Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes

Conditions

Type 1 Diabetes Mellitus

Keywords

Dapagliflozin, Efficacy, Safety, Add on to insulin, Oral Antidiabetic, Type 1 diabetes

Brief summary

The purpose of this study is to determine if adding dapagliflozin to insulin is a safe and effective therapy to improve glycemic control in patients with type 1 diabetes.

Detailed description

Study Classification: Safety, Efficacy and Pharmacokinetics/dynamics

Victor Sokolov, Tatiana A. Yakovleva, Robert C. Penland, David W. Boulton, Weifeng Tang

Frontiers in Pharmacology2023-10-25

10.3389/fphar.2023.1229255

Dapagliflozin Pharmacokinetics Is Similar in Adults With Type 1 and Type 2 Diabetes Mellitus

Johanna Melin, Weifeng Tang, Dinko Rekić, Bengt Hamrén, Robert C. Penland et al. (7 authors)

The Journal of Clinical Pharmacology2022-04-117 citations

10.1002/jcph.2062

Effect of dapagliflozin as an adjunct to insulin over 52 weeks in individuals with type 1 diabetes: post-hoc renal analysis of the DEPICT randomised controlled trials.

Groop PH, Dandona P, Phillip M, Gillard P, Edelman S, Jendle J, Xu J, Scheerer MF, Thoren F, Iqbal N, Repetto E, Mathieu C.

2020-10-0156 citations

10.1016/s2213-8587(20)30280-1

Benefit/risk profile of dapagliflozin 5 mg in the <scp>DEPICT</scp> ‐1 and ‐2 trials in individuals with type 1 diabetes and body mass index ≥27 kg/m <sup>2</sup>

Chantal Mathieu, Paresh Dandona, Andreas L. Birkenfeld, Troels Krarup Hansen, Nayyar Iqbal et al. (10 authors)

Diabetes Obesity and Metabolism2020-07-2128 citations

10.1111/dom.14144

1231-P: Dapagliflozin (DAPA) in Type 1 Diabetes (T1D): Pooled Outcomes from DEPICT-1 and -2

Paresh Dandona, Chantal Mathieu, Moshe Phillip, Lars Hansen, Fredrik Thorén et al. (8 authors)

Diabetes2019-06-013 citations

10.2337/db19-1231-p

Model‐based characterization of the relationship between dapagliflozin systemic exposure and HbA1c response in patients with type 1 diabetes mellitus

Joanna Parkinson, Weifeng Tang, Magnus Åstrand, Johanna Melin, Ella Ekholm et al. (7 authors)

Diabetes Obesity and Metabolism2019-02-139 citations

10.1111/dom.13664

Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial

Chantal Mathieu, Paresh Dandona, Pieter Gillard, Peter Senior, Christoph Hasslacher et al. (100 authors)

Diabetes Care2018-07-19245 citations

10.2337/dc18-0623

Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type 1 Diabetes—DEPICT-2 Study

Chantal Mathieu, Paresh Dandona, Pieter Gillard, Peter Senior, Christoph Hasslacher et al. (13 authors)

Diabetes2018-06-2213 citations

10.2337/db18-213-or

Dose-Response and Exposure-Response (HbA1c) of Dapagliflozin in T1DM Patients

Joanna Parkinson, Johanna Melin, Magnus Åstrand, Bengt Hamrén, David W. Boulton et al. (6 authors)

Diabetes2018-06-225 citations

10.2337/db18-1190-p

Interventions

DRUGDapagliflozin

Tablets

OTHERPlacebo for dapagliflozin

Tablets

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

No

Inclusion criteria

* Diagnosis of Type 1 Diabetes mellitus (T1DM) * Central laboratory C-peptide \< 0.7 ng/ml (0.23 nmol/L) * Insulin use for at least 12 months per patient reported or medical records * Method of insulin administration (MDI or CSII) must have been unchanged for at least 3 months prior to screening * Subjects must be on a total insulin dose of ≥ 0.3 U/kg/day for at least 3 months prior to screening * If on MDI insulin administration, subject must be on ≥ 3x injections per day * Screening Visit: Central laboratory HbA1c ≥ 7.7% and ≤ 11.0% * Body mass index (BMI) ≥ 18.5 kg/m2

Exclusion criteria

* History of Type 2 Diabetes mellitus (T2DM) or maturity onset diabetes of the young (MODY), pancreatic surgery, or chronic pancreatitis that could result in decreased beta cell capacity * Taking any non-insulin antihyperglicemic agent within 1 month prior to screening * Taking GLP-1 receptor agonist within 2 months prior to screening for once weekly administration and within 1 month prior to screening for once or twice daily administration * Taking metformin and/or thiazolidinediones within 2 months prior to screening * History of diabetes ketoacidosis requiring medical intervention within 1 month prior to screening * History of hospital admission for glycemic control (either hyperglycemia or hypoglycemia) within 1 month prior to screening * Frequent episodes of severe hypoglycemia (more than one episode requiring medical assistance, emergency care), and/or glucagon therapy administered by a third-party individual within 1 month prior to screening * History of Addison's disease

Design outcomes

Primary

Measure	Time frame	Description
Adjusted Mean Change From Baseline in HbA1c at Week 24	Baseline and 24 weeks	To compare the change from baseline in HbA1c between dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Secondary

Measure	Time frame	Description
Adjusted Mean Percentage Change From Baseline in Body Weight at Week 24	Baseline and 24 weeks	To compare the percentage change from baseline in body weight with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
Adjusted Mean Change From Baseline in 24-hour Continuous Glucose Monitoring (CGM) Mean Value at Week 24	Baseline and 24 weeks	To compare the change from baseline in mean value of 24-hour glucose readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
Adjusted Mean Percentage Change From Baseline in Total Daily Insulin Dose at Week 24	Baseline and 24 weeks	To compare the percent change from baseline in total daily insulin dose with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
Change From Baseline in the Percent of 24-hour Glucose Readings Obtained From CGM That Falls Within the Target Range of > 70 mg/dL and <= 180 mg/dL (%) at Week 24	Baseline and 24 weeks	To compare the change from baseline in the percent of 24-hour glucose readings obtained from CGM that falls within the target range of \>70 mg/dL and \<=180 mg/dL with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment
Percentage of Subjects With HbA1c Reduction From Baseline to Week 24 Last Observation Carried Forward (LOCF) >= 0.5% and Without Severe Hypoglycemia Events at Week 24	Baseline and 24 weeks	To compare dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin for the proportion of subjects achieving an HbA1c reduction from baseline to Week 24 visit \>=0.5% without severe hypoglycemia events
Adjusted Mean Change From Baseline in 24-hour CGM Mean Amplitude of Glycemic Excursion (MAGE) Value at Week 24	Baseline and 24 weeks	To compare the change from baseline in mean amplitude of glucose excursions (MAGE) of 24-hour glucose readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Countries

Argentina, Belgium, Canada, Chile, Germany, Japan, Netherlands, Poland, Russia, Sweden, Switzerland, United Kingdom, United States

Participant flow

Recruitment details

The results on this form are from the 24 week short-term double-blind treatment period. This study was conducted at 148 centers in 13 countries from 8 July 2015 to 2 Sep 2017.

Pre-assignment details

815 participants were randomized. Of the 195 participants not randomized: 97 No longer met study criteria, 44 withdrew consent, 13 were lost to follow-up, and 41 did not continue for other reasons. Two participants did not receive any study drug and were excluded from analyses. Thus, the total number of subjects is 813.

Participants by arm

Arm	Count
DAPA 5 MG + INS Dapagliflozin 5 mg plus insulin	271
DAPA 10 MG + INS Dapagliflozin 10 mg plus insulin	270
PLA + INS Placebo plus insulin	272
Total	813

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	17	11	11
Overall Study	Discontinued due to DKA/hypoglycemia	2	5	4
Overall Study	Lost to Follow-up	2	3	1
Overall Study	Pregnancy	0	0	2
Overall Study	Protocol Violation	1	1	1
Overall Study	Withdrawal by Subject	5	5	14

Baseline characteristics

Characteristic	DAPA 5 MG + INS	DAPA 10 MG + INS	PLA + INS	Total
Age, Continuous	42.7 Years STANDARD_DEVIATION 13.35	42.4 Years STANDARD_DEVIATION 12.8	43.0 Years STANDARD_DEVIATION 13.73	42.7 Years STANDARD_DEVIATION 13.29
Race/Ethnicity, Customized Asian	57 Participants	44 Participants	59 Participants	160 Participants
Race/Ethnicity, Customized Black or African-American	4 Participants	7 Participants	1 Participants	12 Participants
Race/Ethnicity, Customized Other	0 Participants	0 Participants	4 Participants	4 Participants
Race/Ethnicity, Customized White	210 Participants	219 Participants	208 Participants	637 Participants
Sex: Female, Male Female	153 Participants	149 Participants	153 Participants	455 Participants
Sex: Female, Male Male	118 Participants	121 Participants	119 Participants	358 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 271	0 / 270	0 / 272
other Total, other adverse events	79 / 271	77 / 270	63 / 272
serious Total, serious adverse events	18 / 271	7 / 270	5 / 272

Outcome results

Primary

Adjusted Mean Change From Baseline in HbA1c at Week 24

To compare the change from baseline in HbA1c between dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Time frame: Baseline and 24 weeks

Population: The analysis population for this endpoint is the number of subjects in the full analysis set with non-missing baseline and at least one post-baseline value. The full analysis set consists of all randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
DAPA 5 MG + INS	Adjusted Mean Change From Baseline in HbA1c at Week 24	-0.34 HbA1c (%)
DAPA 10 MG + INS	Adjusted Mean Change From Baseline in HbA1c at Week 24	-0.39 HbA1c (%)
PLA + INS	Adjusted Mean Change From Baseline in HbA1c at Week 24	0.03 HbA1c (%)

Comparison: Difference vs. placebo in adjusted mean change from baselinep-value: <0.000195% CI: [-0.49, -0.26]Mixed Models Analysis

Comparison: Difference vs. placebo in adjusted mean change from baselinep-value: <0.000195% CI: [-0.53, -0.3]Mixed Models Analysis

Secondary

Adjusted Mean Change From Baseline in 24-hour CGM Mean Amplitude of Glycemic Excursion (MAGE) Value at Week 24

To compare the change from baseline in mean amplitude of glucose excursions (MAGE) of 24-hour glucose readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Time frame: Baseline and 24 weeks

Population: Number of subjects in the full analysis set with non-missing baseline and at least one post-baseline value

Arm	Measure	Value (LEAST_SQUARES_MEAN)
DAPA 5 MG + INS	Adjusted Mean Change From Baseline in 24-hour CGM Mean Amplitude of Glycemic Excursion (MAGE) Value at Week 24	-10.17 mg/dL
DAPA 10 MG + INS	Adjusted Mean Change From Baseline in 24-hour CGM Mean Amplitude of Glycemic Excursion (MAGE) Value at Week 24	-9.68 mg/dL
PLA + INS	Adjusted Mean Change From Baseline in 24-hour CGM Mean Amplitude of Glycemic Excursion (MAGE) Value at Week 24	-0.33 mg/dL

Comparison: Difference vs. placebo in adjusted mean change from baselinep-value: <0.000195% CI: [-14.66, -5.03]Mixed Models Analysis

Comparison: Difference vs. placebo in adjusted mean change from baselinep-value: 0.000195% CI: [-14.16, -4.55]Mixed Models Analysis

Secondary

Adjusted Mean Change From Baseline in 24-hour Continuous Glucose Monitoring (CGM) Mean Value at Week 24

To compare the change from baseline in mean value of 24-hour glucose readings obtained from CGM with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Time frame: Baseline and 24 weeks

Population: The number of subjects in the full analysis set with non-missing baseline and at least one post-baseline value

Arm	Measure	Value (LEAST_SQUARES_MEAN)
DAPA 5 MG + INS	Adjusted Mean Change From Baseline in 24-hour Continuous Glucose Monitoring (CGM) Mean Value at Week 24	-6.46 mg/dL
DAPA 10 MG + INS	Adjusted Mean Change From Baseline in 24-hour Continuous Glucose Monitoring (CGM) Mean Value at Week 24	-10.54 mg/dL
PLA + INS	Adjusted Mean Change From Baseline in 24-hour Continuous Glucose Monitoring (CGM) Mean Value at Week 24	9.20 mg/dL

Comparison: Difference vs. placebo in adjusted mean change from baselinep-value: <0.000195% CI: [-20.26, -11.05]Mixed Models Analysis

Comparison: Difference vs. placebo in adjusted mean change from baselinep-value: <0.000195% CI: [-24.34, -15.14]Mixed Models Analysis

Secondary

Adjusted Mean Percentage Change From Baseline in Body Weight at Week 24

To compare the percentage change from baseline in body weight with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Time frame: Baseline and 24 weeks

Population: Number of subjects in full analysis set with non-missing baseline and at least one post-baseline value

Arm	Measure	Value (LEAST_SQUARES_MEAN)
DAPA 5 MG + INS	Adjusted Mean Percentage Change From Baseline in Body Weight at Week 24	-3.22 Percentage change
DAPA 10 MG + INS	Adjusted Mean Percentage Change From Baseline in Body Weight at Week 24	-3.76 Percentage change
PLA + INS	Adjusted Mean Percentage Change From Baseline in Body Weight at Week 24	-0.02 Percentage change

Comparison: Difference vs. placebo in adjusted mean percentage change from baselinep-value: <0.000195% CI: [-3.96, -2.45]Mixed Models Analysis

Comparison: Difference vs. placebo in adjusted mean percentage change from baselinep-value: <0.000195% CI: [-4.49, -2.99]Mixed Models Analysis

Secondary

Adjusted Mean Percentage Change From Baseline in Total Daily Insulin Dose at Week 24

To compare the percent change from baseline in total daily insulin dose with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Time frame: Baseline and 24 weeks

Population: Number of subjects in full analysis set with non-missing baseline and at least one post-baseline value

Arm	Measure	Value (LEAST_SQUARES_MEAN)
DAPA 5 MG + INS	Adjusted Mean Percentage Change From Baseline in Total Daily Insulin Dose at Week 24	-8.73 Percentage change
DAPA 10 MG + INS	Adjusted Mean Percentage Change From Baseline in Total Daily Insulin Dose at Week 24	-9.05 Percentage change
PLA + INS	Adjusted Mean Percentage Change From Baseline in Total Daily Insulin Dose at Week 24	2.29 Percentage change

Comparison: Difference vs. placebo in adjusted mean percentage change from baselinep-value: <0.000195% CI: [-13.73, -7.72]Mixed Models Analysis

Comparison: Difference vs. placebo in adjusted mean percentage change from baselinep-value: <0.000195% CI: [-14.04, -8.02]Mixed Models Analysis

Secondary

Change From Baseline in the Percent of 24-hour Glucose Readings Obtained From CGM That Falls Within the Target Range of > 70 mg/dL and <= 180 mg/dL (%) at Week 24

To compare the change from baseline in the percent of 24-hour glucose readings obtained from CGM that falls within the target range of \>70 mg/dL and \<=180 mg/dL with dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin after 24 weeks of double-blinded treatment

Time frame: Baseline and 24 weeks

Population: Number of subjects in the full analysis set with non-missing baseline and at least one post-baseline value

Arm	Measure	Value (LEAST_SQUARES_MEAN)
DAPA 5 MG + INS	Change From Baseline in the Percent of 24-hour Glucose Readings Obtained From CGM That Falls Within the Target Range of > 70 mg/dL and <= 180 mg/dL (%) at Week 24	5.92 % of readings
DAPA 10 MG + INS	Change From Baseline in the Percent of 24-hour Glucose Readings Obtained From CGM That Falls Within the Target Range of > 70 mg/dL and <= 180 mg/dL (%) at Week 24	7.60 % of readings
PLA + INS	Change From Baseline in the Percent of 24-hour Glucose Readings Obtained From CGM That Falls Within the Target Range of > 70 mg/dL and <= 180 mg/dL (%) at Week 24	-3.10 % of readings

Comparison: Difference vs. placebo in adjusted mean change from baselinep-value: <0.000195% CI: [6.97, 11.06]Mixed Models Analysis

Comparison: Difference vs. placebo in adjusted mean change from baselinep-value: <0.000195% CI: [8.66, 12.74]Mixed Models Analysis

Secondary

Percentage of Subjects With HbA1c Reduction From Baseline to Week 24 Last Observation Carried Forward (LOCF) >= 0.5% and Without Severe Hypoglycemia Events at Week 24

To compare dapagliflozin 5 mg or 10 mg plus adjustable insulin versus placebo plus adjustable insulin for the proportion of subjects achieving an HbA1c reduction from baseline to Week 24 visit \>=0.5% without severe hypoglycemia events

Time frame: Baseline and 24 weeks

Population: Number of subjects in the full analysis set with non-missing baseline and Week 24 (LOCF) values.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
DAPA 5 MG + INS	Percentage of Subjects With HbA1c Reduction From Baseline to Week 24 Last Observation Carried Forward (LOCF) >= 0.5% and Without Severe Hypoglycemia Events at Week 24	Number of Responders	105 Participants
DAPA 10 MG + INS	Percentage of Subjects With HbA1c Reduction From Baseline to Week 24 Last Observation Carried Forward (LOCF) >= 0.5% and Without Severe Hypoglycemia Events at Week 24	Number of Responders	111 Participants
PLA + INS	Percentage of Subjects With HbA1c Reduction From Baseline to Week 24 Last Observation Carried Forward (LOCF) >= 0.5% and Without Severe Hypoglycemia Events at Week 24	Number of Responders	54 Participants

Comparison: Odds Ratio vs. Placebop-value: <0.000195% CI: [1.81, 4.06]Regression, Logistic

Comparison: Odds Ratio vs. Placebop-value: <0.000195% CI: [2.05, 4.6]Regression, Logistic

Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Adjusted Mean Change From Baseline in HbA1c at Week 24

Adjusted Mean Change From Baseline in 24-hour CGM Mean Amplitude of Glycemic Excursion (MAGE) Value at Week 24

Adjusted Mean Change From Baseline in 24-hour Continuous Glucose Monitoring (CGM) Mean Value at Week 24

Adjusted Mean Percentage Change From Baseline in Body Weight at Week 24

Adjusted Mean Percentage Change From Baseline in Total Daily Insulin Dose at Week 24

Change From Baseline in the Percent of 24-hour Glucose Readings Obtained From CGM That Falls Within the Target Range of > 70 mg/dL and <= 180 mg/dL (%) at Week 24

Percentage of Subjects With HbA1c Reduction From Baseline to Week 24 Last Observation Carried Forward (LOCF) >= 0.5% and Without Severe Hypoglycemia Events at Week 24