A healthy volunteer study to determine the effectiveness of a needle-free test for the diagnosis of adrenal insufficiency
| ISRCTN | ISRCTN62724177 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN62724177 |
| IRAS number | 1006488 |
| Secondary identifying numbers | SCH-2732b, IRAS 1006488, CPMS 55547 |
- Submission date
- 17/02/2023
- Registration date
- 28/09/2023
- Last edited
- 10/06/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Background and study aims
The adrenal glands produce cortisol, an essential hormone that is released as part of the body's stress response and helps to control blood pressure and blood sugar levels. Adrenal insufficiency (AI) describes the inability of the body to produce adequate levels of cortisol which, without treatment with replacement cortisol, can lead to serious illness and death. The Short Synacthen Test (SST) is the most popular diagnostic test for AI worldwide. Synacthen (tetracosactide) is a drug which stimulates the adrenal glands to produce cortisol. The SST requires intravenous cannulation and blood sampling before and after the Synacthen is given. It is thus invasive, requires trained staff to deliver the test, and is unpleasant for the patient, especially children. A non-invasive, needle-free alternative to the SST has been developed, the Nasacthin test, with the tetracosactide given nasally via a spray and the resultant cortisol and cortisone (the salivary equivalent to cortisol) response measured in saliva samples. The STARLIT-2 study will be looking to verify that the Nasacthin test does not produce a lower cortisol response compared to the SST.
Who can participate?
Healthy men, women and children aged 4-69 years old
What does the study involve?
Participants will attend 4 separate study visits and will receive a different drug at each visit (either nasal tetracosactide (Nasacthin), nasal placebo, IV tetracosactide (Synacthen) or IV placebo). The order in which they receive the drugs will be decided randomly before their first visit. Participants will be asked to provide pairs of samples (one blood and one saliva sample) at baseline (pre-drug) and then at 30, 60, 90 and 120 minutes after the drug is given. Additional saliva samples will be collected by participants at home after 180, 240, 360 and 480 minutes, and returned to the study team. All participants will receive a safety telephone call 24-48 hours after each study visit to check for any adverse events.
Participants will also be asked to complete a short paper questionnaire at each of the visits during the 90- and 120-minute sample interval, to explore the acceptability and tolerability of the study drug they received at that visit, and of the associated study procedures. During the final visit, participants will be asked to complete an additional short questionnaire, which will ask about the overall acceptability and tolerability, comparing both the nasal and IV tests.
What are the possible benefits and risks of participating?
While there will be no direct benefit to participants, the study will be an important step in the development of the test towards its routine use in the NHS, which would ultimately benefit patients being investigated for AI in the future.
Participants must have a cannula inserted at each visit for IV drugs to be given and for blood sampling, which may be briefly painful or can rarely cause slight bruising or local swelling. Synacthen and Nasacthin do not cause any long-term side effects, but mild and short-lived effects such as watery eyes, sneezing, coughing or a vinegary taste may be experienced after the nasal spray, and with both drugs, there is also a very small risk of a potentially severe allergic reaction.
There is also a very small chance that the sample results might show lower-than-normal levels of cortisol in response to the drugs, which would require further investigation via the standard care pathway.
Where is the study run from?
University of Sheffield (UK)
When is the study starting and how long is it expected to run for?
September 2022 to October 2025
Who is funding the study?
Medical Research Council (MRC) (UK)
Who is the main contact?
Dr Charlotte Elder, c.j.elder@sheffield.ac.uk
Contact information
Public
Clinical Trial Manager
Hull Health Trials Unit
Allam Medical Building
University of Hull
Cottingham Road
Hull
HU6 7RX
United Kingdom
| Phone | +44 (0)1482 464770 |
|---|---|
| kathryn.date@hyms.ac.uk |
Scientific
Sheffield Children’s Hospital
Western Bank
Sheffield
S10 2TH
United Kingdom
 ORCID ID |
0000-0003-2390-5593 |
|---|---|
| c.j.elder@sheffield.ac.uk |
Study information
| Study design | Randomized placebo-controlled double-blinded four-way cross-over study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Diagnostic, Safety, Efficacy |
| Participant information sheet | Participant information can be found at: https://hhtu.hull.ac.uk/starlit-2/#tab-1564 |
| Scientific title | Clinical validation of a non-invasive diagnostic test for adrenal insufficiency using comparative pharmacodynamic equivalence in a healthy population |
| Study acronym | STARLIT-2 |
| Study objectives | Current study hypothesis as of 09/10/2024: A. To determine whether 500mcg Nasacthin and 250mcg Synacthen produce a similar rise in serum cortisol levels at 30 minutes (using the values measured in the analysis). B. To determine the proportion of participants for which the Nasacthin produced a rise above a certain value at 30 minutes, out of the total participants for which Synacthen produced a rise above the same value. C. To determine whether the Nasacthin active treatment induces a response in serum cortisol levels at 30 minutes compared to the placebo treatment (using change from levels measured at baseline). D. To determine whether the Synacthen active treatment induces a response in serum cortisol levels at 30 minutes compared to the placebo treatment (using change from levels measured at baseline). E. To determine whether 500mcg Nasacthin and 250mcg Synacthen produce a similar rise in salivary cortisone levels at 60 minutes (using the values measured in the analysis). F. To determine whether 500mcg Nasacthin and 250mcg Synacthen produce a similar rise in serum cortisol levels at 30 minutes (using change from levels measured at baseline). G. To determine whether 500mcg Nasacthin and 250mcg Synacthen produce a similar rise in serum cortisol levels at 60 minutes (using the values measured in the analysis). H. To determine whether 500mcg Nasacthin and 250mcg Synacthen produce a similar rise in serum cortisol levels at 60 minutes (using change from levels measured at baseline). I. To demonstrate the safety of Nasacthin by recording any adverse events occurring during the study. J. To explore the acceptability, usability and tolerability of Nasacthin administration in staff and participants. Previous study hypothesis: A. To determine whether 500mcg Nasacthin and 250mcg Synacthen produce a similar rise in serum cortisol levels at 30 minutes (using the values measured in the analysis). B. To determine the proportion of participants for which the Nasacthin produced a rise above a certain value at 30 minutes, out of the total participants for which Synacthen produced a rise above the same value. C. To determine whether the Nasacthin active treatment induces a response in serum cortisol levels at 30 minutes compared to the placebo treatment (using change from levels measured at baseline). D. To determine whether the Synacthen active treatment induces a response in serum cortisol levels at 30 minutes compared to the placebo treatment (using change from levels measured at baseline). E. To determine whether 500mcg Nasacthin and 250mcg Synacthen produce a similar rise in salivary cortisone levels at 60 minutes (using the values measured in the analysis). F. To determine whether 500mcg Nasacthin and 250mcg Synacthen produce a similar rise in serum cortisol levels at 30 minutes (using change from levels measured at baseline). G. To demonstrate the safety of Nasacthin by recording any adverse events occurring during the study. H. To explore the acceptability, usability and tolerability of Nasacthin administration in staff and participants. |
| Ethics approval(s) |
Approved 21/09/2023, South Central – Hampshire A Research Ethics Committee (Health Research Authority, 2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)20 710 48120; hampshirea.rec@hra.nhs.uk), ref: 23/SC/0073 |
| Health condition(s) or problem(s) studied | Adrenal insufficiency |
| Intervention | Participants will attend 4 separate visits and will receive a different drug (either 500µg nasal tetracosactide (Nasacthin), nasal placebo, 250µg IV tetracosactide (Synacthen) (or 145µg/m2 for paediatric participants) or IV placebo) at each visit in a double-blind, randomised sequence, determined in advance of the first visit via an integrated randomisation function within the study’s secure web-based data capture system. For each drug, there is a single administration on the day of the visit. Nasal formulations (Nasacthin/nasal placebo) are administered using a primed mucosal atomiser device, 0.1ml to each nostril (total volume 0.2ml). Synacthen and IV placebo are administered via the cannula as a slow bolus. All participants will be asked to complete a short questionnaire during each visit to explore the acceptability and tolerability of the study drug, and will also receive a safety telephone call from a member of the study team 24-48 hours after each visit to check for any adverse events. In addition, at the end of the study, healthcare professionals involved in delivering the study will be asked to complete a questionnaire on the comparative acceptability of administration of the tests, and a focus group of key stakeholders (e.g. endocrinologists, nurses, clinicians from other heavy steroid-using specialities, primary and community care providers, commissioners and service managers) will be convened to discuss the usability and practicalities of the different testing methods. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacodynamic |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Nasal tetracosactide (Nasacthin), intravenous tetracosactide (Synacthen) |
| Primary outcome measure | 1. Comparison of mean serum cortisol concentration post-Nasacthin and Synacthen administration, measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS) at baseline (pre-drug) and 30 minutes post-drug administration 2. Proportion of participants for which the Nasacthin test produces a rise above a pre-set threshold, out of those for whom the Synacthen test also produces a rise above a pre-set threshold, measured using LC-MS/MS at baseline and 30 minutes post-drug administration 3. Comparison of mean change from baseline in serum cortisol concentration post-active Nasacthin and nasal placebo administration, measured using LC-MS/MS at baseline and 30 minutes post-drug administration 4. Comparison of mean change from baseline in serum cortisol concentration post-active Synacthen and IV placebo administration, measured using LC-MS/MS at baseline and 30 minutes post-drug administration |
| Secondary outcome measures | Current secondary outcome measures as of 09/10/2024: 1. Comparison of mean salivary cortisone concentration post-Nasacthin and Synacthen administration, measured using LC-MS/MS at baseline and 60 minutes post-drug administration. 2. Comparison of mean change from baseline in serum cortisol concentration post-Nasacthin and Synacthen administration, measured using LC-MS/MS at baseline and 30 minutes post-drug administration. 3. Comparison of mean serum cortisol concentration post-Nasacthin and Synacthen administration, measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS) at baseline (pre-drug) and 60 minutes post-drug administration. 4. Comparison of mean change from baseline in serum cortisol concentration post-Nasacthin and Synacthen administration, measured using LC-MS/MS at baseline and 60 minutes post-drug administration. 5. Frequency of adverse events (AEs), serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) by the treatment arm, as reported by participants up to 48 hours after the study visit. 6. Analysis of participant and clinical workforce acceptability, usability and tolerability, measured using non-validated questionnaires, for participants at each study visit and for healthcare professionals at the end of the study; optional participant interviews after completion of study visits; and a stakeholder focus group at the end of the study. Previous secondary outcome measures: 1. Comparison of mean salivary cortisone concentration post-Nasacthin and Synacthen administration, measured using LC-MS/MS at baseline and 60 minutes post-drug administration. 2. Comparison of mean change from baseline in serum cortisol concentration post-Nasacthin and Synacthen administration, measured using LC-MS/MS at baseline and 30 minutes post-drug administration. 3. Frequency of adverse events (AEs), serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) by the treatment arm, as reported by participants up to 48 hours after the study visit. 4. Analysis of participant and clinical workforce acceptability, usability and tolerability, measured using non-validated questionnaires, for participants at each study visit and for healthcare professionals at the end of the study; optional participant interviews after completion of study visits; and a stakeholder focus group at the end of the study. |
| Overall study start date | 01/09/2022 |
| Completion date | 31/10/2025 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Mixed |
| Lower age limit | 4 Years |
| Upper age limit | 69 Years |
| Sex | Both |
| Target number of participants | 44 |
| Total final enrolment | 38 |
| Key inclusion criteria | Current participant inclusion criteria as of 17/11/2023: 1. Healthy men, women and children aged 4-69 years old 2. Able to comply with passive drool salivary sampling requirements 3. Provision of signed written informed consent Previous participant inclusion criteria: 1. Healthy men, women and children aged 2-69 years old 2. Able to comply with passive drool salivary sampling requirements 3. Provision of signed written informed consent |
| Key exclusion criteria | Current participant exclusion criteria as of 09/10/2024: 1. Known adrenal insufficiency, Cushing's syndrome or any other adrenal or pituitary gland disorder 2. Ongoing pregnancy 3. Use of oestrogen-containing hormonal contraception / Hormone Replacement Therapy (due to the effect on cortisol levels) 4. Known condition requiring daily administration of a medication that interferes with the metabolism of glucocorticoids, e.g. known to affect corticosteroid binding globulin (CBG), including all oestrogens, or the hypothalamic-pituitary-adrenal (HPA) axis, including opioids, oral antifungals, loperamide 5. Currently prescribed anti-epileptic medication, such as sodium valproate, phenytoin, clonazepam, nitrazepam, phenobarbital or primidone 6. Known and active protein-losing disorders, e.g. enteropathy or nephrotic syndrome, who may have a cortisol-binding globulin abnormality 7. Known clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the upper limit of normal (ULN) or elevated liver function tests (alanine transaminase (ALT) or aspartate transaminase (AST) >3 times the ULN). 8. Participants on regular, inhaled, topical, nasal, ocular, rectal, oral or intra-articular steroids for any indication in the last 3 months 9. Current uncontrolled active infection 10. BMI >35 kg/m² (or BMI >3 standard deviations (SD) above the mean for age and sex if <16 years) 11. Known or suspected alcohol dependence or drug misuse 12. Current smoker or vaper (or within 6 months of cessation) 13. Recent (within 1 week) liquorice ingestion (preparations containing glycyrrhizic acid only) 14. Individuals with a history of known salivary gland or oral mucosa pathology who are unable to produce a suitable salivary sample (e.g. as a consequence of drugs that cause dry mouth) 15. Previous severe allergic reaction or anaphylaxis or adverse reaction to any antigen of ACTH or Synacthen 16. Participation in another clinical trial of an investigational or licensed drug within the 3 months prior to inclusion in study, unless it is a clinical trial of the same IMP (i.e. Nasacthin), in which case only a 7-day washout period applies 17. Participants unable to comply with the requirements of the protocol 18. Participants with any other significant medical or psychiatric conditions that in the opinion of the investigator would preclude participation in the trial 19. For nasal visits only: coryzal symptoms within the last week (and will be asked to report any new symptoms occurring within 24 hours of the test) or heavy nosebleed within the previous 48 hours - just excluded from that visit Previous participant exclusion criteria: 1. Known adrenal insufficiency, Cushing's syndrome or any other adrenal or pituitary gland disorder 2. Ongoing pregnancy 3. Use of oestrogen-containing hormonal contraception / Hormone Replacement Therapy (due to the effect on cortisol levels) 4. Known condition requiring daily administration of a medication that interferes with the metabolism of glucocorticoids, e.g. known to affect corticosteroid binding globulin (CBG), including all oestrogens, or the hypothalamic-pituitary-adrenal (HPA) axis, including opioids, oral antifungals, loperamide 5. Known and active protein-losing disorders, e.g. enteropathy or nephrotic syndrome, who may have a cortisol-binding globulin abnormality 6. Known clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the upper limit of normal (ULN) or elevated liver function tests (alanine transaminase (ALT) or aspartate transaminase (AST) >3 times the ULN). 7. Participants on regular, inhaled, topical, nasal, ocular, rectal, oral or intra-articular steroids for any indication in the last 3 months 8. Current uncontrolled active infection 9. BMI >35 kg/m² (or BMI >3 standard deviations (SD) above the mean for age and sex if <16 years) 10. Known or suspected alcohol dependence or drug misuse 11. Current smoker or vaper (or within 6 months of cessation) 12. Recent (within 1 week) liquorice ingestion (preparations containing glycyrrhizic acid only) 13. Individuals with a history of known salivary gland or oral mucosa pathology who are unable to produce a suitable salivary sample (e.g. as a consequence of drugs that cause dry mouth) 14. Previous severe allergic reaction or anaphylaxis or adverse reaction to any antigen of ACTH or Synacthen 15. Participation in another clinical trial of an investigational or licensed drug within the 3 months prior to inclusion in study 16. Participants unable to comply with the requirements of the protocol 17. Participants with any other significant medical or psychiatric conditions that in the opinion of the investigator would preclude participation in the trial 18. For nasal visits only: coryzal symptoms within the last week (and will be asked to report any new symptoms occurring within 24 hours of the test) |
| Date of first enrolment | 14/12/2023 |
| Date of final enrolment | 20/04/2025 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Sheffield
S10 2TH
United Kingdom
Sheffield
S10 2JF
United Kingdom
Sponsor information
University/education
Western Bank
Sheffield
S10 2TH
England
United Kingdom
| Phone | +44 (0)114 226 7980 |
|---|---|
| keith.pugh1@nhs.net | |
| Website | https://www.sheffieldchildrens.nhs.uk |
"ROR" |
https://ror.org/02md8hv62 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/10/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on websites 5. Other publication 6. Submission to regulatory authorities |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 22/12/2024 | 20/01/2025 | Yes | No |
Editorial Notes
10/06/2025: The following changes were made:
1. The overall end date was changed from 30/06/2025 to 31/10/2025.
2. The target number of participants was changed from 32 to 44.
3. Total final enrolment was added.
10/03/2025: Contact details updated.
03/03/2025: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/12/2025 to 20/04/2025.
2. The overall end date was changed from 31/12/2025 to 30/06/2025.
3. The plain English summary was updated to reflect these changes.
20/01/2025: Publication reference added.
21/10/2024: The participant level data sharing statement was added.
09/10/2024: The following changes were made:
1. The study hypothesis was updated.
2. The study setting was changed from pharmaceutical testing facility to hospital.
3. The pharmaceutical study type pharmacokinetic was removed.
4. The study phase was added.
5. The secondary outcome measures were updated.
6. The study website was added.
7. A link to the participant information sheet was added.
8. The participant exclusion criteria were updated.
9. The recruitment end date was changed from 30/09/2025 to 31/12/2025.
10. The overall study end date was changed from 30/09/2025 to 31/12/2025.
12/09/2024: The following changes were made:
1. The overall study end date was changed from 28/02/2025 to 30/09/2025.
2. The recruitment end date was changed from 30/09/2024 to 30/09/2025.
3. The intention to publish date was changed from 31/10/2025 to 31/10/2026.
09/07/2024: The following changes were made to the trial record:
1. The overall end date was changed from 30/08/2024 to 28/02/2025.
2. The recruitment end date was changed from 28/06/2024 to 30/09/2024.
07/12/2023: The recruitment start date was changed from 04/12/2023 to 14/12/2023.
16/11/2023: The following changes were made:
1. The study setting Hospital was removed.
2. The participant inclusion criteria were changed.
3. The lower age limit (number) was changed from 2.0 to 4.0 years.
4. The recruitment start date was changed from 20/11/2023 to 04/12/2023.
5. The recruitment end date was changed from 28/02/2024 to 28/06/2024.
04/10/2023: Internal review.
28/09/2023: ISRCTN received notification of combined HRA/MHRA approval for this trial on 28/09/2023
17/02/2023: Trial's existence confirmed by NHS HRA.
