Condition category
Nutritional, Metabolic, Endocrine
Date applied
02/11/2016
Date assigned
03/11/2016
Last edited
04/11/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Graves’ disease, also known as Graves’ hyperthyroidism, is one of the most common conditions affecting the thyroid gland. The thyroid gland, located in the neck, is responsible for making thyroid hormones which play an important role in the regulation of brain activity, heart rate and gut function. In Graves’ disease, the immune system mistakenly attacks the thyroid gland, causing it to become overactive and produce too much thyroid hormone. Treating Graves’ disease is much more difficult in young people because the available drugs are less likely to cure the condition and are more likely to be associated with side-effects. Only 1 in 4 affected young people will be cured after a 2 year course of standard therapy, usually with the drug Carbimazole, (CBZ). The other treatments used to treat Graves’ disease (surgery and treatment with radioactive iodine) are associated with additional risks in the young and could make the person dependent on life-long thyroid hormone replacement. Rituximab (RTX) is a medication used in the treatment of many immune disorders and works by targeting certain types of white blood cell, which are responsible for attacking the healthy parts of the body. The aim of this study is to find out whether the effects of RTX increase the likelihood of curing Graves’ disease in young people when given with a shortened course of standard CBZ treatment.

Who can participate?
Graves’ disease patients aged between 12-20 years who are at the beginning (first six weeks) of receiving treatment.

What does the study involve?
All participants receive a single dose of Rituximab through a drip at the start of the study. A relatively low dose of RTX is used (500mg) because it has recently been shown that this amount has the desired effect on the immune system in adults. Patients also receive a 12 month course of standard treatment with a drug such as Carbimazole. Over a period of two years, participants provide around 15 blood samples so that the effectiveness of the RTX treatment with the short course of standard therapy can be assessed.

What are the possible benefits and risks of participating?
The potential benefit of taking part is that treatment with RTX will reduce the likelihood of the thyroid gland over-activity returning when ATD is stopped. Around half of the people receiving a Rituximab infusion have a risk of experiencing some side effects. These can include, feeling hot or cold, shivering, feeling sick, or itchiness. Paracetamol, piriton and methylprednisolone (a steroid medicine) are used to help prevent this. If symptoms do develop then the treatment will be stopped for a few minutes and then restarted at a slower rate when the patient feels better. In addition, because RTX is acting on the immune system, there is a small risk (1 in 50) that patients will develop an infection, such as pneumonia, after the they are given the drug through a drip (infusion). If this happens then subjects will receive antibiotic treatment. Most people have RTX without any infection occurring as a result.

Where is the study run from?
Department of Paediatric Endocrinology, Royal Victoria Infirmary (Lead centre) and nine other NHS hospitals in England and Scotland (UK)

When is the study starting and how long is it expected to run for?
September 2016 to June 2020

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Dr Anne Marie Hynes
ann.hynes@ncl.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Dr Ann Marie Hynes

ORCID ID

http://orcid.org/0000-0001-6308-5177

Contact details

Newcastle Clinical Trials Unit
1-4 Claremont Terrace
Newcastle University
Newcastle upon Tyne
NE2 4AE
United Kingdom
+44 191 208 2519
ann.hynes@ncl.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

32511

Study information

Scientific title

Adjuvant rituximab – a potential treatment for the young patient with Graves’ hyperthyroidism

Acronym

RIGD

Study hypothesis

This aim of this study is to examine whether the effects of rituximab (RTX) increase the likelihood of Graves’ hyperthyroidism resolving in young people when administered in association with an abbreviated course of standard Carbimazole (CBZ) treatment.

Ethics approval

Tyne and Wear South, 15/08/2016, ref: 16/NE/0253

Study design

Non-randomised; Both; Design type: Treatment, Drug, Cohort study

Primary study design

Interventional

Secondary study design

Non randomised study

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

Specialty: Children, Primary sub-specialty: Diabetes and endocrinology; UKCRC code/ Disease: Metabolic and Endocrine/ Disorders of thyroid gland

Intervention

The trial involves administering a 500mg dose of Rituximab (RTX) together with a 12 month course of anti-thyroid drug (Carbimazole [CBZ] or Propylthiouracil [PTU]) to each participant with Graves’ hyperthyroidism. The trial team will follow the subjects for 2 years and the outcome will be whether or not they are in remission and hence no longer hyperthyroid at the end of this period. Typically 20 to 30 % of young patients with Graves’ hyperthyroidism enter remission after a 2 year course of anti-thyroid drug (ATD). If this pilot trial provides evidence that the remission rate is plausibly 40% or more, 2 years after a single dose of RTX and a 12 month course of ATD, then this will indicate a likely effect of RTX on disease outcome and justify a randomised efficacy evaluation of this adjuvant RTX regimen.

Only participants who have consented and who have then screened negative for hepatitis and who have submitted a negative pregnancy test will be recruited to this trial. All participants will receive the RTX infusion during the course of a day-case admission that will last around 6 hours. Participants will then be seen in clinic every 4 weeks for the first 6 months, every 8 weeks for the following 6 months and then every 3 months in the second year of the trial. The final trial visit will be 2 years after the RTX infusion. Subjects will undergo a routine clinical examination at each clinic visit and they will be asked about possible adverse events. A blood sample will be taken at each visit so that a range of parameters including thyroid status and markers of immune function can be assessed. There will be phone contact after each clinic visit so that participants can be informed of their blood results with advice regarding the potential need for a revised ATD regimen during the first 12 months.

Intervention type

Drug

Phase

Phase II

Drug names

1. Rituximab
2. Carbimazole
3. Propylthiouracil

Primary outcome measures

Remission as assessed through measuring serum FT3 levels and serum thyroid stimulating hormone (TSH) concentrations in blood samples or the need for alternative treatment at 2 years.

Secondary outcome measures

1. TRAb titre and related thyroid hormone status measured in blood samples taken at the time of RTX administration, 1 year after RTX and then at 2 years post RTX at the final trial visit
2. Time to recovery of B cell lymphocyte numbers (CD 19+ cells) to the normal local lab reference range in relation to thyroid hormone status. The B cell lymphocyte numbers will be measured in a blood sample taken at baseline, then 4, 12, 28, 36, 52 weeks and then 2 years after the RTX infusion
3. Cumulative dose of ATD (mg/kg) in relation to thyroid hormone status 2 years post RTX treatment. The cumulative ATD dose will be calculated from information collected at each clinic visit. This information will be collected at the clinic visits that take place every 4 weeks for the first 6 months, every 8 weeks for the next 6 months and then every 3 months in the second year post RTX treatment
4. The time taken for TSH and thyroid hormone concentrations to normalise to within the local laboratory reference range post RTX and thyroid status in the period between cessation of ATD and the final trial visit 2 years post RTX. The TSH and thyroid hormone concentrations will be measured in blood samples taken every 4 weeks for the first 6 months, every 8 weeks for the next 6 months and then every 3 months in the second year post RTX treatment
5. The frequency and nature of adverse events. The information will be collected throughout the trial with subjects asked specifically about potential adverse events at clinic visits that take place every 4 weeks for the first 6 months, every 8 weeks for the next 6 months and then every 3 months in the second year post RTX treatment. They will also be encouraged to contact the trial team between clinic visits if they are unwell

Overall trial start date

30/09/2016

Overall trial end date

30/06/2020

Reason abandoned

Eligibility

Participant inclusion criteria

1. Excess thyroid hormone concentrations at diagnosis: elevated free tri-iodothyronine (FT3) and / or free thyroxine (based on local assay)
2. Suppressed (un-recordable) TSH (based on local assay)
3. Patients between the ages of 12-20 years inclusive who are less than 6 weeks from the initiation of anti-thyroid drug treatment (carbimazole or propylthiouracil) for the first time
4. Elevated thyroid binding inhibitory immunoglobulin or thyroid receptor antibodies (TRAb including TBII) based on local assay. Patients may or may not have a raised TPO antibody titre
5. All patients must be willing to use effective forms of contraception for 12 months post-treatment with Rituximab
6. If females are of childbearing potential, they must have a negative pregnancy test at screening. This will need to be repeated on the day of RTX administration if more than 7 days has elapsed since the screening visit or a negative pregnancy test.
7. Able and willing to adhere to a 2 year study period

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 27; UK Sample Size: 27

Participant exclusion criteria

1. Previous episodes of autoimmune thyroid disease
2. Patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections) or severely immunocompromised patients
3. Patients with known allergy or contraindication to carbimazole and propylthiouracil
4. Participants with previous use of immunosuppressive or cytotoxic drugs (including Rituximab and methylprednisolone but excluding inhaled glucocorticoid and oral glucocorticoid for asthma or topical glucocorticoid for eczema)
5. Chromosomal disorders known to be associated with an increased risk of autoimmune thyroid disease including Downs’ syndrome and Turners’ syndrome
6. Pregnancy, planned pregnancy during the study period or current breast-feeding
7. Absence of informed consent from parent/legal guardian for participants age < 16 years
8. Participants with previous use of immunosuppressive or cytotoxic drugs (including Rituximab and methylprednisolone but excluding inhaled glucocorticoid and oral glucocorticoid for asthma or topical glucocorticoid for eczema)
9. Participants with significant chronic cardiac, respiratory or renal disorder or non-autoimmune liver disease. • Participants with known allergy or contraindication to Rituximab or methylprednisolone
10. Participants with evidence of Hepatitis B/C infection, assessed by determining hepatitis ‘B’ surface antigen (HBsAg) status, hepatitis ‘B’ Core antibody (HB Core antibody) status and hepatitis ‘C’ virus antibody (HCV antibody) status
11. Participants in families who know they will be moving out of the catchment areas during the 2 years following RTX treatment
12. Participants currently involved in any other clinical trial of an IMP or who have taken an IMP within 30 days prior to trial entry

Recruitment start date

04/11/2016

Recruitment end date

28/02/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Victoria Infirmary
Department of Paediatric Endocrinology
Newcastle upon Tyne
NE1 4LP
United Kingdom

Trial participating centre

Royal Hospital for Sick Children
9 Sciennes Road
Edinburgh
EH9 1LF
United Kingdom

Trial participating centre

Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh
EH16 4SA
United Kingdom

Trial participating centre

Birmingham Children's Hospital
Steelhouse Lane
Birmingham
B4 6NH
United Kingdom

Trial participating centre

Queen Elizabeth Medical Centre
Mindelsohn Way
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Sheffield Children's Hospital
Western Bank
Sheffield
S10 2TH
United Kingdom

Trial participating centre

Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom

Trial participating centre

Children & Young People's Diabetes Centre
Level 1, Multi-Speciality Outpatient Department St. James's University Hospital
Leeds
LS9 7TF
United Kingdom

Trial participating centre

St James’s University Hospital
Leeds Centre for Diabetes & Endocrinology Beckett Street
Leeds
LS14 3AR
United Kingdom

Trial participating centre

Doncaster Royal Infirmary
Armthorpe Road
Doncaster
DN2 5LT
United Kingdom

Sponsor information

Organisation

Newcastle Upon Tyne Hospitals NHS Foundation Trust

Sponsor details

Freeman Hospital
Freeman Road
High Heaton
Newcastle Upon Tyne
NE7 7DN
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Research council

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal

IPD Sharing plan:
The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository EudraCT (https://eudract.ema.europa.eu/) and are available upon request from Dr Tim Cheetham (Chief Investigator, Tim.Cheetham@nuth.nhs.uk)

Intention to publish date

30/06/2021

Participant level data

Available on request

Results - basic reporting

Publication summary

not available

Publication citations

Additional files

Editorial Notes

04/11/2016: Verified study information with principal investigator.