Vaginal Prednisone Administration for Prevention of Adrenal Crisis

Study Overview
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Brief Summary
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Patients with chronic adrenal insufficiency need to adapt their glucocorticoid replacement dose in conditions of physical or psychological stress to prevent life threatening adrenal crisis. In cases of more severe impairment or unsecure gastrointestinal absorption (e.g. gastroenteritis, severe infectious disease), rapid and highly dosed administration of glucocorticoids is crucial. The study is conducted to offer female patients the possibility to perform efficient prednisone self-administration in emergency situations in a way of administration, which is easy to perform and accepted by the patients. Therefore, pharmacokinetics and safety of vaginal prednisone administration will be studied and compared to rectal administration.

Detailed Description
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As patients with adrenal insufficiency still die from adrenal crisis, improvement of both prevention and also emergency management is needed. It is clear that perfect equipment and education of patients is key for further crisis prevention and management. Vaginal administration of prednisone-suppositories is easy to perform and independent of the gastro-intestinal system. Thus, this study aims at the efficacy, feasibility and safety of vaginal administration of prednisone-suppositories. Recruitment: Patients with primary adrenal insufficiency will be recruited. The adrenal insufficiency registry of Würzburg comprises more than 150 patients with primary adrenal insufficiency. Several patients have already indicated their interest to participate in the study. According to the European Medicines Agency (EMA) notes for guidance on the investigation of bioavailability and bioequivalence the number of 12 participants is regarded as the minimum required number. Trial flow: Pharmacokinetic studies will be performed at two different study visits. Patients will receive a 100mg prednisone suppository (Rectodelt® 100 mg) vaginal and rectal on two different study visits (interval longer then one week). Blood samples for determination of prednisone and adrenocorticotropic Hormone (ACTH) levels will be collected over a time period of 6 hours. Patients receive a diary to document eventual local or systemic adverse events during the following 7 days. Stopping rules: Participation of patients is fully voluntarily. Patients are able to stop participation in the study at any point in time. In addition, patients might claim the elimination of all data material at any point in time. Furthermore, study participation will be stopped for the individual patient, if new safety issues occur (e. g. new diagnosis of Diabetes mellitus, pregnancy or acute infectious disease) during the study. Relevant risks to the patients are highly unlikely. However, if 2 or more patients experience serious adverse events associated with the vaginal administration of prednisone with high likelihood, the study will be stopped. Written informed consent: A consent document including patient information upon the nature, scope and possible consequence of the trial must have been approved by the Institutional Review Board. Patients amenable for inclusion in the trial will be given sufficient time to study the written information, as well as possibility to ask questions before signing the consent document. Analysis: Documentation and analysis will be performed at the Department of Medicine I, Endocrine and Diabetes Unit, University of Würzburg, Germany. Data will be documented after pseudonymisation in a data base. Data analysis is mainly descriptive (bioequivalence of vaginal prednisone administration compared to rectal application, estimation of the patients regarding convenience and tolerability of different modes of drug administration, safety aspects). Safety: In the course of the trial, changes in physical findings as well as clinical signs and symptoms that may reflect adverse effects will be documented. Furthermore, all adverse events will be documented on the appropriate report form. When an adverse event occurs it will be graded according to the National cancer Institute - common toxicity criteria (NCI-CTC) (version 4.0). Patients receive a diary to document any local or systemic adverse event during the following 7 days after intervention. In addition, patients will be contacted by phone 3(±1) and 7(±1) days after vaginal administration of prednisone. If patients report any adverse events that are possibly related to the vaginal administration route, they will be called-in for further physical examination and detailed documentation. To further enhance individual patient's safety during the study, a safety assessment will be performed prior to the subsequent intervention. In addition, a safety assessment will be performed after 4 and 8 subsequent vaginal administrations of prednisone with evaluation of events during the 7 day follow up period after administration.

Official Title
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Vaginal Prednisone Administration for Prevention of Adrenal Crisis - a Bioequivalence Study

Conditions
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Adrenal Insufficiency

Intervention / Treatment
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* Drug: 100mg prednisone suppository


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients with chronic primary adrenal insufficiency due to autoimmune adrenalitis or bilateral adrenalectomy (disease duration at least 6 months) Age ≥ 18 years Patient´s written informed consent Ability to comply with the protocol procedures Established stable replacement therapy, no anticipated change in medication Negative pregnancy test and contraception (besides oral contraceptive pill) in pre-menopausal females Exclusion Criteria: Diabetes mellitus Infectious disease with fever at time of investigation Known intolerance to the study drug or constituents Oral contraception Pregnancy or breast feeding Renal failure (creatinine >2.5 ULN) Disposition to vaginal mycosis (requiring treatment in the last 6 months or of necessity >2 antimycotic therapies/year) Recurrent urinary tract infections (of necessity >2 antibiosis therapies/year)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: vaginal administration first<br>Intervention first visit: vaginal administration of 100mg prednisone suppository, Intervention second visit: rectal administration of 100mg prednisone suppository | Drug: 100mg prednisone suppository<br>* vaginal administration of 100mg prednisone suppository (Rectodelt)<br>* Other names: Rectodelt (approval number 6329964.00.00);|
| Other: rectal administration first<br>Intervention first visit: rectal administration of 100mg prednisone suppository, Intervention second visit: vaginal administration 100mg prednisone suppository | Drug: 100mg prednisone suppository<br>* vaginal administration of 100mg prednisone suppository (Rectodelt)<br>* Other names: Rectodelt (approval number 6329964.00.00);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bioequivalence of vaginal prednisone administration compared to rectal application, assessed by repeated determination of prednisolon levels (in blood) | The hypothesis is that the same prednisolone levels can be achieved within the same time frame after vaginale administration compared to rectal application. | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of the vaginal administration of prednisone compared to rectal application, assessed by the number of participants with treatment-related adverse events (using the NCI-CTC, version 4.0). |  | up to 12 months | 
| Suppressive effects on ACTH levels after vaginal administration of prednisone compared to rectal application, assessed by repeated determination of ACTH-levels | ACTH-levels are measured in plasma | up to 1 week | 
| Tolerability by the patients assessed by a questionnaire | Questions record the preference of the patients between vaginal and rectal application. | up to 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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addison disease, adrenal crisis, prednisone