ACTH Stimulation Test in Normal Volunteers
- ClinicalTrials.gov ID
- NCT03752190
- Acronym / sponsor ID
- IRB00193457
- Conditions
- Adrenal Insufficiency
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Change in personnel leading to inability to conduct study.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Study start
- Jul 2019 (estimated)
- Primary completion
- 30 Sep 2020 (estimated)
- Study completion
- 31 Dec 2020 (estimated)
- First posted
- 23 Nov 2018 (actual)
- 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.
Cosyntropin (synthetic ACTH) stimulation test is considered the optimal test for diagnosis of primary and long-standing secondary adrenal insufficiency.
The standard cosyntropin stimulation test is performed by administering 250 µg cosyntropin intravenously. Serum cortisol is measured before, and at 30 and 60 minutes after the bolus injection. Peak cortisol levels below 500 nmol/L (18.1 µg/dL) at 30 or 60 minutes after cosyntropin administration indicate adrenal insufficiency per recent guidelines, without specification of how the cosyntropin is administered (intravenously or intramuscularly). However, the peak stimulated cortisol cutoff value is based on old, fluorometric or radio-immunological methods that are known to detect significant amounts of glucocorticoids other than cortisol. For this reason, peak cortisol levels, as determined by older assays, may set higher thresholds than what might be considered necessary using a newer, more specific assay.
The widely-used old Elecsys® Cortisol Immunoassay from Roche Diagnostics (Cortisol I) is now replaced worldwide (including Johns Hopkins Hospital) by a new Elecsys® Cortisol assay from Roche Diagnostics (Cortisol II). The new Cortisol II assay employs a monoclonal as opposed to a polyclonal capturing antibody, which was used in the old Cortisol I assay. This results in greater specificity for cortisol. The new Cortisol II assay was shown to have strong correlation with cortisol levels measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) which is considered the gold standard for cortisol measurement.
Previous studies addressing the cortisol cutoff levels for the diagnosis of adrenal insufficiency with different cortisol assays have been heterogeneous in terms of the dose and route of administration of cosyntropin used, and the wide variety of subjects being tested including healthy subjects that are occasionally on oral estrogen therapy and patients with adrenal insufficiency.
Many clinical centers use intramuscular cosyntropin injections given its convenience, and as mentioned earlier, many institutions are now using the new Roche Cortisol II assay.
Investigators will conduct a study looking at healthy subjects to establish the expected range of peak cosyntropin-stimulated cortisol levels with two different cosyntropin administration modalities. The goal of this study is to compare intravenous (IV) and intramuscular (IM) administration, and to generate a normal range of post-cosyntropin serum cortisol measure with the new assay.
The two aims of the study are: (1) Compare the cortisol values at baseline, 30 minutes and 60 minutes after IV and IM cosyntropin stimulation testing in the same subjects. (2) Generate assay-specific normal ACTH stimulation test results
Detailed description
Investigators will conduct a study looking at healthy subjects to establish the expected range of peak cosyntropin-stimulated cortisol levels in normal healthy subjects with two different cosyntropin administration modalities. The goal of this study is to compare intravenous (IV) and intramuscular (IM) administration, and to generate a normal range of post-cosyntropin serum cortisol measure with the new assay.
The two aims of the study are: (1) Compare the cortisol values at baseline, 30 minutes and 60 minutes after IV and IM cosyntropin stimulation testing in the same subjects. (2) Study the values obtained using the new Roche Cortisol II assay and establish a new reference range for cosyntropin-stimulated cortisol levels in healthy subjects for both cosyntropin administration modalities.
The widely-used old Elecsys® Cortisol Immunoassay from Roche Diagnostics (Cortisol I) is now being replaced worldwide by a new Elecsys® Cortisol assay from Roche Diagnostics (Cortisol II). The new Cortisol II assay is also a competitive immunoassay, but employs a monoclonal as opposed to a polyclonal capturing antibody, which was used in the old Cortisol I assay. This results in greater specificity for cortisol with less interference from other endogenous or exogenous glucocorticoids. The new Cortisol II assay was shown to have strong correlation with cortisol levels measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) which is considered the gold standard for cortisol measurement. It has been shown in earlier studies that Cortisol II assay generates cortisol values that are approximately 20-30% lower than the older Cortisol I immunoassay with proposed new cortisol cutoff for the diagnosis of adrenal insufficiency between 350-375 nmol/L (12.7-13.6 µg/dL).
This is a prospective study on healthy subjects. Investigators will perform two cosyntropin stimulation tests on participants on two separate visits, one using intravenous and another one using intramuscular cosyntropin (250 µg). Investigators will allow a minimum of one week and a maximum of 2 months between the two tests.
Blood samples for each of the two tests will be drawn at baseline, before cosyntropin administration, then at 30 minutes and 60 minutes after cosyntropin administration from indwelling catheter. A maximum of 5 ml of blood will be drawn at each time point. Serum will be separated, and samples will be stored at - 80o C after collection until analyzed.
All of the blood samples will be tested to measure cortisol levels using the new Roche Cortisol II assay. The Cortisol assay kits will be provided from Roche Diagnostics.
Overall study duration will be 18 months. There will be two study visits. Investigators will allow a minimum of one week and a maximum of 2 months between the two visits.
The study will include 40 healthy subjects between the ages of 18 and 65. Investigators will exclude subjects with known hypothalamic-pituitary adrenal axis or other endocrine disease, glucocorticoid use (chronic, current, or within 3 months), pregnancy or oral estrogen use. Women will be studied during the same menstrual cycle phase for each of the 2 tests. Participants will be recruited by word of mouth and adds placed within the medical school campus. Participants will provide written informed consent.
Study Statistics
- Primary outcome variable.
- Comparison between peak cosyntropin-stimulated cortisol levels measured using IV and IM cosyntropin administration in the same subjects
- Establishing new reference range for expected peak cosyntropin-stimulated cortisol levels using the new Cortisol II assay for both cosyntropin administration modalities.
- Secondary outcome variables.
- Statistical plan including sample size justification and interim data analysis.
To test the hypothesis that the cortisol levels after IM administration of cosyntropin is slightly lower than IV administration, the investigator assume that 1) proportional analytical variability (constant CV) for both methods; 2) a difference > 50% of analytical variability is clinically meaningful (i.e., an effect size of 0.5). A sample size of 30 subjects will provide 85% power at a significance level of 5% using one-sided paired t-test. When the two time point data are analyzed together, the power will be higher.
For correlation estimation, the sample size of 30 produces a two-sided 95% confidence interval with a width < 0.153, assuming the sample correlation is >0.900.
With the proposed 40 healthy subjects, the distance of the reference range (defined as 95 percentile of the reference population) from the upper-bound of the estimated 95% confidence interval will be < 22%.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Intravenous and intramuscular administration | Experimental | Drug: CosyntropinSubjects will receive intravenous and intramuscular ACTH on different days |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Healthy volunteers
Key exclusion criteria (1 listed)
- Know history of pituitary or adrenal disease. Current or recent use of glucocorticoids, and use of oral estrogen, pregnancy
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 |
|---|---|---|
| Cosyntropinintramuscular and intravenous administration | Drug | Intravenous and intramuscular administration |
Primary outcome
peak serum cortisol
Time frame: 60 minutes
We will obtain peak serum cortisol level in nmol/L form each participant and determine the average
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 May 2019.
- Individual participant dataSharing planned: No
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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.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Cosyntropin in people with Adrenal Insufficiency, run by Johns Hopkins University.
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 1 inclusion and 1 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: withdrawn, as of the sponsor's last update on 10 May 2019. Status can change between updates, so confirm with the study contact before making plans.
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 was withdrawn before enrolling participants, so there are no results.
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?
peak serum cortisol (time frame: 60 minutes). 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 10 May 2019.