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-1 52-Week Study

Paresh Dandona, Chantal Mathieu, Moshe Phillip, Lars Hansen, Diethelm Tschöpe et al. (100 authors)

Diabetes Care2018-10-23228 citations

10.2337/dc18-1087

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

Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial.

Dandona P, Mathieu C, Phillip M, Hansen L, Griffen SC, Tschöpe D, Thorén F, Xu J, Langkilde AM, DEPICT-1 Investigators.

2017-09-14226 citations

10.1016/s2213-8587(17)30308-x

Interventions

DRUGDapagliflozin

Tablets

DRUGPlacebo 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 metformin and/or thiazolidinediones within 2 months prior to screening * Taking any antidiabetic medication (other than insulin), 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 * 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 in HbA1c From Baseline at Week 24	From Baseline to Week 24	Adjusted mean change from baseline in HbA1c at Week 24 (Repeated Measures Model\[RMM\]).

Secondary

Measure	Time frame	Description
Adjusted Mean Percent Change in Body Weight From Baseline at Week 24	From Baseline to Week 24	Adjusted mean percent change from baseline in body weight at Week 24 (Repeated Measures Model\[RMM\])
Adjusted Mean Change in 24-hour Mean Continuous Glucose Monitoring Glucose From Baseline at Week 24	From Baseline to Week 24	Adjusted mean change in 24-hour mean Continuous Glucose Monitoring glucose from baseline at Week 24 (Repeated Measures Model\[RMM\])
Adjusted Mean Percent Change in Total Daily Insulin Dose From Baseline at Week 24	From Baseline to Week 24	Adjusted mean change from baseline in Total Daily Insulin Dose at Week 24 (Repeated Measures Model\[RMM\])
Adjusted Mean Change in Percent 24-hour Continuous Glucose Monitoring Glucose > 70 and <= 180 (mg/dL) From Baseline at Week 24	From Baseline to Week 24	Adjusted Mean Change in Percent 24-hour Continuous Glucose Monitoring Glucose \> 70 and \<= 180 (mg/dL) from Baseline at Week 24 (Repeated Measures Model\[RMM\])
Subjects With HbA1c Reduction From Baseline to Week 24 (LOCF) >= 0.5% and Without Severe Hypoglycemia Events	From Baseline to Week 24	Subjects with HbA1c reduction from baseline to week 24 (LOCF) \>= 0.5% and without severe hypoglycemia events
Adjusted Mean Change in 24-hour Continuous Glucose Monitoring MAGE From Baseline at Week 24	From Baseline to Week 24	Adjusted Mean Change in 24-hour Continuous Glucose Monitoring Mean Amplitude of Glucose Excursions (MAGE) from Baseline at Week 24 (Repeated Measures Model\[RMM\])

Countries

Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Mexico, Romania, Spain, Sweden, United Kingdom, United States

Participant flow

Recruitment details

The first subject was enrolled on 11 November 2014. The last subject completed the 24-week short-term treatment period 04 January 2017 and the last subject completed the study 25 August 2017. This study was conducted at 138 sites in 17 countries.

Pre-assignment details

833 participants were randomized to a treatment group. Of the 771 participants not randomized to a treatment group: 585 No longer met study criteria, 125 withdrew consent, 26 were lost to follow-up, and 35 did not continue for other reasons

Participants by arm

Arm	Count
Dapagliflozin 5 mg + Insulin Dapagliflozin 5 mg oral tablet once daily + background insulin	277
Dapagliflozin 10 mg + Insulin Dapagliflozin 10 mg oral tablet once daily + background insulin	296
Placebo + Insulin Placebo oral tablet once daily + background insulin	260
Total	833

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	11	14	9
Overall Study	Lack of Efficacy	1	0	2
Overall Study	Lost to Follow-up	3	3	4
Overall Study	Not entering long-term period	2	3	5
Overall Study	Other reasons	7	3	3
Overall Study	Poor/non-compliance	2	1	2
Overall Study	Pregnancy	2	2	1
Overall Study	Subject no longer meets study criteria	0	2	0
Overall Study	Subject request to discontinue treatment	10	8	6
Overall Study	Withdrawal by Subject	4	5	10

Baseline characteristics

Characteristic	Dapagliflozin 5 mg + Insulin	Dapagliflozin 10 mg + Insulin	Placebo + Insulin	Total
Age, Continuous	42.1 Years STANDARD_DEVIATION 13.94	43.4 Years STANDARD_DEVIATION 13.89	42.7 Years STANDARD_DEVIATION 13.57	42.7 Years STANDARD_DEVIATION 13.8
Age, Customized < 65 years	262 Participants	279 Participants	246 Participants	787 Participants
Age, Customized >= 75 years	0 Participants	1 Participants	0 Participants	1 Participants
Age, Customized Between 65 and 75 years	15 Participants	16 Participants	14 Participants	45 Participants
Sex: Female, Male Female	158 Participants	144 Participants	128 Participants	430 Participants
Sex: Female, Male Male	119 Participants	152 Participants	132 Participants	403 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 277	0 / 296	1 / 260
other Total, other adverse events	123 / 277	118 / 296	99 / 260
serious Total, serious adverse events	37 / 277	40 / 296	30 / 260

Outcome results

Primary

Adjusted Mean Change in HbA1c From Baseline at Week 24

Adjusted mean change from baseline in HbA1c at Week 24 (Repeated Measures Model\[RMM\]).

Time frame: From Baseline to Week 24

Population: All randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period. The first 55 randomized subjects will be excluded from the full analysis dataset due to the presence of a randomization system error.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Dapagliflozin 5 mg + Insulin	Adjusted Mean Change in HbA1c From Baseline at Week 24	-0.45 Percentage of hemoglobin	Standard Error 0.0537
Dapagliflozin 10 mg + Insulin	Adjusted Mean Change in HbA1c From Baseline at Week 24	-0.47 Percentage of hemoglobin	Standard Error 0.0538
Placebo + Insulin	Adjusted Mean Change in HbA1c From Baseline at Week 24	-0.03 Percentage of hemoglobin	Standard Error 0.054

p-value: <0.000195% CI: [-0.56, -0.28]RMM

p-value: <0.000195% CI: [-0.58, -0.31]RMM

Secondary

Adjusted Mean Change in 24-hour Continuous Glucose Monitoring MAGE From Baseline at Week 24

Adjusted Mean Change in 24-hour Continuous Glucose Monitoring Mean Amplitude of Glucose Excursions (MAGE) from Baseline at Week 24 (Repeated Measures Model\[RMM\])

Time frame: From Baseline to Week 24

Population: All randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period. The first 55 randomized subjects will be excluded from the full analysis dataset due to the presence of a randomization system error.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Dapagliflozin 5 mg + Insulin	Adjusted Mean Change in 24-hour Continuous Glucose Monitoring MAGE From Baseline at Week 24	-14.92 mg/dL	Standard Error 1.9915
Dapagliflozin 10 mg + Insulin	Adjusted Mean Change in 24-hour Continuous Glucose Monitoring MAGE From Baseline at Week 24	-16.55 mg/dL	Standard Error 2.0419
Placebo + Insulin	Adjusted Mean Change in 24-hour Continuous Glucose Monitoring MAGE From Baseline at Week 24	2.38 mg/dL	Standard Error 2.0477

p-value: <0.000195% CI: [-22.46, -12.14]RMM

p-value: <0.000195% CI: [-24.13, -13.73]RMM

Secondary

Adjusted Mean Change in 24-hour Mean Continuous Glucose Monitoring Glucose From Baseline at Week 24

Adjusted mean change in 24-hour mean Continuous Glucose Monitoring glucose from baseline at Week 24 (Repeated Measures Model\[RMM\])

Time frame: From Baseline to Week 24

Population: All randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period. The first 55 randomized subjects will be excluded from the full analysis dataset due to the presence of a randomization system error.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Dapagliflozin 5 mg + Insulin	Adjusted Mean Change in 24-hour Mean Continuous Glucose Monitoring Glucose From Baseline at Week 24	-10.28 mg/dL	Standard Error 1.8862
Dapagliflozin 10 mg + Insulin	Adjusted Mean Change in 24-hour Mean Continuous Glucose Monitoring Glucose From Baseline at Week 24	-12.97 mg/dL	Standard Error 1.9231
Placebo + Insulin	Adjusted Mean Change in 24-hour Mean Continuous Glucose Monitoring Glucose From Baseline at Week 24	5.06 mg/dL	Standard Error 1.932

p-value: <0.000195% CI: [-20.22, -10.46]RMM

p-value: <0.000195% CI: [-22.95, -13.11]RMM

Secondary

Adjusted Mean Change in Percent 24-hour Continuous Glucose Monitoring Glucose > 70 and <= 180 (mg/dL) From Baseline at Week 24

Adjusted Mean Change in Percent 24-hour Continuous Glucose Monitoring Glucose \> 70 and \<= 180 (mg/dL) from Baseline at Week 24 (Repeated Measures Model\[RMM\])

Time frame: From Baseline to Week 24

Population: All randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period. The first 55 randomized subjects will be excluded from the full analysis dataset due to the presence of a randomization system error.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Dapagliflozin 5 mg + Insulin	Adjusted Mean Change in Percent 24-hour Continuous Glucose Monitoring Glucose > 70 and <= 180 (mg/dL) From Baseline at Week 24	6.98 Percentage	Standard Error 0.8824
Dapagliflozin 10 mg + Insulin	Adjusted Mean Change in Percent 24-hour Continuous Glucose Monitoring Glucose > 70 and <= 180 (mg/dL) From Baseline at Week 24	8.52 Percentage	Standard Error 0.9
Placebo + Insulin	Adjusted Mean Change in Percent 24-hour Continuous Glucose Monitoring Glucose > 70 and <= 180 (mg/dL) From Baseline at Week 24	-2.13 Percentage	Standard Error 0.9032

p-value: <0.000195% CI: [6.83, 11.39]RMM

p-value: <0.000195% CI: [8.35, 12.94]RMM

Secondary

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

Adjusted mean percent change from baseline in body weight at Week 24 (Repeated Measures Model\[RMM\])

Time frame: From Baseline to Week 24

Population: All randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period. The first 55 randomized subjects will be excluded from the full analysis dataset due to the presence of a randomization system error.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Dapagliflozin 5 mg + Insulin	Adjusted Mean Percent Change in Body Weight From Baseline at Week 24	-3.00 Kg	Standard Error 0.233
Dapagliflozin 10 mg + Insulin	Adjusted Mean Percent Change in Body Weight From Baseline at Week 24	-3.67 Kg	Standard Error 0.2299
Placebo + Insulin	Adjusted Mean Percent Change in Body Weight From Baseline at Week 24	0.05 Kg	Standard Error 0.2407

p-value: <0.000195% CI: [-3.68, -2.41]RMM

p-value: <0.000195% CI: [-4.34, -3.08]RMM

Secondary

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

Adjusted mean change from baseline in Total Daily Insulin Dose at Week 24 (Repeated Measures Model\[RMM\])

Time frame: From Baseline to Week 24

Population: All randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period. The first 55 randomized subjects will be excluded from the full analysis dataset due to the presence of a randomization system error.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Dapagliflozin 5 mg + Insulin	Adjusted Mean Percent Change in Total Daily Insulin Dose From Baseline at Week 24	-7.74 IU	Standard Error 1.4881
Dapagliflozin 10 mg + Insulin	Adjusted Mean Percent Change in Total Daily Insulin Dose From Baseline at Week 24	-12.16 IU	Standard Error 1.4326
Placebo + Insulin	Adjusted Mean Percent Change in Total Daily Insulin Dose From Baseline at Week 24	1.16 IU	Standard Error 1.6593

p-value: <0.000195% CI: [-12.56, -4.88]RMM

p-value: <0.000195% CI: [-16.75, -9.43]RMM

Secondary

Subjects With HbA1c Reduction From Baseline to Week 24 (LOCF) >= 0.5% and Without Severe Hypoglycemia Events

Subjects with HbA1c reduction from baseline to week 24 (LOCF) \>= 0.5% and without severe hypoglycemia events

Time frame: From Baseline to Week 24

Population: All randomized subjects who took at least one dose of double-blind study medication during the short-term double-blind period. The first 55 randomized subjects will be excluded from the full analysis dataset due to the presence of a randomization system error.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Dapagliflozin 5 mg + Insulin	Subjects With HbA1c Reduction From Baseline to Week 24 (LOCF) >= 0.5% and Without Severe Hypoglycemia Events	Responders	127 Participants
Dapagliflozin 10 mg + Insulin	Subjects With HbA1c Reduction From Baseline to Week 24 (LOCF) >= 0.5% and Without Severe Hypoglycemia Events	Responders	129 Participants
Placebo + Insulin	Subjects With HbA1c Reduction From Baseline to Week 24 (LOCF) >= 0.5% and Without Severe Hypoglycemia Events	Responders	65 Participants

p-value: <0.000195% CI: [2.1, 4.56]Regression, Logistic

p-value: <0.000195% CI: [2.23, 4.85]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 in HbA1c From Baseline at Week 24

Adjusted Mean Change in 24-hour Continuous Glucose Monitoring MAGE From Baseline at Week 24

Adjusted Mean Change in 24-hour Mean Continuous Glucose Monitoring Glucose From Baseline at Week 24

Adjusted Mean Change in Percent 24-hour Continuous Glucose Monitoring Glucose > 70 and <= 180 (mg/dL) From Baseline at Week 24

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

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

Subjects With HbA1c Reduction From Baseline to Week 24 (LOCF) >= 0.5% and Without Severe Hypoglycemia Events