Efficacy and Safety of Alogliptin Combined With Metformin in Participants With Type 2 Diabetes Mellitus

Official Title: “A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of SYR110322 (SYR-322) When Used in Combination With Metformin in Subjects With Type 2 Diabetes”

The purpose of this study is to evaluate the efficacy and safety of alogliptin, once daily (QD), combined with metformin in adults with type 2 diabetes mellitus.

There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% are type 2. The prevalence of type 2 diabetes varies among racial and ethnic populations and has been shown to correlate with age, obesity, family history, history of gestational diabetes, and physical inactivity. Over the next decade, a marked increase in the number of adults with diabetes mellitus is expected.

Takeda is developing SYR-322 (alogliptin) for the improvement of glycemic control in patients with type 2 diabetes mellitus. Alogliptin is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes.

The aim of the current study is to evaluate the effectiveness of alogliptin in combination with metformin in individually who are inadequately controlled on metformin alone.

Individuals who participate in this study will be required to commit to a screening visit and up to 14 additional visits at the study center. Study participation is anticipated to be about 34 weeks (or 8.5 months).

Intervention(s) in this Clinical Trial

• Drug: Alogliptin and metformin
  • Alogliptin 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.
• Drug: Alogliptin and metformin
  • Alogliptin 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.
• Drug: Metformin
  • Alogliptin placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Alogliptin 12.5 mg QD
• Experimental: Alogliptin 25 mg QD
• Placebo Comparator: Metformin

Primary Measures

• Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26.
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No

Secondary Measures

• Change From Baseline in Glycosylated Hemoglobin (Week 4).
  • Time Frame: Baseline and Week 4.
    Safety Issue?: No
• Change From Baseline in Glycosylated Hemoglobin (Week 8).
  • Time Frame: Baseline and Week 8.
    Safety Issue?: No
• Change From Baseline in Glycosylated Hemoglobin (Week 12).
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Glycosylated Hemoglobin (Week 16).
  • Time Frame: Baseline and Week 16.
    Safety Issue?: No
• Change From Baseline in Glycosylated Hemoglobin (Week 20).
  • Time Frame: Baseline and Week 20.
    Safety Issue?: No
• Change From Baseline in Fasting Plasma Glucose (Week 1).
  • Time Frame: Baseline and Week 1.
    Safety Issue?: No
• Change From Baseline in Fasting Plasma Glucose (Week 2).
  • Time Frame: Baseline and Week 2.
    Safety Issue?: No
• Change From Baseline in Fasting Plasma Glucose (Week 4).
  • Time Frame: Baseline and Week 4.
    Safety Issue?: No
• Change From Baseline in Fasting Plasma Glucose (Week 8).
  • Time Frame: Baseline and Week 8.
    Safety Issue?: No
• Change From Baseline in Fasting Plasma Glucose (Week 12).
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Fasting Plasma Glucose (Week 16).
  • Time Frame: Baseline and Week 16.
    Safety Issue?: No
• Change From Baseline in Fasting Plasma Glucose (Week 20).
  • Time Frame: Baseline and Week 20.
    Safety Issue?: No
• Change From Baseline in Fasting Plasma Glucose (Week 26).
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Number of Participants With Marked Hyperglycemia (Fasting Plasma Glucose ≥ 200 mg Per dL).
  • Time Frame: 26 Weeks.
    Safety Issue?: No
• Number of Participants Requiring Rescue.
  • Time Frame: 26 Weeks.
    Safety Issue?: No
• Change From Baseline in Fasting Proinsulin (Week 4).
  • Time Frame: Baseline and Week 4.
    Safety Issue?: No
• Change From Baseline in Fasting Proinsulin (Week 8).
  • Time Frame: Baseline and Week 8.
    Safety Issue?: No
• Change From Baseline in Fasting Proinsulin (Week 12).
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Fasting Proinsulin (Week 16).
  • Time Frame: Baseline and Week 16.
    Safety Issue?: No
• Change From Baseline in Fasting Proinsulin (Week 20).
  • Time Frame: Baseline and Week 20.
    Safety Issue?: No
• Change From Baseline in Fasting Proinsulin (Week 26).
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Change From Baseline in Insulin (Week 4).
  • Time Frame: Baseline and Week 4.
    Safety Issue?: No
• Change From Baseline in Insulin (Week 8).
  • Time Frame: Baseline and Week 8.
    Safety Issue?: No
• Change From Baseline in Insulin (Week 12).
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Insulin (Week 16).
  • Time Frame: Baseline and Week 16.
    Safety Issue?: No
• Change From Baseline in Insulin (Week 20).
  • Time Frame: Baseline and Week 20.
    Safety Issue?: No
• Change From Baseline in Insulin (Week 26).
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Change From Baseline in Proinsulin/Insulin Ratio (Week 4).
  • Time Frame: Baseline and Week 4.
    Safety Issue?: No
• Change From Baseline in Proinsulin/Insulin Ratio (Week 8).
  • Time Frame: Baseline and Week 8.
    Safety Issue?: No
• Change From Baseline in Proinsulin/Insulin Ratio (Week 12).
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Proinsulin/Insulin Ratio (Week 16).
  • Time Frame: Baseline and Week 16.
    Safety Issue?: No
• Change From Baseline in Proinsulin/Insulin Ratio (Week 20).
  • Time Frame: Baseline and Week 20.
    Safety Issue?: No
• Change From Baseline in Proinsulin/Insulin Ratio (Week 26).
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Change From Baseline in C-peptide (Week 4).
  • Time Frame: Baseline and Week 4.
    Safety Issue?: No
• Change From Baseline in C-peptide (Week 8).
  • Time Frame: Baseline and Week 8.
    Safety Issue?: No
• Change From Baseline in C-peptide (Week 12).
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in C-peptide (Week 16).
  • Time Frame: Baseline and Week 16.
    Safety Issue?: No
• Change From Baseline in C-peptide (Week 20).
  • Time Frame: Baseline and Week 20.
    Safety Issue?: No
• Change From Baseline in C-peptide (Week 26).
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Number of Participants With Glycosylated Hemoglobin ≤ 6.5%.
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Number of Participants With Glycosylated Hemoglobin ≤ 7.0%.
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Number of Participants With Glycosylated Hemoglobin ≤ 7.5%.
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 0.5%.
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.0%.
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.5%.
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 2.0%.
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No
• Change From Baseline in Body Weight (Week 8).
  • Time Frame: Baseline and Week 8.
    Safety Issue?: No
• Change From Baseline in Body Weight (Week 12).
  • Time Frame: Baseline and Week 12.
    Safety Issue?: No
• Change From Baseline in Body Weight (Week 20).
  • Time Frame: Baseline and Week 20.
    Safety Issue?: No
• Change From Baseline in Body Weight (Week 26).
  • Time Frame: Baseline and Week 26.
    Safety Issue?: No

Inclusion Criteria

• Diagnosis of type 2 diabetes mellitus currently treated with metformin alone but, experiencing inadequate glycemic control. The participant should have received the metformin monotherapy for at least the 3 months prior to Screening; and must have a stable dose of greater than or equal to 1500 mg metformin for at least 8 weeks prior to randomization. Participants with a maximum tolerated dose that is documented to be less than 1500 mg of metformin may also be enrolled if this dose has been stable for 8 weeks prior to randomization.
• No treatment with antidiabetic agents other than metformin within the 3 months prior to Screening. (Exception: if a participant has received other antidiabetic therapy for less than 7 days within the 3 months prior to Screening.)
• Body mass index greater than or equal to 23 kg/m2 and less than or equal to 45 kg/m2
• Fasting C-peptide concentration greater than or equal to 0.8 ng per mL. (If this screening criterion is not met, the participant still qualifies if C-peptide is greater than or equal to 1.5 ng per mL after a challenge test.
• Glycosylated hemoglobin concentration between 7.0% and 10.0%, inclusive
• If regular use of other, non-excluded medications, must be on a stable dose for at least the 4 weeks prior to Screening. However, as needed use of prescription or over-the-counter medications is allowed at the discretion of the investigator.
• Systolic blood pressure less than or equal to 180 mm Hg and diastolic pressure less than or equal to 110 mm Hg
• Hemoglobin greater than or equal to 12 g per dL for males and greater than or equal to 10 g per dL for females
• Alanine aminotransferase less than or equal to 3 time the upper limit of normal
• Serum creatinine less than1.5 mg per dL for males and less than 1.4 mg per dL for females
• Thyroid-stimulating hormone level less than or equal to the upper limit of the normal range and the participant is clinically euthyroid.
• Neither pregnant nor lactating.
• Female participants of childbearing potential must be practicing adequate contraception. Adequate contraception must be practiced for the duration of participation in the study.
• Able and willing to monitor their own blood glucose concentrations with a home glucose monitor
• No major illness or debility that in the investigator's opinion prohibits the participant from completing the study
• Able and willing to provide written informed consent

Exclusion Criteria

• Urine albumin to creatinine ratio of greater than 1000 μg per mg at Screening. If elevated, the participant may be rescreened within 1 week.
• History of cancer, other than squamous cell or basal cell carcinoma of the skin, that has not been in full remission for at least 5 years prior to Screening. (A history of treated cervical intraepithelial neoplasia I or cervical intraepithelial neoplasia II is allowed.)
• History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening
• History of treated diabetic gastric paresis
• New York Heart Association Class III or IV heart failure regardless of therapy.
• Currently treated participants who are stable at Class I or II are candidates for the study.
• History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 6 months prior to Screening
• History of any hemoglobinopathy that may affect determination of glycosylated hemoglobin
• History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus
• History of a psychiatric disorder that will affect the participant's ability to participate in the study
• History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors
• History of alcohol or substance abuse within the 2 years prior to Screening
• Receipt of any investigational drug within the 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within the 3 months prior to Screening
• Prior treatment in an investigational study of alogliptin
• Excluded Medications:
• Treatment with antidiabetic agents other than study drug or metformin is not allowed within the 3 months prior to Screening and through the completion of the end-of treatment/early termination procedures.
• Treatment with weight-loss drugs, any investigational antidiabetics, or oral or systemically injected glucocorticoids is not allowed from 3 months prior to randomization through the completion of the end-of-treatment/early termination procedures. Inhaled corticosteroids are allowed.
• Participants must be instructed not to take any medications, including over-the-counter products, without first consulting with the investigator.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Takeda Global Research & Development Center, Inc. Industry

Overall Clinical Trial Officials and Contacts

VP Biological Sciences Study Director Takeda Global Research & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00286442

Study ID Number: SYR-322-MET-008

ClinicalTrials.gov Identifier: NCT00286442

Health Authority: United States: Food and Drug Administration