| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adrenal Insufficiency (AI) |
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| E.1.1.1 | Medical condition in easily understood language |
| adults with adrenal insufficiency |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052381 |
| E.1.2 | Term | Primary adrenal insufficiency |
| E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Efficacy - To compare Chronocort to Plenadren in terms of morning serum cortisol levels.
Safety - To compare Chronocort to Plenadren in terms of safety and tolerability; in terms of blood pressure; in terms of glycated haemoglobin (HbA1c) levels; in terms of stress dosing (use of participant administered emergency treatment pack); in terms of lipid profile.
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| E.2.2 | Secondary objectives of the trial |
Efficacy - To compare Chronocort to Plenadren in terms of:
- morning fatigue using the Multidimensional Assessment of Fatigue (MAF) questionnaire within 1 hour of waking
- achieving physiological morning cortisol levels.
- closeness of overall salivary cortisone levels during the day to a normal physiological profile
- adrenocorticotropic hormone (ACTH) control in the morning
- the impact on the bone marker of osteocalcin.
- morning fatigue using the Patient-Reported Outcomes Measurement Information System (PROMIS® 7b) questionnaire within 1 hour of waking
- QoL using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™)
- QoL using the Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire
- QoL using the 36-Item Short Form Health Survey (SF-36®) questionnaire.
Exploratory Efficacy - activity; Sleep; preference for treatment; QoL using the Diurnal Alertness visual analogue scale (VAS); QoL using the General Anxiety Disorder-7 (GAD-7)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female participants aged ≥18 years.
2. Participants with known (documented) primary AI, defined as early morning pre-dose cortisol <50 nmol/L and currently treated with glucocorticoid as replacement therapy. Primary AI includes any cause of acquired or congenital primary adrenal failure including autoimmune Addison’s disease and bilateral adrenalectomy (except when performed for Cushing’s syndrome).
3. Participants on stable glucocorticoid treatment for ≥3 months prior to the Screening Visit
4. Participants on a stable dose of fludrocortisone (if applicable) for ≥3 months prior to the Screening Visit.
5. Male participants must agree to use contraception as detailed in Appendix 4 during the Screening, Treatment, and Follow-up Periods and refrain from donating sperm during these periods and for 7 days after the last dose of study treatment.
6. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and for whom at least one of the following conditions applies: not a woman of childbearing potential (WOCBP) as defined in Appendix 4, or a WOCBP with a negative urine pregnancy test at entry into the study who agrees to follow the contraceptive guidance described in Appendix 4 during the Screening, Treatment and Follow-up Periods and for 7 days after the last dose of study treatment. Note: Females presenting with oligomenorrhea or amenorrhea who are ≤55 years should be considered potentially fertile (unless permanently sterile) and therefore, as well as undergoing pregnancy testing like all other female participants, will be expected to use an acceptable method of contraception as described in Appendix 4 during the Screening, Treatment and Follow-up Periods and for 7 days after the last dose of study treatment.
7. Capable of giving signed informed consent (as described in Appendix 1), which includes compliance with the requirements and restrictions listed in the ICF and in this protocol |
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| E.4 | Principal exclusion criteria |
1. Participants with CAH.
2. Participants with secondary and tertiary AI.
3. Past or current history of Cushing’s syndrome.
4. Adrenal suppression and/or AI induced by exogenous steroids.
5. Drug-induced AI.
6. Clinical or biochemical evidence of hepatic disease: elevated liver function tests (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3 times the upper limit of normal [ULN]).
7. Clinical or biochemical evidence of renal disease: serum creatinine level of >221 µmol/L (2.5 mg/dL) or calculated creatinine clearance of <25 mL/min.
8. History of malignant brain tumours or traumatic brain injury.
9. History of malignancy within the last 5 years or treated basal cell carcinoma within the past year.
10. Participants who have type 1 diabetes or type 2 diabetes receiving regular insulin.
11. Participants with type 2 diabetes whose screening HbA1c exceeds 9%.
12. Participants who have elective surgical procedures scheduled during the study.
13. Participants with significant medical or psychiatric conditions that in the opinion of the Investigator would preclude participation in the study.
14. Participants who have had bariatric surgery within the past 6 months and participants who plan to undertake a major weight loss and/or exercise program during the same time period as anticipated study involvement.
15. Restless legs syndrome/Willis-Ekbom disease.
16. Participants who have increased gastrointestinal motility e.g., chronic diarrhoea, that may be at risk of impaired cortisol exposure. There are no data in patients with confirmed slow gastric emptying or decreased motility disease/disorder so the clinical response should be monitored in patients with these conditions.
17. Participants anticipating regular prophylactic use of additional steroids e.g., for strenuous exercise.
18. Participants with co-morbidities requiring daily administration of a medication (or consumption of any material) that interferes with the metabolism of glucocorticoids.
19. Participants on regular daily inhaled, topical, nasal, or oral steroids for any indication other than AI.
20. Participants who have received intra-articular steroid injections within 1 year prior to the Screening Visit or for whom such injections are planned during the study.
21. Participants who are receiving <10 mg hydrocortisone dose at the Screening Visit or the hydrocortisone dose equivalent.
22. Participants taking sleeping medication.
23. Participants treated at screening with either Chronocort or Plenadren.
24. Participation in another clinical study of an investigational or licensed drug or device within 12 weeks or 5 half-lives prior to the Screening Visit or at any time during study participation.
25. Active alcohol or drug abuse within 1 year prior to the Screening Visit.
26. Participants who routinely work night shifts and do not sleep during the usual night-time hours.
27. Participants who intend to travel and cross a time zone of greater than ±3 hours within 1 week of the scheduled visit dates.
28. Participants unable to comply with the requirements of the protocol in the opinion of the Investigator.
29. Participants with a known hypersensitivity to any of the components of the Chronocort capsules, the Plenadren tablets, the Chronocort placebo, or the Plenadren placebo |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. To compare Chronocort to Plenadren in terms of morning serum cortisol levels.
The treatment effect (Chronocort minus Plenadren, after logarithmic transformation) will be estimated in the efficacy evaluable analysis set (EEAS) (defined as participants with morning serum cortisol assessed at baseline and after each treatment period, with no "major significant" protocol deviations) using a linear mixed model. Superiority of Chronocort to Plenadren will be declared if the 95% confidence interval (CI) for the treatment effect is wholly above zero
2. To compare Chronocort to Plenadren in terms of morning fatigue using the Multidimensional Assessment of Fatigue (MAF) questionnaire within 1 hour of waking.
The treatment effect (Chronocort minus Plenadren) will be estimated in the EEAS using a linear mixed model. Superiority of Chronocort to Plenadren will be declared if the 95% CI for the treatment effect is wholly above zero, provided superiority of Chronocort to Plenadren
has been declared in the primary analysis. Analyses of fatigue at other timepoints are supplementary analyses.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. The primary efficacy outcome variable is the 07:00 hour serum cortisol level after 4 weeks of treatment.
2. The key secondary efficacy outcome variable is the MAF morning fatigue score after 4 weeks of treatment.
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| E.5.2 | Secondary end point(s) |
The secondary outcomes are focused on whether this reduces fatigue and improves QoL in patients with AI. Therefore, the same total daily dose of Plenadren and Chronocort will be used.
1. To compare Chronocort to Plenadren in terms of achieving physiological morning cortisol levels.
2. To compare Chronocort to Plenadren in terms of closeness of overall salivary cortisone levels during the day to a normal physiological profile.
3. To compare Chronocort to Plenadren in terms of ACTH control in the morning.
4. To compare Chronocort to Plenadren in terms of the impact on the bone marker of osteocalcin.
5. To compare Chronocort to Plenadren in terms of morning fatigue using the Patient-Reported Outcomes Measurement Information System (PROMIS® 7b) questionnaire within 1 hour of waking.
6. To compare Chronocort to Plenadren in terms of QoL using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™).
7. To compare Chronocort to Plenadren in terms of QoL using the Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire
8. To compare Chronocort to Plenadren in terms of QoL using the 36-Item Short Form Health Survey (SF-36®) questionnaire
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 07:00 hour serum cortisol before the morning dose of >140 nmol/L after 4 weeks of treatment
2. A salivary cortisone profile score will be derived at the end of 4 weeks of treatment.
3. The 07:00 hour plasma ACTH level after 4 weeks of treatment
4. Osteocalcin levels after 4 weeks of treatment
5. Morning fatigue, using the PROMIS 7b questionnaire, within 1 hour of waking after 4 weeks of treatment
6. QoL, using the EQ-5D-5L after 4 weeks of treatment
7. QoL, using the AddiQoL questionnaire after 4 weeks of
treatment
8. QoL, using SF-36 questionnaire after 4 weeks of treatment |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| A Double-Blind, Double-Dummy, Two-Way Cross-Over, Randomized, Phase II Study |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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