Continuous Subcutaneous Hydrocortisone Infusion In Addison's Disease and Type 1 Diabetes
Condition: Addison Disease; Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Addison Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      The conventional glucocorticoid replacement therapy in primary adrenal insufficiency
      (Addison's disease) renders the cortisol levels unphysiological, which may cause symptoms and
      long-term complications.

      The majority of Addison's patients have other organ-specific autoimmune disease, which poses
      challenges to the replacement therapy. Of particular interest is the combination of Addison's
      disease and type 1 diabetes, since cortisol affects glucose homeostasis. The clinical
      experience is that this subgroup of patients is difficult to treat, but very little research
      has been done to understand and improve their situation.

      Glucocorticoid replacement is technically feasible by continuous subcutaneous hydrocortisone
      infusion, and can mimic the normal diurnal cortisol rhythm. This pilot study aims to further
      evaluate continuous subcutaneous hydrocortisone infusion treatment in terms of metabolic
      effects especially glycemic control in patients with the combination of Addison's disease and
      type 1 diabetes in an 5 months cross-over design open clinical pilot study.
    

Detailed description: 
      Treatment of Addison's disease includes glucocorticoid and mineralocorticoid replacement.
      Despite optimized therapy with these steroids, many patients suffer from impaired quality of
      life and increased mortality. The etiology of the premature death is complicated and may
      include a combination of inadequate treatment of adrenal crisis, patient non-compliance, and
      undetected hypoglycemia, in addition to being associated with increased cardiovascular,
      malignant, and infectious disease deaths. The relative risk of death for patients with Type 1
      Diabetes is 3.8 in Sweden. Having Type 1 diabetes and Addison's disease significantly
      increased the risk of death when compared with having adrenal insufficiency alone. The risk
      for premature death in patients with the combination of Type 1 diabetes and Addison's disease
      has not been extensively studied and appears to contribute to a small portion of the
      increased mortality seen in patients with Addison's disease.

      Cortisol has particularly potent effects on blood glucose levels, otherwise Addison's disease
      affects the production of cortisol, an important counterregulatory hormone for hypoglycaemia.
      Lack of cortisol might increase the risk of hypoglycemic episodes, whereas over-replacement
      might cause hyperglycemia. Because steroid replacement may cause significant insulin
      resistance, it is challenging to adjust insulin doses to maintain optimal glycemic control.
      Little is known about the effects of unphysiological glucocorticoid replacement therapy on
      glucose and lipid metabolism, but there has been concern about long-term metabolic
      consequence. Current glucocorticoid replacement results in large fluctuations in the cortisol
      levels directly influencing glucose homeostasis and, consequently, making accompanying
      insulin treatment difficult to manage. Different types, regimens and doses of glucocorticoids
      are now used in adrenal insufficiency, but none approximate the physiological rhythm.
      Hydrocortisone administration via a subcutaneous pump is a novel strategy that restores
      circadian cortisol rhythm in most patients.

      The study will be open-labelled, cross-over designed, with comparison of two glucocorticoid
      replacement modalities to glycemic events in randomised order within each patient, as
      illustrated in figure.

      Treatment A is optimised oral hydrocortisone ( Cortef 5 mg) replacement according to Mah et
      al, and treatment B is continuous subcutaneous hydrocortisone infusion therapy. The patients
      will be assigned a participation number and randomised to any of two treatment sequences (A-B
      or B-A). Should the need for an extra glucocorticoid dose occur (intercurrent illness,
      exercises) during the study, for safety reasons, the patients should administer their
      previous glucocorticoid and insulin replacement. If the dose of insulin is changed, new
      testing by self-monitoring of blood glucose and continuous glucose monitor system should be
      done.

      The period of dose adjustments for insulin treatment during both glucocorticoids replacement
      modalities will take 2 weeks for each and 6 weeks assessment of glycemic control by
      continuous glucose monitor system, followed by a minimal of one month during which the
      patients use their previous glucocorticoid replacement and previous insulin therapy (wash-out
      period).

      Patients will be educated in groups, and dose adjustments will be co-ordinated with regular
      visits at the outpatient clinic/telephone consultation combined with laboratory analyses.
      After the principal study period participants will be offered a 3 months' continuous
      subcutaneous hydrocortisone infusion treatment extension period. Infusion gear and
      Solu-Cortef 50mg/ml infusate will be refunded over the study budget. Hydrocortisone infusion
      will be given as Solu-Cortef Act-o-Vial 50mg/ml produced by Pfizer. Pump designed for
      subcutaneous insulin infusion can be used for subcutaneous administration.

      glucose levels are stable.

      Withdrawal criteria/Adverse Events The patient is free to withdraw at any time. If a patient
      is having major difficulties managing the infusion pump/equipment/continuous glucose monitor
      after thorough education and instructions, the investigator will consider withdrawal. In the
      best interest of the patient, the investigator and the sponsor can decide to withdraw the
      patient from the study. Compliance of the patients will be checked according to the report
      from remote control - Patients Diabetes Manager and continuous glucose monitor.
      Unfortunately, there are available no methods how to follow up the compliance to the oral
      treatment. If a patient develops conditions meeting the exclusion criteria, the patient will
      be withdrawn from the study. In case of serious adverse events the patient may be withdrawn
      from the study.

      Any adverse event will be registered and reported to the Norwegian and Swedish Medicines
      Agency. Any serious adverse events will be reported within 15 days, and in case of lethal or
      life threatening events immediately. The patients will report any problems or discomfort in
      the patient diary, any need for extra doses with glucocorticoids will also be documented
      there. In addition, we ask them to contact the study group directly in case of
      problems/adverse events between consultations.

      The study documentation and research date will be stored 15 years after the termination of
      the study. After the termination of the study we will notify ethical committee by 90 days and
      the final report will be prepared and delivered to ethical committee. If needed to terminate
      the study earlier, we will notify the ethical committee by 15 days.

      Statistical considerations The studies are academic, investigator-driven pilot studies,
      limited in number by expensive techniques and rare diseases.
    

Intervention name(s): Cortef; Solu-cortef
Intervention type(s): Other; Other
Intervention description(s): Treatment A is oral hydrocortisone replacement ( Cortef 5 mg) administered according to weight-adjusted doses for 2 months; Treatment B is continuous subcutaneous hydrocortisone infusion with the initial standard dose of 10mg/m2/24hrs. Body surface area will be calculated according to the nomogram from the formula of Du Bois and Du Bois.
This part of the study will take 2 months.
Intervention MeSH terms: Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Addison disease; Type 1 diabetes; treatment