Balancing "bad" and "good" immune cells: testing a novel method for monitoring an immunosuppression strategy in people with Type 1 diabetes
| ISRCTN | ISRCTN85031369 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN85031369 |
| IRAS number | 336032 |
| Secondary identifying numbers | 24/WA/0283 |
- Submission date
- 14/01/2025
- Registration date
- 07/03/2025
- Last edited
- 07/03/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Background and study aims
Type 1 diabetes (T1D) is caused by autoimmunity when the body’s own white blood cells damage the insulin-producing cells (beta-cells). Researchers are trying to develop treatments (immunotherapies) that can stop autoimmunity by switching off these damaging white cells that work in silence until it is too late to intervene. We currently have no way of measuring the activity of the autoimmune process in T1D, so we have to design research studies by measuring the individual’s insulin production. These effects change slowly requiring long studies that are often found to be unsuccessful after lots of money and time had been spent. We want to develop a way to identify potentially effective drugs based on their effect on autoimmunity in smaller and quicker studies. This study aims to establish a robust and quick method to test the impact of immunotherapies on the autoimmune process.
Who can participate?
Patients aged 18 to 50 years who have been diagnosed with Type 1 diabetes 3 months to 5 years before entering the study
What does the study involve?
We will give participants two drugs: abatacept and interleukin-2, which have been shown to slow autoimmune processes in other diseases. Both drugs are licensed for use in other diseases and have been used in T1D research. They have a very good safety profile but when used separately they showed a modest effect on preserving insulin-producing cells. We think that combination will work better because abatacept will deal with “bad” cells (drivers of the autoimmunity) whilst IL-2 will protect “good” cells (controllers of autoimmunity). These interventions will elicit predictable changes in immune cells that will allow us to test our sampling method.
We will use state-of-the-art cell-tracking techniques (“heavy water” labelling and flow cytometry) to isolate and analyse individual cells and perform mathematical modelling of trajectories of immune cells. We will look into blood and lymph nodes. Lymph nodes are little glands throughout the body that are full of white blood cells that are relevant for the autoimmune process.
Once proven, our method can be used to triage promising drugs before proceeding with the assessment of their metabolic effect in a large clinical trial.
What are the possible benefits and risks of participating?
This study demands substantial patient commitment due to its complexity and frequency of visits. The researchers consulted their Patient and Public Involvement (PPI) panel through our Type 1 UK Immunotherapy Consortium. PPI members were very supportive of the study and acknowledged the importance of making a paradigm change in the treatment approach to T1D i.e., preventing rather than replacing the loss of insulin. They emphasised the importance of the balance between altruistic motives for participation and potential individual benefit from the study intervention in this complex study. Based on the PPI panel, the researchers made the following changes in the study design to make the study more acceptable for the potential participants:
1. The researchers will recruit patients with residual insulin production/C peptide (who have a prospect of benefit and active autoimmune response), which was particularly welcomed by the PPI panel.
2. The researchers will offer home visits to reduce the number of hospital-based study visits.
3. The researchers will tailor the timing of study visits to the participant’s schedule (evenings, early mornings, weekends, school holidays) as long as it can be coordinated and supported by laboratories and research centres.
4. The researchers will use local databases to recruit local people to reduce the burden of long commutes to the study centre.
5. The researchers will make sure that the study is presented and explained to the potential
participants by a consultant or other senior health care professional as the PPI panel emphasised that this procedure-heavy study needs to be explained to them by a knowledgeable person who they trust.
The researchers will make sure that participants are immunocompetent before entering the trial and have no evidence of latent tuberculosis or infections such as hepatitis or HIV. They will be regularly monitored during the study by a medical doctor and by doing safety blood tests.
Lymph node aspiration is routine, safe, short (less than 30 minutes including preparation) and minimally invasive technique widely used in clinical practice that will be performed by experienced consultant radiologists. The researchers' experience in using it in the research setting with over 50 patients is that it is very well tolerated and accepted by participants.
Participants will be explained the procedure in detail including that it is done under local anaesthetic, which may feel as a light sting when administered.
Participants will have bottles of heavy water in their homes. They will be reassured that this is not toxic or radioactive material. They will receive instructions for the storage and disposal of the heavy water.
As they aim to test different methods (such as “heavy water” labelling, cytometry - method to sort, isolate and analyse cells on an individual basis and immune assays) the researchers require large blood volumes. Importantly no more than 470 ml will be taken over the course of 16 weeks, which is in concordance with guidance for blood donors. 470 ml is the volume normally taken during a single blood donation session. The researchers will make sure that participants way more than 50 kg (as per blood donation guidelines) and that they have normal red cell count, which will be regularly monitored during the study.
Where is the study run from?
It will be conducted in NHS sites affiliated with Cardiff University (University Hospital of Wales) and University College London (Royal Free Hospital London) (UK)
When is the study starting and how long is it expected to run for?
October 2024 to January 2027
Who is funding the study?
1. Steve Morgan Foundation
2. Breakthrough T1D
3. Diabetes UK
Who is the main contact?
Dr Danijela Tatovic, tatovicd@cardiff.ac.uk
Contact information
Public, Scientific, Principal Investigator
Heath Park
Cardiff
CF14 4XN
United Kingdom
 ORCID ID |
0000-0002-3879-2686 |
|---|---|
| Phone | +44 (0)2920742182 |
| SMART@cardiff.ac.uk |
Study information
| Study design | Two-centre open-label mechanistic feasibility study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Other |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Treg-sparing co-stimulation blockade: testing a novel method for monitoring an immunosuppression strategy in people with Type 1 diabetes |
| Study acronym | SMART |
| Study objectives | Immunotherapy in Type 1 diabetes (T1D) aims to stop beta-cell destruction in order to preserve the individual’s ability to make their own insulin. This could lead to better control or even disease prevention. Recent FDA approval of teplizumab, the first-ever immunotherapy for T1D highlights the promise of this approach. However, new and better immunotherapies are needed, and we currently lack a good way to measure their effectiveness. Clinical trial endpoints are measured only through metabolic outcomes (stimulated C-peptide production), which change slowly, requiring long, large and expensive trials. Combination treatments that have revolutionised cancer immunotherapy, may bring breakthroughs in T1D too, but predicting which therapies will work best together presents a challenge. A logical approach would be to triage potentially effective therapies based on their immune effect in smaller and quicker mechanistic studies followed by larger clinical trials designed to assess metabolic efficacy. This mechanistic study aims to establish a quick, effective, state-of-the-art method of identifying agents with favourable immunomodulatory profiles. Once identified, these can be tested for their impact on metabolic outcomes i.e., preservation of endogenous insulin production in early stages of T1D. The researchers have chosen to use the combination of two drugs, abatacept and interleukin 2 (IL-2) because of their established safety profiles and the suggestion that in combination they will induce predictable changes to immune cells that would be suitable to test our methodology. |
| Ethics approval(s) |
Approved 23/10/2024, Wales REC 1 (Castlebridge 4, 15-19 Cowbridge Road East, Cardiff, CF11 9AB, United Kingdom; +44 (0)292078738; wales.rec1@wales.nhs.uk), ref: 24/WA/0283 |
| Health condition(s) or problem(s) studied | Type 1 diabetes |
| Intervention | Group 1: Abatacept at weeks 0, 2, 4 and 8 in combination with Interleukin-2 only for 16 weeks starting at week 0 Group 2: Abatacept only at week 0, 2, 4 and 8 Abatacept Participants will receive 10 mg/kg intravenously (maximum 1000 mg per dose) at 0, 2, 4 and 8 weeks. Interleukin-2 0.45 x 10e6 IU/m2 of body surface will be given twice weekly (every 3+/-1 days) subcutaneously. |
| Intervention type | Other |
| Primary outcome measure | The feasibility of detecting that the decrease in Treg frequency associated with abatacept treatment in T1D is inhibited by appropriately dosed IL-2 therapy, measured using flow cytometry at Week 20 in comparison to baseline. |
| Secondary outcome measures | There are no secondary outcome measures |
| Overall study start date | 01/10/2024 |
| Completion date | 21/01/2027 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 50 Years |
| Sex | Both |
| Target number of participants | 24 |
| Key inclusion criteria | 1. Aged 18-50 years 2. Diagnosis of Type 1 diabetes in the last 5 years, but not earlier than 3 months 3. Written and witnessed informed consent to participate 4. Detectable non-fasting C-peptide in the blood at screening |
| Key exclusion criteria | 1. Females who are pregnant, breastfeeding, anticipating being pregnant within 14 weeks of the last study drug administration or not using adequate forms of contraception. Males whose partners are WOCBP and not using an adequate form of contraception. The following birth control methods should be used (considered highly effective with a failure rate of less than 1% per year when used consistently and correctly): 1.1. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, transdermal 1.2. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable 1.3. Intrauterine device (IUD) 1.4. Intrauterine hormone-releasing system (IUS) 1.5. Bilateral tubal occlusion 1.6. Vasectomised partner (provided that the partner is the sole sexual partner of the trial participant, and that medical assessment of azoospermia has been confirmed) 1.7. Sexual abstinence (defined as refraining from heterosexual intercourse during the duration of the trial) 2. Use of immunosuppressive or immunomodulatory therapies, including systemic steroids within 1 month prior to randomisation and any monoclonal antibody therapy given for any indication 3. Immunisations with live vaccines within 1 month from screening 4. Immunodeficient or have clinically significant lymphopaenia 5. Patients with White Blood Count (WBC) <4.000/mm3; platelets < 100.000/mm3; haematocrit (HCT) <30%. 6. Have an active infection at the time of randomisation 7. Have positive Purified Protein Derivative (PPD) or IGRA (interferon-gamma release assay) result or history of previously treated tuberculosis 8. Have serological evidence of current or past HIV, Hepatitis B (positive for Hepatitis B core antibody or surface antigen), or Hepatitis C infection 9. Have a history of malignancies 10. Have multiple sclerosis 11. Patients with a significant history or current evidence of severe cardiac disease 12. Patients with pre-existing severe major organ dysfunction 13. Patients with seizure disorders 14. Patients with organ allografts 15. Patients with pre-existing auto-immune disease except for Type 1 diabetes and primary hypothyroidism 16. Patients with serum bilirubin (except for Gilbert’s syndrome) and creatinine outside normal range 17. Weight <50 kg 18. Any other medical condition, which, in the opinion of investigators, could affect the safety of the subject’s participation 19. Recent subject’s involvement in other research studies which, in the opinion of investigators, may adversely affect the safety of the subjects or the results of the study 20 .HbA1c >90 mmol/mol measured in the last 3 months |
| Date of first enrolment | 21/01/2025 |
| Date of final enrolment | 21/01/2026 |
Locations
Countries of recruitment
- England
- United Kingdom
- Wales
Study participating centres
University Hospital of Wales
Heath Park
Cardiff
CF14 4XN
United Kingdom
Pond Street
London
NW3 2QG
United Kingdom
Sponsor information
University/education
Cardiff Joint Research Office
Cardiff
CF14 4XN
Wales
United Kingdom
| Phone | +44 (0)29 2087 9277 |
|---|---|
| resgov@cardiff.ac.uk | |
| Website | https://www.cardiff.ac.uk/ |
"ROR" |
https://ror.org/03kk7td41 |
Funders
Funder type
Charity
No information available
No information available
No information available
Results and Publications
| Intention to publish date | 21/01/2028 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in peer-reviewed journal. |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date |
Editorial Notes
14/01/2025: Study's existence confirmed by Wales REC 1.
