Plain English Summary
Background and study aims:
Addisons disease is caused by an autoimmune attack leading to destruction of the adrenal glands. RADS2 aims to prevent the autoimmune attack on the adrenal gland and stimulate re-growth and regeneration of adrenal function.
Who can participate?
Patients aged 10 to 65 years, diagnosed with autoimmune Addisons disease within the previous 28 days.
What does the study involve?
Two infusions of rituximab are given, each lasting 6 hours. Also, alternate day injections of an adrenal gland stimulating hormone, ACTH are given.
What are the possible benefits and risks of participating?
The benefit is that your adrenal failure might go into remission, or even be cured. The risk is that the trial medication wont work, or that you could have a reaction to it.
Where is the study run from?
Newcastle University, UK, with participating centres in Cambridge and Exeter, UK.
When is study starting and how long is it expected to run for?
November 2012, running for 4 years.
Who is funding the study?
Medical Research Council, UK.
Who is the main contact?
Prof Simon Pearce
s.h.s.pearce@ncl.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Prof Simon Pearce
ORCID ID
Contact details
Institute of Genetic Medicine
Newcastle University
International Centre for Life
Newcastle upon Tyne
NE1 3BZ
United Kingdom
+44 (0)191 2418674
s.h.s.pearce@ncl.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
RADS2v2.1:08/12
Study information
Scientific title
Combined immunotherapy and trophic adrenocortical stimulation in new onset autoimmune Addisons disease
Acronym
RADS2
Study hypothesis
This study will answer the following principal questions:
In people with new-onset autoimmune Addisons disease, who have residual steroidogenic capacity:
1. Will the therapeutic regimen of rituximab and adrenocorticotropic hormone (ACTH) allow improvement or recovery of adrenocortical function?
2. Will this therapeutic regimen result in amelioration of the humoral immune response by reducing autoantibody titres?
3. What are the adverse effects of this therapeutic regimen?
4. Will the regimen be acceptable and well-tolerated by patients?
5. What is the early natural history of conventionally treated autoimmune Addisons disease (AAD)?
Ethics approval
National Research Ethics Service (NRES) Committee North East - Sunderland, 24 September 2012, ref: 12/NE/0339
Study design
Multicentre study conducted in 2 parts
Part A: Open-label interventional study of rituximab and synacthen
Part B: Observational study of the natural history of autoimmune Addisons disease
Primary study design
Interventional
Secondary study design
Non randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Autoimmune Addison's disease
Intervention
Part A
1. Subjects will receive 125mg IV methylprednisolone followed by 1g IV rituximab on day 1 & day 15.
2. Depot synacthen 1mg will be self-administered on alternate days (week 1-12, followed by an 8 week tail)
3. Daily oral hydrocortisone and fludrocortisone will continue in regular replacement doses (eg. Hydrocortisone 10 & 5mg, or 10 & 5 & 5mg; fludrocortisone 50-150 ìg)
4. Adrenal function, circulating B cell numbers, adrenal autoantibody titres and wellbeing will be assessed at baseline, 6, 12, 24, 48, and 72 weeks.
5. Replacement steroids will be weaned off, if serum cortisol concentrations improve to >400nmol/l.
The last (72 week) visit of the last participant will mark the end of the study
Part B: Observation only
1. Adrenal function, adrenal autoantibodies and wellbeing will be assessed at baseline & 48 weeks.
2. The last (48 week) visit of the last participant will mark the end of the study for these participants.
Intervention type
Other
Phase
Not Applicable
Drug names
Primary outcome measure
Restoration of normal glucocorticoid secretion (peak cortisol >550nmol/l after repeat synacthen testing at 48 weeks)
Secondary outcome measures
1. Restoration of normal glucocorticoid secretion (peak cortisol >550nmol/l after repeat synacthen testing at 6,12, 24, and 72 weeks)
2. Improvement of basal and peak cortisol response (>100nmol/l over baseline) to synacthen testing
3. Normalisation of ACTH, Dehydroepiandrosterone (DHEAS), 17á OH-progesterone and recumbent renin and aldosterone levels
Overall trial start date
01/11/2012
Overall trial end date
31/10/2016
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Part A:
1. Clear evidence of adrenocortical failure with subnormal cortisol response to 250 µg IV synacthen (peak cortisol <300nmol/l) plus either clinical or biochemical evidence to confirm elevated ACTH, or evidence of mineralcorticoid insufficiency
2. Basal or ACTH stimulated serum cortisol >50nmol/l
3. Patients are less than 4 weeks from first diagnosis of AAD
4. Positive serum 21-hydroxylase autoantibodies (>1.0 IU/l on RSR assay)
5. Normal or atrophic adrenal glands on CT scan
6. Willingness to travel to the Wilson Horne Immunotherapy Centre, Newcastle for study
7. Willingness to attend education sessions about indications for parenteral glucocorticoid administration and technique of administration
8. Willingness to use secure contraception during and for 12 months post-treatment with rituximab ((women of childbearing potential)
For Part B, only the first 4 criteria are relevant
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Part A (15 participants); part B ( 15 participants)
Total final enrolment
13
Participant exclusion criteria
1. Active viral illness, including HIV, Hepatitis B or C, shingles/Zoster
2. Recent or partially treated TB or unexplained radiographic abnormality on chest X-ray
3 .Previous use of immunosuppressive or cytotoxic drugs (excluding glucocorticoid)
4. Significant cardio-respiratory (inc. asthma), chronic renal or non-autoimmune liver disease
5. Pregnant or breastfeeding and with plan for pregnancy/ breastfeeding within 24 months
6. Known allergy or contraindication to synacthen, synacthen depot, rituximab or methylprednisolone
Recruitment start date
01/11/2012
Recruitment end date
31/10/2016
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Institute of Genetic Medicine
Newcastle upon Tyne
NE1 3BZ
United Kingdom
Sponsor information
Organisation
Newcastle upon Tyne Hospitals NHS Foundation Trust
Sponsor details
Royal Victoria Infirmary
Queen Victoria Road
Newcastle upon Tyne
NE1 4LP
United Kingdom
-
amanda.tortice@ncl.ac.uk
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Research council
Funder name
Medical Research Council (MRC) (UK) ref: MR/J002526
Alternative name(s)
MRC
Funding Body Type
unknown
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2019 results in https://doi.org/10.1210/clinem/dgz287 (added 30/10/2020)
2020 results in https://pubmed.ncbi.nlm.nih.gov/31863094/ (added 05/01/2021)