Clinical Trial Results:
The Effect of an SGLT2 inhibitor on Glucose Flux, Lipolysis and Ketogenesis following insulin withdrawal in people with absolute or relative endogenous insulin deficiency
Summary
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EudraCT number |
2015-002094-38 |
Trial protocol |
GB |
Global end of trial date |
02 Aug 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
12 May 2021
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First version publication date |
12 May 2021
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Other versions |
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Summary report(s) |
Abstract |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
0584
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Additional study identifiers
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ISRCTN number |
ISRCTN16404006 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
University of Leicester
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Sponsor organisation address |
Research Governance Office, Academic Department, Leicester General Hospital, Leicester, United Kingdom, LE5 4PW
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Public contact |
Roselle Herring, Royal Surrey County Hospital, 0044 07777621085, roselle.herring@nhs.net
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Scientific contact |
Roselle Herring, Royal Surrey County Hospital, 0044 07777621085, roselle.herring@nhs.net
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Mar 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
28 Mar 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Aug 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To determine the difference in glucose concentration of Dapagliflozin when compared with placebo treatment following insulin withdrawal.
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Protection of trial subjects |
Participants received dapagliflozin (10 mg daily) or placebo in random order for 7 days. During the intake of the trial medication, that is, 6 days prior to the study visit, they were made aware of potential changes in glycaemic control and were asked to record trial medication administration, any concomitant medication (to include insulin), hypoglycaemia frequency (capillary glucose level <4mmol/L), fasting ketone levels and any adverse events.
During the study visit 2 and 3, the metabolic study was terminated at 600 minutes (10 hours) or in the event of blood glucose of 18mmol/L, bicarbonate <15mmol/L or venous pH <7.35 or point of care capillary ketone level of >5.0 mmol/L the metabolic study and participants commenced on rescue intravenous insulin infusion and 5% dextrose until blood glucose levels stabilised.
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Background therapy |
Allowable concomitant type 1 and type 3c diabetes therapy: Insulin Patients with type 1 diabetes were on pump therapy. Permitted concomitant therapy: statins, antihypertensives.. | ||
Evidence for comparator |
Investigational product: Dapagliflozin 10 mg Dosage form and strength: Green, plain, diamond shaped, film-coated 10 mg tablet Manufacturer: AstraZeneca Ltd Investigational product: Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, film-coated tablet Dapagliflozin is a SGLT2 inhibitors are highly potent, selective and reversible orally active inhibitors of renal SGLT2 the major transporter responsible for renal glucose reabsorption. Therapeutic indications o Forxiga is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control as: o Monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance. o Add-on combination therapy in combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control o Estimated cumulative exposure of clinical study participants: 7 days In this trial, the incidence of adverse events was minimal and their severity was mild or moderate and self-limiting. Should the data suggest that Dapagliflozin was effective, then it could be said that it has a favourable risk-benefit profile. There are no important or significant risks associated with taking Dapagliflozin. This conclusion is based on the available data at the time of creation of this document. Comparator- a matching placebo tablet. | ||
Actual start date of recruitment |
01 Feb 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 14
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Worldwide total number of subjects |
14
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EEA total number of subjects |
14
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
14
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment: From Diabetes Clinics at Cedar centre, Royal Surrey County Hospital Surrey, UK- between 30/01/2018 and 17/03/2018. Identification: Diabetes Consultants, from diabetes clinics at the Cedar centre, Royal Surrey County Hospital, will identify Participants with type 1 diabetes or type3c diabetes. | |||||||||||||||
Pre-assignment
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Screening details |
No washout or pre assignment periods for this study. 14 patients were recruited, 13 patients with type 1 diabetes and 1 with type 3c diabetes. 1 patient with T1D was withdrawn due to inability to be cannulated while attending VISIT 2 at the end of the first dosing of either Dapagliflozin or placebo. 1 patient with T3cD was not included in analysis. | |||||||||||||||
Period 1
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Period 1 title |
Overall period
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Investigator, Monitor, Data analyst, Subject | |||||||||||||||
Blinding implementation details |
This is a double blind crossover study. Subjects were randomised into 2 groups. One group received
once daily one tablet of dapagliflozin taken orally for 7 days followed by a 4 week washout then once daily one tablet of placebo taken orally for 7 days. The other group received once daily one tablet of placebo taken orally for 7 days followed by a 4 week washout then once daily one tablet of dapagliflozin taken orally for 7 days. The placebo and dapagliflozin tablets are indistinguishable.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Dapagliflozin | |||||||||||||||
Arm description |
Dapagliflozin and placebo are considered as investigational medicinal product (IMP). insulin is not considered an investigational product but is an allowed antidiabetic medication to be taken concomitantly. Identity of investigational products(s) Dapagliflozin was supplied as 10 mg Dosage form and strength: Green, plain, diamond shaped, film-coated 10 mg tablet once daily for 7 days. Dapagliflozin and its matching placebo will be supplied in bottles. The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals | |||||||||||||||
Arm type |
cross over | |||||||||||||||
Investigational medicinal product name |
Dapagliflozin
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Investigational medicinal product code |
461432-26-8, Cayman Chemical
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Other name |
Farxiga,
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Investigational product: Dapagliflozin 10 mg Dosage form and strength: Green, plain, diamond shaped, film-coated 10 mg tablet
Manufacturer: AstraZeneca Ltd
Dapagliflozin and its matching placebo will be supplied in bottles. The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals.
Used once daily
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Investigational medicinal product name |
Comparator to Dapagliflozin
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Investigational medicinal product code |
PL1
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Other name |
Placebo
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Investigational product: Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, film-coated tablet
Dapagliflozin and its matching placebo will be supplied in bottles. The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals.
Once daily
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Arm title
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placebo | |||||||||||||||
Arm description |
Dapagliflozin and placebo are considered as investigational medicinal product (IMP). Insulin is not considered an investigational product but is an allowed antidiabetic medication to be taken concomitantly. Identity of investigational products(s) Dapagliflozin 10 mg Dosage form and strength: Green, plain, diamond shaped, film-coated 10 mg tablet Manufacturer: AstraZeneca Ltd Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, film-coated tablet Dapagliflozin and its matching placebo were supplied in bottles. The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals. | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
Placebo
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, film-coated tablet
Dapagliflozin and its matching placebo were supplied in bottles. The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals.
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Baseline characteristics reporting groups [1]
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Reporting group title |
Overall period
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Reporting group description |
Overall trial n=12 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: The study was designed to investigate the effects of dapagliflozin versus placebo in two cohorts of patients with type 1 and type 3C diabetes. 13 T1D were recruited of which 12 completed the study. We failed to recruit the full quota for T3c D. one subject was recruited to the T3cD cohort who received both dapagliflozin and placebo with no adverse event. Baseline characteristics reported here are for those participants who completed the study that is T1D cohort of n=12. |
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End points reporting groups
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Reporting group title |
Dapagliflozin
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Reporting group description |
Dapagliflozin and placebo are considered as investigational medicinal product (IMP). insulin is not considered an investigational product but is an allowed antidiabetic medication to be taken concomitantly. Identity of investigational products(s) Dapagliflozin was supplied as 10 mg Dosage form and strength: Green, plain, diamond shaped, film-coated 10 mg tablet once daily for 7 days. Dapagliflozin and its matching placebo will be supplied in bottles. The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals | ||
Reporting group title |
placebo
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Reporting group description |
Dapagliflozin and placebo are considered as investigational medicinal product (IMP). Insulin is not considered an investigational product but is an allowed antidiabetic medication to be taken concomitantly. Identity of investigational products(s) Dapagliflozin 10 mg Dosage form and strength: Green, plain, diamond shaped, film-coated 10 mg tablet Manufacturer: AstraZeneca Ltd Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, film-coated tablet Dapagliflozin and its matching placebo were supplied in bottles. The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals. |
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End point title |
Plasma glucose concentration | ||||||||||||
End point description |
Glucose concentration (mmol/L) at 600 minutes following insulin cessation at the end of 7 days treatment with dapagliflozin or placebo (visits V2 or V3 depending on the randomisation). Dapagliflozin or placebo was administered at 0 min. Study was terminated when one of the rescue parameters was reached. Results are mean ± SEM.
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End point type |
Primary
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End point timeframe |
Plasma glucose concentration at 600 minutes following insulin cessation or at the time of glycaemic rescue, whichever occurs first
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Notes [1] - One subject was withdrawn due to inability to insert a cannula for venous sampling. |
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Statistical analysis title |
Superiority testing | ||||||||||||
Statistical analysis description |
The primary end point was glucose concentration at 600 min. Final glucose concentration was statistically analysed as the response variable in a general linear mixed model (using PROC MIXED procedure in SAS software), with treatment, period, treatment by period interaction, as fixed effects, and the baseline glucose concentration as a covariate. The participant was a random effect in the model. The denominator degrees of freedom were adjusted using the Kenward-Roger approximations.
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Comparison groups |
Dapagliflozin v placebo
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Number of subjects included in analysis |
24
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
≤ 0.0001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
6.1865
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
3.4573 | ||||||||||||
upper limit |
8.9157 | ||||||||||||
Variability estimate |
Standard error of the mean
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Notes [2] - Statistical analysis was performed using R version 3.5.1 and SAS version 9.4 or above. All hypothesis tests were two sided and evaluated at a significance level of 5%. General linear mixed model , with treatment, period, treatment by period interaction, as fixed effects, and the baseline glucose concentration as a covariate. The participant was a random effect in the model. The denominator degrees of freedom were adjusted using the Kenward-Roger approximations. |
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Adverse events information
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Timeframe for reporting adverse events |
This includes events from the first trial related activity after the subject has signed the informed consent
and until post treatment follow-up period as defined in the protocol.
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Adverse event reporting additional description |
The following criteria were used to identify adverse events: Any unfavourable or unintended sign or
symptom, Any deterioration in laboratory data, vital signs or found on physical examination.
All concomitant medications taken during the study were recorded.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Dapagliflozin
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Reporting group description |
Dapagliflozin and placebo are considered as investigational medicinal product (IMP). insulin is not considered an investigational product but is an allowed antidiabetic medication to be taken concomitantly. Identity of investigational products(s) Dapagliflozin was supplied as 10 mg Dosage form and strength: Green, plain, diamond shaped, film-coated 10 mg tablet once daily for 7 days. Dapagliflozin and its matching placebo will be supplied in bottles. The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals | |||||||||||||||||||||||||||||||||
Reporting group title |
placebo
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Reporting group description |
Dapagliflozin and placebo are considered as investigational medicinal product (IMP). Insulin is not considered an investigational product but is an allowed antidiabetic medication to be taken concomitantly. Identity of investigational products(s) Dapagliflozin 10 mg Dosage form and strength: Green, plain, diamond shaped, film-coated 10 mg tablet Manufacturer: AstraZeneca Ltd Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, film-coated tablet Dapagliflozin and its matching placebo were supplied in bottles. The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals. | |||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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02 Jun 2017 |
Change of site for Final Quality Person (QP) release and certification of the IMP: Dapagliflozin and its matching placebo tablet and its randomisation |
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02 Jun 2017 |
Administrative change and overnight insulin requirements. |
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01 Apr 2019 |
To improve Type 3c recruitment and extend the recruitment period to the 3rd August 2019. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
1- Urinary ketone excretion was not measured. 2- We were unable to recruit patients with Type 3c diabetes. | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/32641376 |