The PK and PD 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 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02582840

Enrollment

Registered

2015-10-21

Start date

2015-10-31

Completion date

2016-06-30

Last updated

2019-01-18

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 randomized, single-blind, 3 arm, parallel group, placebo controlled PK/PD study will enrol 30 Japanese male and female patients with T1DM and age 18 to 65 years, with inadequate glycemic control on insulin defined as HbA1c ≥ 7.0% and ≤ 10.0% at screening visit. lacebo-controlled design. Patients will be randomized in a 1:1:1 ratio into one of the 3 single-blinded treatment arms; dapagliflozin 5 mg, dapagliflozin 10 mg or placebo. CSII user are excluded.

Interventions

DRUGDapagliflozin 5mg

Dapagliflozin, a blood glucose lowering drug. Oral dose

DRUGDapagliflozin 10mg

Dapagliflozin, a blood glucose lowering drug. Oral dose

DRUGPlacebo tablet

Placebo tablet. Oral dose

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

SINGLE (Subject)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

* Signed Written Informed Consent Subjects or their legally responsible representatives must be willing and able to give signed and dated written informed consent. * Target Population Diagnosis of T1DM. In addition, the following criteria also needs to be met; Central laboratory test of C-peptide \< 0.7 ng/mL Subject re-enrolment: This study does not permit the re-enrolment of a subject who has discontinued the study as a screen failure * Insulin use for at least 12 months prior to the enrolment per subject report or medical records and Method of insulin administration (MDI) 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. CSII users are excluded. MDI insulin administration subject must be on ≥ 3x injections per day. * Gender and reproductive Status Japanese men and women. * HbA1c eligibility criteria include: Screening Visit: Central laboratory HbA1c ≥ 7.0 % and ≤ 10.0 % (One repeat HbA1c test for subjects in screening if their initial test result was an HbA1c ± 0.2% of the cut off values) * BMI ≥ 20.0 kg/m², ≤ 35.0 kg/m² at visit 1 * Ages 18 to 65 years, inclusive - ≥ 18 years old and \< 20 years old must have assent forms signed and dated by their parents or guardians

Exclusion criteria

* Target Disease Exceptions History of T2DM In cases where the subject has a history of T2DM and has a documented history of being auto-antibody positive for GAD65, tyrosine phosphatase IA-2/IA-2β, or Zinc Transporter 8 (ZnT8), or fasting c-peptide value below the lower limit of detection performed by local or central laborator, the subject will be eligible for screening * Maturity onset diabetes of young (MODY), Pancreatic surgery, chronic pancreatitis, or other pancreatic disorders that could result in decreased β-cell capacity (eg, pancreatogenous diabetes) * Any antihyperglycemic agent use, other than thiazolidinediones, or insulin, within 1 month prior to the screening visit. Use of thiazolidinediones within 6 months prior to the screening visit. * History of DKA requiring medical intervention (eg, emergency room visit and/or hospitalization) 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 * 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 Unstable pre-proliferative and proliferative retinopathy (untreated or under treatment). * 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 ≤ 60 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
24-hour Urinary Glucose (g/24h) Mean Change From Baseline on Day 7 - Pharmacodynamic (PD) Set	Baseline (the last available assessment prior to the first dose of study medication), Day 7	The 24-hour period is defined based on the morning void, from the first morning void to the one of the next day.
Dapagliflozin 3-O-Glucuronide Maximum Observed Plasma Concentration (Cmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set	Day 1-7	Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).
Dapagliflozin 3-O-Glucuronide Minimum Observed Plasma Concentration (Cmin) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set	Day 1-7	Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).
Dapagliflozin 3-O-Glucuronide Time of Maximum Observed Plasma Concentration (Tmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set	Day 1-7	Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).
Dapagliflozin 3-O-Glucuronide Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set	Day 1-7	Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).
Dapagliflozin Ratio of Metabolite to Parent AUC of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set	Day 1-7	Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).
Dapagliflozin Minimum Observed Plasma Concentration (Cmin) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set	Day 1-7	Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).
Dapagliflozin Maximum Observed Plasma Concentration (Cmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set	Day 1-7	Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).
Dapagliflozin Time of Maximum Observed Plasma Concentration (Tmax) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set	Day 1-7	Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).
Dapagliflozin Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of 7 Days Repeated Doses of Dapagliflozin - Pharmacokinetic (PK) Set	Day 1-7	Serial blood samples for determination of study drug were collected predose Day 1, Day 7 (60 minutes prior to dose), Day 7 (0, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose).

Secondary

Measure	Time frame	Description
Total Daily Insulin (IU) Percent Change From Baseline to Day 7 - Pharmacodynamic (PD) Set	Baseline (the last available assessment on or prior to the first dose of study medication), Day 7	Total daily insulin dose is defined as the sum of all insulin doses (basal+bolus+premixed) for each day. Mean percent change from baseline was calculated using the geometric mean back-transformed from the results calculated under the logarithm transformation.
Daily Basal Insulin (IU) Percent Change From Baseline to Day 7 - Pharmacodynamic (PD) Set	Baseline (the last available assessment on or prior to the first dose of study medication), Day 7	Mean percent change from baseline was calculated using the geometric mean back-transformed from the results calculated under the logarithm transformation.
Daily Bolus Insulin (IU) Percent Change From Baseline to Day 7 - Pharmacodynamic (PD) Set	Baseline (the last available assessment on or prior to the first dose of study medication), Day 7	Mean percent change from baseline was calculated using the geometric mean back-transformed from the results calculated under the logarithm transformation.
Fasting Plasma Glucose (FPG) (mg/dL) Change From Baseline to Day 7 - Pharmacodynamic (PD) Set	Baseline (the last available assessment on or prior to the first dose of study medication), Day 7	—
Seated Systolic Blood Pressure (mmHG) Change From Baseline to Day 7 - Pharmacodynamic (PD) Set	Baseline (the last available assessment on or prior to the first dose of study medication), Day 7	—

Countries

Japan

Participant flow

Recruitment details

26 October 2015 to 04 June 2016, Japan, patients with type 1 diabetes mellitus.

Pre-assignment details

Of 62 patients who signed informed consent, 42 eligible patients randomized and completed the 7-day treatment period (Part A) of the study.

Participants by arm

Arm	Count
Placebo + Insulin Placebo administered orally once daily in the morning.	14
Dapagliflozin 5mg + Insulin Dapagliflozin 5 mg administered orally once daily in the morning.	14
Dapagliflozin 10 mg + Insulin Dapagliflozin 10 mg administered orally once daily in the morning.	14
Total	42

Baseline characteristics

Characteristic	Placebo + Insulin	Dapagliflozin 5mg + Insulin	Dapagliflozin 10 mg + Insulin	Total
Age, Continuous	42.6 years STANDARD_DEVIATION 10.62	37.0 years STANDARD_DEVIATION 10.05	37.1 years STANDARD_DEVIATION 10.21	38.9 years STANDARD_DEVIATION 10.38
Age, Customized <45 Years	10 Participants	10 Participants	10 Participants	30 Participants
Age, Customized >=45 Years	4 Participants	4 Participants	4 Participants	12 Participants
C-Peptide < 0.1 ng/mL	12 Participants 0.083	13 Participants 0.107	11 Participants 0.036	0.12 Participants 0.079
C-Peptide >= 0.1 ng/mL	2 Participants	1 Participants	3 Participants	6 Participants
Duration of Type 1 Diabetes	16.89 years STANDARD_DEVIATION 10.53	15.94 years STANDARD_DEVIATION 9.235	14.69 years STANDARD_DEVIATION 12.368	15.84 years STANDARD_DEVIATION 10.561
Fasting Plasma Glucose (FPG)	134.00 mg/dL STANDARD_DEVIATION 63.898	142.93 mg/dL STANDARD_DEVIATION 49.93	133.36 mg/dL STANDARD_DEVIATION 42.239	136.76 mg/dL STANDARD_DEVIATION 51.675
Hemoglobin A1c (HbA1c)%	8.13 percent of hemoglobin STANDARD_DEVIATION 0.835	7.91 percent of hemoglobin STANDARD_DEVIATION 0.61	7.89 percent of hemoglobin STANDARD_DEVIATION 0.553	7.98 percent of hemoglobin STANDARD_DEVIATION 0.669
Race/Ethnicity, Customized Asian	14 Participants	14 Participants	14 Participants	42 Participants
Region of Enrollment Japan	14 Participants	14 Participants	14 Participants	42 Participants
Sex: Female, Male Female	11 Participants	6 Participants	7 Participants	24 Participants
Sex: Female, Male Male	3 Participants	8 Participants	7 Participants	18 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 14	0 / 14	0 / 14
other Total, other adverse events	1 / 14	2 / 14	5 / 14
serious Total, serious adverse events	0 / 14	0 / 14	0 / 14

Outcome results

Primary

24-hour Urinary Glucose (g/24h) Mean Change From Baseline on Day 7 - Pharmacodynamic (PD) Set

The 24-hour period is defined based on the morning void, from the first morning void to the one of the next day.

Time frame: Baseline (the last available assessment prior to the first dose of study medication), Day 7

Population: Pharmacodynamic set Part A (PD-A): The PD set consisted of all randomized subjects who received at least one dose of randomized study medication for Part A, and who had a non missing baseline value and at least one post-baseline value for at least one pharmacodynamic variable.

Arm	Measure	Value (MEAN)	Dispersion
Dapagliflozin 5mg + Insulin	24-hour Urinary Glucose (g/24h) Mean Change From Baseline on Day 7 - Pharmacodynamic (PD) Set	-6.16 g/24-hour	Standard Deviation 30.337
Dapagliflozin 10mg + Insulin	24-hour Urinary Glucose (g/24h) Mean Change From Baseline on Day 7 - Pharmacodynamic (PD) Set	96.55 g/24-hour	Standard Deviation 30.083
Dapagliflozin 10mg + Insulin	24-hour Urinary Glucose (g/24h) Mean Change From Baseline on Day 7 - Pharmacodynamic (PD) Set	101.28 g/24-hour	Standard Deviation 20.129

Primary