Design

The PlenadrEMA study is an investigator-initiated open-label switch pilot trial. Included patients will be observed for 5 weeks on their usual treatment (two or three times daily hydrocortisone). Assessments of QoL, in terms of EMA assessments, to be used as baseline measurement in the study, will be collected at the beginning of the trial period for 20 days preceded by a 5-day technology adaptation phase (see figure 1), that is, EMA collection will begin on day 6 of the trial period. Thereafter, participants will be shifted to dual-release hydrocortisone (Plenadren) once daily, on an equivalent dose as per Summary of Product Characteristics. Assessments of QoL to be used as primary outcome will be performed 12.5 weeks after initiation of the intervention treatment, in order to take into consideration the period of readjustment of the body after the switch from conventional hydrocortisone to Plenadren. As done at the baseline observation, 20 days of EMA measurements will be preceded by a 5-day technology adaptation phase (figure 1). At the end of the intervention treatment period, the patients will be shifted to their usual hydrocortisone treatment and will be followed at the outpatient clinic according to the standard directives of the clinic.

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Figure 1

Study period for an individual participant, total duration: 21 weeks. EMA, ecological momentary assessment.

Study population

All patients with a diagnosis of adrenal insufficiency due to hypopituitarism who are referred to or followed at the Department of Endocrinology at Copenhagen University Hospital Rigshospitalet will be considered for participation in this trial. Patients may enter the PlenadrEMA study if they comply with the inclusion and exclusion criteria.

Inclusion criteria: age ≥18 years; diagnosis of adrenal insufficiency due to hypopituitarism; in steady two or three times daily (10–40 mg) hydrocortisone replacement treatment; written informed consent; for women: use of reliable methods of contraception in clinical trials in accordance with the definition by the Danish Health and Medicines Authority; intrauterine devices or hormonal methods (oral contraceptives, contraceptive implants, transdermal patches, hormonal vaginal devices or injections with prolonged release).

Exclusion criteria: pregnancy; breast feeding; acromegaly; Cushing’s disease; diabetes mellitus; other major confounding disease; known or expected hypersensitivity to any of the excipients; lack of compliance (attendance and medication).

Given that the method of EMA measurement of fatigue is novel, power calculations to determine the correct sample size cannot be conducted on a sufficiently informed basis, since the magnitude of the expected change and the variability is unknown. In order to obtain reliable estimates of variability and magnitude of expected differences, a sample size of N=30 was decided for this pilot study, after discussion with an experienced biostatistician. Several other pilot studies have investigated EMA for measuring symptoms. These studies have included between 19 and 33 participants,10–15 which corresponds well with our chosen sample size.

Intervention

The investigational medicinal product in this study is the dual-release hydrocortisone, Plenadren. It is produced and delivered by Shire in tablets containing 5 mg and 20 mg hydrocortisone and will be stored according to Summary of Product Characteristics. The initial dose of Plenadren is equal to the total daily dose of the patients’ usual conventional hydrocortisone. Patients will be instructed to take the Plenadren tablets orally in fasting state in the morning (between 6:00 and 8:00). The duration of the intervention period is 16 weeks, including a run-in period of 12.5 weeks.

The usual hydrocortisone replacement regimen of the patients, that is, conventional hydrocortisone, is used as comparator in the trial. Doses include variable combinations of hydrocortisone 20 mg tablets produced by TAKEDA and an unlicensed preparation of hydrocortisone 5 mg tablets produced by Glostrup Pharmacy. The total dose per day is between 10 and 40 mg and is administered in two to three daily doses. The individual, usual dose of the patient will not be altered on entering the trial unless the patient shows clinical symptoms of insufficient replacement.

Collection of EMA data

In our research group, we have developed a smartphone application for collection of EMA data. It follows state-of-the-art standards for electronic EMA instruments as described in the field of EMA research.16 This includes, for example, individually adjusted diurnal rhythm, a possibility to delay a data entry for up to 1 hour, and time stamping of data entries in order to evaluate compliance. The EMA application is integrated with the trial management system PROgmatic.17 The integrated system handles patient flow, electronic case report forms and collection of EMA data from mobile devices. EMA data are stored on mobile devices and uploaded to a secure, encrypted back-end system each night. From here, data are pulled also on a nightly basis to PROgmatic, where data completeness can be surveyed in real-time, enabling appropriate action to secure data quality, that is, avoid missing data. The system is approved by the Danish Data Protection Agency (local identifier at Rigshospitalet: 30–1233).

Outcome measures

The primary outcome of the study is variability and difference in fatigue between conventional and dual-release hydrocortisone treatment. Fatigue is measured by the standardised, validated fatigue instrument: Multidimensional Fatigue Inventory (MFI-20),18 which will be adapted to EMA. The MFI-20 is formulated in a way that makes it relatively easy to convert into an EMA-measure. Four times daily, at semi-randomised time points, the participants are prompted by the EMA application to respond to eight brief questions from the MFI-20. Four items from the General Fatigue scale are administered every day during the observation period as well as four items from one of the four remaining scales (Physical Fatigue, Mental Fatigue, Reduced Activity and Reduced Motivation). The reason for administrating only one of the four specific scales per day is to reduce response burden; thus, these scales are administered in cycles of 4 days: Physical Fatigue on day 1, Mental Fatigue on day 2, Reduced Activity on day 3 and Reduced Motivation on day 4.

Secondary outcome assessment is specified in table 1 and includes the standardised, validated questionnaires: Fatigue Impact Scale, Addison Disease-specific QoL questionnaire and the Short Form Health Survey, all of which will be administered on visit 2 and 4. Furthermore, blood samples, dual-energy X-ray absorptiometry primarily for evaluation of body composition, 24 hours blood pressure, salivary cortisol and recording of adverse events (AEs) will be assessed as part of the safety evaluation of Plenadren on visit 2 and 4. Patients will be asked to pause their hydrocortisone treatment and blood samples will be collected at least 12 hours after last hydrocortisone dosage. Blood samples consist of cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting blood glucose, glycated haemoglobin, C reactive protein, electrolytes, fibrinogen, plasminogen activator inhibitor-1, cortisol, adrenocorticotropic hormone, cortisol binding globulin, serum type 1 procollagen and collagen type 1 cross-linked C-telopeptide, osteocalcin, receptor activator of nuclear factor kappa-B ligand, osteoprotegerin and sclerostin.

Biobank

A research biobank of serum and plasma will be established for analysis of biochemical markers specified in the outcome measures section and for future use. Participants are informed orally and in writing, and will consent to the withdrawal and storing of biological material. Blood samples for the biobank are collected at visit 2 and 4. Access to material of the biobank for further analysis, not included in the study protocol, will require a specific authorisation from the Committees of Health Research Ethics. The material will be stored according to requirements of the Danish Data Protections Agency.

Monitoring

The trial will be monitored by the Good Clinical Practice unit at Copenhagen University Hospital.

Data and statistical analysis

For each of the two EMA reporting periods, four diurnal fatigue profiles are generated for each participant. Each diurnal fatigue profile consists of four daily measurement points. One diurnal profile summarises General Fatigue responses during the day across all 20 days. For each of the other four scales, a profile summarising the responses during the day across the 5 days they were administered is generated. Scale means will be calculated for conventional treatment versus dual-release hydrocortisone by mixed models for repeated measures. The scale with the largest change in score will be selected as the best suited EMA outcome, of which difference in mean and SD will be used for sample size calculations for future randomised clinical trials. Diurnal curves will be generated for the General Fatigue scale and inspected as well as statistically tested for temporal patterns (mixed models), by dividing the day into 3-hour blocks and testing for significant variation in scores.19 All analyses will be conducted as intention-to-treat analyses, with two-sided significance level at 5%.

Patient safety and AE recording

Independent of treatment period, in case of intercurrent illness or physical or mental stress, participants will be instructed to take additional substitution of immediate release hydrocortisone tablets (rescue medication) according to current guidelines. The need for rescue medication will be assessed at trial visits according to table 1. Participants are questioned about AEs according to table 1. In addition, participants are instructed to contact their trial contact person if they experience symptoms suggestive of AEs. Any identified AE will be registered in the case report form of the patient and will be reported to the Regional Research Ethics Committee and the Danish Health and Medicines Authority according to the Good Clinical Practice regulations. When a possible serious adverse event (SAE), serious adverse reaction (SAR) or suspected unexpected serious adverse reaction (SUSAR) is identified, the event will be followed up by the sponsor–investigator or delegated (medically qualified). Details about the event will be sought from the patient’s medical record and through direct contact with the patient or relatives (in case of an event leading to death or incapacitation of the participant). The event will be assessed for causality between Plenadren and the event by the sponsor–investigator or delegated based on a clinical evaluation. Any SAE, SAR or SUSAR will be reported as an outcome measure.