Plain English Summary
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
Trial website
Contact information
Type
Scientific
Primary contact
Dr Roselle Herring
ORCID ID
https://orcid.org/0000-0002-8267-6236
Contact details
Cedar Centre
Royal Surrey County Hospital
Egerton Road
Guildford
GU2 7XX
United Kingdom
+44 (0)1483 571122 Ext 2414
roselle.herring@nhs.net
Additional identifiers
EudraCT number
2015-002094-38
ClinicalTrials.gov number
Nil known
Protocol/serial number
3, IRAS 215268
Study information
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
Acronym
SIDS
Study hypothesis
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
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
Study design
Phase IV single centre randomized double-blind controlled trial
Primary study design
Interventional
Secondary study design
Randomised cross over 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
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
Phase
Phase IV
Drug names
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 trial start date
21/08/2015
Overall trial end date
01/08/2019
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
12
Total final enrolment
12
Participant 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
Recruitment start date
29/01/2018
Recruitment end date
01/08/2019
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Centre for Endocrinology Diabetes and Research
Royal Surrey County Hospital
Egerton Road
Guildford
GU2 7XX
United Kingdom
Sponsor information
Organisation
University of Leicester
Sponsor details
Diabetes Research Centre/Department of Health Sciences
University of Leicester
Leicester
LE5 4PW
United Kingdom
+44 (0)116 258 6481
uolsponsor@le.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
Charity
Funder name
Diabetes UK
Alternative name(s)
Funding Body Type
private sector organisation
Funding Body Subtype
other non-profit
Location
United Kingdom
Funder name
AstraZeneca
Alternative name(s)
AstraZeneca PLC
Funding Body Type
private sector organisation
Funding Body Subtype
For-profit companies (industry)
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Presentation at national and international conferences and publication in a peer-reviewed journal.
IPD sharing statement:
All data generated or analysed during this study will be included in the subsequent results publication.
Intention to publish date
01/01/2020
Participant level data
Other
Basic results (scientific)
Publication list