The Safety and Efficacy of Dapagliflozin Therapy in Combination With Insulin in Japanese Subjects With T1DM

A Clinical Pharmacology and Long Term Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Dapagliflozin Therapy in Combination With Insulin in Japanese Subjects With Type 1 Diabetes Who Have Inadequate Glycemic Control

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02582814

Enrollment

151

Registered

2015-10-21

Start date

2015-10-26

Completion date

2017-06-15

Last updated

2019-04-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Type 1 Diabetes Mellitus

Keywords

Japanese patients with type 1 diabetes with inadequate glycemic control on insulin

Brief summary

This study will enroll eligible subjects into a long-term safety study (Part B). Japanese male and female patients with T1DM and age 18 to 75 years, with inadequate glycemic control on insulin defined as HbA1c ≥ 7.5% and ≤ 10.5% at screening visit. As a condition of enrollment, subjects must be on a total daily insulin dose of ≥ 0.3 U/kg/day for at least 3 months prior to the screening visit. The study design of Part B is a randomized, open-label, 2 arm, parallel-group design. 140 Japanese subjects in total will be randomized in a 1:1 ratio into one of the two treatment arms; dapagliflozin 5 mg or dapagliflozin 10 mg.

Interventions

DRUGDapagliflozin 5 mg

Dapagliflozin, a blood glucose lowering drug. Oral dose

DRUGDapagliflozin 10mg

Dapagliflozin, a blood glucose lowering drug. Oral dose

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Masking description

Open Label

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Signed Written Informed Consent * Diagnosis of T1DM. In addition, the following criteria also needs to be met; Central laboratory test of C-peptide \< 0.7 ng/mL * Insulin use for at least 12 months prior to the enrolment per subject report or medical records and Method of insulin administration (MDI or CSII) must have been unchanged for at least 3 months prior to the enrolment per subject report or medical records. Subjects must be taking a total daily insulin dose of ≥ 0.3 U/kg/day for at least 3 months prior to the enrolment. If on MDI insulin administration subject must be on ≥ 3x injections per day. * Japanese men and women * Screening Visit: Central laboratory HbA1c ≥ 7.5% and ≤ 10.5% * BMI ≥ 20.0 kg/m² at visit 1 * Age 18 to 75 years, inclusive

Exclusion criteria

\- Target Disease Exceptions History of T2DM Maturity onset diabetes of young (MODY) Any anti-hyperglycemic agent use, other than α-GI or insulin, within 1 month prior to the enrolment. Use of thiazolidinediones within 6 months prior to the enrolment History of DKA requiring medical intervention within 1 month prior to the enrolment History of hospital admission for glycemic control (either hyperglycemia or hypoglycemia) within 1 month prior to the enrolment * Medical History and Concurrent Diseases Malignancy within 5 years of the enrolment (with the exception of treated basal cell or treated squamous cell carcinoma) History of bladder cancer History of radiation therapy to the lower abdomen or pelvis at any time * Physical and Laboratory Test Findings Aspartate aminotransferase (AST) \> 3x upper limit of normal (ULN) Alanine aminotransferase (ALT) \> 3x ULN Serum total bilirubin (TB) \> 2.0 mg/dL (34.2 μmol/L) Estimated GFR (eGFR) by the Japanese Society of Nephrology formula ≤ 45 mL/min/1.73m2 Hemoglobin ≤ 11.0 g/dL (110 g/L) for men; hemoglobin ≤ 10.0 g/dL (100 g/L) for women. Positive for hepatitis B surface antigen or anti-hepatitis C virus antibody Abnormal Free T4

Design outcomes

Primary

Measure	Time frame	Description
Hypoglycemia	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Overall Adverse Event Summary	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Diabetic Ketoacidosis (DKA)	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Vital Signs (Heart Rate)	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
ECGs	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.
Vital Signs (Blood Pressure)	From baseline to 52 weeks	To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Secondary

Measure	Time frame	Description
Proportion of Subjects Achieving HbA1c Reduction of 0.5 Percent	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin
Adjusted Change From Baseline in HbA1c	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Change From Baseline in SBP in Subjects With Baseline SBP/DBP >= 140/90 mmHg	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin
Proportion of Subjects Achieving HbA1c < 7.0 Percent	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin
Adjusted Percent Change From Baseline in Total Daily Insulin Dose	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Percent Change From Baseline in Body Weight	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Change From Baseline in Glycoalbumin	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Change From Baseline in Average Daily Glucose Measured by 6-point SMBG	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Adjusted Change From Baseline in Post-prandial Glucose Measured by 6-point SMBG	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.
Proportion of Subjects Achieving HbA1c Reduction of 0.5 Percent Without Severe Hypoglycemia	From baseline to 24/52 weeks	To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin

Countries

Japan

Participant flow

Participants by arm

Arm	Count
Dapagliflozin 5mg + Insulin dapagliflozin tablet 5mg + adjustable insulin	76
Dapagliflozin 10mg + Insulin dapagliflozin tablet 10mg + adjustable insulin	75
Total	151

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	4	4
Overall Study	Study-specific withdrawal criteria	1	0
Overall Study	Withdrawal by Subject	4	3

Baseline characteristics

Characteristic	Dapagliflozin 5mg + Insulin	Dapagliflozin 10mg + Insulin	Total
Age, Continuous	47.7 years STANDARD_DEVIATION 12.85	48.9 years STANDARD_DEVIATION 12.93	48.3 years STANDARD_DEVIATION 12.86
Body Mass Index	25.28 kg/m2 STANDARD_DEVIATION 3.635	24.66 kg/m2 STANDARD_DEVIATION 2.806	24.97 kg/m2 STANDARD_DEVIATION 3.254
C-peptide < 0.1 ng/mL	63 Participants	65 Participants	128 Participants
C-peptide >= 0.1 ng/mL	13 Participants	10 Participants	23 Participants
Duration of T1DM	14.60 years STANDARD_DEVIATION 8.42	15.94 years STANDARD_DEVIATION 10.328	15.27 years STANDARD_DEVIATION 9.409
HbA1c	8.43 Percent STANDARD_DEVIATION 0.711	8.40 Percent STANDARD_DEVIATION 0.715	8.42 Percent STANDARD_DEVIATION 0.711
Race/Ethnicity, Customized Asian	76 Participants	75 Participants	151 Participants
Sex: Female, Male Female	33 Participants	42 Participants	75 Participants
Sex: Female, Male Male	43 Participants	33 Participants	76 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 76	0 / 75
other Total, other adverse events	66 / 76	55 / 75
serious Total, serious adverse events	7 / 76	3 / 75

Outcome results

Primary

Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Time frame: From baseline to 52 weeks

Population: Subjects with non-missing post-baseilne measurements were included.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Dapagliflozin 5mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	UACR (> 1800mg/g)	0 Participants
Dapagliflozin 5mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Hematocrit (> 55%)	1 Participants
Dapagliflozin 5mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Hemoglobin (> 18g/dL)	2 Participants
Dapagliflozin 5mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Creatinine (>1.5 x ULN pre Rx)	0 Participants
Dapagliflozin 5mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Creatin kinase (> 5x ULN)	1 Participants
Dapagliflozin 5mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Bicarbonate (<= 13 mEq/L)	1 Participants
Dapagliflozin 5mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	P (<=1.8/2.1mg/dL for age<=/>65)	1 Participants
Dapagliflozin 10mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	UACR (> 1800mg/g)	1 Participants
Dapagliflozin 10mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Creatin kinase (> 5x ULN)	1 Participants
Dapagliflozin 10mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Hematocrit (> 55%)	0 Participants
Dapagliflozin 10mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	P (<=1.8/2.1mg/dL for age<=/>65)	1 Participants
Dapagliflozin 10mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Hemoglobin (> 18g/dL)	1 Participants
Dapagliflozin 10mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Bicarbonate (<= 13 mEq/L)	0 Participants
Dapagliflozin 10mg + Insulin	Clinical Laboratory Measures, Urine Test Results (Any Marked Abnormality)	Creatinine (>1.5 x ULN pre Rx)	1 Participants

Primary

Diabetic Ketoacidosis (DKA)

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Time frame: From baseline to 52 weeks

Arm	Measure	Group	Category	Value (COUNT_OF_PARTICIPANTS)
Dapagliflozin 5mg + Insulin	Diabetic Ketoacidosis (DKA)	Definite DKA	At least one events	2 Participants
Dapagliflozin 5mg + Insulin	Diabetic Ketoacidosis (DKA)	Possible DKA	At least one events	1 Participants
Dapagliflozin 5mg + Insulin	Diabetic Ketoacidosis (DKA)	Unlikely DKA	At least one events	0 Participants
Dapagliflozin 10mg + Insulin	Diabetic Ketoacidosis (DKA)	Definite DKA	At least one events	1 Participants
Dapagliflozin 10mg + Insulin	Diabetic Ketoacidosis (DKA)	Possible DKA	At least one events	0 Participants
Dapagliflozin 10mg + Insulin	Diabetic Ketoacidosis (DKA)	Unlikely DKA	At least one events	0 Participants

Primary

ECGs

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Time frame: From baseline to 52 weeks

Arm	Measure	Group	Category	Value (COUNT_OF_PARTICIPANTS)
Dapagliflozin 5mg + Insulin	ECGs	Baseline	NORMAL	65 Participants
Dapagliflozin 5mg + Insulin	ECGs	Baseline	ABNORMAL	11 Participants
Dapagliflozin 5mg + Insulin	ECGs	Baseline	NOT REPORTED	0 Participants
Dapagliflozin 5mg + Insulin	ECGs	Week 52	NORMAL	69 Participants
Dapagliflozin 5mg + Insulin	ECGs	Week 52	ABNORMAL	5 Participants
Dapagliflozin 5mg + Insulin	ECGs	Week 52	NOT REPORTED	2 Participants
Dapagliflozin 10mg + Insulin	ECGs	Week 52	ABNORMAL	8 Participants
Dapagliflozin 10mg + Insulin	ECGs	Baseline	NORMAL	67 Participants
Dapagliflozin 10mg + Insulin	ECGs	Week 52	NORMAL	67 Participants
Dapagliflozin 10mg + Insulin	ECGs	Baseline	ABNORMAL	8 Participants
Dapagliflozin 10mg + Insulin	ECGs	Week 52	NOT REPORTED	0 Participants
Dapagliflozin 10mg + Insulin	ECGs	Baseline	NOT REPORTED	0 Participants

Primary

Hypoglycemia

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Time frame: From baseline to 52 weeks

Arm	Measure	Group	Category	Value (COUNT_OF_PARTICIPANTS)
Dapagliflozin 5mg + Insulin	Hypoglycemia	Probable Symptomatic Hypoglycemia	At least one events	13 Participants
Dapagliflozin 5mg + Insulin	Hypoglycemia	Severe Hypoglycemia	At least one events	2 Participants
Dapagliflozin 5mg + Insulin	Hypoglycemia	Asymptomatic Hypoglycemia	At least one events	60 Participants
Dapagliflozin 5mg + Insulin	Hypoglycemia	Any Hypoglycemia Episodes	At least one events	75 Participants
Dapagliflozin 5mg + Insulin	Hypoglycemia	Relative Hypoglycemia	At least one events	14 Participants
Dapagliflozin 5mg + Insulin	Hypoglycemia	Documented Symptomatic Hypoglycemia	At least one events	67 Participants
Dapagliflozin 10mg + Insulin	Hypoglycemia	Relative Hypoglycemia	At least one events	11 Participants
Dapagliflozin 10mg + Insulin	Hypoglycemia	Documented Symptomatic Hypoglycemia	At least one events	73 Participants
Dapagliflozin 10mg + Insulin	Hypoglycemia	Probable Symptomatic Hypoglycemia	At least one events	14 Participants
Dapagliflozin 10mg + Insulin	Hypoglycemia	Any Hypoglycemia Episodes	At least one events	75 Participants
Dapagliflozin 10mg + Insulin	Hypoglycemia	Severe Hypoglycemia	At least one events	5 Participants
Dapagliflozin 10mg + Insulin	Hypoglycemia	Asymptomatic Hypoglycemia	At least one events	64 Participants

Primary

Overall Adverse Event Summary

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Time frame: From baseline to 52 weeks

Arm	Measure	Group	Category	Value (COUNT_OF_PARTICIPANTS)
Dapagliflozin 5mg + Insulin	Overall Adverse Event Summary	Related Adverse Events	At least one events	23 Participants
Dapagliflozin 5mg + Insulin	Overall Adverse Event Summary	AEs leading to discontinuation	At least one events	4 Participants
Dapagliflozin 5mg + Insulin	Overall Adverse Event Summary	SAE	At least one events	7 Participants
Dapagliflozin 5mg + Insulin	Overall Adverse Event Summary	Death	At least one events	0 Participants
Dapagliflozin 5mg + Insulin	Overall Adverse Event Summary	Adverse Events	At least one events	67 Participants
Dapagliflozin 10mg + Insulin	Overall Adverse Event Summary	Death	At least one events	0 Participants
Dapagliflozin 10mg + Insulin	Overall Adverse Event Summary	Adverse Events	At least one events	55 Participants
Dapagliflozin 10mg + Insulin	Overall Adverse Event Summary	Related Adverse Events	At least one events	22 Participants
Dapagliflozin 10mg + Insulin	Overall Adverse Event Summary	SAE	At least one events	3 Participants
Dapagliflozin 10mg + Insulin	Overall Adverse Event Summary	AEs leading to discontinuation	At least one events	4 Participants

Primary

Vital Signs (Blood Pressure)

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Time frame: From baseline to 52 weeks

Population: Subjects with both non-missing baseline and non-missing Week 52 were included.

Arm	Measure	Group	Value (MEAN)	Dispersion
Dapagliflozin 5mg + Insulin	Vital Signs (Blood Pressure)	Change from baseline in SBP(mmHg) at Week 52	-3.4 mmHg	Standard Deviation 11.41
Dapagliflozin 5mg + Insulin	Vital Signs (Blood Pressure)	Change from baseline in DBP(mmHg) at Week 52	-0.6 mmHg	Standard Deviation 8.21
Dapagliflozin 10mg + Insulin	Vital Signs (Blood Pressure)	Change from baseline in SBP(mmHg) at Week 52	-2.9 mmHg	Standard Deviation 12.55
Dapagliflozin 10mg + Insulin	Vital Signs (Blood Pressure)	Change from baseline in DBP(mmHg) at Week 52	-1.0 mmHg	Standard Deviation 7.89

Primary

Vital Signs (Heart Rate)

To evaluate safety and tolerability of long-term treatment (52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM with inadequate glycemic control under standard insulin therapy.

Time frame: From baseline to 52 weeks

Population: Subjects with both non-missing baseline and non-missing Week 52 were included.

Arm	Measure	Value (MEAN)	Dispersion
Dapagliflozin 5mg + Insulin	Vital Signs (Heart Rate)	-0.3 bpm	Standard Deviation 10.07
Dapagliflozin 10mg + Insulin	Vital Signs (Heart Rate)	0.4 bpm	Standard Deviation 8.89

Secondary

Adjusted Change From Baseline in Average Daily Glucose Measured by 6-point SMBG

To assess the efficacy of long-term treatment (24/52 weeks) of dapagliflozin 5mg and 10 mg in Japanese patients with T1DM inadequately controlled on insulin therapy.