Low Blood glucose & the Effects of Systemic antiThrombotics IN Type 2 Diabetes (BEST-IN-T2D)
| ISRCTN | ISRCTN53525957 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN53525957 |
| EudraCT/CTIS number | 2021-002906-28 |
| IRAS number | 1003876 |
| Secondary identifying numbers | CPMS 51549, IRAS 1003876 |
- Submission date
- 28/06/2022
- Registration date
- 18/07/2022
- Last edited
- 11/03/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Background and study aims
Heart attacks and strokes cause more deaths in people with type 2 diabetes (T2D) than any other cause and mostly result from the formation of blood clots inside blood vessels supplying the heart and brain. A common side-effect of treating high blood sugar levels in T2D is episodes of low sugar levels, called hypoglycaemia (‘hypos’). We have discovered that hypos cause inflammation and increased clotting tendency in T2D. In this study, we will study what effects two commonly-used anti-clotting drugs, aspirin and prasugrel, have on the harmful effects of hypos in T2D. This may indicate the most promising anti-clotting medication in T2D patients, especially in those at risk of hypos and heart disease.
Who can participate?
People with confirmed T2D who are aged between 18-65 years old and are either taking tablets or insulin for their diabetes but have not had previous heart attacks or strokes.
What does the study involve?
The study will involve health screening and then a period of either taking aspirin, prasugrel or no medication for 12 to 16 days. Medical records will be reviewed at the screening visit to obtain medical history, medication records, laboratory results and imaging test results to ensure eligibility for the study. Specifically, we will confirm a diabetes diagnosis and assess if there is a history of medical conditions that could exclude potential participants from the study because of increased risk from hypos and/or from the use of anti-clotting medications. These include previous heart disease, stroke, peripheral vascular disease, kidney problems, cancer, and significant eye damage from diabetes. Participants will be asked to wear a continuous glucose monitoring (CGM) device to monitor their blood sugars for up to 10 days in this period. This will be followed by a full day at the Clinical Research Facility at Northern General Hospital to have drips of insulin and glucose given into their veins to control their blood sugar and bring it into the hypo range for a brief period of time. Participants will also have blood tests during this visit. Participants will then be seen the following day to do more blood tests and to be fitted with a CGM device for another week before coming back for a final set of blood tests. We will also keep in contact by telephone until 2 weeks after the full-day visit to hospital when their blood sugar was controlled. Overall, there will be 6 in-person visits which include one full-day visit and 2 telephone calls with the study team.
What are the possible benefits and risks of participating?
There are no guaranteed benefits to participants taking part in this trial.
The risks to participants of being involved in this study are minimal. The study medications, aspirin and prasugrel, are routinely used in the care of patients having, or have had, a heart attack and are usually well tolerated. However, both medications commonly increase the risk of bleeding and participants receiving these medications may notice they bleed longer if they cut themselves. All participants will have their blood sugar lowered (hypo) for 60 minutes (the lowest level is 2.5 mmol/l); the symptoms any individual experiences with a hypo can vary from person to person. It is, however, common to feel shaky, hungry, and sweaty and for them to be aware of their heartbeat more strongly during the hypo but this subsides when their blood sugars are brought up to the normal level. Putting the cannula in can sometimes cause a bruise or slight inflammation, which may be uncomfortable, but usually settles down in a few days.
Where is the study run from?
Northern General Hospital (United Kingdom)
When is the study starting and how long is it expected to run for?
October 2020 to November 2025
Who is funding the study?
Medical Research Council (MRC) (United Kingdom)
Who is the main contact?
Dr Ahmed Iqbal (Principal Investigator) (United Kingdom)
ahmed.iqbal@sheffield.ac.uk
Contact information
Scientific
Directorate Research Coordinator
Academic Directorate of Diabetes & Endocrinology
Sheffield Teaching Hospitals NHS Foundation Trust
Sheffield
S10 2JF
United Kingdom
| Phone | +44 (0) 114 226 5976 |
|---|---|
| sharon.caunt@nhs.net |
Scientific
Department of Oncology and Metabolism
E Floor
The Medical School
Beech Hill Road
Sheffield
S10 2RX
United Kingdom
 ORCID ID |
0000-0002-5648-0539 |
|---|---|
| Phone | +44 (0)114 215 9238 |
| ahmed.iqbal@sheffield.ac.uk |
Study information
| Study design | Randomized interventional proof-of-concept open-label single-centre parallel-group-assignment study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | 41997 PIS_ICF Best-in-T2D v1.4 14jan22.pdf |
| Scientific title | A proof-of-concept randomised intervention trial to establish the impact of prasugrel versus aspirin on the proinflammatory and prothrombotic effects of experimental hypoglycaemia in type 2 diabetes |
| Study acronym | BEST-IN-T2D |
| Study objectives | P2Y12 inhibitors and aspirin will differentially modulate the deleterious proinflammatory and prothrombotic consequences of experimental hypoglycaemia in type 2 diabetes with prasugrel providing superior protection from these consequences compared with aspirin |
| Ethics approval(s) | Approved 31/01/2022, East Midlands – Leicester South Research Ethics Committee (Equinox House, City Link, Nottingham, NG2 4LA, United Kingdom; +44 (0)207 104 8115; leicestersouth.rec@hra.nhs.uk), ref: 21/EM/0276 |
| Health condition(s) or problem(s) studied | Type 2 diabetes |
| Intervention | We hypothesise that P2Y12 inhibitors and aspirin will differentially modulate the deleterious proinflammatory and prothrombotic consequences of experimental hypoglycaemia in type 2 diabetes (T2D) with prasugrel providing superior protection from these consequences compared with aspirin. We aim to test this hypothesis in a proof-of-concept, open-label, single-centre, randomised clinical trial of three independent parallel groups of participants with T2D (n=45). Participants will be randomised to aspirin 75 mg orally per day for 14 ± 2 days (n=15) or prasugrel 10 mg orally per day for 14 ± 2 days (n=15), or to a no antiplatelet control group (n=15). All participants will then undergo hyperinsulinaemic-hypoglycaemia. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Prasugrel |
| Primary outcome measure | The increase in pre-treatment baseline plasma IL-6 levels measured using enzyme-linked immunosorbent assay (ELISA) in participants with T2D receiving prasugrel (10 mg or 5 mg orally/day according to body weight) compared with aspirin (75 mg orally/day) at 60 minutes of recovery (180 minutes clamp time point) following 60 minutes of hyperinsulinaemic-hypoglycaemia at 2.5 mmol/l |
| Secondary outcome measures | Changes in the levels of: 1. Inflammatory cytokines measured using ELISA 2. White cell kinetics measured using a clinical grade haematology analyser 3. Platelets measured using impedance aggregometry 4. Thrombus formation measured using multi-colour flow cytometry - in participants with T2D receiving prasugrel (10 mg or 5 mg orally/day according to body weight) or with aspirin (75 mg orally/day) compared with no antiplatelet drugs in the medication period from 0 to 180 minutes clamp time points |
| Overall study start date | 06/10/2020 |
| Completion date | 30/11/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 65 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 45; UK Sample Size: 45 |
| Key inclusion criteria | 1. Provision of informed consent prior to any study-specific procedures 2. Male or female aged between 18 and 65 years old 3. Confirmed diagnosis of T2D taking oral hypoglycaemic agents and/or glucagon-like peptide 1 analogs/insulin: participants treated with insulin will be eligible if the duration of treatment with insulin is 2 years 4. Screening glycated haemoglobin A1c (HbA1c) 6.5-10.5% (48-91 mmol/mol), if the screening HbA1c is outside this range then participants will be ineligible |
| Key exclusion criteria | 1. History of previous myocardial infarction or any other acute coronary syndrome event, ischaemic heart disease as a clinical diagnosis and/or proven through percutaneous coronary intervention (PCI) and/or cardiac imaging modalities 2. History of cardiac arrhythmia other than ectopic beats 3. History of heart failure (clinical diagnosis and/or based on echocardiographic findings) 4. History of peripheral vascular disease (clinical diagnosis and/or based on vascular imaging studies) 5. History of stroke (haemorrhagic or ischaemic) 6. History of transient ischaemic attack (TIA) 7. Significant visual impairment due to retinopathy in the opinion of the investigator, untreated stage 3 or above diabetic retinopathy, evidence of active retinal haemorrhage as determined by ongoing treatment and/or ophthalmology follow up 8. Diabetic nephropathy defined as an album-to-creatinine ratio > 30 mg/mmol on routine clinical tests performed within the last year or an estimated glomerular filtration rate <30 ml/min/1.73m2 on bloods performed at screening 9. Clinically significant abnormality on resting 12-lead ECG, including a resting heart rate outside the range of 50-100 beats per minute but excluding atrial or ventricular ectopic beats on an ECG performed at screening 10. Significant symptoms suggestive of CV disease 11. Known untreated hyperthyroidism 12. Epilepsy or previous seizures 13. Participants on blockers or QT interval prolonging drugs 14. Cardiac autonomic neuropathy as measured at screening 15. Serious intercurrent illness within the last 6 weeks 16. Previous history of deep vein thrombosis or pulmonary embolism 17. Any active malignant disease (under active treatment and/or oncology follow-up) or a history of any malignant disease in the last 5 years 18. Family history of sudden death 19. Inability to communicate in English 20. Treatment or planned treatment with antiplatelet (including aspirin, prasugrel, clopidogrel, ticagrelor, dipyridamole, cilostazol, or glycoprotein IIb/IIIa antagonists), anti-inflammatory/immunomodulatory (oral, topical or inhaled corticosteroids; disease-modifying anti-rheumatic drugs; immunosuppressants; chemotherapy drugs; oral or topical antihistamines) anticoagulant medications (warfarin, dabigatran, rivaroxaban, edoxaban, apixaban, parenteral anticoagulants) or fibrinolytic agents within 2 months of randomisation 21. Any planned surgery or other procedure that may require suspension or discontinuation of trial medication expected to occur within 2 months of randomisation 22. Current or planned use of a non-steroidal anti-inflammatory drug 23. Known hypersensitivity to aspirin, salicylic acid (including certain asthma patients who may suffer an asthma attack or faint), prasugrel or excipients 24. Clinically significant liver disease, defined as known or suspected diagnosis of hepatic cirrhosis with current Child-Pugh class B or C; or elevation of serum alanine transferase or aspartate transferase greater than 3 times the upper limit of the normal range for the processing laboratory on bloods performed at screening 25. Abnormal clotting profile on screening that in the opinion of the investigator, would preclude safe involvement in the study or compromise its scientific credibility 26. Abnormal full blood count on screening that in the opinion of the investigator, would preclude safe involvement in the study or compromise its scientific credibility 27. Evidence of active pathological bleeding or peptic ulceration, or history of peptic ulceration or gastrointestinal haemorrhage 28. History of alcohol or drug abuse, defined as regular use of an illicit substance for recreational purposes or regular consumption of greater than 50 units (males) or 35 units (females) of alcohol per week, in the last year 29. Participants with a clinically significant CV, respiratory, metabolic, renal, hepatic, gastrointestinal, haematological, dermatological, neurological, psychiatric,or other major disorder that, in the opinion of the investigator, would preclude safe involvement in the study or compromise its scientific credibility 30. Any clinically significant abnormal laboratory test results at screening that, in the opinion of the investigator, would preclude safe involvement in the study 31. Pregnant or breast-feeding women 32. Methotrexate used at doses >15 mg/week 33. Active gout 34. Haemorrhagic diathesis; coagulation disorders such as haemophilia and thrombocytopenia 35. Any contraindication for prasugrel or aspirin treatment as detailed in the respective SmPCs 36. Women of child-bearing potential (WOCBP)A unless negative pregnancy test at screening and willing to use highly-effective contraception for the duration of treatment with study medication |
| Date of first enrolment | 01/09/2022 |
| Date of final enrolment | 31/10/2025 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
C Floor, Huntsmnan Building
Herries Road
Sheffield
S5 7AU
United Kingdom
Sponsor information
Hospital/treatment centre
Northern General Hospital
Herries Road
Sheffield
S5 7AU
England
United Kingdom
| Phone | +44 (0)114 2265931 |
|---|---|
| sth.researchadministration@nhs.net | |
| Website | http://www.sth.nhs.uk/ |
"ROR" |
https://ror.org/018hjpz25 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/10/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request, Published as a supplement to the results publication |
| 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 are/will be available upon request. Dr Ahmed Iqbal (Principal Investigator) (United Kingdom), ahmed.iqbal@sheffield.ac.uk, will act as the point of contact for data set enquiries for 2 years from the end of the trial period (indicative date Mar 25). This can only be summary data supplementary to the publication of the main results and will be anonymised. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 1.4 | 14/01/2022 | 15/07/2022 | No | Yes |
| HRA research summary | 26/07/2023 | No | No |
Additional files
Editorial Notes
11/03/2025: The following changes were made to the study record:
1. The recruitment end date was changed from 28/02/2025 to 31/10/2025.
2. The overall study end date was changed from 30/03/2025 to 30/11/2025.
16/10/2024: Individual participant data (IPD) sharing plan and summary were added.
09/09/2024: The recruitment end date was changed from 30/09/2024 to 28/02/2025.
09/04/2024: The following changes were made:
1. The recruitment end date was changed from 30/04/2024 to 30/09/2024.
2. The overall end date was changed from 30/09/2024 to 30/03/2025.
3. The intention to publish date was changed from 31/03/2025 to 01/10/2025.
11/12/2023: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/12/2023 to 30/04/2024.
2. The overall end date was changed from 17/02/2024 to 30/09/2024.
3. The intention to publish date was changed from 30/09/2024 to 31/03/2025.
4. The plain English summary was updated to reflect these changes.
20/06/2023: The following changes were made to the study record:
1. The recruitment end date was changed from 01/12/2023 to 31/12/2023.
2. The overall end date was changed from 01/07/2024 to 17/02/2024.
3. The intention to publish date was changed from 01/01/2025 to 30/09/2024.
4. The plain English summary was updated to reflect these changes.
08/06/2023: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/06/2023 to 01/12/2023.
2. The overall end date was changed from 31/08/2023 to 01/07/2024.
3. The intention to publish date was changed from 31/08/2024 to 01/01/2025.
4. The plain English summary was updated to reflect these changes.
28/06/2022: Trial's existence confirmed by the NIHR.
