Rescue of ADdiSon’s disease 2

Plain English Summary

Background and study aims:
Addison’s 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 Addison’s 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 won’t 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

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

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

RADS2v2.1:08/12

Scientific title

Combined immunotherapy and trophic adrenocortical stimulation in new onset autoimmune Addison’s disease

Acronym

RADS2

Study hypothesis

This study will answer the following principal questions:
In people with new-onset autoimmune Addison’s 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 Addison’s 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 Addison’s 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 measures

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

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)

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

Countries of recruitment

United Kingdom

Trial participating centre

Institute of Genetic Medicine
Newcastle upon Tyne
NE1 3BZ
United Kingdom

Organisation

Newcastle upon Tyne Hospitals Foundation NHS Trust (UK)

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

http://www.newcastle-hospitals.org.uk/

Funder type

Research council

Funder name

Medical Research Council (MRC) (UK) ref: MR/J002526

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations