BMS - Safety, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Dapagliflozin in Type 1 Diabetes

Conditions

Type 1 Diabetes Mellitus

Brief summary

To obtain safety and tolerability information in patients with type 1 diabetes where Dapagliflozin is added on to Insulin (for 14 days)

Detailed description

Study Classification : Safety, Pharmacokinetics and Pharmacodynamics

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

Dapagliflozin Exposure Response in Japanese vs. Non-Japanese Patients with Type 1 Diabetes

Victor Sokolov, Tatiana A. Yakovleva, Shinya Ueda, Joanna Parkinson, Robert C. Penland et al. (7 authors)

Diabetes2018-06-221 citations

10.2337/db18-1174-p

Interventions

DRUGDapagliflozin

Tablets, Oral, 1 mg, Once daily, 14 days

DRUGPlacebo matching Dapagliflozin

Tablets, Oral, 0 mg, Once daily, 14 days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

No

Inclusion criteria

* Type 1 diabetes with central lab Glycosylated hemoglobin (A1C) ≥ 7.0% and ≤ 10.0% * Insulin use for at least 12 months and initiation immediately after diagnosis of diabetes * Method of Insulin administration \[multiple daily injections (MDI) or continuous subcutaneous Insulin infusion (CSII)\] stable ≥ 3 months * Stable basal Insulin dose ≥ 2 weeks * Ages 18 to 65 years * Central laboratory C-peptide value of \< 0.7 ng/mL * Body mass index (BMI) 18.5 to 35.0 kg/m2

Exclusion criteria

* History of type 2 diabetes mellitus (T2DM), maturity onset diabetes of young (MODY), pancreatic surgery or chronic pancreatitis * Oral hypoglycemic agents * History of diabetes ketoacidosis (DKA) within 24 weeks * History of hospital admission for glycemic control within 6 months * Frequent episodes of hypoglycemia (2 unexplained within 3 months) or hypoglycemic unawareness * Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) or Serum total bilirubin \> 2X Upper limit of normal (ULN) * Abnormal Free T4 \[if screening Thyroid Stimulating Hormone (TSH) abnormal\] * Estimated glomerular filtration rate (eGFR) Modification of Diet in Renal Disease (MDRD) formula ≤ 60 mL/min/1.73m2 * Cardiovascular (CV)/Vascular Diseases within 6 months

Design outcomes

Primary

Measure	Time frame	Description
Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7	From Baseline to Day 7	7-PGM was measured as milligrams per deciliter (mg/dL) by a central laboratory. Baseline was defined as the assessment on Day -1, prior to the start date and time of the first dose of the double-blind study medication. 7-PGM included the average of all available glucose values before and 2-hour (hr) after each meal (breakfast, lunch, dinner) as well as bedtime. Measurements were on Day -1, and Day 7 in the double-blind period.

Secondary

Measure	Time frame	Description
Dapagliflozin Pharmacokinetic Parameters on Day 7 - Time of Maximum Observed Plasma Concentration (Tmax)	Day 7 (0 hr to 24 hr post dose)	Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The Tmax was recorded directly from experimental observations.
Dapagliflozin Pharmacokinetic Parameters on Day 7 - Area Under the Concentration-Time Curve in One Dosing Interval (AUC[TAU])	Day 7 (0 hr to 24 hr post dose)	Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The concentrations below the lower limit of quantitation (\<LLOQ) were set as missing for the calculation of PK parameters as well as summary statistics. AUC\[TAU\], was calculated by a mixture of logand linear-trapezoidal summations.
Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Maximum Observed Plasma Concentration (Cmax)	Day 7 (0 hr to 24 hr post dose)	Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The Cmax was recorded directly from experimental observations.
Dapagliflozin Pharmacokinetic Parameters on Day 7 - Maximum Observed Plasma Concentration (Cmax)	Day 7 (0 hr to 24 hr post dose)	Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The Cmax was recorded directly from experimental observations.
Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Area Under the Concentration-Time Curve in One Dosing Interval (AUC[TAU])	Day 7 (0 hr to 24 hr post dose)	Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The concentrations below the lower limit of quantitation (\<LLOQ) were set as missing for the calculation of PK parameters as well as summary statistics. AUC\[TAU\], was calculated by a mixture of logand linear-trapezoidal summations.
Pharmacokinetic Parameters on Day 7 - Ratio of Metabolite (RM) to Parent AUC[TAU]	Day 7 (0 hr to 24 hr post dose)	Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The concentrations below the lower limit of quantitation (\<LLOQ) were set as missing for the calculation of PK parameters as well as summary statistics. MR was calculated as the ratio of metabolite to parent AUC(TAU), corrected for molecular weights of dapagliflozin and dapagliflozin 3-O-glucuronide (408.82 and 584.99, respectively).
Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Time of Maximum Observed Plasma Concentration (Tmax)	Day 7 (0 hr to 24 hr post dose)	Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The Tmax was recorded directly from experimental observations.

Countries

United States

Participant flow

Recruitment details

Of 171 participants enrolled, 76 completed a screening period. Of these 76 participants, 70 were randomized and received treatment. Of these 70 participants, 62 completed double-blind treatment period.

Participants by arm

Arm	Count
Placebo + Insulin Tablets, oral, once daily for 2 weeks	13
Dapagliflozin 1 mg + Insulin Tablets, oral, once daily for 2 weeks	13
Dapagliflozin 2.5 mg + Insulin Tablets, oral, once daily for 2 weeks	15
Dapagliflozin 5 mg + Insulin Tablets, oral, once daily for 2 weeks	14
Dapagliflozin 10 mg + Insulin Tablets, oral, once daily for 2 weeks	15
Total	70

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG003	FG004
Overall Study	Adverse Event	0	0	1	0
Overall Study	No longer met criteria, etc	0	0	0	2
Overall Study	Withdrawal by Subject	1	1	2	1

Baseline characteristics

Characteristic	Dapagliflozin 5 mg + Insulin	Placebo + Insulin	Dapagliflozin 1 mg + Insulin	Dapagliflozin 2.5 mg + Insulin	Dapagliflozin 10 mg + Insulin	Total
Age, Continuous	34.8 Years STANDARD_DEVIATION 14	34.5 Years STANDARD_DEVIATION 12.18	33.7 Years STANDARD_DEVIATION 9.11	35.7 Years STANDARD_DEVIATION 13.93	37.5 Years STANDARD_DEVIATION 15.24	35.3 Years STANDARD_DEVIATION 12.86
Age, Customized 45 years and older	5 Participants	3 Participants	2 Participants	4 Participants	5 Participants	19 Participants
Age, Customized Younger than 45 years	9 Participants	10 Participants	11 Participants	11 Participants	10 Participants	51 Participants
Race/Ethnicity, Customized Asian	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Black/African American	0 Participants	1 Participants	1 Participants	1 Participants	2 Participants	5 Participants
Race/Ethnicity, Customized Other	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized White	14 Participants	11 Participants	11 Participants	14 Participants	12 Participants	62 Participants
Sex/Gender, Customized Female	6 Participants	5 Participants	8 Participants	4 Participants	7 Participants	30 Participants
Sex/Gender, Customized Male	8 Participants	8 Participants	5 Participants	11 Participants	8 Participants	40 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	8 / 13	5 / 13	7 / 15	7 / 14	6 / 15
serious Total, serious adverse events	0 / 13	0 / 13	0 / 15	1 / 14	0 / 15

Outcome results

Primary

Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7

7-PGM was measured as milligrams per deciliter (mg/dL) by a central laboratory. Baseline was defined as the assessment on Day -1, prior to the start date and time of the first dose of the double-blind study medication. 7-PGM included the average of all available glucose values before and 2-hour (hr) after each meal (breakfast, lunch, dinner) as well as bedtime. Measurements were on Day -1, and Day 7 in the double-blind period.

Time frame: From Baseline to Day 7

Population: All randomized participants who received study medication and had nonmissing values at baseline and Day 7

Arm	Measure	Value (MEAN)	Dispersion
Placebo + Insulin	Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7	-16.52 mg/dL	Standard Error 14.6316
Dapagliflozin 1 mg + Insulin	Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7	-19.01 mg/dL	Standard Error 10.992
Dapagliflozin 2.5 mg + Insulin	Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7	-17.29 mg/dL	Standard Error 7.1451
Dapagliflozin 5 mg + Insulin	Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7	-23.40 mg/dL	Standard Error 9.4334
Dapagliflozin 10 mg + Insulin	Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7	-17.55 mg/dL	Standard Error 10.843

95% CI: [-40.85, 35.86]Descriptive statistics

95% CI: [-35.36, 33.82]Descriptive statistics

95% CI: [-42.21, 28.45]Descriptive statistics

95% CI: [-39.22, 37.16]Descriptive statistics

Secondary

Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Area Under the Concentration-Time Curve in One Dosing Interval (AUC[TAU])

Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The concentrations below the lower limit of quantitation (\<LLOQ) were set as missing for the calculation of PK parameters as well as summary statistics. AUC\[TAU\], was calculated by a mixture of logand linear-trapezoidal summations.

Time frame: Day 7 (0 hr to 24 hr post dose)