Clinical trial NCT01481116: Efficacy and Safety of TAK-875 Compared to Glimepiride When Used With Metformin in Participants With Type 2 Diabetes
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-11-29
Enrollment: 2454
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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).

Primary outcomes:
measure: Change From Baseline in HbA1c at Weeks 78 and 104
timeFrame: Baseline and Weeks 78 and 104
Secondary outcomes:
measure: Percentage of Participants With Hypoglycemia
timeFrame: Day 1 up to Weeks 78 and 104
measure: Change From Baseline in Body Weight at Weeks 78 and 104
timeFrame: Baseline and Weeks 78 and 104
measure: Change From Baseline in HbA1c at Weeks 26 and 52
timeFrame: Baseline and Weeks 26 and 52
measure: Percentage of Participants With HbA1c <7%
timeFrame: Weeks 26, 52, 78 and 104
measure: Percentage of Participants With HbA1c <7% for Participants Who Did Not Report Hypoglycemia
timeFrame: Weeks 26, 52, 78 and 104
measure: Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104
timeFrame: Baseline and Weeks 26, 52, 78 and 104
Other outcomes:
Locations:
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city: Charlotte
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city: Greensboro
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city: Mooresville
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city: Morganton
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city: Raleigh
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city: Maumee
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city: Oklahoma City
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city: Greer
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state: South Carolina
city: Spartanburg
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city: Dallas
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state: Texas
city: El Paso
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city: Ft. Worth
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city: Houston
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city: New Braunfels
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city: San Antonio
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city: Spring
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city: Tomball
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state: Texas
city: Salt Lake City
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state: Utah
city: Burke
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state: Virginia
city: Hampton
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state: Virginia
city: Manassas
country: United States
state: Virginia
city: Ciudad Autonoma de Buenos Aires
country: Argentina
state: Ciudad Autonoma Buenos Aires
city: Rosario
country: Argentina
state: Santa Fe
city: Ciudad Autonoma Buenos Aires
country: Argentina
city: Cordoba
country: Argentina
city: Corrientes
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city: Canberra
country: Australia
state: Australian Capital Territory
city: Brookvale
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state: New South Wales
city: Mosman
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city: Woy Woy
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city: Canberra
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city: Blagoevgrad
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city: Pleven
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state: British Columbia
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city: Mirabel
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city: Pointe Claire
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city: Ville Saint-Laurent
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city: Bogota
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city: Medellin
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city: Benatky nad Jizerou
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city: Brno
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city: Ceske Budejovice
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city: Chocen
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city: Jindrichuv Hradec
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city: Marianske Lazne
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city: Olomouc
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city: Ostrava - Moravska Ostrava
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city: Ostrava - Vitkovice
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city: Ostrava
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city: Prague 10
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city: Praha 10
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city: Praha 4 - Krc
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city: Paide
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city: Beer Sheva
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city: Petach Tikwa
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city: Limbazi
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city: Alytus
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country: Lithuania
city: Klaipeda
country: Lithuania
city: Vilnius
country: Lithuania
city: Ipoh
country: Malaysia
state: Perak
city: Taiping, Perak
country: Malaysia
state: Perak
city: Taiping
country: Malaysia
state: Perak
city: Petaling Jaya
country: Malaysia
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city: Kuala Lumpur
country: Malaysia
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country: Malaysia
city: Putrajaya
country: Malaysia
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country: Malaysia
city: Mexico
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state: Distrito Federal
city: Cuernavaca
country: Mexico
state: Morelos
city: Auckland
country: New Zealand
city: Christchurch
country: New Zealand
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city: Palmerston North
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country: New Zealand
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country: Philippines
city: Davao City
country: Philippines
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country: Philippines
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country: Philippines
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country: Philippines
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country: Philippines
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country: Philippines
city: Bialystok
country: Poland
city: Bydgoszcz
country: Poland
city: Gdansk
country: Poland
city: Grodzisk Mazowiecki
country: Poland
city: Kamieniec Zabkowicki
country: Poland
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country: Poland
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country: Poland
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country: Poland
city: Lublin
country: Poland
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country: Poland
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country: Poland
city: Plock
country: Poland
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country: Poland
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country: Poland
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country: Poland
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country: Poland
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country: Poland
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country: Poland
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country: Poland
city: Zgierz
country: Poland
city: Bacau
country: Romania
city: Baia Mare
country: Romania
city: Bucuresti
country: Romania
city: Constanta
country: Romania
city: Iasi
country: Romania
city: Oradea
country: Romania
city: Ploiesti
country: Romania
city: Targu Mures
country: Romania
city: Timisoara
country: Romania
city: Kazan
country: Russian Federation
city: Kemerovo
country: Russian Federation
city: Krasnoyarsk
country: Russian Federation
city: Moscow
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Yaroslavl
country: Russian Federation
city: Port Elizabeth
country: South Africa
state: Eastern Cape
city: Bloemfontein
country: South Africa
state: Free State
city: Johannesburg
country: South Africa
state: Gauteng
city: Kempton Park
country: South Africa
state: Gauteng
city: Krugersdorp
country: South Africa
state: Gauteng
city: Pretoria
country: South Africa
state: Gauteng
city: Durban
country: South Africa
state: KwaZulu-Natal
city: Middelburg
country: South Africa
state: Mpumalanga
city: Cape Town
country: South Africa
state: Western Cape
city: Somerset West
country: South Africa
state: Western Cape
city: Stellenbosch
country: South Africa
state: Western Cape
city: Worcester
country: South Africa
state: Western Cape
city: Chia-Yi City
country: Taiwan
city: New Taipei City
country: Taiwan
city: Taichung
country: Taiwan
city: Tainan
country: Taiwan
city: Taipei
country: Taiwan
city: Dnipropetrovsk
country: Ukraine
city: Ivano-Frankivsk
country: Ukraine
city: Kharkiv
country: Ukraine
city: Kiev
country: Ukraine
city: Kyiv
country: Ukraine
city: Lugansk
country: Ukraine
city: Lviv
country: Ukraine
city: Mykolayiv
country: Ukraine
city: Poltava
country: Ukraine
city: Ternopil
country: Ukraine
city: Vinnytsia
country: Ukraine
city: Zaporizhzhia
country: Ukraine
city: Cheadle
country: United Kingdom
state: Cheshire
city: Plymouth
country: United Kingdom
state: Devon
city: Hull
country: United Kingdom
state: East Riding of Yorkshire
city: Bexhill on Sea
country: United Kingdom
state: East Sussex
city: Watford
country: United Kingdom
state: Hertfordshire
city: Thornton-Cleveleys
country: United Kingdom
state: Lancashire
city: Liverpool
country: United Kingdom
state: Merseyside
city: Northwood
country: United Kingdom
state: Middlesex
city: Bath
country: United Kingdom
state: Somerset
city: Swansea
country: United Kingdom
state: South Glamorgan
city: Cardiff
country: United Kingdom
Study officials:
affiliation: Takeda
name: Senior Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.