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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
EudraCT number	2015-002094-38
Trial protocol	GB
Global end of trial date	02 Aug 2019

Results information
Results version number	v1(current)
This version publication date	12 May 2021
First version publication date	12 May 2021
Other versions
Summary report(s)	Abstract

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

0584

ISRCTN number

ISRCTN16404006

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University of Leicester

Sponsor organisation address

Research Governance Office, Academic Department, Leicester General Hospital, Leicester, United Kingdom, LE5 4PW

Public contact

Roselle Herring, Royal Surrey County Hospital, 0044 07777621085, roselle.herring@nhs.net

Scientific contact

Roselle Herring, Royal Surrey County Hospital, 0044 07777621085, roselle.herring@nhs.net

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Mar 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

28 Mar 2019

Global end of trial reached?

Yes

Global end of trial date

02 Aug 2019

Was the trial ended prematurely?

Main objective of the trial

To determine the difference in glucose concentration of Dapagliflozin when compared with placebo treatment following insulin withdrawal.

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.

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

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 14

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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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.

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 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

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.

Are arms mutually exclusive

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

Investigational medicinal product code

461432-26-8, Cayman Chemical

Other name

Farxiga,

Pharmaceutical forms

Tablet

Routes of administration

Oral use

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

Investigational medicinal product name

Comparator to Dapagliflozin

Investigational medicinal product code

PL1

Other name

Placebo

Pharmaceutical forms

Tablet

Routes of administration

Oral use

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

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

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

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.

Number of subjects in period 1	Dapagliflozin	placebo
Started	13	12
Completed	12	12
Not completed	1	0
Physician decision	1	-

Baseline characteristics

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Reporting group title

Overall period

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.

Reporting group values	Overall period	Total
Number of subjects	13	13
Age categorical
Units: Subjects
In utero		0
Preterm newborn infants (gestational age < 37 wks)		0
Newborns (0-27 days)		0
Infants and toddlers (28 days-23 months)		0
Children (2-11 years)		0
Adolescents (12-17 years)		0
Adults (18-64 years)		0
From 65-84 years		0
85 years and over		0
Age continuous
Units: years
arithmetic mean (standard deviation)	40.7 ( 13.4 )	-
Gender categorical
Female
Units: Subjects
Female	9	9
Male	4	4
HbA1C
Haemoglobin A1C
Units: mmol/mol
arithmetic mean (standard deviation)	59.9 ( 7.9 )	-
Body weight
Body weight at baseline
Units: Kg
arithmetic mean (standard deviation)	81.7 ( 18.9 )	-
BMI
Body mass index
Units: kg/m2
arithmetic mean (standard deviation)	26.8 ( 5.0 )	-
Systolic BP
Systolic blood pressure
Units: mmHg
arithmetic mean (standard deviation)	126 ( 7 )	-
Diastolic BP
Diastolic blood pressure
Units: mmHg
arithmetic mean (standard deviation)	74 ( 8 )	-

End points

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Reporting group title

Dapagliflozin

Reporting group description

Reporting group title

placebo

Reporting group description

Primary: Plasma glucose concentration

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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.

End point type

Primary

End point timeframe

Plasma glucose concentration at 600 minutes following insulin cessation or at the time of glycaemic rescue, whichever occurs first

End point values	Dapagliflozin	placebo
Number of subjects analysed	12 ^[1]	12
Units: mmol/L
arithmetic mean (standard error)	8.5 ( 0.7 )	14.3 ( 1.1 )

Notes
[1] - One subject was withdrawn due to inability to insert a cannula for venous sampling.

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.

Comparison groups

Dapagliflozin v placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

≤ 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

6.1865

Confidence interval

level

95%

sides

2-sided

lower limit

3.4573

upper limit

8.9157

Variability estimate

Standard error of the mean

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.

Adverse events

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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.

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.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Dapagliflozin

Reporting group description

Reporting group title

placebo

Reporting group description

Serious adverse events	Dapagliflozin	placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 14 (0.00%)	0 / 13 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Dapagliflozin	placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 14 (14.29%)	2 / 13 (15.38%)
Renal and urinary disorders
Polyuria
subjects affected / exposed	2 / 14 (14.29%)	1 / 13 (7.69%)
occurrences all number	2	1
Infections and infestations
Viral upper respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

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

02 Jun 2017

Administrative change and overnight insulin requirements.

01 Apr 2019

To improve Type 3c recruitment and extend the recruitment period to the 3rd August 2019.

Were there any global interruptions to the trial? No

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.

http://www.ncbi.nlm.nih.gov/pubmed/32641376

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Plasma glucose concentration

Primary: Plasma glucose concentration

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Plasma glucose concentration

Primary: Plasma glucose concentration

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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