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

NCT ID: NCT01481116

Last Updated: 2016-06-01

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 2454 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-01-31
• Study Completion Date: 2014-04-30

Brief Summary

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).

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.

Conditions

Diabetes Mellitus, Type 2

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

TAK-875 25 mg QD

Group Type: EXPERIMENTAL

TAK-875

Intervention Type: DRUG

TAK-875 25 mg, tablets, orally, once daily and metformin ≥1500 mg or Maximum Tolerated Dose (MTD) for up to 104 weeks.

TAK-875 50 mg QD

Group Type: EXPERIMENTAL

TAK-875

Intervention Type: DRUG

TAK-875 50 mg, tablets, orally, once daily and metformin ≥1500 mg or MTD for up to 104 weeks.

Glimepiride 1-2 mg QD

Group Type: ACTIVE_COMPARATOR

Glimepiride

Intervention Type: DRUG

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.

Interventions

TAK-875

TAK-875 25 mg, tablets, orally, once daily and metformin ≥1500 mg or Maximum Tolerated Dose (MTD) for up to 104 weeks.

Intervention Type: DRUG

TAK-875

TAK-875 50 mg, tablets, orally, once daily and metformin ≥1500 mg or MTD for up to 104 weeks.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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.

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.

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Senior Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

Davao City, , Philippines

Iloilo City, , Philippines

Lipa City, , Philippines

Quezon City, , Philippines

Tarlac City, , Philippines

Taytay, , Philippines

Bialystok, , Poland

Bydgoszcz, , Poland

Gdansk, , Poland

Grodzisk Mazowiecki, , Poland

Kamieniec Ząbkowicki, , Poland

Katowice, , Poland

Lodz, , Poland

Lublin, , Poland

Oświęcim, , Poland

Parczew, , Poland

Poznan, , Poland

Puławy, , Poland

Płock, , Poland

Ruda Śląska, , Poland

Rzeszów, , Poland

Sopot, , Poland

Torun, , Poland

Wroclaw, , Poland

Zgierz, , Poland

Łęczyca, , Poland

Bacau, , Romania

Baia Mare, , Romania

Bucharest, , Romania

Constanța, , Romania

Iași, , Romania

Oradea, , Romania

Ploieşti, , Romania

Târgu Mureş, , Romania

Timișoara, , Romania

Kazan', , Russia

Kemerovo, , Russia

Krasnoyarsk, , Russia

Moscow, , Russia

Novosibirsk, , Russia

Saint Petersburg, , Russia

Yaroslavl, , Russia

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 City, , Taiwan

Taipei, , Taiwan

Dnipropetrovsk, , Ukraine

Ivano-Frankivsk, , Ukraine

Kharkiv, , Ukraine

Kiev, , Ukraine

Kyiv, , Ukraine

Luhansk, , Ukraine

Lviv, , Ukraine

Mykolayiv, , Ukraine

Poltava, , Ukraine

Ternopil, , Ukraine

Vinnytsia, , Ukraine

Zaporizhzhia, , Ukraine

Cardiff, Cardiff, 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

Dothan, Alabama, United States

Muscle Shoals, Alabama, United States

Goodyear, Arizona, United States

Phoenix, Arizona, United States

Tempe, Arizona, United States

Long Beach, California, United States

Mission Hills, California, United States

North Hollywood, California, United States

Norwalk, California, United States

Pismo Beach, California, United States

Bradenton, Florida, United States

Clearwater, Florida, United States

Coral Gables, Florida, United States

Hialeah, Florida, United States

Orlando, Florida, United States

Pembroke Pines, Florida, United States

Decatur, Georgia, United States

Avon, Indiana, United States

Topeka, Kansas, United States

Oxon Hill, Maryland, United States

Flint, Michigan, United States

Jackson, Mississippi, United States

Omaha, Nebraska, United States

Elizabeth, New Jersey, United States

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

Maumee, Ohio, United States

Oklahoma City, Oklahoma, United States

Greer, South Carolina, United States

Spartanburg, South Carolina, United States

Dallas, Texas, United States

El Paso, Texas, United States

Fort Worth, Texas, United States

Houston, Texas, United States

New Braunfels, Texas, United States

San Antonio, Texas, United States

Spring, Texas, United States

Tomball, Texas, United States

Salt Lake City, Utah, United States

Burke, Virginia, United States

Hampton, Virginia, United States

Manassas, Virginia, United States

Buenos Aires, Ciudad Autonoma Buenos Aires, Argentina

Ciudad Autonoma Buenos Aires, Ciudad Autonoma Buenos Aires, Argentina

Corrientes, Corrientes Province, Argentina

Córdoba, Córdoba Province, Argentina

Rosario, Santa Fe Province, Argentina

Córdoba, , Argentina

Canberra, Australian Capital Territory, Australia

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

Sevlievo, , Bulgaria

Sofia, , Bulgaria

Stara Zagora, , Bulgaria

Varna, , Bulgaria

Victoria, British Columbia, Canada

Oakville, Ontario, Canada

Ottawa, Ontario, Canada

Thornhill, Ontario, Canada

Toronto, Ontario, Canada

Laval, Quebec, Canada

Longueuil, Quebec, Canada

Mirabel, Quebec, Canada

Pointe-Claire, Quebec, Canada

Saint-Laurent, Quebec, Canada

Bogotá, , Colombia

Medellín, , Colombia

Benátky nad Jizerou, , Czechia

Brno, , Czechia

Choceň, , Czechia

České Budějovice, , Czechia

Jindřichův Hradec, , Czechia

Mariánské Lázně, , Czechia

Olomouc, , Czechia

Ostrava, , Czechia

Ostrava - Moravska Ostrava, , Czechia

Ostrava - Vitkovice, , Czechia

Prague, , Czechia

Praha 4 - Krc, , Czechia

Znojmo, , Czechia

Paide, , Estonia

Rakvere, , Estonia

Saku, , Estonia

Tallinn, , Estonia

Tartu, , Estonia

Võru, , Estonia

Hong Kong, , Hong Kong

New Territories, , Hong Kong

Ashkelon, , Israel

Beer Yaakov, , Israel

Beersheba, , Israel

Giv‘atayim, , Israel

Hadera, , Israel

Haifa, , Israel

Holon, , Israel

Jerusalem, , Israel

Kfar Saba, , Israel

Nahariya, , Israel

Petah Tikva, , Israel

Raanana, , Israel

Ramat Gan, , Israel

Rehovot, , Israel

Rishon LeZiyyon, , Israel

Safed, , Israel

Tel Aviv, , Israel

Jelgava, , Latvia

Limbaži, , Latvia

Ogre, , Latvia

Riga, , Latvia

Talsi, , Latvia

Valmiera, , Latvia

Alytus, , Lithuania

Kaunas, , Lithuania

Klaipėda, , Lithuania

Vilnius, , Lithuania

Kuala Lumpur, Kuala Lumpur, Malaysia

Malacca, Melaka, Malaysia

Ipoh, Perak, Malaysia

Taiping, Perak, Malaysia

Taiping, Perak, Perak, Malaysia

Putrajaya, Putrajaya, Malaysia

Petaling Jaya, Selangor, Malaysia

Terengganu, Terengganu, Malaysia

Terengganu, , Malaysia

Mexico City, Mexico City, Mexico

Cuernavaca, Morelos, Mexico

Auckland, , New Zealand

Christchurch, , New Zealand

Hamilton, , New Zealand

Palmerston North, , New Zealand

Rotorua, , New Zealand

Tauranga, , New Zealand

Wellington, , New Zealand

Cebu City, , Philippines

Countries

United States; Argentina; Australia; Bulgaria; Canada; Colombia; Czechia; Estonia; Hong Kong; Israel; Latvia; Lithuania; Malaysia; Mexico; New Zealand; Philippines; Poland; Romania; Russia; South Africa; Taiwan; Ukraine; United Kingdom

References

Shavadia JS, Sharma A, Gu X, Neaton J, DeLeve L, Holmes D, Home P, Eckel RH, Watkins PB, Granger CB. Determination of fasiglifam-induced liver toxicity: Insights from the data monitoring committee of the fasiglifam clinical trials program. Clin Trials. 2019 Jun;16(3):253-262. doi: 10.1177/1740774519836766. Epub 2019 Mar 18.

Reference Type: DERIVED

PMID: 30880443 (View on PubMed)

Other Identifiers

2011-001731-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1124-2296

Identifier Type: REGISTRY

Identifier Source: secondary_id

TAK-875_304CTIL

Identifier Type: OTHER

Identifier Source: secondary_id

DOH-27-0512-3913

Identifier Type: REGISTRY

Identifier Source: secondary_id

11-057

Identifier Type: REGISTRY

Identifier Source: secondary_id

NMRR-11-882-10318

Identifier Type: REGISTRY

Identifier Source: secondary_id

HKCTR-1616

Identifier Type: REGISTRY

Identifier Source: secondary_id

262

Identifier Type: REGISTRY

Identifier Source: secondary_id

12/WA/0245

Identifier Type: REGISTRY

Identifier Source: secondary_id

TAK-875_304

Identifier Type: -

Identifier Source: org_study_id