Empa Add on to Insulin in Japanese Patient With Type 1 Diabetes Mellitus

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02702011
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 48
• Locations: 4
• Arms: 4
• Actual Duration (Months): 6.5
• Patients Per Site: 12
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of once daily oral doses of empagliflozin in Japanese patients with type 1 diabetes mellitus as adjunctive therapy to insulin.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: empagliflozin medium dose; Drug: empagliflozin low dose; Drug: empagliflozin high dose; Drug: placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel Group Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Once Daily, Oral Doses of Empagliflozin as Adjunctive to Insulin Therapy for 28 Days in Japanese Patients With Type 1 Diabetes Mellitus
• Actual Study Start Date: Mar 20, 2016
• Actual Primary Completion Date: Sep 5, 2016
• Actual Study Completion Date: Oct 3, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: empagliflozin low dose	Drug: empagliflozin low dose
Experimental: empagliflozin medium dose	Drug: empagliflozin medium dose
Experimental: empagliflozin high dose	Drug: empagliflozin high dose
Placebo Comparator: placebo	Drug: placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in 24 Hour UGE on Day 7 [Baseline and 7 days]

   Change from baseline in 24 hour urinary glucose excretion on Day 7 calculated as: UGE on Day 7 - UGE on baseline. Baseline is defined as the last observation prior to the first intake of any randomised trial medication.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Signed and dated written informed consent by the date of Visit 1 (screening) in accordance with Good Clinical Practice (GCP) and local legislation

• Japanese male or female patient receiving insulin for treatment of documented diagnosis of type 1 diabetes mellitus (T1DM) for at least 1 year at the time of Visit 1 (screening).

• Fasting C-peptide value of < 0.6 ng/mL at Visit 2 (placebo run-in) measured by the central laboratory

• Use of, and be willing, based on the investigator's judgment, to continue throughout the duration of the trial Multiple daily injection(MDI) of insulin consisting of at least 1 basal insulin injection and at least 3 daily bolus injections The total daily insulin dose must be>=0.3 U/kg and <=1.5 U/kg at Visit 1 (screening)

• HbA1c of 7.5% to 10.0% at Visit 1 (screening) measured by the central laboratory and provided that the patients HbA1c does not increase by > 0.5% within 3 months before Visit 1 (screening)

• Based on the investigator's judgment, patient must have a good understanding of his/her disease and how to manage it, and be willing and capable of performing the following study assessments (assessed at Visits 1 to 3 and just before randomization)

• patient-led management and adjustment of insulin therapy

• reliable approach to insulin dose adjustment for meals, such as carbohydrate counting

• reliable and regular home-based blood glucose monitoring

• recognize the symptoms of DKA (Diabetic Ketoacidosis), and reliably monitor for ketones

• implementation of an established "sick day" management regimen

• Age >=20 years and <=65 years at Visit 1 (screening)

• Body mass index (BMI) >=18.5 kg/m2 and<=35.0 kg/m2 at Visit 1 (screening)

• Estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73m² and <=150 mL/min/1.73m² as calculated by Japanese equation based on creatinine measured by the central laboratory at Visit 1 (screening)

• Compliance with trial drug administration must be between 80% and 120% during the placebo run-in period, to be judged at Visit 4 and before randomization

Exclusion criteria:

• History of T2DM (Type 2 Diabetes Mellitus), maturity onset diabetes of the young (MODY), pancreatic surgery or chronic pancreatitis

• Pancreas, pancreatic islet cells or renal transplant recipient

• T1DM treatment with any other anti-hyperglycaemic drug (e.g., metformin, alpha-glycosidase inhibitors, glucagon-like-peptide 1 (GLP-1) receptor agonists, SGLT-2 (Sodium-Glucose co-transporter-2) inhibitors, pramlintide, inhaled insulin, pre-mixed insulins, etc.) within 3 months except subcutaneous basal and bolus insulin before Visit 1 (screening) or any history of clinically relevant hypersensitivity according to the investigator's judgment

• Occurrence of severe hypoglycemia involving coma and/or seizure that required hospitalization or hypoglycemia-related treatment by an emergency physician or paramedic within 3 months before Visit 1 (screening)

• Occurrence of DKA within 3 months before Visit 1 (screening) and until randomization at Visit 4 (Day 1)

• Irregular sleep/wake cycle (e.g., patients who habitually sleep during the day and work during the night) based on the investigator's judgment

• Acute coronary syndrome (non-STEMI, STEMI, and unstable angina pectoris), stroke or transient ischemic attack within 3 months before Visit 1 (screening)

• Diagnosis of severe gastro paresis based on investigator's judgment

• Diagnosis of brittle diabetes based on the investigator's judgment

• Indication of liver impairment, defined by serum levels of either alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase above 3 x upper limit of normal (ULN) at Visit 1 (screening) as measured by the central laboratory

• Eating disorders such as bulimia or anorexia nervosa

• Treatment with anti-obesity drugs (e.g., Mazindol), surgery or aggressive diet regimen leading to unstable body weight (based on the investigator's judgment) 3 months before Visit 1 (screening) and until randomization

• Treatment with systemic corticosteroids or planned initiation of such therapy at Visit 1 (screening). Inhaled use of corticosteroids (e.g., for asthma/chronic obstructive pulmonary disease) is acceptable

• Change in dose of thyroid hormones within 6 weeks before Visit 1 (screening) or planned change or initiation of such a therapy at Visit 1 (screening)

• Medical history of cancer or treatment for cancer in the last 5 years before Visit 1 (screening). Resected basal cell carcinoma considered cured is exempted

• Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells (e.g., malaria, babesiosis, hemolytic anemia) at Visit 1 (screening)

• Pre-menopausal women (last menstruation <=1 year before informed consent) who:

• are nursing or pregnant or

• are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, intra uterine devices/systems, oral contraceptives, complete sexual abstinence, double barrier method and vasectomized partner

• Alcohol or drug abuse within 3 months before Visit 1 (screening) that would interfere with trial participation based on the investigator's judgment

• Intake of an investigational drug in another trial within 30 days before Visit 1 (screening)

• Patient not able to understand and comply with study requirements based on the investigator's judgment

• Any other clinical condition that, based on investigator's judgment, would jeopardise patient safety or would affect the study outcome (e.g. immunocompromised patients who might be at higher risk of developing genital or mycotic infections, patients with chronic viral infections, etc.) during trial participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Souseikai Hakata Clinic	Fukuoka, Fukuoka		Japan	812-0025
2	Nishikumamoto Hospital	Kumamoto, Kumamoto		Japan	861-4157
3	Shinjuku Research Park Clinic	Tokyo, Shinjyuku-ku		Japan	169-0073
4	SOUSEIKAI Sumida Hospital	Tokyo, Sumida-ku		Japan	130-0004

Sponsors and Collaborators

• Boehringer Ingelheim
• Eli Lilly and Company

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Synopsis Link

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02702011
• Other Study ID Numbers: 1245.113
• First Posted: Mar 8, 2016
• Last Update Posted: Apr 2, 2018
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Empagliflozin

Study Results

Participant Flow

Arm/Group Title	Placebo	Empagliflozin 2.5 mg	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral administration of matching placebo of 2.5 mg, 10 mg and 25 mg of empagliflozin film-coated tablets once daily during the 28 days randomized double-blinded treatment period.	Oral administration of 2.5 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 10 mg and 25 mg of empagliflozin during the 28 days randomized double-blinded treatment period	Oral administration of 10 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 2.5 mg and 25 mg of empagliflozin during the 28 days randomized double-blinded treatment period.	Oral administration of 25 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 2.5 mg and 10 mg of empagliflozin during the 28 days randomized double-blinded treatment period.
Period Title: Overall Study
STARTED	11	13	12	12
COMPLETED	11	12	12	12
NOT COMPLETED	0	1	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Empagliflozin 2.5 mg	Empagliflozin 10 mg	Empagliflozin 25 mg	Total
Arm/Group Description	Oral administration of matching placebo of 2.5 mg, 10 mg and 25 mg of empagliflozin film-coated tablets once daily during the 28 days randomized double-blinded treatment period.	Oral administration of 2.5 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 10 mg and 25 mg of empagliflozin during the 28 days randomized double-blinded treatment period	Oral administration of 10 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 2.5 mg and 25 mg of empagliflozin during the 28 days randomized double-blinded treatment period.	Oral administration of 25 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 2.5 mg and 10 mg of empagliflozin during the 28 days randomized double-blinded treatment period.	Total of all reporting groups
Overall Participants	11	13	12	12	48
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.9 (11.7)	44.2 (12.6)	44.5 (11.8)	46.6 (10.8)	44.8 (11.4)
Sex: Female, Male (Count of Participants)
Female	6 54.5%	8 61.5%	8 66.7%	4 33.3%	26 54.2%
Male	5 45.5%	5 38.5%	4 33.3%	8 66.7%	22 45.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in 24 Hour UGE on Day 7
Description	Change from baseline in 24 hour urinary glucose excretion on Day 7 calculated as: UGE on Day 7 - UGE on baseline. Baseline is defined as the last observation prior to the first intake of any randomised trial medication.
Time Frame	Baseline and 7 days

Outcome Measure Data

Analysis Population Description

The primary analysis was performed on the FAS with last observation carried forward (LOCF) imputation.

Arm/Group Title	Placebo	Empagliflozin 2.5 mg	Empagliflozin 10 mg	Empagliflozin 25 mg
Arm/Group Description	Oral administration of matching placebo of 2.5 mg, 10 mg and 25 mg of empagliflozin film-coated tablets once daily during the 28 days randomized double-blinded treatment period.	Oral administration of 2.5 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 10 mg and 25 mg of empagliflozin during the 28 days randomized double-blinded treatment period	Oral administration of 10 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 2.5 mg and 25 mg of empagliflozin during the 28 days randomized double-blinded treatment period.	Oral administration of 25 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 2.5 mg and 10 mg of empagliflozin during the 28 days randomized double-blinded treatment period.
Measure Participants	11	13	12	12
Least Squares Mean (Standard Error) [gram per 24 hours (g/24 h)]	-0.46 (7.96)	64.63 (7.31)	80.73 (7.68)	97.64 (7.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 2.5 mg
	Comments	An analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline as a linear covariate was fitted to the change from baseline of 24 hour UGE (g/24h) on Day 7, where baseline refers to the last observation prior to the first intake of any randomised trial medication.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	65.10
	Confidence Interval	(2-Sided) 95%; 43.29 to 86.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.81
	Estimation Comments	Mean Difference was calculated as: (mean change from baseline in 24 hour UGE at Day 7 in Empagliflozin 2.5 mg group) - (mean change from baseline in 24 hour UGE at Day 7 in Placebo group)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 10 mg
	Comments	An analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline as a linear covariate was fitted to the change from baseline of 24 hour UGE (g/24h) on Day 7, where baseline refers to the last observation prior to the first intake of any randomised trial medication.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	81.19
	Confidence Interval	(2-Sided) 95%; 58.80 to 103.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.10
	Estimation Comments	Mean Difference was calculated as: (mean change from baseline in 24 hour UGE at Day 7 in Empagliflozin 10 mg group) - (mean change from baseline in 24 hour UGE at Day 7 in Placebo group)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Empagliflozin 25 mg
	Comments	An analysis of covariance (ANCOVA) model with treatment as a fixed effect and baseline as a linear covariate was fitted to the change from baseline of 24 hour UGE (g/24h) on Day 7, where baseline refers to the last observation prior to the first intake of any randomised trial medication.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	98.11
	Confidence Interval	(2-Sided) 95%; 75.91 to 120.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.01
	Estimation Comments	Mean Difference was calculated as: (mean change from baseline in 24 hour UGE at Day 7 in Empagliflozin 25 mg group) - (mean change from baseline in 24 hour UGE at Day 7 in Placebo group)

Adverse Events

Time Frame	From first drug administration till 7 days after last drug intake; up to 35 days
Adverse Event Reporting Description	Treated set (TS): This analysis set included all patients treated with at least one dose of randomised study drug.
Arm/Group Title	Placebo		Empagliflozin 2.5 mg		Empagliflozin 10 mg		Empagliflozin 25 mg
Arm/Group Description	Oral administration of matching placebo of 2.5 mg, 10 mg and 25 mg of empagliflozin film-coated tablets once daily during the 28 days randomized double-blinded treatment period.		Oral administration of 2.5 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 10 mg and 25 mg of empagliflozin during the 28 days randomized double-blinded treatment period		Oral administration of 10 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 2.5 mg and 25 mg of empagliflozin during the 28 days randomized double-blinded treatment period.		Oral administration of 25 milligram (mg) of empagliflozin film-coated tablets once daily along with one matching placebo each of 2.5 mg and 10 mg of empagliflozin during the 28 days randomized double-blinded treatment period.
All Cause Mortality
	Placebo		Empagliflozin 2.5 mg		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Empagliflozin 2.5 mg		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/13 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Empagliflozin 2.5 mg		Empagliflozin 10 mg		Empagliflozin 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/11 (100%)		12/13 (92.3%)		12/12 (100%)		12/12 (100%)
Eye disorders
Retinal haemorrhage	0/11 (0%)		1/13 (7.7%)		0/12 (0%)		0/12 (0%)
Gastrointestinal disorders
Abdominal pain	1/11 (9.1%)		0/13 (0%)		0/12 (0%)		0/12 (0%)
Abdominal pain upper	1/11 (9.1%)		0/13 (0%)		0/12 (0%)		0/12 (0%)
Faeces soft	1/11 (9.1%)		0/13 (0%)		0/12 (0%)		0/12 (0%)
Infections and infestations
Vulvovaginal candidiasis	0/11 (0%)		1/13 (7.7%)		0/12 (0%)		1/12 (8.3%)
Injury, poisoning and procedural complications
Contusion	0/11 (0%)		0/13 (0%)		0/12 (0%)		1/12 (8.3%)
Investigations
Alanine aminotransferase increased	1/11 (9.1%)		0/13 (0%)		0/12 (0%)		0/12 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	11/11 (100%)		12/13 (92.3%)		12/12 (100%)		12/12 (100%)
Decreased appetite	0/11 (0%)		0/13 (0%)		1/12 (8.3%)		0/12 (0%)
Musculoskeletal and connective tissue disorders
Connective tissue inflammation	0/11 (0%)		0/13 (0%)		1/12 (8.3%)		0/12 (0%)
Nervous system disorders
Headache	0/11 (0%)		1/13 (7.7%)		1/12 (8.3%)		0/12 (0%)
Dizziness postural	1/11 (9.1%)		0/13 (0%)		0/12 (0%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract inflammation	0/11 (0%)		0/13 (0%)		1/12 (8.3%)		0/12 (0%)
Oropharyngeal pain	1/11 (9.1%)		0/13 (0%)		0/12 (0%)		0/12 (0%)

Limitations/Caveats

A limitation of the current study is its short duration and small sample size. Another limitation of this study was that patients in the placebo group had to go through unnecessary dose adjustments of insulin.

More Information

Certain Agreements

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.