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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

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    Trial identification
    Sponsor protocol code
    0584
    Additional study identifiers
    ISRCTN number
    ISRCTN16404006
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    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
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    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?
    No
    General information about the trial
    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
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    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)
    14
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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
    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
    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.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    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

    Arm title
    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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    Baseline characteristics reporting groups [1]
    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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    End points reporting groups
    Reporting group title
    Dapagliflozin
    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
    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.

    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.
    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.
    Comparison groups
    Dapagliflozin v placebo
    Number of subjects included in analysis
    24
    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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    Adverse events information
    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 used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Dapagliflozin
    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
    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.

    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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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    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

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