Comparison of Fasiglifam (TAK-875) to Placebo and Sitagliptin in Combination With Metformin in Participants With Type 2 Diabetes

A Multicenter, Randomized, Double-Blind, Placebo- and Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-875 25 mg and 50 mg Compared to Placebo and Sitagliptin 100 mg When Used in Combination With Metformin in Subjects With Type 2 Diabetes

The purpose of this study is to evaluate the efficacy of 2 doses of TAK-875 (25 mg and 50 mg), once daily (QD), plus metformin compared to placebo plus metformin and sitagliptin plus metformin on lowering blood sugar.

Study Overview

• Status: Terminated
• Conditions: Glycemic Control
• Intervention / Treatment: Drug: Placebo; Drug: Fasiglifam (TAK-875); Drug: Sitagliptin

Detailed Description

TAK-875 is being developed at Takeda Development Center, Inc. as an adjunct to diet and exercise to improve glycemic control in participants with Type 2 Diabetes Mellitus (T2DM) whose blood glucose level is inadequately controlled with metformin.

This study will evaluate the efficacy of TAK-875 (25 mg and 50 mg) plus metformin compared to placebo plus metformin and sitagliptin plus metformin on glycemic control as measured by change from baseline in glycosylated hemoglobin (HbA1c) over a 24-week Treatment Period. Participants completing the 24-week Treatment Period may enter an optional 80-week extension period for a total of 104 weeks of treatment.

Due to concerns about potential 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.

• Study Type: Interventional
• Enrollment (Actual): 916
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia
    • Maroubra, New South Wales, Australia
  • Queensland
    • Redcliffe, Queensland, Australia
  • South Australia
    • Adelaide, South Australia, Australia
    • Daw Park, South Australia, Australia
  • Victoria
    • Box Hill, Victoria, Australia
    • Fitzroy, Victoria, Australia
    • Melbourne, Victoria, Australia
• Bulgaria
  • Byala, Bulgaria
  • Kazanlak, Bulgaria
  • Plovdiv, Bulgaria
  • Sofia, Bulgaria
• Croatia
  • Cakovec, Croatia
  • Karlovac, Croatia
  • Krapinske Toplice, Croatia
  • Rijeka, Croatia
  • Slavonski Brod, Croatia
  • Split, Croatia
  • Zadar, Croatia
  • Zagreb, Croatia
• Czech Republic
  • Beroun, Czech Republic
  • Brno, Czech Republic
  • Havlickuv Brod, Czech Republic
  • Kladno, Czech Republic
  • Kromeriz, Czech Republic
  • Mlada Boleslav, Czech Republic
  • Ostrava, Czech Republic
  • Ostrava - Moravska Ostrava, Czech Republic
  • Pardubice, Czech Republic
  • Pisek, Czech Republic
  • Plzen, Czech Republic
  • Praha 11, Czech Republic
  • Praha 2, Czech Republic
  • Praha 5, Czech Republic
  • Praha 6, Czech Republic
  • Praha 8, Czech Republic
  • Usti nad Labem, Czech Republic
• Hungary
  • Baja, Hungary
  • Balatonfured, Hungary
  • Budaors, Hungary
  • Budapest, Hungary
  • Debrecen, Hungary
  • Eger, Hungary
  • Godollo, Hungary
  • Gyongyos, Hungary
  • Gyula, Hungary
  • Hodmezovasarhely, Hungary
  • Kecskemet, Hungary
  • Kistelek, Hungary
  • Kisvarda, Hungary
  • Komarom, Hungary
  • Mohacs, Hungary
  • Nyiregyhaza, Hungary
  • Pecs, Hungary
  • Szeged, Hungary
  • Szekszard, Hungary
  • Szikszo, Hungary
  • Szolnok, Hungary
  • Szombathely, Hungary
  • Urhida, Hungary
  • Veszprem, Hungary
  • Zalaegerszeg, Hungary
• Italy
  • Firenze, Italy
  • Milano, Italy
  • Pavia, Italy
  • Milano
    • Sesto San Giovanni, Milano, Italy
• Korea, Republic of
  • Incheon, Korea, Republic of
  • Seoul, Korea, Republic of
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, Korea, Republic of
    • Seongnam-Si, Gyeonggi-do, Korea, Republic of
• Malaysia
  • Kelantan, Malaysia
  • Kuala Lumpur, Malaysia
  • Johor
    • Johor Bahru, Johor, Malaysia
  • Kedah
    • Alor Setar, Kedah, Malaysia
  • Kelantan
    • Kota Bharu, Kelantan, Malaysia
  • Kuala Lumpur
    • Cheras, Kuala Lumpur, Malaysia
    • Lembah Pantai, Kuala Lumpur, Malaysia
  • Selangor
    • Petaling Jaya, Selangor, Malaysia
• Slovakia
  • Banska Bystrica, Slovakia
  • Bardejov, Slovakia
  • Bratislava, Slovakia
  • Kosice, Slovakia
  • Kosice - Saca, Slovakia
  • Levice, Slovakia
  • Lucenec, Slovakia
  • Moldava nad Bodvou, Slovakia
  • Nitra, Slovakia
  • Pezinok, Slovakia
  • Presov, Slovakia
  • Prievidza, Slovakia
  • Sahy, Slovakia
  • Stropkov, Slovakia
  • Sturovo, Slovakia
  • Svidnik, Slovakia
  • Trebisov, Slovakia
  • Trencin, Slovakia
  • Zilina, Slovakia
• Thailand
  • Bangkok, Thailand
  • Khon Kaen, Thailand
  • Bangkok
    • Patumwan, Bangkok, Thailand
    • Rachathevi, Bangkok, Thailand
    • Rajtevi, Bangkok, Thailand
    • Ratchathewi, Bangkok, Thailand
  • Chiang Mai
    • Muang, Chiang Mai, Thailand
  • Nakhon Ratchasima
    • Muang, Nakhon Ratchasima, Thailand
  • Songkhla
    • Hatyai, Songkhla, Thailand
• United States
  • Alabama
    • Muscle Shoals, Alabama, United States
  • Arizona
    • Mesa, Arizona, United States
    • Peoria, Arizona, United States
    • Phoenix, Arizona, United States
  • California
    • Chula Vista, California, United States
    • El Cajon, California, United States
    • La Mesa, California, United States
    • Laguna Hills, California, United States
    • National City, California, United States
    • Paramount, California, United States
    • San Diego, California, United States
    • Stockton, California, United States
    • Tustin, California, United States
    • West Hills, California, United States
  • Connecticut
    • Trumbull, Connecticut, United States
  • Florida
    • Coral Gables, Florida, United States
    • Jacksonville, Florida, United States
    • Miami, Florida, United States
    • New Port Richey, Florida, United States
    • Ocala, Florida, United States
    • West Palm Beach, Florida, United States
  • Idaho
    • Meridian, Idaho, United States
  • Illinois
    • Chicago, Illinois, United States
  • Indiana
    • Greenfield, Indiana, United States
    • Muncie, Indiana, United States
  • Kentucky
    • Lexington, Kentucky, United States
    • Owensboro, Kentucky, United States
  • Maryland
    • Hyattsville, Maryland, United States
  • Michigan
    • Troy, Michigan, United States
  • Mississippi
    • Picayune, Mississippi, United States
  • Missouri
    • St. Louis, Missouri, United States
  • New Jersey
    • Haddon Heights, New Jersey, United States
  • New York
    • Rosedale, New York, United States
  • North Carolina
    • Calabash, North Carolina, United States
    • Charlotte, North Carolina, United States
    • Monroe, North Carolina, United States
    • Morehead City, North Carolina, United States
    • Winston-Salem, North Carolina, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Cleveland, Ohio, United States
    • Dayton, Ohio, United States
  • Oklahoma
    • Norman, Oklahoma, United States
  • Pennsylvania
    • Lancaster, Pennsylvania, United States
    • Levittown, Pennsylvania, United States
  • South Carolina
    • Spartanburg, South Carolina, United States
  • Tennessee
    • Crossville, Tennessee, United States
    • Memphis, Tennessee, United States
  • Texas
    • Carrollton, Texas, United States
    • Houston, Texas, United States
    • Irving, Texas, United States
    • Katy, Texas, United States
    • McKinney, Texas, United States
    • Plano, Texas, United States
    • San Antonio, Texas, United States
    • Spring, Texas, United States
  • Utah
    • Salt Lake City, Utah, United States
    • West Jordan, Utah, United States
  • Virginia
    • Richmond, Virginia, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The participant is male or female and 18 years of age or older with a historical diagnosis of type II diabetes mellitus.

2. The participant meets one of the following criteria:

   1. The participant has an HbA1c level ≥7.5 and <10.5%, and has been on a stable daily dose of ≥1500 mg (or documented maximum tolerated dose [MTD]) of metformin for at least 2 months prior to Screening. This participant will immediately enter the Placebo Run-in Period according to Study Schedule A, 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 according to Study Schedule B. Following this 8-week period, the participant must qualify for entry into the Placebo Run-in Period by completing the Week -3 procedures including having an HbA1c level ≥7.5 and <10.5%.
3. 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).
4. The participant has a body mass index (BMI) ≤45 kg/m² at Screening.
5. 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.
6. 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 subject diaries.

Exclusion Criteria:

1. The participant donated or received any blood products within 12 weeks prior to Screening or is planning to donate blood during the study.
2. Hemoglobin ≤12 g/dL (≤120 g/L) for males and ≤10 g/dL (≤100 g/L) for females at Screening Visit.
3. The participant has systolic blood pressure ≥160 mm Hg or diastolic pressure ≥95 mm Hg at Screening Visit. (If the participant meets this exclusion criterion, the assessment may be repeated once at least 30 minutes after the initial measurement.)
4. The participant has a history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening.
5. The participant has had treatment for gastric banding or gastric bypass surgery within one year prior to Screening.
6. The participant had coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, unstable angina pectoris, clinically significant abnormal ECG, cerebrovascular accident or transient ischemic attack within 3 months prior to or at Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Fasiglifam (TAK-875) 25 mg; Fasiglifam 25 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.	Drug: Fasiglifam (TAK-875); Fasiglifam (TAK-875) tablets
EXPERIMENTAL: Fasiglifam (TAK-875) 50 mg; Fasiglifam 50 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.	Drug: Fasiglifam (TAK-875); Fasiglifam (TAK-875) tablets
ACTIVE_COMPARATOR: Sitagliptin 100 mg; Sitagliptin 100 mg, tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. TAK-875 placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.	Drug: Sitagliptin; Sitagliptin tablets; Other Names: Januvia
PLACEBO_COMPARATOR: Placebo; Fasiglifam (TAK-875) placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Sitagliptin placebo-matching tablets, orally, once daily for a 24-week Treatment Period followed by an optional 80-week extension period for up to 104 weeks of treatment. Metformin ≥1500 mg or Maximum Tolerated Dose (MTD) needs to continue at a stable dose.	Drug: Placebo; Placebo-matching tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin (HbA1c)	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at Week 24 relative to Baseline. A Mixed Model Repeated Measures (MMRM) model was used for analysis with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with Baseline value and Baseline value by visit interaction as covariates with an unstructured covariance structure.	Baseline and Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of HbA1c <7%	Incidence (percentage) of participants with glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) less than 7% at Week 24.	24 Weeks
Change From Baseline in Fasting Plasma Glucose (FPG)	The change between FPG collected at week 24 relative to Baseline. A MMRM model was used for analysis with treatment, country, schedule, visit and visit by treatment interaction as fixed factors and with Baseline value and Baseline value by visit interaction as covariates with an unstructured covariance structure.	Baseline and Week 24

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (ACTUAL): March 1, 2014
• Study Completion (ACTUAL): March 1, 2014

Study Registration Dates

• First Submitted: March 6, 2012
• First Submitted That Met QC Criteria: March 6, 2012
• First Posted (ESTIMATE): March 9, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): June 2, 2016
• Last Update Submitted That Met QC Criteria: April 20, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate
• Other Study ID Numbers: TAK-875_302; 2011-001752-10 (EUDRACT_NUMBER); U1111-1124-2225 (REGISTRY: WHO); NMRR-12-446-11314 (REGISTRY: NMRR (Malaysia))