Trial Outcomes & Findings for Pioglitazone Tablets Special Drug Use Surveillance "Combined Use of Biguanides / Long-term Treatment" (NCT NCT02003014)

NCT ID: NCT02003014

Last Updated: 2016-11-10

Results Overview

Adverse drug reactions are defined as adverse events (AEs) which are in the investigator's opinion of causal relationship to the study treatment. AEs are defined as any unfavorable and unintended signs, symptoms or diseases temporally associated with the use of a medicinal product reported from the first dose of study drug to the last dose of study drug.

• Recruitment status: COMPLETED
• Target enrollment: 899 participants
• Primary outcome timeframe: Baseline up to 12 months
• Results posted on: 2016-11-10

Participant Flow

Participants took part in the study at 152 investigative sites in Japan from 23 February 2009 to 31 January 2012.

Participants with a historical diagnosis of type 2 diabetes mellitus who failed to respond adequately to treatment with biguanides were enrolled to receive pioglitazone 15 milligram (mg) - 30 mg for up to 12 months.

Participant milestones

Measure	Pioglitazone Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Overall Study STARTED	899
Overall Study COMPLETED	880
Overall Study NOT COMPLETED	19

Reasons for withdrawal

Measure	Pioglitazone Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Overall Study Case report forms uncollected	9
Overall Study Treatment started after contract period	1
Overall Study Patient did not visit the study site	5
Overall Study Investigator's transfer	4

Baseline Characteristics

Pioglitazone Tablets Special Drug Use Surveillance "Combined Use of Biguanides / Long-term Treatment"

Baseline characteristics by cohort

Measure	Pioglitazone n=880 Participants Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Age, Continuous	58.9 years STANDARD_DEVIATION 11.69 • n=93 Participants
Sex: Female, Male Female	334 Participants n=93 Participants
Sex: Female, Male Male	546 Participants n=93 Participants
Pregnancy status Not pregnant	334 participants n=93 Participants
Pregnancy status Pregnant	0 participants n=93 Participants
Time from diagnosis of type 2 diabetes Less than (<) 1 years	36 participants n=93 Participants
Time from diagnosis of type 2 diabetes Greater than equal to (>=) 1 to <5 years	194 participants n=93 Participants
Time from diagnosis of type 2 diabetes >=5 to <10 years	239 participants n=93 Participants
Time from diagnosis of type 2 diabetes >=10 years	354 participants n=93 Participants
Time from diagnosis of type 2 diabetes Unknown	57 participants n=93 Participants
Predisposition to Hypersensitivity Had no predisposition to hypersensitivity	856 participants n=93 Participants
Predisposition to Hypersensitivity Had predisposition to hypersensitivity	24 participants n=93 Participants
Details Regarding Predisposition to Hypersensitivity Drug	12 participants n=93 Participants
Details Regarding Predisposition to Hypersensitivity Food	5 participants n=93 Participants
Details Regarding Predisposition to Hypersensitivity Other	7 participants n=93 Participants
Drinking Habits None	474 participants n=93 Participants
Drinking Habits Former drinker	46 participants n=93 Participants
Drinking Habits Current drinker	346 participants n=93 Participants
Drinking Habits Unknown	14 participants n=93 Participants
Smoking Habits None	520 participants n=93 Participants
Smoking Habits Former smoker	145 participants n=93 Participants
Smoking Habits Current smoker	203 participants n=93 Participants
Smoking Habits Unknown	12 participants n=93 Participants
Weight < 40 kilogram (kg)	3 participants n=93 Participants
Weight >=40 to <50 kg	54 participants n=93 Participants
Weight >=50 to <60 kg	163 participants n=93 Participants
Weight >=60 to <70 kg	268 participants n=93 Participants
Weight >=70 kg	384 participants n=93 Participants
Weight Unknown	8 participants n=93 Participants
Body Mass Index < 18.5 kilogram per square meter (kg/m^2)	14 participants n=93 Participants
Body Mass Index >=18.5 to <25 kg/m^2	382 participants n=93 Participants
Body Mass Index >=25 to <30 kg/m^2	346 participants n=93 Participants
Body Mass Index >=30 kg/m^2	124 participants n=93 Participants
Body Mass Index Unknown	14 participants n=93 Participants
Medical History Had no presence of medical history	672 participants n=93 Participants
Medical History Had presence of medical history	206 participants n=93 Participants
Medical History Unknown	2 participants n=93 Participants
Breakdown of Medical History Liver disease	6 participants n=93 Participants
Breakdown of Medical History Renal disease	4 participants n=93 Participants
Breakdown of Medical History Heart disease	20 participants n=93 Participants
Breakdown of Medical History Cerebrovascular disease	21 participants n=93 Participants
Breakdown of Medical History Malignant tumor	23 participants n=93 Participants
Breakdown of Medical History Other	154 participants n=93 Participants
Medical Complications Had no presence of medical complications	100 participants n=93 Participants
Medical Complications Had presence of medical complications	780 participants n=93 Participants
Breakdown of Complications Diabetic retinopathy	63 participants n=93 Participants
Breakdown of Complications Diabetic nephropathy	75 participants n=93 Participants
Breakdown of Complications Diabetic neuropathy	58 participants n=93 Participants
Breakdown of Complications Dyslipidaemia	217 participants n=93 Participants
Breakdown of Complications Hypertension	203 participants n=93 Participants
Breakdown of Complications Heart disease	85 participants n=93 Participants
Breakdown of Complications Liver disease (all types of liver disease)	79 participants n=93 Participants
Breakdown of Complications Hepatic steatosis	58 participants n=93 Participants
Breakdown of Complications Alcoholic liver injury	11 participants n=93 Participants
Breakdown of Complications Viral liver injury	1 participants n=93 Participants
Breakdown of Complications Other liver disease	19 participants n=93 Participants
Breakdown of Complications Renal disease (other than diabetic nephropathy)	14 participants n=93 Participants
Breakdown of Complications Renal disease (including diabetic nephropathy)	85 participants n=93 Participants
Breakdown of Complications Malignant tumor	8 participants n=93 Participants
Breakdown of Complications Cerebrovascular disease	38 participants n=93 Participants
Breakdown of Complications Other	234 participants n=93 Participants

PRIMARY outcome

Timeframe: Baseline up to 12 months

Population: The safety analysis set was defined as all participants who were enrolled and completed the study.

Adverse drug reactions are defined as adverse events (AEs) which are in the investigator's opinion of causal relationship to the study treatment. AEs are defined as any unfavorable and unintended signs, symptoms or diseases temporally associated with the use of a medicinal product reported from the first dose of study drug to the last dose of study drug.

Outcome measures

Measure	Pioglitazone n=880 Participants Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Number of Participants Reporting One or More Adverse Drug Reactions	79 participants

PRIMARY outcome

Timeframe: Baseline up to 12 months

Population: The safety analysis set was defined as all participants who were enrolled and completed the study.

Serious adverse drug reactions are defined as serious adverse events (SAEs) which are in the investigator's opinion of causal relationship to the study treatment. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Outcome measures

Measure	Pioglitazone n=880 Participants Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Number of Participants Reporting One or More Serious Adverse Drug Reactions	1 participants

SECONDARY outcome

Timeframe: Baseline, Months 3, 6, 9, 12 and final assessment (up to Month 12)

Population: The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available.

The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at 3 months, 6 months, 9 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline.

Outcome measures

Measure	Pioglitazone n=824 Participants Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Change From Baseline in Glycosylated Hemoglobin (HbA1c) Baseline (n = 824)	8.34 percentage of glycosylated hemoglobin Standard Deviation 1.217
Change From Baseline in Glycosylated Hemoglobin (HbA1c) Change at Month 3 (n = 802)	-0.71 percentage of glycosylated hemoglobin Standard Deviation 0.943
Change From Baseline in Glycosylated Hemoglobin (HbA1c) Change at Month 6 (n = 721)	-0.79 percentage of glycosylated hemoglobin Standard Deviation 1.064
Change From Baseline in Glycosylated Hemoglobin (HbA1c) Change at Month 9 (n = 650)	-0.85 percentage of glycosylated hemoglobin Standard Deviation 1.066
Change From Baseline in Glycosylated Hemoglobin (HbA1c) Change at Month 12 (n = 624)	-0.91 percentage of glycosylated hemoglobin Standard Deviation 1.080
Change From Baseline in Glycosylated Hemoglobin (HbA1c) Change at Final Assessment (n = 824)	0.85 percentage of glycosylated hemoglobin Standard Deviation 1.120

SECONDARY outcome

Timeframe: Baseline, Months 3, 6, 9, 12 and final assessment (up to Month 12)

Population: The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available.

The change between the fasting blood glucose value collected at 3 months, 6 months, 9 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline.

Outcome measures

Measure	Pioglitazone n=210 Participants Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Change From Baseline in Fasting Blood Glucose Baseline (n = 210)	174.1 milligram per deciliter (mg/dL) Standard Deviation 62.02
Change From Baseline in Fasting Blood Glucose Change at Month 3 (n = 179)	-27.4 milligram per deciliter (mg/dL) Standard Deviation 59.41
Change From Baseline in Fasting Blood Glucose Change at Month 6 (n = 152)	-27.9 milligram per deciliter (mg/dL) Standard Deviation 52.29
Change From Baseline in Fasting Blood Glucose Change at Month 9 (n = 143)	-20.8 milligram per deciliter (mg/dL) Standard Deviation 65.77
Change From Baseline in Fasting Blood Glucose Change at Month 12 (n = 146)	-28.4 milligram per deciliter (mg/dL) Standard Deviation 48.44
Change From Baseline in Fasting Blood Glucose Change at Final Assessment (n = 210)	-28.1 milligram per deciliter (mg/dL) Standard Deviation 51.31

SECONDARY outcome

Timeframe: Baseline, Months 3, 6, 9, 12 and final assessment (up to Month 12)

Population: The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available.

Change relative to baseline in participant's weight measured at 3 months, 6 months, 9 months, 12 months or final visit (last visit for a participant in the study, up to Month 12).

Outcome measures

Measure	Pioglitazone n=788 Participants Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Change From Baseline in Body Weight Baseline (n = 788)	68.971 kg Standard Deviation 14.1768
Change From Baseline in Body Weight Change at Month 3 (n = 733)	0.667 kg Standard Deviation 1.9398
Change From Baseline in Body Weight Change at Month 6 (n = 660)	1.180 kg Standard Deviation 2.4136
Change From Baseline in Body Weight Change at Month 9 (n = 587)	1.440 kg Standard Deviation 2.6187
Change From Baseline in Body Weight Change at Month 12 (n = 582)	1.407 kg Standard Deviation 2.7272
Change From Baseline in Body Weight Change at Final Assessment (n = 788)	1.465 kg Standard Deviation 2.8322

SECONDARY outcome

Timeframe: Baseline, Months 3, 6, 9, 12 and final assessment (up to Month 12)

Population: The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available.

The change in the value of IRI (portion of insulin in blood measured by immunochemical methods for the hormone; presumed to represent the free [unbound] and biologically active fraction of total blood insulin) collected at 3 months, 6 months, 9 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline.

Outcome measures

Measure	Pioglitazone n=44 Participants Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Change From Baseline in Immunoreactive Insulin (IRI) Baseline (n = 44)	10.320 micro units per milliliter (mcU/mL) Standard Deviation 6.5620
Change From Baseline in Immunoreactive Insulin (IRI) Change at Month 3 (n = 29)	-1.390 micro units per milliliter (mcU/mL) Standard Deviation 4.1813
Change From Baseline in Immunoreactive Insulin (IRI) Change at Month 6 (n = 32)	-2.438 micro units per milliliter (mcU/mL) Standard Deviation 3.7622
Change From Baseline in Immunoreactive Insulin (IRI) Change at Month 9 (n = 20)	-2.970 micro units per milliliter (mcU/mL) Standard Deviation 5.5698
Change From Baseline in Immunoreactive Insulin (IRI) Change at Month 12 (n = 27)	-1.774 micro units per milliliter (mcU/mL) Standard Deviation 4.6780
Change From Baseline in Immunoreactive Insulin (IRI) Change at Final Assessment (n = 44)	-1.077 micro units per milliliter (mcU/mL) Standard Deviation 4.7957

SECONDARY outcome

Timeframe: Baseline, Months 3, 6, 9, 12 and final assessment (up to Month 12)

Population: The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points available.

The change between homeostasis model assessment of insulin resistance collected at 3 months, 6 months, 9 months, 12 months or final visit (last visit for a participant in the study, up to Month 12) relative to baseline. Homeostasis Model assessment of insulin resistance Measures insulin resistance, calculated by insulin times glucose, divided by a constant (22.5). A higher score indicates higher insulin resistance.

Outcome measures

Measure	Pioglitazone n=43 Participants Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Change From Baseline Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Baseline (n = 43)	3.92 HOMA-IR score Standard Deviation 2.751
Change From Baseline Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Change at Month 3 (n = 28)	-0.85 HOMA-IR score Standard Deviation 2.173
Change From Baseline Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Change at Month 6 (n = 31)	-1.41 HOMA-IR score Standard Deviation 1.936
Change From Baseline Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Change at Month 9 (n = 20)	-1.49 HOMA-IR score Standard Deviation 2.779
Change From Baseline Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Change at Month 12 (n = 26)	-1.26 HOMA-IR score Standard Deviation 1.974
Change From Baseline Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Change at Final Assessment (n = 43)	-0.75 HOMA-IR score Standard Deviation 2.098

Adverse Events

Pioglitazone

Serious events: 12 serious events

Other events: 36 other events

Deaths: 0 deaths

Serious adverse events

Measure	Pioglitazone n=880 participants at risk Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
Infections and infestations Appendicitis	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bile duct cancer	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Psychiatric disorders Mania	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Nervous system disorders Cerebral infarction	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Nervous system disorders Convulsion	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Nervous system disorders VIIth nerve paralysis	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Cardiac disorders Acute myocardial infarction	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Cardiac disorders Angina pectoris	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Gastrointestinal disorders Ascites	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Gastrointestinal disorders Gastric ulcer	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Hepatobiliary disorders Biliary cirrhosis primary	0.11% 1/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.

Other adverse events

Measure	Pioglitazone n=880 participants at risk Pioglitazone 15 mg - 30 mg, tablet, orally, once daily for up to 12 months in participants based upon the disease severity.
General disorders Oedema	2.3% 20/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.
Investigations Weight Increased	1.8% 16/880 • Baseline up to 12 months At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Only adverse drug reactions were collected in this study.

Additional Information

Medical Director

Takeda

Phone: +1-877-825-3327

Email: trialdisclosures@takeda.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER