ADD: Efficacy of Pioglitazone in Participants With Inadequately Controlled Type 2 Diabetes Mellitus Treated With Stable Triple Oral Therapy

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01972724
• Collaborator: (none)
• Enrollment: 114
• Locations: 9
• Arms: 3
• Actual Duration (Months): 34
• Patients Per Site: 12.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of pioglitazone 30 mg on glycemic control when used in participants with inadequately controlled type 2 diabetes mellitus treated with stable combinations of metformin and sulfonylurea.

Condition or Disease	Intervention/Treatment	Phase
Type II Diabetes Mellitus	Drug: Pioglitazone; Drug: Metformin; Drug: Sulfonylurea	Phase 4

Detailed Description

The drug being tested in this study is called pioglitazone. Pioglitazone is being tested to treat glycemic control in adults with inadequately controlled type 2 diabetes mellitus. This study will look at glycemic control in people who take triple oral therapy of metformin, sulfonylurea, and pioglitazone 15 mg.

The study will enroll approximately 114 patients. All participants will be asked to take one pioglitazone tablet at the same time each day throughout the study as well as continuing their previous dose of metformin and sulfonylurea.

This multi-center trial will be conducted in Korea. The overall time to participate in this study is up to 25 weeks. Participants will make 4 visits to the hospital or endocrinologist's office, and will be contacted by telephone 7 days after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 114 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 24-Week, Open Label, Phase IV Trial to Evaluate the Efficacy of Pioglitazone 30 mg in Patients With Inadequately Controlled Type 2 Diabetes Mellitus Treated With Stable Triple Oral Therapy of Metformin, Sulfonylurea, and Pioglitazone 15 Mg (ADD Trial)
• Actual Study Start Date: Dec 16, 2013
• Actual Primary Completion Date: Oct 17, 2016
• Actual Study Completion Date: Oct 17, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pioglitazone 15 mg (Double-Blind) Pioglitazone 15 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Drug: Pioglitazone; Pioglitazone tablets; Other Names: ACTOS ; Drug: Metformin; Metformin as prescribed in clinical practice; Drug: Sulfonylurea; Sulfonylurea as prescribed in clinical practice
Experimental: Pioglitazone 30 mg (Double-Blind) Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Drug: Pioglitazone; Pioglitazone tablets; Other Names: ACTOS ; Drug: Metformin; Metformin as prescribed in clinical practice; Drug: Sulfonylurea; Sulfonylurea as prescribed in clinical practice
Experimental: Pioglitazone 30 mg (Open-Label) Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Drug: Pioglitazone; Pioglitazone tablets; Other Names: ACTOS ; Drug: Metformin; Metformin as prescribed in clinical practice; Drug: Sulfonylurea; Sulfonylurea as prescribed in clinical practice

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 [Baseline and Week 24]

   The change from baseline in glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at Week 24. A negative change from baseline indicates improvement.

Secondary Outcome Measures

1. Change From Baseline in Fasting Plasma Glucose at Week 24 [Baseline and Week 24]

   The change between the value of fasting serum glucose collected at Week 24 and fasting serum glucose collected at baseline. A negative change from baseline indicates improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

Participants meeting the following criteria will be considered for inclusion in the study:

1. Institutional Review Board (IRB)-approved written informed consent form (ICF) must be obtained from the participant or legally authorized representative prior to any trial related procedure (including withdrawal of prohibited medication, if applicable).

2. Participants with a history of clinical diagnosis of established type 2 diabetes mellitus defined by the American Diabetes Association (ADA) criteria 2012.

3. Male or female between 18 and 80 years of age.

4. Participants with stable triple oral therapy of metformin + sulfonylurea + pioglitazone (ACTOS) 15 mg or ACTOSMET(Pioglitazone 15mg/Metformin 850mg) and sulfonylurea for at least 12 weeks at the screening visit.

5. Participants with glycosylated hemoglobin (HbA1c) ≥7.0% at the screening visit.

6. Participants with C-peptide ≥1.0 ng/mL at the screening visit.

7. Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from screening throughout the duration of the study, up to 30 days after the last dose of the study medication.

Exclusion Criteria

Participants meeting any of the following criteria will be excluded from enrollment:

1. Participants with type 1 diabetes mellitus or secondary forms of diabetes.

2. Participants who have been treated with insulin for ≥7 days within 3 months prior to the screening visit.

3. Participants with a history of bladder cancer or participants with active bladder cancer.

4. Participants with a history of acute diabetic complications such as diabetic ketoacidosis.

5. Participants with a history of acute or chronic metabolic acidosis, including diabetic ketoacidosis.

6. Participants with unstable or rapidly progressive diabetic retinopathy, nephropathy (estimated glomerular filtration rate [eGFR] <60mL/min/1.73m2).

7. Participants with cardiac insufficiency (e.g., a myocardial infarction, a coronary angioplasty or bypass graft, unstable angina, transient ischemic attacks, or a documented cerebrovascular accident within 6 months prior to the screening visit).

8. Participants with cardiac failure or history of cardiac failure (New York Heart Association [NYHA] Stages 3 to 4).

9. Participants with a serum alanine transaminase (ALT) level ≥2.5 times the upper limit of normal (ULN), active liver disease, or jaundice.

10. Participants taking concomitant gemfibrozil or other strong cytochrome P450 (CYP)2C8 inhibitors.

11. Participants with a history of recurrent or severe hypoglycemia.

12. Participants with a history of any hemoglobinopathy (such as hemolytic anemias or sickle cell disease) that may affect determination of HbA1c.

13. Participants with uninvestigated microscopic hematuria

14. Participants with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, since the study drug contains lactose.

15. Participants with any other condition judged by the Investigator as unsuitable for the study.

16. Participants who have used any investigational or experimental drugs or devices within 60 days of the screening visit.

17. Lactating or pregnant female. A positive pregnancy test before the first administration of investigational medicinal product (IMP) or breastfeeding.

18. Male participants planning to father during clinical trial conduct or within 3 months after the last planned dose of the IMP.

19. Participants were previously enrolled into the current clinical trial.

20. The participants participated in the active treatment phase of another clinical trial where a persisting pharmacodynamic effect of the IMP of that clinical trial cannot be excluded.

21. Participants are considered unable or unwilling to co-operate adequately, i.e., to follow clinical trial procedures after Investigator has adequately instructed (e.g., language difficulties, etc.) or participants are anticipated not to be available for scheduled clinical trial visits/procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Chagwon		Korea, Republic of
2		Daegu		Korea, Republic of
3		Daejeon		Korea, Republic of
4		Gwangju		Korea, Republic of
5		Gyeonggi-do		Korea, Republic of
6		Jeonju		Korea, Republic of
7		Seoul		Korea, Republic of
8		Ulsan		Korea, Republic of
9		Wonju		Korea, Republic of

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• ACTOS® Package Insert

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01972724
• Other Study ID Numbers: PG-9999-301-KR; U1111-1145-8222
• First Posted: Oct 30, 2013
• Last Update Posted: Sep 12, 2018
• Last Verified: Aug 1, 2018

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Pioglitazone

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 15 investigative sites in Korea from 16 December 2013 to 17 October 2016.
Pre-assignment Detail	Participants with a diagnosis of Type 2 Diabetes Mellitus were enrolled equally in one of 2 treatment groups in the Double-Blind study: pioglitazone15 mg + metformin + sulfonylurea or pioglitazone pioglitazone 30 mg plus metformin + sulfonylurea. Participants received pioglitazone 30 mg + metformin + sulfonylurea in the Open Label study.

Arm/Group Title	Pioglitazone 15 mg (Double-Blind)	Pioglitazone 30 mg (Double-Blind)	Pioglitazone 30 mg (Open-Label)
Arm/Group Description	Pioglitazone 15 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.
Period Title: Double-Blind
STARTED	19	18	0
Intent-to-treat:Received Study Drug	17	17	0
COMPLETED	10	9	0
NOT COMPLETED	9	9	0
Period Title: Double-Blind
STARTED	0	0	77
COMPLETED	0	0	72
NOT COMPLETED	0	0	5

Baseline Characteristics

Arm/Group Title	Pioglitazone 15 mg (Double-Blind)	Pioglitazone 30 mg (Double-Blind)	Pioglitazone 30 mg (Open-Label)	Total
Arm/Group Description	Pioglitazone 15 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Total of all reporting groups
Overall Participants	17	17	77	111
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	59.6 (8.73)	57.0 (12.0)	59.2 (7.88)	58.6
Sex: Female, Male (Count of Participants)
Female	9 52.9%	7 41.2%	35 45.5%	51 45.9%
Male	8 47.1%	10 58.8%	42 54.5%	60 54.1%
Race/Ethnicity, Customized (Count of Participants)
Not Hispanic or Latino	17 100%	17 100%	77 100%	111 100%
Race/Ethnicity, Customized (Count of Participants)
Asian	17 100%	17 100%	77 100%	111 100%
Region of Enrollment (Count of Participants)
Korea, Republic Of	17 100%	17 100%	77 100%	111 100%
Height (cm) [Mean (Full Range) ]
Mean (Full Range) [cm]	161.94 (8.392)	163.50 (9.702)	163.25 (9.148)	162.89
Weight (kg) [Mean (Full Range) ]
Mean (Full Range) [kg]	70.39	71.20	70.38	70.65
Body Mass Index (BMI) (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	26.86	26.46	26.25	26.52

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
Description	The change from baseline in glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) at Week 24. A negative change from baseline indicates improvement.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population was defined as all participants who took at least 1 dose of the study drug. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Pioglitazone 15 mg (Double-Blind)	Pioglitazone 30 mg (Double-Blind)	Pioglitazone 30 mg (Open-Label)
Arm/Group Description	Pioglitazone 15 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.
Measure Participants	17	17	76
Mean (Standard Deviation) [percentage of glycosylated hemoglobin]	-0.0003 (0.00725)	-0.0030 (0.00894)	-0.0275 (0.21126)

2. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose at Week 24
Description	The change between the value of fasting serum glucose collected at Week 24 and fasting serum glucose collected at baseline. A negative change from baseline indicates improvement.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population was defined as all participants who took at least 1 dose of the study drug.

Arm/Group Title	Pioglitazone 15 mg (Double-Blind)	Pioglitazone 30 mg (Double-Blind)	Pioglitazone 30 mg (Open-Label)
Arm/Group Description	Pioglitazone 15 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.	Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.
Measure Participants	17	17	77
Mean (Standard Deviation) [mmol/L]	0.6727 (1.80662)	-0.4278 (1.88067)	-0.4412 (2.30378)

Adverse Events

Time Frame	First dose of study drug up to 30 days after the last dose of study drug (Up to Week 28)
Adverse Event Reporting Description	At each visit investigator had to document any occurrence of adverse events (AEs) and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment. For other AEs a result of 0 in the table means there are no participants at a threshold of >=5%.
Arm/Group Title	Pioglitazone 15 mg (Double-Blind)		Pioglitazone 30 mg (Double-Blind)		Pioglitazone 30 mg (Open-Label)
Arm/Group Description	Pioglitazone 15 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.		Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.		Pioglitazone 30 mg tablets, orally, once daily, and metformin and sulfonylurea administered according to the prescribing information of the approved Korean label, for up to 24 weeks.
All Cause Mortality
	Pioglitazone 15 mg (Double-Blind)		Pioglitazone 30 mg (Double-Blind)		Pioglitazone 30 mg (Open-Label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Pioglitazone 15 mg (Double-Blind)		Pioglitazone 30 mg (Double-Blind)		Pioglitazone 30 mg (Open-Label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)		0/17 (0%)		3/77 (3.9%)
Injury, poisoning and procedural complications
Facial bones fracture	0/17 (0%)		0/17 (0%)		1/77 (1.3%)
Pneumothorax traumatic	0/17 (0%)		0/17 (0%)		1/77 (1.3%)
Rib fracture	0/17 (0%)		0/17 (0%)		1/77 (1.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/17 (0%)		0/17 (0%)		1/77 (1.3%)
Rotator cuff syndrome	0/17 (0%)		0/17 (0%)		1/77 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	1/17 (5.9%)		0/17 (0%)		0/77 (0%)
Other (Not Including Serious) Adverse Events
	Pioglitazone 15 mg (Double-Blind)		Pioglitazone 30 mg (Double-Blind)		Pioglitazone 30 mg (Open-Label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/17 (17.6%)		7/17 (41.2%)		0/77 (0%)
Eye disorders
Conjunctival haemorrhage	1/17 (5.9%)		0/17 (0%)		0/77 (0%)
Eyelid oedema	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Gastrointestinal disorders
Vomiting	1/17 (5.9%)		0/17 (0%)		0/77 (0%)
General disorders
Oedema	0/17 (0%)		2/17 (11.8%)		0/77 (0%)
Infections and infestations
Folliculitis	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Herpes zoster	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Nasopharyngitis	1/17 (5.9%)		0/17 (0%)		0/77 (0%)
Onychomycosis	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Tinea pedis	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Injury, poisoning and procedural complications
Ligament injury	1/17 (5.9%)		0/17 (0%)		0/77 (0%)
Venom poisoning	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Osteoarthritis	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Nervous system disorders
Post herpetic neuralgia	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Skin and subcutaneous tissue disorders
Pruritus	0/17 (0%)		1/17 (5.9%)		0/77 (0%)
Urticaria	0/17 (0%)		1/17 (5.9%)		0/77 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.