Clinical Trial Results:
A Randomized, Double-Blind, Placebo-controlled, Single-center Phase 1 Inpatient Pilot Study to Explore the Safety and Efficacy of DAPAglifozin as Add-on to day and night closed-loop control using the DreaMed Substance Administration Device Software in Adolescent and Adult Subjects with Type 1 Diabetes mellitus

Trial information Top of page
Trial identification
Sponsor protocol code	ESR-15-11453
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Stiftung Hannoversche Kinderheilanstalt
Sponsor organisation address	Janusz-Korczak-Allee12, Hannover, Germany, 30173
Public contact	Deputy Principal Investigator, Stiftung Hannoversche Kinderheilanstalt, Kinder - und Jugendkrankenhaus AUF DER BULT, , 0049 51181153344, biester@hka.de
Scientific contact	Deputy Principal Investigator, Stiftung Hannoversche Kinderheilanstalt, 0049 51181153344, biester@hka.de
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	18 Dec 2020
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	19 Dec 2017
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	The purpose of the pilot study is to collect clinical data of a single-dose of 10mg dapagliflozin as add-on to night and day closed-loop control using the DreaMed Algorithm on the time within glucose range 70-180 mg/dl (3.9-10mmol/l) [%] for the ensuing 24 hours with two oral mixed-meals.
Protection of trial subjects	Close monitoring of patients onsite and remotely.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	22 Feb 2017
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Germany: 30
Worldwide total number of subjects	30
EEA total number of subjects	30
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)	15
Adults (18-64 years)	15
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	31 did receive treatment, one subject discontinued, 30 completed the study
Pre-assignment
Screening details	34 subjects were screened
Period 1
Period 1 title	Overall trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator
Arms
Are arms mutually exclusive	No
Arm title	Sequence 1
Arm description	dapa - Placebo
Arm type	Sequence
Investigational medicinal product name	Forxiga
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	10 mg x 2
Arm title	Sequence 2
Arm description	Placebo - Dapa
Arm type	Sequence
Investigational medicinal product name	No investigational medicinal product assigned in this arm
Number of subjects in period 1 Sequence 1 Sequence 2 Started 30 30 Completed 30 30

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Overall trial
Reporting group description	-
Reporting group values Overall trial Total Number of subjects 30 30 Age categorical Units: Subjects     In utero 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0     Newborns (0-27 days) 0 0     Infants and toddlers (28 days-23 months) 0 0     Children (2-11 years) 0 0     Adolescents (12-17 years) 15 15     Adults (18-64 years) 15 15     From 65-84 years 0 0     85 years and over 0 0 Gender categorical Males and females were screened. Units: Subjects     Female 19 19     Male 11 11
Subject analysis sets
Subject analysis set title	Dapagliflozin
Subject analysis set type	Per protocol
Subject analysis set description	Time in glucose range 70-180 mg/dL
Subject analysis set title	Placebo
Subject analysis set type	Per protocol
Subject analysis set description	Tine in glucose range 70-180 mg/dL
Subject analysis sets values Dapagliflozin Placebo Number of subjects 30 30 Age categorical Units: Subjects     In utero 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0     Newborns (0-27 days) 0 0     Infants and toddlers (28 days-23 months) 0 0     Children (2-11 years) 0 0     Adolescents (12-17 years) 15 15     Adults (18-64 years) 15 15     From 65-84 years 0 0     85 years and over 0 0 Age continuous Units:      ( ) ( ) Gender categorical Males and females were screened. Units: Subjects     Female 19 19     Male 11 11

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Sequence 1
Reporting group description	dapa - Placebo
Reporting group title	Sequence 2
Reporting group description	Placebo - Dapa
Subject analysis set title	Dapagliflozin
Subject analysis set type	Per protocol
Subject analysis set description	Time in glucose range 70-180 mg/dL
Subject analysis set title	Placebo
Subject analysis set type	Per protocol
Subject analysis set description	Tine in glucose range 70-180 mg/dL

End points Top of page

Primary: Time within glucose range 70-180 mg/dl Top of page
End point title	Time within glucose range 70-180 mg/dl
End point description	Time within glucose range 70-180 mg/dl (3.9-10mmol/l) [%] during night and day closed-loop control using the DreaMed automated insulin delivery with two oral mixed-meals after oral administration of 10mg dapagliflozin
End point type	Primary
End point timeframe	24 hours
End point values Dapagliflozin Placebo Number of subjects analysed 30 30 Units: percentage     arithmetic mean (standard deviation) 68 ( 6 ) 50 ( 13 )
Statistical analysis title	t-test
Statistical analysis description	one sided
Comparison groups	Placebo v Dapagliflozin
Number of subjects included in analysis	60
Analysis specification	Pre-specified
Analysis type	non-inferiority
P-value	< 0.001
Method	t-test, 1-sided
Parameter type	Mean difference (final values)
Confidence interval

Primary: Time within glucose range 70-180 mg/dl Top of page

Secondary: insulin dose reduction Top of page
End point title	insulin dose reduction
End point description	To investigate the degree of insulin dose reduction during the DreaMed automated insulin delivery 24 hours after a single dose of 10mg dapagliflozin in patients with type 1 diabetes
End point type	Secondary
End point timeframe	24 hours
End point values Dapagliflozin Placebo Number of subjects analysed Units: IU     arithmetic mean (standard deviation) 40 ( 13 ) 31 ( 10 )
No statistical analyses for this end point

Secondary: insulin dose reduction Top of page

Secondary: on urinary glucose excretion Top of page
End point title	on urinary glucose excretion
End point description	To investigate the effect on urinary glucose excretion
End point type	Secondary
End point timeframe	24 hours
End point values Dapagliflozin Placebo Number of subjects analysed Units: mg/dL     arithmetic mean (standard deviation) 149 ( 42 ) 49 ( 23 )
No statistical analyses for this end point

Secondary: on urinary glucose excretion Top of page

Secondary: Post prandial insulin need Top of page
End point title	Post prandial insulin need
End point description	To investigate if dapagliflozin influences postprandial insulin need.
End point type	Secondary
End point timeframe	post prandial
End point values Dapagliflozin Placebo Number of subjects analysed Units: IU/kg/24h     arithmetic mean (standard deviation) 0.425 ( 0.09 ) 0.57 ( 0.1 )
No statistical analyses for this end point

Secondary: Post prandial insulin need Top of page

Secondary: ßhydroxybutyrate levels Top of page
End point title	ßhydroxybutyrate levels
End point description	To investigate if dapagliflozin is associated with elevated ßhydroxybutyrate levels.
End point type	Secondary
End point timeframe	24 hours
End point values Dapagliflozin Placebo Number of subjects analysed Units: mmol/L     arithmetic mean (confidence interval 95%) 0.29 (0.28 to 0.31) 0.16 (0.15 to 0.18)
No statistical analyses for this end point

Secondary: ßhydroxybutyrate levels Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Up to 72 days
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	23
Reporting groups
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 / 30 (0.00%) 0 / 30 (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 5 / 30 (16.67%) 7 / 30 (23.33%) Investigations Blood bilirubin      subjects affected / exposed 0 / 30 (0.00%) 1 / 30 (3.33%)      occurrences all number 0 1 Injury, poisoning and procedural complications Thermal burn      subjects affected / exposed 0 / 30 (0.00%) 1 / 30 (3.33%)      occurrences all number 0 1 Nervous system disorders Headache      subjects affected / exposed 3 / 30 (10.00%) 0 / 30 (0.00%)      occurrences all number 3 0 Gastrointestinal disorders Vomiting      subjects affected / exposed 1 / 30 (3.33%) 0 / 30 (0.00%)      occurrences all number 1 0 Respiratory, thoracic and mediastinal disorders Oropharyngeal pain      subjects affected / exposed 0 / 30 (0.00%) 1 / 30 (3.33%)      occurrences all number 0 1 Musculoskeletal and connective tissue disorders Pain in extremity      subjects affected / exposed 0 / 30 (0.00%) 1 / 30 (3.33%)      occurrences all number 0 1 Infections and infestations Gastroenteritis      subjects affected / exposed 1 / 30 (3.33%) 1 / 30 (3.33%)      occurrences all number 1 1 Nasopharyngitis      subjects affected / exposed 2 / 30 (6.67%) 4 / 30 (13.33%)      occurrences all number 2 4 Otitis media      subjects affected / exposed 0 / 30 (0.00%) 1 / 30 (3.33%)      occurrences all number 0 1 Periodentitis      subjects affected / exposed 1 / 30 (3.33%) 0 / 30 (0.00%)      occurrences all number 1 0 Metabolism and nutrition disorders Hyperglycaemia      subjects affected / exposed 0 / 30 (0.00%) 1 / 30 (3.33%)      occurrences all number 0 1

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
30 Nov 2016	Double dose of dapagliflozin: Dapagliflozin dose was increased from 1x10mg to 2x10mg over a period of 2 days (10mg/day) due to short term efficacy of Dapagliflozin.
13 Mar 2017	02 Informed Consent Form (ICF) on visit 1: The written consent can occur on visit 1 since patients and parents (where applicable) were already informed about the study before screening visit.
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.
None reported
Online references
http://www.ncbi.nlm.nih.gov/pubmed/3321711

More information Top of page