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Efficacy and Safety of TAK-875 Compared to Glimepiride When Used With Metformin in Participants With Type 2 Diabetes

This study has been terminated.
(Due to potential concerns about liver safety (See Detailed Description))
Information provided by (Responsible Party):
Takeda Identifier:
First received: November 25, 2011
Last updated: April 24, 2016
Last verified: April 2016

The purpose of this study is to determine the efficacy and safety of TAK-875, once daily (QD), plus metformin compared to glimepiride plus metformin in participants with type 2 diabetes mellitus (T2DM).

The purpose of this study is to determine the efficacy and safety of TAK-875, once daily (QD), plus metformin compared to glimepiride plus metformin in participants with type 2 diabetes mellitus (T2DM).

Condition Intervention Phase
Diabetes Mellitus, Type 2 Drug: TAK-875 Drug: Glimepiride Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-875 25 mg and 50 mg Compared to Glimepiride When Used in Combination With Metformin in Subjects With Type 2 Diabetes

Resource links provided by NLM:

Further study details as provided by Takeda:

Primary Outcome Measures:
  • Change From Baseline in HbA1c at Weeks 78 and 104 [ Time Frame: Baseline and Weeks 78 and 104 ]
    The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) to be collected at Weeks 78 and 104 relative to baseline.

Secondary Outcome Measures:
  • Percentage of Participants With Hypoglycemia [ Time Frame: Day 1 up to Weeks 78 and 104 ]
    Participants were provided diaries to document any hypoglycemic events that occurred between study visits. Any experience of hypoglycemic signs and symptoms (regardless of the blood glucose value by glucometer) or had a blood glucose value less than or equal to (<=) 70 milligram per deciliter (mg/dL) (3.9 millimole per liter (mmol/L) by glucometer (regardless of symptoms) were to be recorded.

  • Change From Baseline in Body Weight at Weeks 78 and 104 [ Time Frame: Baseline and Weeks 78 and 104 ]
    The change between the body weight to be collected at Weeks 78 and 104 relative to baseline.

  • Change From Baseline in HbA1c at Weeks 26 and 52 [ Time Frame: Baseline and Weeks 26 and 52 ]
    The change in the value of HbA1c collected at Weeks 26 and 52 relative to baseline.

  • Percentage of Participants With HbA1c <7% [ Time Frame: Weeks 26, 52, 78 and 104 ]
  • Percentage of Participants With HbA1c <7% for Participants Who Did Not Report Hypoglycemia [ Time Frame: Weeks 26, 52, 78 and 104 ]
  • Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104 [ Time Frame: Baseline and Weeks 26, 52, 78 and 104 ]
    The change between the fasting plasma glucose value to be collected at Weeks 26, 52, 78 and 104 relative to baseline.

Enrollment: 2454
Study Start Date: January 2012
Study Completion Date: April 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TAK-875 25 mg QD Drug: TAK-875
TAK-875 25 mg, tablets, orally, once daily and metformin ≥1500 mg or Maximum Tolerated Dose (MTD) for up to 104 weeks.
Experimental: TAK-875 50 mg QD Drug: TAK-875
TAK-875 50 mg, tablets, orally, once daily and metformin ≥1500 mg or MTD for up to 104 weeks.
Active Comparator: Glimepiride 1-2 mg QD Drug: Glimepiride
Glimepiride 1 mg, tablets, orally, once daily (up-titrated to 2 mg after 1 week of treatment. Up-titrated to a maximum of 6 mg in 2 mg increments/down titrated if recurrent (or severe) hypoglycemia occurs) and metformin ≥1500 mg or MTD for up to 104 weeks.

Detailed Description:

Type 2 diabetes mellitus (T2DM) has increased dramatically throughout the world over the past decades despite the availability of several different treatment options. Current pharmacologic treatments include insulin, thiazolidinediones, sulfonylureas, metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) mimetics. A number of these treatments are associated with clinically important side effects such as low blood sugar (hypoglycemia), weight gainflud retention, exaggeration of pre-existent heart failure, and gastrointestinal side effects. These side effects and the disadvantages associated with many of the currently available antidiabetic agents can reduce compliance and limit their long-term use.

Insulin is a hormone that is produced by the body to regulate blood sugar (glucose). In individuals with T2DM, the insulin produced by the body does not effectively control the amount of sugar in the bloodstream. If not properly managed, T2DM may cause elevated blood sugar levels (hyperglycemia) and ultimately result in serious health problems.

In response to this problem, Takeda is developing TAK-875 (an investigational drug) as an addition to diet and exercise to improve blood sugar control in patients with T2DM. TAK-875 may affect the production of insulin and may improve how the body uses the sugar in the blood.

The aim of this study is to find out if TAK-875, when taken for approximately 2 years in combination with current diabetes medicine (called metformin), is safe and effective at helping people with T2DM control their high blood sugar when compared to glimepiride (a type of medication called a sulfonylurea). The study is being done to find out if the combination of TAK-875 plus metformin works as well as the combination of glimepiride plus metformin.

Approximately 2430 patients worldwide aged 18 or over with T2DM, will take part in this study and will be involved in the study for up to 110 or 120 weeks.

TAK-875 is being developed at Takeda Global Research and Development, Inc. as an adjunct to diet and exercise to improve glycemic control in participants with T2DM.

This study will investigate TAK-875 in participants with type 2 diabetes mellitus whose blood sugar level is inadequately controlled with metformin monotherapy.

Due to potential concerns about liver safety, on balance, the benefits of treating patients with fasiglifam (TAK-875) do not outweigh the potential risks.

For this reason, Takeda has decided voluntarily to terminate the development activities for fasiglifam.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
  2. The participant or, when applicable, the participant'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.
  3. The participant is male or female and 18 years of age or older with a historical diagnosis of T2DM.
  4. The participant meets one of the following criteria:

    1. The participant has an HbA1c level ≥7.0 and <10.0%, and has been on a stable daily dose of ≥1500 mg (or documented MTD) of metformin for at least 2 months prior to Screening. This participant will immediately enter the Placebo Run-in Period, or;
    2. The participant has an HbA1c level ≥ 7.5 and <10.5%, and has been on a stable daily dose of <1500 mg of metformin without documented MTD for at least 2 months prior to Screening. After completing the Screening Visit, this participant will have their metformin dose immediately increased to ≥1500 mg (or MTD) for an 8-week Titration Period. Following this 8-week period, the participant must qualify for entry into the Placebo Run-in Period by completing the Week -3 procedures and having an HbA1c concentration ≥7.0 and <10.0%.
  5. The participant has had no treatment with antidiabetic agents other than metformin within 2 months prior to Screening (Exception: if a participant has received other antidiabetic therapy for ≤7 days within the 2 months prior to Screening).
  6. The participant has a body mass index (BMI) of ≤45 kg/m2 at Screening.
  7. Participants regularly using other, non-excluded medications, must be on a stable dose for at least 4 weeks prior to Screening. However, PRN (as needed) use of prescription or over-the-counter medications is allowed at the discretion of the investigator.
  8. The participant is able and willing to monitor glucose with a home glucose monitor and consistently record his or her own blood glucose concentrations and complete participant diaries.

Additional Inclusion Criteria Prior to Randomization

  1. The participant has an HbA1c concentration ≥7.0% and <10.0%, and a FPG ≤270 mg/dL (15.0 mmol/L) at the Week -1 Visit. (If the subject does not qualify for randomization based on these criteria, the assessment may be repeated weekly, for a maximum of 2 additional weeks).
  2. The participant's compliance with the single-blind study medication during the Placebo Run-in Period is at least 75% and does not exceed 125% based on tablet/capsule counts performed by the study staff.
  3. A female participant of childbearing potential must have a negative urine hCG pregnancy test at Baseline (Day 1) prior to Randomization and prior to administration of the first dose of double-blind study medication.

Exclusion Criteria:

  1. The participant has received any investigational compound within 30 days prior to Screening or has received an investigational antidiabetic drug within the 3 months prior to Screening.
  2. The participant has been randomized into a previous TAK-875 study
  3. The participant is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.
  4. The participant donated or received any blood products within 12 weeks prior to Screening or is planning to donate blood during the study.
  5. The participant has a hemoglobin ≤12 g/dL (≤120 gm/L) for males and ≤10 g/dL (≤100 gm/L) for females at Screening.
  6. The participant has a systolic blood pressure ≥160 mm Hg or diastolic pressure ≥95 mm Hg at Screening (If the participant meets this exclusion criterion, the assessment may be repeated once at least 30 minutes after the initial measurement).
  7. The participant has history of cancer that has been in remission for <5 years prior to Screening. A history of basal cell carcinoma or stage 1 squamous cell carcinoma of the skin is allowed.
  8. The participant has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels >2.0x upper limit of normal (ULN) at Screening.
  9. The participant has a total bilirubin level greater than the ULN at Screening. Exception: if a participant has documented Gilbert's Syndrome the participant will be allowed with an elevated bilirubin level per the investigator's discretion.
  10. The participant has a serum creatinine ≥1.5 mg/dL(males) and ≥1.4 mg/dL(females) and/or estimated glomerular filtration rate (GFR) <60 mL/min/1.73m2 at Screening.
  11. The participant has uncontrolled thyroid disease.
  12. The participant has a history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening.
  13. The participant has had gastric banding, or gastric bypass surgery within one year prior to Screening.
  14. The participant has a known history of infection with human immunodeficiency virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV).
  15. The participant had coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, unstable angina pectoris, clinically significant abnormal electrocardiogram (ECG), cerebrovascular accident or transient ischemic attack within 3 months prior to or at Screening.
  16. The participant has a history of hypersensitivity, allergies, or has had an anaphylactic reaction(s) to any component of TAK-875, metformin, or glimepiride.
  17. The participant has a history of drug abuse (defined as illicit drug use) or a history of alcohol abuse within 2 years prior to Screening.
  18. The participant received excluded medications prior to Screening or is expected to receive excluded medication.
  19. If female, the participant is pregnant (confirmed by laboratory testing, i.e., serum/urine human chorionic gonadotropin (hCG), in females of childbearing potential) or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.
  20. The participant is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available.
  21. The participant has any other physical or psychiatric disease or condition that in the judgment of the investigator may affect life expectancy or may make it difficult to successfully manage and follow the participant according to the protocol.

Additional Exclusion Criteria Prior to Randomization

  1. The participant has received excluded medications listed in the protocol during the Placebo Run-in Period (topical and inhaled corticosteroids are allowed).
  2. The participant has a systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥95 mm Hg at Baseline (Day 1) (If the subject meets this exclusion criterion, the assessment may be repeated once at least 30 minutes after the initial measurement and decision will be made based on the second measurement).
  3. The participant has a serum creatinine ≥1.5 mg/dL(≥133µmol/L) [males] and ≥1.4 mg/dL (≥124 µmol/L) [females] and/or estimated glomerular filtration rate (GFR) <60 mL/min/1.73m2 at Visit 3 (Schedule B subjects only).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01481116

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United States, Alabama
Dothan, Alabama, United States
Muscle Shoals, Alabama, United States
United States, Arizona
Goodyear, Arizona, United States
Phoenix, Arizona, United States
Tempe, Arizona, United States
United States, California
Long Beach, California, United States
Mission Hills, California, United States
North Hollywood, California, United States
Norwalk, California, United States
Pismo Beach, California, United States
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Clearwater, Florida, United States
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Decatur, Georgia, United States
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Avon, Indiana, United States
United States, Kansas
Topeka, Kansas, United States
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Oxon Hill, Maryland, United States
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Flint, Michigan, United States
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Jackson, Mississippi, United States
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Omaha, Nebraska, United States
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Elizabeth, New Jersey, United States
United States, North Carolina
Calabash, North Carolina, United States
Charlotte, North Carolina, United States
Greensboro, North Carolina, United States
Mooresville, North Carolina, United States
Morganton, North Carolina, United States
Raleigh, North Carolina, United States
United States, Ohio
Maumee, Ohio, United States
United States, Oklahoma
Oklahoma City, Oklahoma, United States
United States, South Carolina
Greer, South Carolina, United States
Spartanburg, South Carolina, United States
United States, Texas
Dallas, Texas, United States
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Ft. Worth, Texas, United States
Houston, Texas, United States
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Salt Lake City, Utah, United States
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Burke, Virginia, United States
Hampton, Virginia, United States
Manassas, Virginia, United States
Ciudad Autonoma de Buenos Aires, Ciudad Autonoma Buenos Aires, Argentina
Rosario, Santa Fe, Argentina
Ciudad Autonoma Buenos Aires, Argentina
Cordoba, Argentina
Corrientes, Argentina
Australia, Australian Capital Territory
Canberra, Australian Capital Territory, Australia
Australia, New South Wales
Brookvale, New South Wales, Australia
Mosman, New South Wales, Australia
Woy Woy, New South Wales, Australia
Canberra, Australia
Blagoevgrad, Bulgaria
Gabrovo, Bulgaria
Pleven, Bulgaria
Plovdiv, Bulgaria
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Sofia, Bulgaria
Stara Zagora, Bulgaria
Varna, Bulgaria
Canada, British Columbia
Victoria, British Columbia, Canada
Canada, Ontario
Oakville, Ontario, Canada
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Toronto, Ontario, Canada
Canada, Quebec
Laval, Quebec, Canada
Longueuil, Quebec, Canada
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Ville Saint-Laurent, Quebec, Canada
Bogota, Colombia
Medellin, Colombia
Czech Republic
Benatky nad Jizerou, Czech Republic
Brno, Czech Republic
Ceske Budejovice, Czech Republic
Chocen, Czech Republic
Jindrichuv Hradec, Czech Republic
Marianske Lazne, Czech Republic
Olomouc, Czech Republic
Ostrava - Moravska Ostrava, Czech Republic
Ostrava - Vitkovice, Czech Republic
Ostrava, Czech Republic
Prague 10, Czech Republic
Praha 10, Czech Republic
Praha 4 - Krc, Czech Republic
Praha 5, Czech Republic
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Znojmo, Czech Republic
Paide, Estonia
Rakvere, Estonia
Saku, Estonia
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Taiping, Perak, Perak, Malaysia
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Terengganu, Malaysia
Mexico, Distrito Federal, Mexico
Cuernavaca, Morelos, Mexico
New Zealand
Auckland, New Zealand
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Hamilton, New Zealand
Palmerston North, New Zealand
Rotorua, New Zealand
Tauranga, New Zealand
Wellington, New Zealand
Cebu City, Philippines
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Lipa City, Philippines
Quezon City, Philippines
Tarlac, Philippines
Taytay, Philippines
Bialystok, Poland
Bydgoszcz, Poland
Gdansk, Poland
Grodzisk Mazowiecki, Poland
Kamieniec Zabkowicki, Poland
Katowice, Poland
Leczyca, Poland
Lodz, Poland
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Poznan, Poland
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Bacau, Romania
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Bucuresti, Romania
Constanta, Romania
Iasi, Romania
Oradea, Romania
Ploiesti, Romania
Targu Mures, Romania
Timisoara, Romania
Russian Federation
Kazan, Russian Federation
Kemerovo, Russian Federation
Krasnoyarsk, Russian Federation
Moscow, Russian Federation
Novosibirsk, Russian Federation
St. Petersburg, Russian Federation
Yaroslavl, Russian Federation
South Africa
Port Elizabeth, Eastern Cape, South Africa
Bloemfontein, Free State, South Africa
Johannesburg, Gauteng, South Africa
Kempton Park, Gauteng, South Africa
Krugersdorp, Gauteng, South Africa
Pretoria, Gauteng, South Africa
Durban, KwaZulu-Natal, South Africa
Middelburg, Mpumalanga, South Africa
Cape Town, Western Cape, South Africa
Somerset West, Western Cape, South Africa
Stellenbosch, Western Cape, South Africa
Worcester, Western Cape, South Africa
Chia-Yi City, Taiwan
New Taipei City, Taiwan
Taichung, Taiwan
Tainan, Taiwan
Taipei, Taiwan
Dnipropetrovsk, Ukraine
Ivano-Frankivsk, Ukraine
Kharkiv, Ukraine
Kiev, Ukraine
Kyiv, Ukraine
Lugansk, Ukraine
Lviv, Ukraine
Mykolayiv, Ukraine
Poltava, Ukraine
Ternopil, Ukraine
Vinnytsia, Ukraine
Zaporizhzhia, Ukraine
United Kingdom
Cheadle, Cheshire, United Kingdom
Plymouth, Devon, United Kingdom
Hull, East Riding of Yorkshire, United Kingdom
Bexhill on Sea, East Sussex, United Kingdom
Watford, Hertfordshire, United Kingdom
Thornton-Cleveleys, Lancashire, United Kingdom
Liverpool, Merseyside, United Kingdom
Northwood, Middlesex, United Kingdom
Bath, Somerset, United Kingdom
Swansea, South Glamorgan, United Kingdom
Cardiff, United Kingdom
Sponsors and Collaborators
Study Director: Senior Medical Director Takeda
  More Information

Responsible Party: Takeda Identifier: NCT01481116     History of Changes
Other Study ID Numbers: TAK-875_304
2011-001731-24 ( EudraCT Number )
U1111-1124-2296 ( Registry Identifier: WHO )
TAK-875_304CTIL ( Other Identifier: Israel MOH )
DOH-27-0512-3913 ( Registry Identifier: SANCTR )
11-057 ( Registry Identifier: ROCTR )
NMRR-11-882-10318 ( Registry Identifier: NMRR )
HKCTR-1616 ( Registry Identifier: HKUCTR )
262 ( Registry Identifier: RoPCCT )
12/WA/0245 ( Registry Identifier: NRES )
Study First Received: November 25, 2011
Results First Received: July 24, 2015
Last Updated: April 24, 2016

Keywords provided by Takeda:
Drug Therapy

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Immunosuppressive Agents
Immunologic Factors processed this record on September 25, 2017