Evaluation of Modified-Release Hydrocortisone Versus Immediate-Release Hydrocortisone on Circadian Rhythms and Quality of Life in Addison's Disease
- Trial ID
- 2023-503584-42-00
Trial statistics
Diseases & Conditions
Objectives
The primary objectives of this study are to evaluate the effect of transitioning from immediate-release **hydrocortisone** to modified-release hydrocortisone Efmody™ therapy on several clinical parameters in patients with **Addison's Disease**. These parameters include quality of life (QoL), sleep efficiency, patient interdaily stability, and dim-light melatonin onset (DLMO). These objectives are clinically relevant as they aim to improve the management of Addison's Disease by potentially enhancing patient well-being and optimizing circadian rhythm regulation.
Secondary objectives include assessing the impact of this transition on various aspects of sleep, such as quality, total sleep time, sleep onset, wake after sleep, and their respective variabilities. Additionally, the study will evaluate changes in 24-hour salivary cortisol and melatonin profiles, systolic and diastolic blood pressure, and the safety and tolerability of Efmody™ compared to immediate-release hydrocortisone. The study will also assess patient preference for Efmody™, as well as the use and reasons for rescue medication. These secondary objectives provide a comprehensive understanding of the broader effects of modified-release hydrocortisone therapy on patient health and treatment satisfaction.
Participants
The clinical trial involves participants diagnosed with **Addison's Disease**, focusing on adults aged 18 years and older. Both male and female subjects are included, with no specific vulnerable populations targeted. Participants are required to have been on a stable regimen of immediate-release hydrocortisone and fludrocortisone for at least four weeks prior to enrollment. The study does not specify the total number of participants, as this information was not provided by the sponsor. Participants must be capable of understanding the study requirements and providing informed consent. Lifestyle factors such as diet and physical activity are not explicitly mentioned as considerations for this trial. The selection criteria emphasize the stability of current treatment and the ability to comply with trial requirements, ensuring a consistent baseline for evaluating the effects of transitioning to modified-release hydrocortisone therapy.
Plans and Procedures
The clinical trial is designed as an open-label, cross-over, multi-site, prospective, phase IIb study aimed at evaluating the effects of **modified-release hydrocortisone** Efmody™ compared to immediate-release hydrocortisone in patients with Addison's Disease. The primary objectives include assessing changes in quality of life (QoL), sleep efficiency, patient interdaily stability, and dim-light melatonin onset (DLMO) when transitioning from immediate-release to modified-release hydrocortisone therapy. The trial is expected to commence on September 1, 2023, and conclude by March 1, 2024, with an estimated duration of six months.
Participants will be involved in the study for a total of 11 weeks per treatment period, with a cross-over design allowing each participant to receive both treatment regimens. The trial will include several key visits: an initial screening visit to confirm eligibility, baseline assessments, and subsequent follow-up visits to monitor treatment effects and safety. The end-of-study visit will involve final assessments and data collection to evaluate the primary and secondary endpoints. Participants must be aged 18 years or older, have a confirmed diagnosis of Addison's Disease, and be on stable immediate-release hydrocortisone and fludrocortisone treatment for at least four weeks prior to enrollment.
Inclusion criteria require participants to provide informed consent and demonstrate effective contraception if applicable. The study will exclude individuals unable to comply with trial requirements or those with conditions that may interfere with the study outcomes. Early termination from the study may occur if participants experience adverse effects, fail to adhere to the protocol, or withdraw consent. The trial's methodology ensures a robust evaluation of the therapeutic benefits of modified-release hydrocortisone, contributing valuable insights into the management of Addison's Disease.
Treatment
The clinical trial involves the administration of several **hydrocortisone**-based treatments to evaluate their effects on patients with Addison's Disease. The primary experimental medication is **Efmody 10 mg modified-release hard capsules**, which contain the active substance **hydrocortisone**. These capsules are designed for oral administration and are classified as modified-release to ensure a controlled release of the active ingredient. The maximum daily dose is 30 mg, with a total maximum dose of 2520 mg over a treatment period of up to 12 months. The medication is produced by Diurnal Europe B.V. and is categorized under the ATC code H02AB09, indicating its classification as a glucocorticoid.
Another experimental treatment in the study is **Efmody 5 mg modified-release hard capsules**, also containing **hydrocortisone**. Similar to the 10 mg formulation, these capsules are administered orally and are designed for modified release. The maximum daily dose for this formulation is 25 mg, with a total maximum dose of 2100 mg over a 12-month period. This formulation is also manufactured by Diurnal Europe B.V. and shares the same ATC classification as a glucocorticoid.
The study includes comparator treatments such as **Hydrocortone 10 mg Tablets**, which are immediate-release tablets containing **hydrocortisone**. These tablets are administered orally, with a maximum daily dose of 40 mg and a total maximum dose of 1120 mg over a 4-month period. The manufacturer of this product is TEVA B.V., and it is classified under the ATC code H02AB09 as a corticosteroid.
Another comparator treatment is **Hydrocortisone 10 mg Tablets**, produced by Renata Pharmaceuticals (Ireland) Limited. These tablets are also immediate-release and administered orally, with the same dosing schedule as Hydrocortone 10 mg Tablets. The classification under the ATC code H02AB09 remains consistent, identifying it as a corticosteroid.
Additionally, the study utilizes **Solu-Cortef Powder for Solution for Injection or Infusion 100 mg**, which is a powder form of **hydrocortisone** intended for reconstitution into a solution for injection or infusion. This formulation is administered via injection or infusion, with a maximum daily dose of 400 mg and a total maximum dose of 400 mg over a 1-day period. The product is manufactured by Pfizer Healthcare Ireland and is classified as a corticosteroid under the ATC code H02AB09.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the impact of transitioning from immediate-release hydrocortisone to modified-release hydrocortisone Efmody™ in patients with **Addison's Disease**. The primary endpoint involves measuring changes in quality of life (QoL) using the Health-related Quality of Life in Addison's disease (AddiQoL) questionnaire. This assessment will occur at baseline and at the end of each 11-week treatment period with Efmody™ compared to immediate-release hydrocortisone. Additionally, secondary endpoints will include changes in QoL as measured by the 36-Item Short Form Health Survey (SF-36®) questionnaire, also evaluated at baseline and at the conclusion of each 11-week treatment period.
The study will also assess the effects on sleep efficiency, patient interdaily stability, and dim-light melatonin onset (DLMO) as part of the primary objectives. These efficacy parameters will be collected and analyzed at specified time points throughout the trial to determine the therapeutic benefits of the modified-release formulation. The trial is designed as an open-label, cross-over, multi-site, prospective, phase IIb study, ensuring a comprehensive evaluation of the treatment's impact on circadian rhythms and overall quality of life in the target patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female participants must be aged 18 years or older
- Ability to comprehend the Patient Information Leaflet and to provide signed and dated informed consent.
- Participants with an established diagnosis of Addison’s disease currently treated with immediate-release hydrocortisone as replacement therapy .
- Participants on stable immediate-release hydrocortisone treatment for ≥ 4 weeks prior to enrolment.
- Participants on a stable dose of fludrocortisone for ≥ 4 weeks prior to enrolment
- Evidence of effective contraception for WOCBP* (see Appendix 11) *Women of childbearing potential (WOCBP) are eligible to participate if they are not pregnant, not breastfeeding and agree to adhere to the contraceptive guidance during the screening and treatment periods. Effective contraception should be maintained until treatment discontinuation. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. The effective methods of contraception are described in Appendix 11
- In the Investigator’s opinion, able and willing to comply with all trial requirements.
Exclusion Criteria
- Participants aged < 18 years
- 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]).
- 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.
- Participants who have type 1 diabetes or type 2 diabetes receiving regular insulin.
- Participants who have elective surgical procedures scheduled during the study.
- Current diagnosis of moderate to severe depression, bipolar disorder, eating disorders, schizophrenia or other psychosis. A past history of psychiatric disorder is not an exclusion criterion, provided the patient is currently well (not on psychoactive treatment) in the investigator’s judgement. Participants with psychiatric conditions that in the opinion of the Investigator would preclude participation in the study: such as severe depression, schizophrenia, eating disorders.
- Participants with an acute medical or surgical illness.
- History of significant medical co-morbidities which disrupt sleep (for example, obstructive sleep apnoea, congestive cardiac failure or restless leg syndrome)
- History of cataracts or other ophthalmologic conditions which could affect retina light perception.
- Conditions that would place the individual at increased risk or preclude the individual’s full compliance with or completion of the study – such as intellectual disability or cognitive impairment
- Patients who have difficulty understanding the required protocol and follow up instructions (e.g. language barriers)
- Participants with life expectancy of less than 6 months.
- Participants with a history of malabsorption and/or motility disorders due to risk of impaired cortisol exposure.
- Participants treated with agents that interfere with corticosteroid metabolism.
- Participants who have received intra-articular steroid injections within 2 months prior to the Screening Visit or for whom such injections are planned during the study.
- Participants who are prescribed inhaled or topical steroid preparations
- Participants with ongoing use of drugs which affect sleep - such as sedatives or antidepressants.
- Patients who have participated in another research trial involving an investigational product in the past 12 weeks.
- Ongoing habitual alcohol intake in excess of 20 units per week.
- History of night-shift work in the previous two years
- Participants who intend to travel and cross a time zone of greater than ±3 hours within 1 week of the scheduled actigraphy and DLMO measurements.
- Participants with a known hypersensitivity to any of the components of the Efmody™ capsules.
- Pregnancy
- Breastfeeding Mothers
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Ireland | Not Recruiting | 01 Sept 2023 | 30 |
Sites & Investigators
Research sites
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Efmody 10 mg modified-release hard capsules | Test | MODIFIED-RELEASE HARD CAPSULES | ORAL | 30 | 12 | PRD8980087 |
Hydrocortone 10 mg Tablets | Comparator | TABLETS | ORAL | 40 | 4 | PRD7436897 |
Solu-Cortef Powder for Solution for Injection or Infusion 100 mg | Other | POWDER FOR SOLUTION FOR INJECTION OR INFUSION | SOLUTION FOR INJECTION OR INFUSION | 400 | 1 | PRD1179840 |
Efmody 5 mg modified-release hard capsules | Test | MODIFIED-RELEASE HARD CAPSULES | ORAL | 25 | 12 | PRD8980051 |
Hydrocortisone 10 mg Tablets | Comparator | TABLETS | ORAL | 40 | 4 | PRD7870342 |