Randomised, placebo-controlled, double-blinded, four-way crossover trial to demonstrate the comparative pharmacodynamic equivalence of a non-invasive diagnostic test for adrenal insufficiency in a healthy population: the STARLIT-2 study protocol.

introductionCortisol is an essential stress hormone and failure of its production, known as adrenal insufficiency (AI), is associated with significant mortality due to adrenal crisis. The Short Synacthen Test (SST) is the current diagnostic test of choice for AI, but it is both invasive and resource intensive. Globally, there is an unmet need for a non-invasive, cost-effective test. A novel formulation, Nasacthin, has been developed, which can be delivered intranasally, with the resultant glucocorticoid levels measured in saliva instead of blood. The Salivary Test of Adrenal Response to Liquid Intranasal Tetracosactide (STARLIT-2) study aims to clinically validate the Nasacthin test in healthy volunteers. METHODS AND ANALYSIS: STARLIT-2 is a randomised, placebo-controlled, double-blinded, four-way crossover trial. 32 healthy adults and children will be randomised to receive each of four study drugs (Synacthen, Nasacthin and their respective placebos) over four study visits (one per visit). Paired blood and saliva samples will be collected from participants at baseline, and then at 30, 60, 90 and 120 min after drug administration. Additional salivary samples will be collected at 180, 240, 360 and 480 min after drug administration. The primary outcome measures are to compare the mean serum cortisol at 30 min after Synacthen or Nasacthin dose, with a view to determine non-inferiority; and to compare the mean change from baseline in serum cortisol at 30 min after active and placebo doses of both Synacthen and Nasacthin, aiming to demonstrate superiority of active over placebo. In addition, the proportion of participants for which Nasacthin produces a rise above a preset serum cortisol threshold at 30 min will be determined, with the negative per cent agreement with the SST calculated using the SST as the reference standard. ETHICS AND DISSEMINATION: The study and its amendments have been reviewed and approved by South Central-Hampshire A Research Ethics Committee. Results will be disseminated in peer-reviewed journals and conference presentations, and feedback to trial participants will be facilitated following consultation with patient and public involvement and engagement groups. TRIAL REGISTRATION NUMBER: ISRCTN62724177.