Study to Evaluate Safety and Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Aged 10-24 Years

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02725593
• Collaborator: Parexel (Industry), Q2 Solutions (Industry), PRA Health Sciences (Industry), Covance Laboratories, Inc (Other)
• Enrollment: 72
• Locations: 42
• Arms: 2
• Actual Duration (Months): 45.5
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

A trial of patients aged 10-24 years with type 2 diabetes mellitus to evaluate the comparative efficacy and safety between dapagliflozin and Placebo.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: Dapagliflozin; Drug: Dapagliflozin placebo	Phase 3

Detailed Description

A 24 Week, Multicenter, Randomized, Double-Blind, Parallel Group, Phase 3 Trial with a 28 Week Long Term Safety Extension Period Evaluating the Safety and Efficacy of Dapagliflozin 10 mg in T2DM Patients aged 10-24 years

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A 24 Week, Multicenter, Randomized, Double-Blind, Parallel Group, Phase 3 Trial With a 28 Week Long Term Safety Extension Period Evaluating the Safety and Efficacy of Dapagliflozin 10 mg in T2DM Patients Aged 10-24 Years
• Actual Study Start Date: Jun 22, 2016
• Actual Primary Completion Date: Apr 6, 2020
• Actual Study Completion Date: Apr 6, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dapagliflozin	Drug: Dapagliflozin; Dapagliflozin 10 mg tablets administered orally once daily, for the 24-week blinded treatment period. Dapagliflozin 10mg tablets administered orally once daily, for the 28-week site and subject blinded long term extension.; Other Names: FORXIGA
Placebo Comparator: Dapagliflozin placebo	Drug: Dapagliflozin placebo; matching placebo tablets, administered orally once daily, for the 24-week blinded treatment period. Dapagliflozin 10mg tablets administered orally once daily,for the 28-week site and subject blinded long term extension.

Outcome Measures

Primary Outcome Measures

1. Adjusted Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 24 [Baseline to Week 24]

Secondary Outcome Measures

1. Adjusted Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 [Baseline to Week 24]

2. Percentage of Participants Who Required Glycemic Rescue Medication or Permanently Discontinued Treatment Due to Lack of Glycemic Control [Baseline to Week 24]

3. Percentage of Participants With Baseline Glycated Haemoglobin (HbA1c) >= 7% Who Achieved HbA1c Level < 7% at Week 24 [Baseline to Week 24]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 24 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Provision of informed consent prior to any study-specific procedures

2. Males and Females, ages 10 years of age, up to but not including 25 years of age at the time of randomization

3. Previously diagnosed as having type 2 diabetes for at least 2 months by WHO/ADA diagnostic criteria

4. HbA1c >= 6.5% and <= 11% obtained at screening visit

5. Currently on diet and exercise and a stable dose of metformin (at least 1000 mg daily) for a minimum of 8 weeks, or stable dose of insulin for a minimum of 8 weeks, or a stable combination of metformin (at least 1000 mg daily) and insulin for a minimum of 8 weeks prior to screening

6. FPG <=255 mg/dL (<= 14.2 mmol/L) obtained at screening visit

Exclusion Criteria:

1. Previous diagnosis of Type 1 diabetes

2. Diabetes ketoacidosis (DKA) within 6 months of screening

3. Current use of the following medications for the treatment of diabetes, or use within the specified timeframe prior to screening for the main study:

• Eight weeks: sulfonylureas, alpha glucosidase inhibitors, metiglinide, or injectable incretins or incretin mimetics or other antidiabetes medications not otherwise specified

• Sixteen weeks: thiazolidinediones

• Any previous history or current use of an SGLT2 inhibitor, including dapagliflozin

1. Initiation or discontinuation of prescription or non-prescription weight loss drugs within 8 weeks of screening.

Use of prescription or non-prescription weight loss drugs must be stable during the study

1. Pregnant, positive serum pregnancy test, planning to become pregnant during the clinical trials, or breastfeeding

2. History of unstable or rapidly progressive renal disease

3. History of unresolved vesico-ureteral reflux

4. Replacement or chronic systemic corticosteroid therapy, defined as any dose of systemic corticosteroid taken for > 4 weeks within 3 months prior to the Day 1 visit.

Note: Topical, nasal, or inhaled corticosteroids are allowed

1. Abnormal renal function, which is defined in subjects < 18 years of age as an estimated glomerular filtration rate (eGFR) calculated by the Schwartz Formula < 80 mL/min/1.73 m2 (1.33 mL/s), and in subjects >= 18 years as an estimated glomerular filtration rate (eGFR) calculated by the MDRD Formula < 60 mL/min/1.73 m2 (1.33 mL/s)

2. Presence of either: antibodies to glutamic acid decarboxylase (GAD) or protein tyrosine phosphatase-like protein antibodies (IA-2)

3. An abnormal TSH value at screening will be further evaluated for free T4. Subjects with abnormal free T4 values will be excluded

4. Hematuria (confirmed by microscopy at screening) with no explanation as judged by the investigator up to randomization

5. Anemia of any etiology defined as hemoglobin <=10.7 g/dL (107 g/L) for females and <= 11.3 g/dL (113 g/L) for males. Subjects who are considered to have anemia according to local guidelines should be excluded

6. Volume-depleted subjects. Subjects at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics, should carefully monitor their volume status

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	New Haven	Connecticut	United States	06514-3434
2	Research Site	Washington	District of Columbia	United States	20010
3	Research Site	Gainesville	Florida	United States	32610
4	Research Site	Homestead	Florida	United States	33032
5	Research Site	Miami	Florida	United States	33015
6	Research Site	Boston	Massachusetts	United States	02215
7	Research Site	Bronx	New York	United States	10467
8	Research Site	Buffalo	New York	United States	14222
9	Research Site	Columbus	Ohio	United States	43205
10	Research Site	Philadelphia	Pennsylvania	United States	19104
11	Research Site	Greenville	South Carolina	United States	29615
12	Research Site	Memphis	Tennessee	United States	38116
13	Research Site	Memphis	Tennessee	United States	38119
14	Research Site	Lampasas	Texas	United States	76550
15	Research Site	McAllen	Texas	United States	78503
16	Research Site	Budapest		Hungary	1023
17	Research Site	Nyíregyháza		Hungary	4400
18	Research Site	Beer Sheva		Israel	84101
19	Research Site	Haifa		Israel	91096
20	Research Site	Jerusalem		Israel	91120
21	Research Site	Ramat Gan		Israel	5265601
22	Research Site	Zerifin		Israel	70300
23	Research Site	Culiacan		Mexico	80230
24	Research Site	Guadalajara		Mexico	44670
25	Research Site	Merida		Mexico	97134
26	Research Site	Monterrey		Mexico	64460
27	Research Site	México, D.F.		Mexico	11410
28	Research Site	Zapopan		Mexico	45116
29	Research Site	Oradea		Romania	410169
30	Research Site	Timisoara		Romania	300011
31	Research Site	Izhevsk		Russian Federation	426009
32	Research Site	Krasnoyarsk		Russian Federation	660022
33	Research Site	Moscow		Russian Federation	117036
34	Research Site	Novosibirsk		Russian Federation	630087
35	Research Site	Pyatigorsk		Russian Federation	357500
36	Research Site	Rostov-on-Don		Russian Federation	344022
37	Research Site	Samara		Russian Federation	443079
38	Research Site	Saratov		Russian Federation	410054
39	Research Site	St. Petersburg		Russian Federation	194100
40	Research Site	Tomsk		Russian Federation	634050
41	Research Site	Kent		United Kingdom	CT9 4AN
42	Research Site	Leicester		United Kingdom	LE15WW

Sponsors and Collaborators

• AstraZeneca
• Parexel
• Q2 Solutions
• PRA Health Sciences
• Covance Laboratories, Inc

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 20, 2017
• Statistical Analysis Plan - Mar 11, 2020

More Information

Additional Information:

• D1690C00017_CSP_redacted
• D1690C00017_SAP_redacted

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02725593
• Other Study ID Numbers: D1690C00017; 2015-005041-31
• First Posted: Apr 1, 2016
• Last Update Posted: Feb 23, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by AstraZeneca: Diabetes Mellitus; Dapagliflozin; Placebo; Insulin resistance; Metabolic Diseases
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Dapagliflozin

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 42 study centres in 7 countries worldwide.

Arm/Group Title	Dapagliflozin 10mg/ Dapagliflozin 10mg	Placebo/ Dapagliflozin 10mg
Arm/Group Description	Dapagliflozin (10 mg) tablet administered orally, once daily for the 24 week double-blinded treatment period. The participants then continued to receive Dapagliflozin (10 mg) once daily for a further 28 weeks in the open label long term-extension.	Matching placebo tablet administered orally, once daily for the 24 weeks double-blinded treatment period. The participants then received Dapagliflozin (10 mg), orally, once daily for a further 28 weeks in the open label long-term extension.
Period Title: Blinded Treatment Period
STARTED	39	33
Received Treatment	39	33
COMPLETED	34	27
NOT COMPLETED	5	6
Period Title: Blinded Treatment Period
STARTED	33	27
COMPLETED	32	24
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	Dapagliflozin 10mg/ Dapagliflozin 10mg	Placebo/ Dapagliflozin 10mg	Total
Arm/Group Description	Dapagliflozin (10 mg) tablet administered orally, once daily for the 24 week double-blinded treatment period. The participants then continued to receive Dapagliflozin (10 mg) once daily for a further 28 weeks in the open label long term-extension.	Matching placebo tablet administered orally, once daily for the 24 weeks double-blinded treatment period. The participants then received Dapagliflozin (10 mg), orally, once daily for a further 28 weeks in the open label long-term extension.	Total of all reporting groups
Overall Participants	39	33	72
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	16.1 (3.3)	16.2 (3.6)	16.1 (3.4)
Age, Customized (Count of Participants)
≥10 and ≤15	16 41%	14 42.4%	30 41.7%
>15 and <18	13 33.3%	10 30.3%	23 31.9%
≥18 and <25	10 25.6%	9 27.3%	19 26.4%
Sex: Female, Male (Count of Participants)
Female	24 61.5%	19 57.6%	43 59.7%
Male	15 38.5%	14 42.4%	29 40.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 30.8%	12 36.4%	24 33.3%
Not Hispanic or Latino	26 66.7%	21 63.6%	47 65.3%
Unknown or Not Reported	1 2.6%	0 0%	1 1.4%
Race/Ethnicity, Customized (Count of Participants)
White	28 71.8%	16 48.5%	44 61.1%
Black or African American	8 20.5%	10 30.3%	18 25%
Asian	0 0%	1 3%	1 1.4%
Native Hawaiian or other Pacific Islander	1 2.6%	0 0%	1 1.4%
American Indian or Alaska Native	2 5.1%	3 9.1%	5 6.9%
Other	0 0%	3 9.1%	3 4.2%
Geographic Region (Count of Participants)
North America	16 41%	16 48.5%	32 44.4%
Latin America	7 17.9%	9 27.3%	16 22.2%
Europe	16 41%	8 24.2%	24 33.3%
Asia/Pacific	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Adjusted Change From Baseline in Glycated Haemoglobin (HbA1c) at Week 24
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set: All participants who were randomized and assigned to a treatment group, with baseline and at least one-post baseline value, prior to rescue therapy initiation or discontinuation from study treatment.

Arm/Group Title	Dapagliflozin 10mg/ Dapagliflozin 10mg	Placebo/ Dapagliflozin 10mg
Arm/Group Description	Dapagliflozin (10 mg) tablet administered orally, once daily for the 24 week double-blinded treatment period. The participants then continued to receive Dapagliflozin (10 mg) once daily for a further 28 weeks in the open label long term-extension.	Matching placebo tablet administered orally, once daily for the 24 weeks double-blinded treatment period. The participants then received Dapagliflozin (10 mg), orally, once daily for a further 28 weeks in the open label long-term extension.
Measure Participants	31	23
Least Squares Mean (Standard Error) [Percentage of HbA1c]	-0.25 (0.30)	0.50 (0.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg/ Dapagliflozin 10mg, Placebo/ Dapagliflozin 10mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.101
	Comments
	Method	Mixed model repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.75
	Confidence Interval	(2-Sided) 95%; -1.65 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.45
	Estimation Comments

2. Secondary Outcome

Title	Adjusted Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set: All participants who were randomized and assigned to a treatment group, with baseline and at least one-post baseline value, prior to rescue therapy initiation or discontinuation from study treatment.

Arm/Group Title	Dapagliflozin 10mg/ Dapagliflozin 10mg	Placebo/ Dapagliflozin 10mg
Arm/Group Description	Dapagliflozin (10 mg) tablet administered orally, once daily for the 24 week double-blinded treatment period. The participants then continued to receive Dapagliflozin (10 mg) once daily for a further 28 weeks in the open label long term-extension.	Matching placebo tablet administered orally, once daily for the 24 weeks double-blinded treatment period. The participants then received Dapagliflozin (10 mg), orally, once daily for a further 28 weeks in the open label long-term extension.
Measure Participants	31	23
Least Squares Mean (Standard Error) [mmol/L]	-0.07 (0.53)	0.72 (0.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg/ Dapagliflozin 10mg, Placebo/ Dapagliflozin 10mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.340
	Comments
	Method	Mixed model repeated measures analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.78
	Confidence Interval	(2-Sided) 95%; -2.42 to 0.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.81
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants Who Required Glycemic Rescue Medication or Permanently Discontinued Treatment Due to Lack of Glycemic Control
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set: All participants who were randomized and assigned to a treatment group.

Arm/Group Title	Dapagliflozin 10mg/ Dapagliflozin 10mg	Placebo/ Dapagliflozin 10mg
Arm/Group Description	Dapagliflozin (10 mg) tablet administered orally, once daily for the 24 week double-blinded treatment period. The participants then continued to receive Dapagliflozin (10 mg) once daily for a further 28 weeks in the open label long term-extension.	Matching placebo tablet administered orally, once daily for the 24 weeks double-blinded treatment period. The participants then received Dapagliflozin (10 mg), orally, once daily for a further 28 weeks in the open label long-term extension.
Measure Participants	39	33
Number [Percentage of participants]	5.1 13.1%	9.1 27.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg/ Dapagliflozin 10mg, Placebo/ Dapagliflozin 10mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.655
	Comments
	Method	Fisher's exact test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.96
	Confidence Interval	(2-Sided) 95%; -20.11 to 9.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With Baseline Glycated Haemoglobin (HbA1c) >= 7% Who Achieved HbA1c Level < 7% at Week 24
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set: All participants who were randomized and assigned to a treatment group, with HbA1c >=7% at baseline, with baseline and at least one-post baseline value, prior to rescue therapy initiation or discontinuation from study treatment.

Arm/Group Title	Dapagliflozin 10mg/ Dapagliflozin 10mg	Placebo/ Dapagliflozin 10mg
Arm/Group Description	Dapagliflozin (10 mg) tablet administered orally, once daily for the 24 week double-blinded treatment period. The participants then continued to receive Dapagliflozin (10 mg) once daily for a further 28 weeks in the open label long term-extension.	Matching placebo tablet administered orally, once daily for the 24 weeks double-blinded treatment period. The participants then received Dapagliflozin (10 mg), orally, once daily for a further 28 weeks in the open label long-term extension.
Measure Participants	28	24
Number [Percentage of participants]	25.0 64.1%	4.2 12.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10mg/ Dapagliflozin 10mg, Placebo/ Dapagliflozin 10mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments
	Method	Fisher's exact test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	20.83
	Confidence Interval	(2-Sided) 95%; 0.50 to 41.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to a maximum of 56 weeks
Arm/Group Title	Dapagliflozin 10mg/ Dapagliflozin 10mg		Placebo/ Dapagliflozin 10mg
Arm/Group Description	Dapagliflozin (10 mg) tablet administered orally, once daily for the 24 week double-blinded treatment period. The participants then continued to receive Dapagliflozin (10 mg) once daily for a further 28 weeks in the open label long term-extension.		Matching placebo tablet administered orally, once daily for the 24 weeks double-blinded treatment period. The participants then received Dapagliflozin (10 mg), orally, once daily for a further 28 weeks in the open label long-term extension.
All Cause Mortality
	Dapagliflozin 10mg/ Dapagliflozin 10mg		Placebo/ Dapagliflozin 10mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		0/33 (0%)
Serious Adverse Events
	Dapagliflozin 10mg/ Dapagliflozin 10mg		Placebo/ Dapagliflozin 10mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/39 (5.1%)		3/33 (9.1%)
Gastrointestinal disorders
Abdominal pain lower	1/39 (2.6%)	1	0/33 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemia	0/39 (0%)	0	2/33 (6.1%)	2
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/39 (0%)	0	1/33 (3%)	1
Psychiatric disorders
Depression	1/39 (2.6%)	1	0/33 (0%)	0
Other (Not Including Serious) Adverse Events
	Dapagliflozin 10mg/ Dapagliflozin 10mg		Placebo/ Dapagliflozin 10mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/39 (61.5%)		19/33 (57.6%)
Gastrointestinal disorders
Diarrhoea	2/39 (5.1%)	2	2/33 (6.1%)	3
Nausea	3/39 (7.7%)	4	0/33 (0%)	0
Toothache	1/39 (2.6%)	1	2/33 (6.1%)	4
Vomiting	2/39 (5.1%)	2	0/33 (0%)	0
General disorders
Fatigue	2/39 (5.1%)	2	1/33 (3%)	2
Infections and infestations
Fungal infection	2/39 (5.1%)	3	1/33 (3%)	1
Gastroenteritis viral	2/39 (5.1%)	2	0/33 (0%)	0
Nasopharyngitis	5/39 (12.8%)	5	2/33 (6.1%)	3
Pharyngitis streptococcal	2/39 (5.1%)	2	1/33 (3%)	1
Pharyngotonsillitis	0/39 (0%)	0	2/33 (6.1%)	2
Upper respiratory tract infection	2/39 (5.1%)	2	0/33 (0%)	0
Urinary tract infection	3/39 (7.7%)	3	1/33 (3%)	1
Investigations
Weight increased	2/39 (5.1%)	2	0/33 (0%)	0
Metabolism and nutrition disorders
Dyslipidaemia	2/39 (5.1%)	2	1/33 (3%)	1
Hyperglycaemia	0/39 (0%)	0	2/33 (6.1%)	3
Hypertriglyceridaemia	1/39 (2.6%)	1	3/33 (9.1%)	3
Vitamin D deficiency	5/39 (12.8%)	5	2/33 (6.1%)	2
Musculoskeletal and connective tissue disorders
Back pain	2/39 (5.1%)	2	1/33 (3%)	2
Pain in extremity	2/39 (5.1%)	2	0/33 (0%)	0
Nervous system disorders
Dizziness	0/39 (0%)	0	2/33 (6.1%)	2
Headache	5/39 (12.8%)	6	4/33 (12.1%)	4
Renal and urinary disorders
Microalbuminuria	1/39 (2.6%)	1	2/33 (6.1%)	2
Respiratory, thoracic and mediastinal disorders
Cough	2/39 (5.1%)	2	2/33 (6.1%)	3
Oropharyngeal pain	4/39 (10.3%)	4	1/33 (3%)	1
Sinus congestion	2/39 (5.1%)	2	0/33 (0%)	0
Skin and subcutaneous tissue disorders
Rash	2/39 (5.1%)	2	1/33 (3%)	1
Vascular disorders
Hypertension	2/39 (5.1%)	2	1/33 (3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.