Continuous Subcutaneous Hydrocortisone Infusion In Addison's Disease and Type 1 Diabetes

February 29, 2024 updated by: Haukeland University Hospital

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

4

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Norway
      • Bergen, Norway, 5021
        • Haukeland University Hospiatl

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

- primary Addison's disease in combination with long-standing Type 1 diabetes

Exclusion Criteria:

  • cardiovascular disease
  • active malignant disease
  • pregnant women
  • pharmacological treatment with glucocorticoids or drugs that interfere with cortisol metabolism (antiepileptics, rifampicin, St. Johns war, estrogens)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Cortef
Treatment A is oral hydrocortisone replacement( Cortef 5 mg)with weight-adjusted doses as suggested by Mah et al , will take 2 months
Other: Solu-cortef

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.
Active Comparator: Solu-cortef
This is the treatment B by continuous subcutaneous hydrocortisone infusion. Solu-cortef 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.
Other: Cortef
Treatment A is oral hydrocortisone replacement ( Cortef 5 mg) administered according to weight-adjusted doses for 2 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
nocturnal hypoglycemic events
Time Frame: 4 months
severe hypoglycemia (needs for another person's assistance, blood glucose ≤ 3.1 mmol ⁄ L or prompt recovery after oral carbohydrate, i.v glucose or glucagon administration) and insulin requirement
4 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
o Nocturnal glycemic variability
Time Frame: 4 months
monitored by continuous glucose monitor system
4 months
hormone and metabolic profile
Time Frame: 4 months
  • Hormone levels : insulin like growth factor 1, growth hormone
  • Steroid metabolism: adrenocorticotropic hormone , cortisol
  • Metabolic profile: fructosamine, HBA1C, lipid levels, C reactive protein , homeostasis model assessment index
4 months
o Subjective health status
Time Frame: 4 months
Self administration of questionnaires
4 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Haukeland University Hospital

Investigators

  • Study Director: Kristian Løvås, MD, PhD, Haukeland University Hospital
  • Principal Investigator: Katerina Simunkova, PhD, Haukeland University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 24, 2013

Primary Completion (Actual)

December 1, 2016

Study Completion (Actual)

December 1, 2016

Study Registration Dates

First Submitted

April 23, 2013

First Submitted That Met QC Criteria

April 23, 2013

First Posted (Estimated)

April 25, 2013

Study Record Updates

Last Update Posted (Actual)

March 1, 2024

Last Update Submitted That Met QC Criteria

February 29, 2024

Last Verified

December 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2012/2218
  • 2012/005516-26 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Type 1 Diabetes

Clinical Trials on Solu-cortef

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in China

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe