PEAK: The Practical Evidence of Antidiabetic Combination Therapy in Korea

Sponsor

Kun-Ho Yoon (Other)

Overall Status

Completed

CT.gov ID

NCT02231021

Collaborator

Takeda (Industry)

216

Enrollment

Location

Arms

52.9

Actual Duration (Months)

4.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study evaluate the efficacy and safety of alogliptin and pioglitazone combination therapy in comparison with either alogliptin or pioglitazone on glucose control in the metformin-treated type 2 diabetic patients in Korea.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: alogliptin Drug: Pioglitazone Drug: alogliptin + pioglitazone	Phase 4

Detailed Description

Pathophysiology of type 2 diabetes is known as insulin resistance and progressive beta cell dysfunction.

Combination therapy with biguanides, glucagon-like peptide-1(GLP-1) agonists or dipeptidyl peptidase-4 inhibitor(DPP4I) and thiazolidinediones(TZD) seems reasonable theoretically, for their effects on different pathophysiologic defects.

Current treatment guidelines recommend a stepwise approach starting with lifestyle modification or lifestyle modification + metformin monotherapy, with recent focusing on patient individualization.

In Korea, Korean Diabetes Association also recommends stepwise approach and at the same time, emphasizes on the initial aggressive treatment including oral combination or insulin therapy according to HbA1c level to achieve target goal <6.5%.

Guide to the efficacy, timing, options of combination therapy is not clearly defined due to lack of sufficient evidences yet.

There is no clear report to demonstrate the clinical benefit of initial TZD and DPP4I combination therapy in the Korean.

Thus it is reasonable to study the effect of combination therapy in the patients with sub-optimal glucose control with metformin therapy only, comparing various combination options metformin with DPP4I only, TZD only, or both.

The hypothesis of this study is that combination therapy of alogliptin and pioglitazone added on the metformin has superior effect on HbA1c reduction than metformin and either alogliptin or pioglitazone in 6 month treatment.

Study Design

Study Type:

Interventional

Actual Enrollment :

216 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Multicenter, Randomized, Double Blind, Three-arm Parallel Group Study to Evaluate Efficacy and Safety of Alogliptin and Pioglitazone Combination Therapy on Glucose Control in Type 2 Diabetes Subjects Who Have Inadequate Control With Metformin Monotherapy in Korea

Actual Study Start Date :

Sep 1, 2014

Actual Primary Completion Date :

Oct 22, 2018

Actual Study Completion Date :

Jan 28, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: alogliptin + pioglitazone alogliptin 25 mg 1 tablet daily for 24 weeks pioglitazone 30 mg 1 tablet daily for 24 weeks metformin for 24 weeks as the same dose and frequency as before enroll	Drug: alogliptin + pioglitazone alogliptin 25 mg and pioglitazone 30 mg add-on background medication metformin Other Names: Nesina Actos
Active Comparator: alogliptin alogliptin 25 mg 1 tablet daily for 24 weeks pioglitazone matching placebo 1 tablet daily for 24 weeks metformin for 24 weeks as the same dose and frequency as before enroll	Drug: alogliptin alogliptin 25 mg add-on background medication metformin Other Names: Nesina
Active Comparator: Pioglitazone alogliptin matching placebo 1 tablet daily for 24 weeks pioglitazone 30 mg 1 tablet daily for 24 weeks metformin for 24 weeks as the same dose and frequency as before enroll	Drug: Pioglitazone pioglitazone 30 mg add-on background medication metformin Other Names: actos

Arm

Intervention/Treatment

Experimental: alogliptin + pioglitazone

alogliptin 25 mg 1 tablet daily for 24 weeks pioglitazone 30 mg 1 tablet daily for 24 weeks metformin for 24 weeks as the same dose and frequency as before enroll

Drug: alogliptin + pioglitazone

alogliptin 25 mg and pioglitazone 30 mg add-on background medication metformin

Other Names:

Nesina

Actos

Active Comparator: alogliptin

alogliptin 25 mg 1 tablet daily for 24 weeks pioglitazone matching placebo 1 tablet daily for 24 weeks metformin for 24 weeks as the same dose and frequency as before enroll

Drug: alogliptin

alogliptin 25 mg add-on background medication metformin

Other Names:

Nesina

Active Comparator: Pioglitazone

alogliptin matching placebo 1 tablet daily for 24 weeks pioglitazone 30 mg 1 tablet daily for 24 weeks metformin for 24 weeks as the same dose and frequency as before enroll

Drug: Pioglitazone

pioglitazone 30 mg add-on background medication metformin

Other Names:

actos

Outcome Measures

Primary Outcome Measures

Change in glycohemoglobin(HbA1c) from baseline [baseline, 24 weeks]

Secondary Outcome Measures

Proportion of subjects achieving HbA1c < 7.0% [24 week]
Proportion of subjects achieving HbA1c <6.5% [24 week]
Changes in glycated albumin(GA) from baseline [baseline, 24 weeks]
Change in GA/HbA1c ratio from baseline [baseline, 24 weeks]
Change in fasting blood sugar from baseline [baseline, 24 weeks]
Incidence of hyperglycemic rescue [12 week]
at Week 12, HbA1c >9.0%
Change in HbA1c from baseline [12 week]
Change in total cholesterol from baseline [baseline, 24 weeks]
Change in triglycerides from baseline [baseline, 24 weeks]
Change in LDL-cholesterol from baseline [baseline, 24 weeks]
Change in HDL-cholesterol from baseline [baseline, 24 weeks]
Changes in glycated albumin(GA) from baseline [baseline, 12 weeks]
Change in GA/HbA1c ratio from baseline [baseline, 12 weeks]
Change in fasting blood sugar from baseline [baseline, 12 weeks]
Change in total cholesterol from baseline [baseline, 12 weeks]
Change in triglycerides from baseline [baseline, 12 weeks]
Change in LDL-cholesterol from baseline [baseline, 12 weeks]
Change in HDL-cholesterol from baseline [baseline, 12 weeks]
Change in Homeostasis Model Assessment-Insulin resistance(HOMA-IR) from baseline [baseline, 24 weeks]
a marker of insulin resistance
Change in Homeostasis Model Assessment - beta cell (HOMA-beta) from baseline [baseline, 24 weeks]
a marker of beta cell function
Change in highly sensitive C reactive protein(hs-CRP) from baseline [baseline, 24 weeks]
a marker of inflammation
Change in Plasmonogen activator inhibitor-1(PAI-1) from baseline [baseline, 24 weeks]
Change in B-type natriuretic pepetide(BNP) from baseline [baseline, 24 weeks]
event rate of hypoglycemia [upto 24 weeks]
A number of total event of hypoglycemia defined as blood glucose <70mg/dL or subjective symptom of typical hypoglycemia
No of subject with adverse event of special interest [upto 24 weeks]
The event of special interest include heart failure cardiovascular effect other than heart failure edema weight gain urinary bladder tumor macular edema fracture of bone pancreatitis
The number of serious adverse events [upto 24 weeks]
The number of subject with hypersensitivity to study drugs [upto 24 weeks]
The number of subject with any abnormality of laboratory evaluation [12 week]
Complete Blood count BUN, Creatinine, AST, ALT, Calcium, Phosphorous, Sodium, Potassium, Total Protein, Albumin, Total Bilirubin, Gamma-glutamyl transferase, Alkaline phosphatase, Creatinine Kinase, amylase, lipase Urine analysis including microscopic examination
The number of subject with any abnormality of laboratory evaluation [24 week]
Complete Blood count Blood urea nigrogen, Creatinine, Aspartate aminotransferase, Alanine Aminotransferase, Calcium, Phosphorous, Sodium, Potassium, Total Protein, Albumin, Total Bilirubin, Gamma-glutamyl transferase, Alkaline phosphatase, Creatinine Kinase, amylase, lipase Urine analysis including microscopic examination
The number of subject with any change of findings in Chest X-ray from baseline [24 week]
The number of subject with any change of findings in electrocardiogram from baseline [24 week]

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements
The subject or, when applicable, the subject's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures
The subjects diagnosed type 2 diabetes mellitus at least 6 months
Male and female and 19 to 75 years, inclusive
7.0% =<HbA1c =<10.0%
18.5 Kg/m2 =<Body Mass Index(BMI) =<45 kg/m2
systolic/diastolic blood pressure =<160/100 at baseline
hemoglobin of at least 12 g/dL for men and at least 10 g/dL for women
A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from singing of informed consent throughout the duration of the study
Patient who receiving maximal tolerated dose of metformin at least 12 weeks without dose change (for metformin, >= 1,000 mg/day
fasting c-peptide greater than 0.78 ng/mL(0.26 nmol/L) at baseline

Exclusion Criteria:

The patient has received investigational compound(alogliptin or pioglitazone) within 180 days prior to baseline
Patient who currently taking or need to take andy medicine which may exert a significant influence on blood glucose control except metformin.
Severe renal disease : estimated glomerular filtration rate <50 mL/min
Severe liver disease or AST, ALT >= 2.5 upper limit of normal
Cardiac status : New York Heart Association III ~ IV
Hypopituitarism or adrenal insufficiency
Patient who has a history of major surgery, Severe infections, Severe traumas within 6 months
Patients who has diagnosed malignancy within 5yrs ,
Patients with active bladder cancer
Patient with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
Patient who has a history of hypersensitivity to Alogliptin, Pioglitazone or their ingredients
Pregnant or lactating woman
Patient who has history of excessive alcohol abuse
Subject who is involved in other clinical trial within 90 days prior to initiation of this study.
Subject who the investigator deems inappropriate to participate in this study