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Vaginal Prednisone Administration for Prevention of Adrenal Crisis (Vapreda)

Primary Purpose

Adrenal Insufficiency

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
100mg prednisone suppository
Sponsored by
Wuerzburg University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Adrenal Insufficiency focused on measuring addison disease, adrenal crisis, prednisone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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)

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Other

    Other

    Arm Label

    vaginal administration first

    rectal administration first

    Arm Description

    Intervention first visit: vaginal administration of 100mg prednisone suppository, Intervention second visit: rectal administration of 100mg prednisone suppository

    Intervention first visit: rectal administration of 100mg prednisone suppository, Intervention second visit: vaginal administration 100mg prednisone suppository

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    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).
    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
    Tolerability by the patients assessed by a questionnaire
    Questions record the preference of the patients between vaginal and rectal application.

    Full Information

    First Posted
    February 8, 2016
    Last Updated
    June 19, 2017
    Sponsor
    Wuerzburg University Hospital
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02689960
    Brief Title
    Vaginal Prednisone Administration for Prevention of Adrenal Crisis
    Acronym
    Vapreda
    Official Title
    Vaginal Prednisone Administration for Prevention of Adrenal Crisis - a Bioequivalence Study
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    May 2017
    Overall Recruitment Status
    Completed
    Study Start Date
    January 2017 (Actual)
    Primary Completion Date
    April 2017 (Actual)
    Study Completion Date
    June 1, 2017 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Wuerzburg University Hospital

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    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
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Adrenal Insufficiency
    Keywords
    addison disease, adrenal crisis, prednisone

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 2
    Interventional Study Model
    Crossover Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    12 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    vaginal administration first
    Arm Type
    Other
    Arm Description
    Intervention first visit: vaginal administration of 100mg prednisone suppository, Intervention second visit: rectal administration of 100mg prednisone suppository
    Arm Title
    rectal administration first
    Arm Type
    Other
    Arm Description
    Intervention first visit: rectal administration of 100mg prednisone suppository, Intervention second visit: vaginal administration 100mg prednisone suppository
    Intervention Type
    Drug
    Intervention Name(s)
    100mg prednisone suppository
    Other Intervention Name(s)
    Rectodelt (approval number 6329964.00.00)
    Intervention Description
    vaginal administration of 100mg prednisone suppository (Rectodelt)
    Primary Outcome Measure Information:
    Title
    Bioequivalence of vaginal prednisone administration compared to rectal application, assessed by repeated determination of prednisolon levels (in blood)
    Description
    The hypothesis is that the same prednisolone levels can be achieved within the same time frame after vaginale administration compared to rectal application.
    Time Frame
    up to 12 months
    Secondary Outcome Measure Information:
    Title
    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).
    Time Frame
    up to 12 months
    Title
    Suppressive effects on ACTH levels after vaginal administration of prednisone compared to rectal application, assessed by repeated determination of ACTH-levels
    Description
    ACTH-levels are measured in plasma
    Time Frame
    up to 1 week
    Title
    Tolerability by the patients assessed by a questionnaire
    Description
    Questions record the preference of the patients between vaginal and rectal application.
    Time Frame
    up to 1 month

    10. Eligibility

    Sex
    Female
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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)
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Stefanie Hahner, MD, Prof.
    Organizational Affiliation
    University Hospital Wuerzburg
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    Citations:
    PubMed Identifier
    25419882
    Citation
    Hahner S, Spinnler C, Fassnacht M, Burger-Stritt S, Lang K, Milovanovic D, Beuschlein F, Willenberg HS, Quinkler M, Allolio B. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab. 2015 Feb;100(2):407-16. doi: 10.1210/jc.2014-3191. Epub 2014 Nov 24.
    Results Reference
    background
    PubMed Identifier
    25200922
    Citation
    Hahner S, Hemmelmann N, Quinkler M, Beuschlein F, Spinnler C, Allolio B. Timelines in the management of adrenal crisis - targets, limits and reality. Clin Endocrinol (Oxf). 2015 Apr;82(4):497-502. doi: 10.1111/cen.12609. Epub 2014 Nov 6.
    Results Reference
    background
    PubMed Identifier
    19955259
    Citation
    Hahner S, Loeffler M, Bleicken B, Drechsler C, Milovanovic D, Fassnacht M, Ventz M, Quinkler M, Allolio B. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol. 2010 Mar;162(3):597-602. doi: 10.1530/EJE-09-0884. Epub 2009 Dec 2.
    Results Reference
    background
    PubMed Identifier
    23672956
    Citation
    Hahner S, Burger-Stritt S, Allolio B. Subcutaneous hydrocortisone administration for emergency use in adrenal insufficiency. Eur J Endocrinol. 2013 Jun 29;169(2):147-54. doi: 10.1530/EJE-12-1057. Print 2013 Aug.
    Results Reference
    background
    PubMed Identifier
    25288693
    Citation
    Allolio B. Extensive expertise in endocrinology. Adrenal crisis. Eur J Endocrinol. 2015 Mar;172(3):R115-24. doi: 10.1530/EJE-14-0824. Epub 2014 Oct 6.
    Results Reference
    background
    PubMed Identifier
    26208266
    Citation
    Smans LC, Van der Valk ES, Hermus AR, Zelissen PM. Incidence of adrenal crisis in patients with adrenal insufficiency. Clin Endocrinol (Oxf). 2016 Jan;84(1):17-22. doi: 10.1111/cen.12865. Epub 2015 Aug 27.
    Results Reference
    background
    PubMed Identifier
    12151163
    Citation
    Anderson M, Kutzner S, Kaufman RH. Treatment of vulvovaginal lichen planus with vaginal hydrocortisone suppositories. Obstet Gynecol. 2002 Aug;100(2):359-62. doi: 10.1016/s0029-7844(02)02117-8.
    Results Reference
    background

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    Vaginal Prednisone Administration for Prevention of Adrenal Crisis

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