Glucose absorption inhibitors given during insulin withdrawal in type 1 and type3c diabetes
| ISRCTN | ISRCTN16404006 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16404006 |
| EudraCT/CTIS number | 2015-002094-38 |
| IRAS number | 215268 |
| Secondary identifying numbers | 3, IRAS 215268 |
- Submission date
- 28/12/2019
- Registration date
- 02/01/2020
- Last edited
- 07/08/2020
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Background and study aims
Diabetes is a lifelong condition that causes a person's blood glucose (sugar) level to become too high.
Dapagliflozin is a new class of drug called a SGLT-2 inhibitor that is taken once a day. It is currently prescribed as a glucose lowering medication in people with type 2 diabetes. The drug may also be beneficial in people with type 1 diabetes to reduce the frequency of low blood glucose levels (<4.0mmol/L) and reduce insulin requirements.
Diabetic ketoacidosis occurs when the body is unable to use blood sugar (glucose) because there isn’t enough insulin. Instead, it breaks down fat as an alternative source of fuel. This causes a build-up of a potentially harmful by products called ketones. Ketones are bad because they make the blood acid and other chemical processes in the cells do not work normally when the blood and tissues are too acid.
Case reports and early pilot clinical trials indicate that when SGLT2 inhibitors are prescribed in patients with known insulin deficiency they may be at risk of developing the potentially life threatening state of ketoacidosis in the presence of a normal glucose level. This condition can be very frightening and may need treatment in an intensive care unit.
When people take the study medication they may not be aware they are at risk of developing ketoacidosis because blood glucose levels may not increase, and the only sign that they have developed ketoacidosis is that their ketone levels have increased or they become unwell and start to vomit. However, unlike blood glucose levels, people do not routinely measure their ketone levels, therefore, an increase in ketones is unlikely to be detected (or may be missed).
The aim of this research is to develop an understanding of how Dapagliflozin regulates blood glucose levels in periods of insulin deficiency. The metabolic assessment day involves inducing a state of insulin deficiency in a controlled way and monitoring glucose and ketone levels. Ketone levels will rise. The study will be stopped and insulin given before the ketones produce a state of acidosis (ketoacidosis). It is not the intention to induce ketoacidosis but to understand how the drug works in insulin deficient patients.
Who can participate?
Patients with type 1 (where the pancreas doesn't produce any insulin) or type 3c (insulin deficiency following pancreatic conditions such as chronic pancreatitis or pancreatic surgery) diabetes, aged 18 – 65 years with HbA1c is greater or equal to 6.5% and less than 9%.
What does the study involve?
Participation in the study will last approximately 64 days.
Participants will be required to attend three visits. One will be a screening visit and the other two visits will be metabolic assessment days. Participants will need to attend at 22.00 the night before the metabolic study day and will go home the next evening around 18.00.
Participants will be randomly allocated to receive Dapagliflozin or placebo for seven days, after which they will have a metabolic assessment. Later, the participants will receive the opposite treatment, again for seven days, followed by another assessment.
To prevent developing ketoacidosis during the metabolic assessment day, the study will be stopped in the event of blood glucose rising above 18mmol/L, bicarbonate dropping below 15mmol/L or if blood becomes acidic, evidenced by venous pH falling below 7.35 or point of care capillary 3-beta Hydroxybutyrate level of >5.0.
What are the possible benefits and risks of participating?
The results of the study will potentially provide a better understanding of how the class of drug works in people with type 1 and type 3c diabetes. Participants' diabetes control may change while taking the study drug and they will receive advice on blood sugar control from the study clinician. Participants are not likely to experience any immediate benefits but there may be benefits for future people with type 1 and type 3c diabetes.
Where is the study run from?
Royal Surrey County Hospital, Guildford, UK
When is the study starting and how long is it expected to run for?
January 2018 to August 2019
Who is funding the study?
1. Diabetes UK
2. AstraZeneca, UK
Who is the main contact?
Dr Roselle Herring
roselle.herring@nhs.net
Contact information
Scientific
Cedar Centre
Royal Surrey County Hospital
Egerton Road
Guildford
GU2 7XX
United Kingdom
 ORCID ID |
0000-0002-8267-6236 |
|---|---|
| Phone | +44 (0)1483 571122 Ext 2414 |
| roselle.herring@nhs.net |
Study information
| Study design | Phase IV single centre randomized double-blind controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Metabolic effects of an SGLT2 inhibitor (dapagliflozin) during a period of acute insulin withdrawal and development of ketoacidosis in people with type 1 diabetes |
| Study acronym | SIDS |
| Study objectives | 1. Treatment with Dapagliflozin will result in a statistically significant difference in fasting plasma glucose concentration at 600 minutes following insulin cessation (or at last measured concentration prior to rescue) when compared to treatment with placebo in each of two independent studies performed on Type 1 and Type 3c people with diabetes. 2. Treatment with Dapagliflozin will result in a statistically significant difference lipid flux of Dapagliflozin when compared to placebo following insulin withdrawal |
| Ethics approval(s) | Approved 07/02/2017, South Central - Berkshire B Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT; +44 (0)207 104 8199; nrescommittee.southcentral-berkshireb@nhs.net), ref: 17/SC/0005 |
| Health condition(s) or problem(s) studied | Type 1 diabetes and Type 3c diabetes |
| Intervention | Participants received in random order 7 days of placebo or dapagliflozin. The expected duration of participant participation is approx. 64 days. Randomisation procedure: The participant will be assigned a study identification number and randomised to receive in random order Dapagliflozin or placebo. To prevent developing ketoacidosis during the metabolic assessment day, the study will be stopped in the event of blood glucose rising above 18mmol/L, bicarbonate dropping below 15mmol/L or if blood becomes acidic, evidenced by venous pH falling below 7.35 or point of care capillary 3-beta Hydroxybutyrate level of >5.0. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Dapagliflozin |
| Primary outcome measure | Plasma glucose concentration at 600 minutes following insulin cessation or at the time of glycaemic rescue, whichever occurs first, measured by blood test |
| Secondary outcome measures | 1. Endogenous glucose production 2. Peripheral glucose uptake 3. Glycerol rate of appearance Stable isotopes of glucose and glycerol will be infused from -120 to 600 minutes. From -120 to 0 minutes, blood samples will be taken to measure glucose and glycerol enrichment 4. Urinary glucose excretion Urine samples will be collected at 2 hour intervals for measurement of spot glucose and urinary ketones (acetoacetic acid and acetone) until 600 minutes 5. Non-esterified fatty acid production 6. Ketone body production NEFA, and 3-beta hydroxybutyrate will be taken at 20minute intervals until 180 minutes and then at 30minute intervals until 600 minutes |
| Overall study start date | 21/08/2015 |
| Completion date | 01/08/2019 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 12 |
| Total final enrolment | 12 |
| Key inclusion criteria | 1. Able in the opinion of the investigator, and willing to give informed consent obtained before any study-related activities 2. Type 1 diabetes or type 3c (chronic pancreatitis or undergone pancreatic surgery) according to clinical judgment 3. Duration of type 1 or type 3c diabetes (chronic pancreatitis or undergone pancreatic surgery) greater than 12 months 4. Current treatment basal bolus insulin regime or insulin pump therapy 5. Aged 18 – 65 years 6. BMI of less than 35 7. HbA1c of greater or equal to 6.5% and less than 9% 8. Able and willing to complete the study 9. Patients who are or who have previously been involved in research are eligible provided they have not received an investigational drug within one month of entry into the study |
| Key exclusion criteria | 1. Cannot adequately understand verbal and / or written explanations given in English 2. LADA –latent autoimmune diabetes in adults due to differing nature of the illness/Type 1 3. Confirmed excessive and compulsive drinking of alcohol i.e. alcohol abuse as determined from GP medical notes by the Fast Alcohol Screening Test (FAST) or history of previous alcohol abuse 4. Restricted food intake (e.g. on VLC diets) - as this depletes the person of calories and may affect your data. Consider excluding Individuals on a severe calorie restricted diet <800cals/day. Determined by history 5. Diagnosis of osteoporosis confirmed by DEXA scan 6. Proliferative retinopathy that has required acute treatment within last three months 7. Moderate to severe renal impairment (creatinine clearance [CrCl] < 60 ml/min or estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m² 8. History of unstable or rapidly progressing renal disease 9. Severe hepatic insufficiency / and or significant abnormal liver function defines as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and / or alanine aminotransferase (ALT) > 3ULN 10. Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody 11. Congestive heart failure defined as New York Heart Association (NYHA) class III and IV, unstable or acute congestive heart failure. Note: eligible patients with congestive heart failure, especially: 11.1. Uncontrolled cardiac arrhythmias 11.2. Uncontrolled hypertension (BP greater than 160/90) 12. Mental incapacity 13. Pregnancy or breastfeeding women 14. Those of child-bearing potential not taking adequate contraception precautions. Adequate protection is defined as barrier protection, oral contraceptive pill or intrauterine device 15. Volume depleted patients, patients at risk of volume depleting due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status 16. History of unstable angina. 17. Recent Cardiovascular Events in a patient: 17.1. Acute Coronary Syndrome (ACS) within 2 months prior to enrolment 17.2. Hospitalisation for unstable angina or acute myocardial infarction within 2 months prior to enrolment 17.3. Acute Stroke or TIA within 2 months prior to enrolment 17.4. Less than 2 months post coronary artery revascularization 17.5. History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g. Accident and Emergency and/or hospitalisation) within 1 month prior to the Screening visit 18. Known or suspected allergy to study products 19. Known lactose-intolerant 20. Any other medical or psychological conditions that would interfere with the study participation |
| Date of first enrolment | 29/01/2018 |
| Date of final enrolment | 01/08/2019 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Egerton Road
Guildford
GU2 7XX
United Kingdom
Sponsor information
University/education
Diabetes Research Centre/Department of Health Sciences
University of Leicester
Leicester
LE5 4PW
England
United Kingdom
| Phone | +44 (0)116 258 6481 |
|---|---|
| uolsponsor@le.ac.uk | |
| Website | http://www.le.ac.uk/ |
"ROR" |
https://ror.org/04h699437 |
Funders
Funder type
Charity
Private sector organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- DIABETES UK LIMITED, British Diabetic Association
- Location
- United Kingdom
Government organisation / For-profit companies (industry)
- Alternative name(s)
- AstraZeneca PLC, Pearl Therapeutics
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/01/2020 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Presentation at national and international conferences and publication in a peer-reviewed journal. |
| IPD sharing plan | All data generated or analysed during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 08/07/2020 | 07/08/2020 | Yes | No |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
07/08/2020: Publication reference added.
31/12/2019: Trial’s existence confirmed by South Central - Berkshire B Research Ethics Committee
