Study of TAK-875 in Adults With Type 2 Diabetes and Cardiovascular Disease or Risk Factors for Cardiovascular Disease

• Sponsor: Takeda (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01609582
• Collaborator: (none)
• Enrollment: 3,207
• Locations: 588
• Arms: 2
• Duration (Months): 23
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to demonstrate no excess risk of cardiovascular (CV) composite events exists following long term treatment with TAK-875 compared with placebo.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes; Cardiovascular Disease	Drug: TAK-875; Drug: TAK-875 Placebo	Phase 3

Detailed Description

The drug being tested in this study is called TAK-875. TAK-875 is being tested to treat people who have diabetes. This study will look at the number of cardiovascular events (for example, heart attacks) of people who take TAK-875 in comparison to placebo in addition to standard care.

The study will enroll approximately 5000 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

• TAK-875 50 mg.

• Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient.

All participants will be asked to take one tablet at the same time each day throughout the study. All participants will be asked to record any time they have low blood sugar symptoms in a diary.

This multi-centre trial will be conducted worldwide, in approximately 700 sites. The overall time to participate in this study is 6 years. Participants will make up to approximately 24 visits to the clinic, with telephone visits conducted on an alternate 6 month schedule starting from Month 27.

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3207 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate Cardiovascular Outcomes of TAK-875, 50 mg in Addition to Standard of Care in Subjects With Type 2 Diabetes and With Cardiovascular Disease or Multiple Risk Factors for Cardiovascular Events
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TAK-875 50 mg TAK-875 50 mg tablets, orally, once daily for up to 6 years.	Drug: TAK-875; TAK-875 tablets
Placebo Comparator: Placebo TAK-875 placebo-matching tablets, orally, once daily for up to 6 years.	Drug: TAK-875 Placebo; TAK-875 placebo-matching tablets

Outcome Measures

Primary Outcome Measures

1. Time to First Occurrence of Any Component of Primary Major Adverse Cardiovascular Event (MACE) Composite [Baseline up to end of study (up to Day 588)]

   The time from randomization to the first occurrences of any event in the primary MACE composite was evaluated using Kaplan-Meier analysis. The primary MACE composite comprised cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, and hospitalization for unstable angina (with or without revascularization).

Secondary Outcome Measures

1. Time to First Occurrence of Any Component of Secondary Major Adverse Cardiovascular Event (MACE) Composite [Baseline up to end of study (up to Day 588)]

   The time from randomization to the first occurrences of any event in the secondary MACE composite was evaluated using Kaplan-Meier analysis. The secondary MACE composite comprised CV death, nonfatal MI, and nonfatal stroke.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. In the opinion of the investigator, the patient is capable of understanding and complying with protocol requirements, including scheduled clinic appointments.

2. The patient or, when applicable, the patient'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. Has a diagnosis of type 2 diabetes mellitus.

4. Has an glycosylated hemoglobin (HbA1c) level between 7.0% and 10.5%, inclusive, at Screening. HbA1c testing may be repeated once during Screening.

5. Meets at least one (1) of the following three (3) High Risk Categories (a-c ):

6. A documented history of myocardial infarction (MI) occurring no less than 2 months (60 days) and no greater than 24 months prior to Screening.

7. Documented symptomatic peripheral arterial disease (PAD) (at least one (1) of the following three (3) criteria must be satisfied): i) Current intermittent claudication together with documented ankle-brachial index ≤0.85. ii) History of previous vascular intervention for intermittent claudication or resting limb ischemia (example: amputation for arterial disease, peripheral bypass, or history of angioplasty/stenting). iii) History of symptomatic carotid artery disease (requiring revascularization with carotid endarterectomy (CEA) or stenting).

8. Documented cerebrovascular disease (at least one (1) of the following two (2) criteria must be satisfied): i) A history of transient ischemic attack (TIA) confirmed by a neurologist no greater than 24 months prior to screening and clinically and neurologically stable at randomization. ii) A history of ischemic stroke (IS) (with a Modified Rankin Scale Score ≤3 documented prior to Randomization) not less than 2 months (60 days) and no greater than 24 months prior to Screening, and clinically and neurologically stable at Randomization. The Modified Rankin Scale is located in appendix in protocol.

Or meets at least one (1) of the following five (5) Intermediate Risk Categories (d-h):

1. Stable angina with coronary disease documented by the presence of inducible ischemia or scar by stress myocardial perfusion imaging (MPI), echocardiogram or magnetic resonance imaging (MRI) in the past 24 months.

2. Multi vessel coronary disease, based on coronary angiography, with or without angina, documented by >50% diameter stenosis in at least 2 of the 3 major coronary distributions.

3. A history of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) at least 2 months prior to Screening.

4. The subject has diabetic nephropathy plus (2) of the clinical criteria listed below (i. to vi.). Diabetic nephropathy is defined as either urinary albumin excretion ≥ 30 µg/mg creatinine (3.4 mg/mmol creatinine) (based on a random spot collection) or urinary albumin excretion ≥ 30 mg/24h (based on a 24 h or timed collection). Results must be confirmed on at least two specimens collected within 12 months prior to Screening and no more than 6 months apart: i)Duration of diabetes ≥ 10 years on pharmacological treatment documented within medical records. ii) Confirmed systolic blood pressure (SBP) ≥150 mm Hg on 2 separate days during Screening despite treatment with at least 2 anti-hypertensive medications administered at doses considered optimal by local standard of care.

1. Presence of dyslipidemia as defined by any one (1) of the following confirmed at screening: A. Low density lipoprotein (LDL) > 100 mg/dl (2.59 mmol/L) while on statin therapy administered at maximum tolerated dose or optimal dose based on local standard of care for at least 4 weeks prior to screening. B. LDL > 130 mg/dL (3.37 mmol/L) when not on statin therapy. C. High density lipoprotein (HDL) < 40 mg/dL (1.04 mmol/L) in males or < 45 mg/dL (1.17 mmol/L) in females. D. Fasting Triglyceride >200 mg/dL(2.26 mmol/L). iv) Currently smoking >10 cigarettes per day at Screening. v) Male ≥65 years of age or female ≥70 years of age. vi) Highly selective C-reactive protein (hs-CRP) > 2.0 mg/L in the absence of intercurrent infection or acute process.

h.) The subject meets at least five (5) of the following clinical criteria: i.) Duration of diabetes ≥10 years on pharmacological treatment documented within medical records. ii) Confirmed systolic blood pressure (SBP) ≥150 mm Hg on 2 separate days during Screening despite treatment with at least 2 anti-hypertensive medications administered at doses considered optimal by local standard of care. iii) Presence of dyslipidemia as defined by any one (1) of the following confirmed at screening: A. Low density lipoprotein (LDL) > 100 mg/dl (2.59 mmol/L) while on statin therapy administered at maximum tolerated dose or optimal dose based on local standard of care for at least 4 weeks prior to screening. B. LDL > 130 mg/dL (3.37 mmol/L) when not on statin therapy. C. High density lipoprotein (HDL) < 40 mg/dL (1.04 mmol/L) in males or < 45 mg/dL (1.17 mmol/L) in females. D. Fasting Triglyceride >200 mg/dL(2.26 mmol/L).

1. Currently smoking >10 cigarettes per day at Screening. v) Male ≥65 years of age or female ≥70 years of age. vi) Highly selective C-reactive protein (hs-CRP) > 2.0 mg/L in the absence of intercurrent infection or acute process.

1. Is able and willing to monitor glucose with a home glucose monitor and consistently record his or her own blood glucose concentrations in patient diaries.

2. A female of childbearing potential who is sexually active with a non-sterilized male partner agrees to routinely use adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after the last dose of study drug.

3. Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3x upper limit of normal (ULN) and if ALT or AST elevated above ULN, have chronic, well-compensated liver disease documented by usual clinical parameters.

Exclusion Criteria:

1. Has received any investigational medication within 30 days prior to Screening or any investigational antidiabetic medication or excluded medications within 3 months prior to Screening.

2. Has been randomized into a previous TAK-875 study.

3. 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 (eg, spouse, parent, biological or legally adopted child, or sibling) or may consent under duress

4. Is diagnosed with type 1 diabetes mellitus or latent autoimmune diabetes in adults.

5. Is hemodynamically unstable, including severe heart failure (New York Heart Association Class IV) at Screening.

6. Is hospitalized at the Screening Visit for the event associated with the CV inclusion criteria. (Patients who have been discharged from an acute hospital to a cardiac rehabilitation center or nursing home at the time of the Screening Visit or Randomization Visit are not excluded).

7. Has ALT and/or AST levels >3.0x ULN at Screening.

8. Has a total bilirubin level >ULN at Screening. Exception: if a patient has documented Gilbert's Syndrome, the patient will be allowed with an elevated bilirubin level per the investigator's discretion.

9. Has an glomerular filtration rate (estimated) (eGFR) ≤ 15 mL/min/1.73m2 based on Modification of Diet in Renal Disease (MDRD) calculation at Screening and is currently on dialysis or expected to start dialysis within the next 6 months.

10. Has uncontrolled thyroid disease, as determined by the investigator and/or clinical investigation.

11. Has a known history of infection with human immunodeficiency virus (HIV).

12. Has a known active infection with Hepatitis B virus (HBV), or Hepatitis C virus (HCV) requiring antiviral treatment.

13. Has a history of drug abuse (defined as illicit drug use) or a history of alcohol abuse within 2 years prior to Screening.

14. Has any major illness or condition that, in the investigator's opinion, prohibits the patient from participating in the study or meeting the planned visit schedule.

15. Has a history of hypersensitivity, allergies, or has had an anaphylactic reaction(s) to TAK-875.

16. If female, is pregnant (confirmed by laboratory testing, ie, serum or urine human chorionic gonadotropin (hCG), in females of childbearing potential) or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.

17. Is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available.

18. Has a 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Dothan	Alabama	United States
3		Mobile	Alabama	United States
4		Muscle Shoals	Alabama	United States
5		Pell City	Alabama	United States
6		Goodyear	Arizona	United States
7		Phoenix	Arizona	United States
8		Tempe	Arizona	United States
9		Tucson	Arizona	United States
10		Little Rock	Arkansas	United States
11		Anaheim	California	United States
12		El Cajon	California	United States
13		Fresno	California	United States
14		Fullerton	California	United States
15		La Mesa	California	United States
16		Laguna Hills	California	United States
17		Los Angeles	California	United States
18		Mission Hills	California	United States
19		National City	California	United States
20		Newport Beach	California	United States
21		Orange	California	United States
22		Paramount	California	United States
23		Pismo Beach	California	United States
24		Redondo Beach	California	United States
25		San Diego	California	United States
26		San Francisco	California	United States
27		San Franciso	California	United States
28		Stockton	California	United States
29		Thousand Oaks	California	United States
30		Torrance	California	United States
31		Valley Village	California	United States
32		Westlake Village	California	United States
33		Denver	Colorado	United States
34		Lakewood	Colorado	United States
35		Bridgeport	Connecticut	United States
36		Danbury	Connecticut	United States
37		Seaford	Delaware	United States
38		Washington	District of Columbia	United States
39		Boynton Beach	Florida	United States
40		Brandon	Florida	United States
41		Chipley	Florida	United States
42		Clearwater	Florida	United States
43		Cocoa	Florida	United States
44		Coral Gables	Florida	United States
45		Coral Springs	Florida	United States
46		Crystal River	Florida	United States
47		Delray Beach	Florida	United States
48		Hialeah	Florida	United States
49		Hollywood	Florida	United States
50		Inverness	Florida	United States
51		Jacksonville Beach	Florida	United States
52		Jacksonville	Florida	United States
53		Melbourne	Florida	United States
54		Miami	Florida	United States
55		North Miami Beach	Florida	United States
56		Ocala	Florida	United States
57		Oviedo	Florida	United States
58		Pembroke Pines	Florida	United States
59		Sarasota	Florida	United States
60		St. Petersburg	Florida	United States
61		Tampa	Florida	United States
62		Trinity	Florida	United States
63		Vero Bearch	Florida	United States
64		Atlanta	Georgia	United States
65		Augusta	Georgia	United States
66		Calhoun	Georgia	United States
67		Conyers	Georgia	United States
68		Cumming	Georgia	United States
69		Norcross	Georgia	United States
70		Roswell	Georgia	United States
71		Suwanee	Georgia	United States
72		Woodstock	Georgia	United States
73		Chicago	Illinois	United States
74		LaGrange	Illinois	United States
75		Springfield	Illinois	United States
76		Anderson	Indiana	United States
77		Avon	Indiana	United States
78		Elkhart	Indiana	United States
79		Greenfield	Indiana	United States
80		Indianapolis	Indiana	United States
81		Muncie	Indiana	United States
82		Ames	Iowa	United States
83		Council Bluffs	Iowa	United States
84		Waterloo	Iowa	United States
85		Augusta	Kansas	United States
86		Hutchinson	Kansas	United States
87		Newton	Kansas	United States
88		Topeka	Kansas	United States
89		Wichita	Kansas	United States
90		Elizabethtown	Kentucky	United States
91		Marrero	Louisiana	United States
92		Monroe	Louisiana	United States
93		Natchitoches	Louisiana	United States
94		New Orleans	Louisiana	United States
95		Sherveport	Louisiana	United States
96		Portland	Maine	United States
97		Annapolis	Maryland	United States
98		Balitmore	Maryland	United States
99		Baltimore	Maryland	United States
100		Fall River	Massachusetts	United States
101		Hyannis	Massachusetts	United States
102		Natick	Massachusetts	United States
103		Springfield	Massachusetts	United States
104		Bay City	Michigan	United States
105		Cadillac	Michigan	United States
106		Flint	Michigan	United States
107		Kalamazoo	Michigan	United States
108		Mt. Clemens	Michigan	United States
109		Novi	Michigan	United States
110		Pontiac	Michigan	United States
111		Saginaw	Michigan	United States
112		Troy	Michigan	United States
113		Baxter	Minnesota	United States
114		St. Cloud	Minnesota	United States
115		St. Paul	Minnesota	United States
116		Columbia	Missouri	United States
117		Kansas City	Missouri	United States
118		St. Louis	Missouri	United States
119		Omaha	Nebraska	United States
120		Las Vegas	Nevada	United States
121		Nashua	New Hampshire	United States
122		Bridgewater	New Jersey	United States
123		Elizabeth	New Jersey	United States
124		Haddon Heights	New Jersey	United States
125		Linden	New Jersey	United States
126		Mine Hill	New Jersey	United States
127		Somerset	New Jersey	United States
128		South Plainfield	New Jersey	United States
129		Toms Rivers	New Jersey	United States
130		Albuquerque	New Mexico	United States
131		Brooklyn	New York	United States
132		Buffalo	New York	United States
133		Mineola	New York	United States
134		New York	New York	United States
135		Saratoga Springs	New York	United States
136		Smithtown	New York	United States
137		Syracuse	New York	United States
138		Burlington	North Carolina	United States
139		Calabash	North Carolina	United States
140		Charlotte	North Carolina	United States
141		Durham	North Carolina	United States
142		Greensboro	North Carolina	United States
143		Hickory	North Carolina	United States
144		Lenoir	North Carolina	United States
145		Mooresville	North Carolina	United States
146		Morganton	North Carolina	United States
147		Raleigh	North Carolina	United States
148		Rocky Mount	North Carolina	United States
149		Winston-Salem	North Carolina	United States
150		Akron	Ohio	United States
151		Canton	Ohio	United States
152		Cincinnati	Ohio	United States
153		Cleveland	Ohio	United States
154		Columbus	Ohio	United States
155		Fairview Park	Ohio	United States
156		Gallipolis	Ohio	United States
157		Kettering	Ohio	United States
158		Marion	Ohio	United States
159		Middleburg Heights	Ohio	United States
160		Perrysburg	Ohio	United States
161		Springfield	Ohio	United States
162		Toledo	Ohio	United States
163		Willoughby Hills	Ohio	United States
164		Norman	Oklahoma	United States
165		Oklahoma City	Oklahoma	United States
166		Tulsa	Oklahoma	United States
167		Portland	Oregon	United States
168		Chambersburg	Pennsylvania	United States
169		Hanleysville	Pennsylvania	United States
170		Harleysville	Pennsylvania	United States
171		Levittown	Pennsylvania	United States
172		Norristown	Pennsylvania	United States
173		Philadelphia	Pennsylvania	United States
174		Philadelphi	Pennsylvania	United States
175		Scotland	Pennsylvania	United States
176		Uniontown	Pennsylvania	United States
177		East Providence	Rhode Island	United States
178		Pawtucket	Rhode Island	United States
179		Columbia	South Carolina	United States
180		Greer	South Carolina	United States
181		Laurens	South Carolina	United States
182		Simpsonville	South Carolina	United States
183		Bristol	Tennessee	United States
184		Crossville	Tennessee	United States
185		Jackson	Tennessee	United States
186		Kingsport	Tennessee	United States
187		Nashville	Tennessee	United States
188		Oak Ridge	Tennessee	United States
189		Tullahoma	Tennessee	United States
190		Austin	Texas	United States
191		Carrollton	Texas	United States
192		Dallas	Texas	United States
193		Fort Worth	Texas	United States
194		Houston	Texas	United States
195		Irving	Texas	United States
196		Katy	Texas	United States
197		Midland	Texas	United States
198		Odessa	Texas	United States
199		Pearland	Texas	United States
200		San Antonio	Texas	United States
201		Spring	Texas	United States
202		Tomball	Texas	United States
203		Victoria	Texas	United States
204		Bountiful	Utah	United States
205		Layton	Utah	United States
206		Salt Lake City	Utah	United States
207		Alexandria	Virginia	United States
208		Danville	Virginia	United States
209		Falls Church	Virginia	United States
210		Hampton	Virginia	United States
211		Manassas	Virginia	United States
212		Wenatchee	Washington	United States
213		Huntington	West Virginia	United States
214		Lewisburg	West Virginia	United States
215		La Crosse	Wisconsin	United States
216		Madison	Wisconsin	United States
217		Milwaukee	Wisconsin	United States
218		Wauwatosa	Wisconsin	United States
219		Bahia Blanca	Buenos Aires	Argentina
220		Haedo	Buenos Aires	Argentina
221		La Plata	Buenos Aires	Argentina
222		Loma Hermosa	Buenos Aires	Argentina
223		Mar del Plata	Buenos Aires	Argentina
224		Quilmes	Buenos Aires	Argentina
225		San Nicolas	Buenos Aires	Argentina
226		Zarate	Buenos Aires	Argentina
227		Trelew	Chubut	Argentina
228		Ciudad Autonoma de Buenos Aires	Ciudad Autonoma Buenos Aires	Argentina
229		Córdoba	Cordoba	Argentina
230		Villa Cabrera	Cordoba	Argentina
231		Villa Maria	Cordoba	Argentina
232		San Salvador de Jujuy	Jujy	Argentina
233		Godoy Cruz	Mendoza	Argentina
234		Cipolletti	Rio Negro	Argentina
235		Rosario	Santa Fe	Argentina
236		Venado Tuerto	Santa Fe	Argentina
237		San Miguel de Tucuman	Tucuman	Argentina
238		Ciudad Autonoma Buenos Aires		Argentina
239		Cordoba		Argentina
240		Corrientes		Argentina
241		Mendoza		Argentina
242		Rosario		Argentina
243		Salta		Argentina
244		Santa Fe		Argentina
245		Santiago del estero		Argentina
246		Bruce	Australian Capital Territory	Australia
247		Canberra	Australian Capital Territory	Australia
248		Garran	Australian Capital Territory	Australia
249		Westmead	New South Wales	Australia
250		Wollongong	New South Wales	Australia
251		Brisbane	Queensland	Australia
252		Meadowbrook	Queensland	Australia
253		Milton	Queensland	Australia
254		Townsville	Queensland	Australia
255		Woolloongabba	Queensland	Australia
256		Adelaide	South Australia	Australia
257		Daw Park	South Australia	Australia
258		Elizabeth Vale	South Australia	Australia
259		Clayton	Victoria	Australia
260		Fitzroy	Victoria	Australia
261		Geelong	Victoria	Australia
262		Melbourne	Victoria	Australia
263		Sale	Victoria	Australia
264		Joondalup	Western Australia	Australia
265		Bruce		Australia
266		Garran		Australia
267		Fortaleza	Ceará	Brazil
268		Brasilia	Distrito Federal	Brazil
269		Goiania	Goiás	Brazil
270		Campina Grande do Sul	Paraná	Brazil
271		Curitiba	Paraná	Brazil
272		Belem	Pará	Brazil
273		Recife	Pernambuco	Brazil
274		Canoas	Rio Grande do Sul	Brazil
275		Caxias do Sul	Rio Grande do Sul	Brazil
276		Passo Fundo	Rio Grande do Sul	Brazil
277		Porto Alegre	Rio Grande do Sul	Brazil
278		Santa Maria	Rio Grande do Sul	Brazil
279		Marilia	Sao Paulo	Brazil
280		São Paulo	Sao Paulo	Brazil
281		Sao Paulo		Brazil
282		Blagoevgrad		Bulgaria
283		Byala		Bulgaria
284		Kazanlak		Bulgaria
285		Pazardzhik		Bulgaria
286		Plovdiv		Bulgaria
287		Sevlievo		Bulgaria
288		Sofia		Bulgaria
289		Stara Zagora		Bulgaria
290		Varna		Bulgaria
291		Calgary	Alberta	Canada
292		Spruce Grove	Alberta	Canada
293		Victoria	British Columbia	Canada
294		Winnipeg	Manitoba	Canada
295		Brampton	Ontario	Canada
296		Etobicoke	Ontario	Canada
297		Hamilton	Ontario	Canada
298		Markham	Ontario	Canada
299		Oakville	Ontario	Canada
300		Ottawa	Ontario	Canada
301		Sudbury	Ontario	Canada
302		Thornhill	Ontario	Canada
303		Toronto	Ontario	Canada
304		Gatineau	Quebec	Canada
305		Laval	Quebec	Canada
306		Longueuil	Quebec	Canada
307		Montreal	Quebec	Canada
308		Pointe Claire	Quebec	Canada
309		St-Jérôme	Quebec	Canada
310		Ville Saint-Laurent	Quebec	Canada
311		Quebec		Canada
312		Cakovec		Croatia
313		Karlovac		Croatia
314		Koprivnica		Croatia
315		Krapinske Toplice		Croatia
316		Osijek		Croatia
317		Rijeka		Croatia
318		Sisak		Croatia
319		Slavonski Brod		Croatia
320		Split		Croatia
321		Virovitica		Croatia
322		Zadar		Croatia
323		Zagreb		Croatia
324		Ceske Budejovice		Czech Republic
325		Chocen		Czech Republic
326		Jindrichuv Hradec		Czech Republic
327		Kromeriz		Czech Republic
328		Marianske Lazne		Czech Republic
329		Moravsky Krumlov		Czech Republic
330		Olomouc		Czech Republic
331		Ostrava - Moravska Ostrava		Czech Republic
332		Ostrava - Vitkovice		Czech Republic
333		Ostrava		Czech Republic
334		Prague 10		Czech Republic
335		Praha 4 - Krc		Czech Republic
336		Praha 5		Czech Republic
337		Slany		Czech Republic
338		Trutnov		Czech Republic
339		Usti nad Labem		Czech Republic
340		Paide		Estonia
341		Tallinn		Estonia
342		Tartu		Estonia
343		Corbeil Essonnes	Essonne	France
344		Corbeil Essonne	Essonne	France
345		Pessac	Gironde	France
346		Nanterre cedex	Hauts de Seine	France
347		Nantes cedex 01	Loire Atlantique	France
348		Pierre-Bénite cedex	Rhone	France
349		Paris		France
350		Friedrichsthal	Baden Wuerttemberg	Germany
351		Falkensee	Brandenburg	Germany
352		Kelkheim	Hessen	Germany
353		Dortmund	Nordrhein Westfalen	Germany
354		Essen	Nordrhein Westfalen	Germany
355		Goch	Nordrhein Westfalen	Germany
356		Kamp-Lintfort	Nordrhein Westfalen	Germany
357		Koeln	Nordrhein Westfalen	Germany
358		Bad Kreuznach	Rheinland Pfalz	Germany
359		Hohenmoelsen	Sachsen Anhalt	Germany
360		Dippoldiswalde	Sachsen	Germany
361		Dresden	Sachsen	Germany
362		Berlin		Germany
363		Hamburg		Germany
364		Hong Kong		Hong Kong
365		New Territories		Hong Kong
366		Baja		Hungary
367		Balatonfured		Hungary
368		Budaors		Hungary
369		Budapest		Hungary
370		Debrecen		Hungary
371		Eger		Hungary
372		Godollo		Hungary
373		Gyula		Hungary
374		Kecskemet		Hungary
375		Kistelek		Hungary
376		Komarom		Hungary
377		Mako		Hungary
378		Pecs		Hungary
379		Szeged		Hungary
380		Szekszard		Hungary
381		Szikszo		Hungary
382		Szombathely		Hungary
383		Urhida		Hungary
384		Veszprem		Hungary
385		Zalaegerszeg		Hungary
386		Ashkelon		Israel
387		Beer Sheva		Israel
388		Beer Yaakov		Israel
389		Beer-Sheva		Israel
390		Givataim		Israel
391		Hadera		Israel
392		Haifa		Israel
393		Holon		Israel
394		Jerusalem		Israel
395		Kfar-Saba		Israel
396		Petach Tikva		Israel
397		Petach Tikwa		Israel
398		Raanana		Israel
399		Tel Aviv		Israel
400		Zefat		Israel
401		San Donato Milanese	Milano	Italy
402		Sesto San Giovanni	Milano	Italy
403		Firenze		Italy
404		Milano		Italy
405		Pavia		Italy
406		Wonju-Si	Gangwon-do	Korea, Republic of
407		Seongnam-si	Gyeonggi-do	Korea, Republic of
408		Yangsan-si	Gyeongsangnam-do	Korea, Republic of
409		Jeonju-si	Jeollabuk-do	Korea, Republic of
410		Busan		Korea, Republic of
411		Gyeonggi		Korea, Republic of
412		Seoul		Korea, Republic of
413		Daugavpils		Latvia
414		Jelgava		Latvia
415		Limbazi		Latvia
416		Ogre		Latvia
417		Riga		Latvia
418		Talsi		Latvia
419		Valmiera		Latvia
420		Alytus		Lithuania
421		Kaunas		Lithuania
422		Klaipeda		Lithuania
423		Johor Bahru	Johor	Malaysia
424		Alor Setar	Kedah	Malaysia
425		Kota Bahru	Kelantan	Malaysia
426		Kota Bharu	Kelantan	Malaysia
427		Lembah Pantai	Kuala Lumpur	Malaysia
428		Ipoh	Perak	Malaysia
429		Taiping, Perak	Perak	Malaysia
430		Taiping	Perak	Malaysia
431		Petaling Jaya	Selangor	Malaysia
432		Kelantan		Malaysia
433		Kuala Lumpur		Malaysia
434		Melaka		Malaysia
435		Selangor		Malaysia
436		Terengganu		Malaysia
437		Tijuana	Baja California Norte	Mexico
438		Torreon	Coahuila	Mexico
439		Cuauhtemoc	Distrito Federal	Mexico
440		Mexico	Distrito Federal	Mexico
441		Cuautitlan Izcalli	Estado de Mexico	Mexico
442		Metepec	Estado de Mexico	Mexico
443		Acapulco de Juárez	Guerrero	Mexico
444		Pachuca	Hidalgo	Mexico
445		Guadalajara	Jalisco	Mexico
446		Zapopan	Jalisco	Mexico
447		Morelia	Michoacán	Mexico
448		Cuernavaca	Morelos	Mexico
449		Monterrey	Nuevo Le=n	Mexico
450		Monterrey	Nuevo Leon	Mexico
451		Monterrey	Nuevo León	Mexico
452		San Luis Potosi	San Luis Potos	Mexico
453		Culiacan	Sinaloa	Mexico
454		Xalapa	Veracruz	Mexico
455		Merida	Yucatán	Mexico
456		Aguascalientes		Mexico
457		Chihuahua		Mexico
458		Durango		Mexico
459		Tamaulipas		Mexico
460		Auckland		New Zealand
461		Christchurch		New Zealand
462		Dunedin		New Zealand
463		Palmerston North		New Zealand
464		Tauranga		New Zealand
465		Wellington		New Zealand
466		Callao		Peru
467		Cusco		Peru
468		Huacho		Peru
469		Ica		Peru
470		La Libertad		Peru
471		Lima		Peru
472		Piura		Peru
473		Baguio City		Philippines
474		Cebu City		Philippines
475		Dasmariñas City, Cavite		Philippines
476		Davao City		Philippines
477		Iloilo City		Philippines
478		Marikina City		Philippines
479		Quezon City		Philippines
480		Tarlac		Philippines
481		Taytay		Philippines
482		Bialystok		Poland
483		Gdansk		Poland
484		Gliwice		Poland
485		Grodzisk Mazowiecki		Poland
486		Kamieniec Zabkowicki		Poland
487		Leczyca		Poland
488		Lodz		Poland
489		Lublin		Poland
490		Oswiecim		Poland
491		Parczew		Poland
492		Poznan		Poland
493		Pulawy		Poland
494		Radom		Poland
495		Ruda Slaska		Poland
496		Rzeszow		Poland
497		Warszawa		Poland
498		Wroclaw		Poland
499		Bacau		Romania
500		Baia Mare		Romania
501		Brasov		Romania
502		Bucuresti		Romania
503		Galati		Romania
504		Iasi		Romania
505		Oradea		Romania
506		Ploiesti		Romania
507		Targu Mures		Romania
508		Timisoara		Romania
509		Arkhangelsk		Russian Federation
510		Barnaul		Russian Federation
511		Kazan		Russian Federation
512		Kemerovo		Russian Federation
513		Moscow		Russian Federation
514		Nizhniy Novgorod		Russian Federation
515		Novosibirsk		Russian Federation
516		Pushkin		Russian Federation
517		Saratov		Russian Federation
518		St. Petersburg		Russian Federation
519		Yaroslavl		Russian Federation
520		Bratislava		Slovakia
521		Komarno		Slovakia
522		Kosice		Slovakia
523		Levice		Slovakia
524		Lucenec		Slovakia
525		Martin		Slovakia
526		Nitra		Slovakia
527		Nove Mesto nad Vahom		Slovakia
528		Presov		Slovakia
529		Sahy		Slovakia
530		Svidnik		Slovakia
531		Trencin		Slovakia
532		Zilina		Slovakia
533		Port Elizabeth	Eastern Cape	South Africa
534		Bloemfontein	Free State	South Africa
535		Johannesburg	Gauteng	South Africa
536		Kempton Park	Gauteng	South Africa
537		Krugersdorp	Gauteng	South Africa
538		Lenasia	Gauteng	South Africa
539		Pretoria	Gauteng	South Africa
540		Durban	KwaZulu-Natal	South Africa
541		Cape Town	Western Cape	South Africa
542		Stellenbosch	Western Cape	South Africa
543		Worcester	Western Cape	South Africa
544		Douliou City		Taiwan
545		Kaohsiung		Taiwan
546		New Taipei City		Taiwan
547		Taichung		Taiwan
548		Tainan		Taiwan
549		Taipei		Taiwan
550		Bangkoknoi	Bangkok	Thailand
551		Dusit	Bangkok	Thailand
552		Patumwan	Bangkok	Thailand
553		Rachathevi	Bangkok	Thailand
554		Rajtevi	Bangkok	Thailand
555		Ratchathewi	Bangkok	Thailand
556		Muang	Chiang Mai	Thailand
557		Muang	Chiang Rai	Thailand
558		Muang	Khon Kaen	Thailand
559		Muang	Nakhon Ratchasima	Thailand
560		Donetsk		Ukraine
561		Kharkiv		Ukraine
562		Kyiv		Ukraine
563		Lugansk		Ukraine
564		Mykolayiv		Ukraine
565		Odesa		Ukraine
566		Poltava		Ukraine
567		Simferopol		Ukraine
568		Ternopil		Ukraine
569		Vinnycia		Ukraine
570		Vinnytsia		Ukraine
571		Zaporizhzhia		Ukraine
572		Truro	Cornwall	United Kingdom
573		Exeter	Devon	United Kingdom
574		Plymouth	Devon	United Kingdom
575		Torquay	Devon	United Kingdom
576		Hull	East Riding of Yorkshire	United Kingdom
577		Bexhill on Sea	East Sussex	United Kingdom
578		Portsmouth	Hampshire	United Kingdom
579		Watford	Hertfordshire	United Kingdom
580		Gillingham	Kent	United Kingdom
581		Thornton-Cleveleys	Lancashire	United Kingdom
582		Leicester	Leicestershire	United Kingdom
583		Liverpool	Merseyside	United Kingdom
584		Harrow	Middlesex	United Kingdom
585		Northwood	Middlesex	United Kingdom
586		Stoke on Trent	Staffordshire	United Kingdom
587		Swansea	West Glamorgan	United Kingdom
588		Cardiff		United Kingdom

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Sr. Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01609582
• Other Study ID Numbers: TAK-875_306; 2011-001732-37; U1111-1129-7824; TAK-875_306CTIL; DOH-27-0313-4117; 12/SC/0504; NMRR-12-433-12087; PHRR130916-000119; 1015031332
• First Posted: Jun 1, 2012
• Last Update Posted: Oct 19, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 469 investigative sites in 31 countries; 192 sites in North America, 175 in the Europe, Middle East, and Africa (EMEA) region (including Russia, Ukraine, Israel, and South Africa), 65 in the Asia Pacific region, and 37 in Latin/South America from 01 June 2012 to 05 May 2014.
Pre-assignment Detail	Participants with a historical diagnosis of type 2 diabetes mellitus (T2DM) and clinically-evident cardiovascular (CV) disease or multiple risk factors for CV events who were inadequately controlled while receiving the standard of care were enrolled in 1 of 2 treatment groups: placebo; fasiglifam 50 milligram (mg).

Arm/Group Title	Placebo	Fasiglifam 50 mg
Arm/Group Description	Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.	Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.
Period Title: Overall Study
STARTED	1603	1604
Treated	1603	1601
COMPLETED	0	0
NOT COMPLETED	1603	1604

Baseline Characteristics

Arm/Group Title	Placebo	Fasiglifam 50 mg	Total
Arm/Group Description	Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.	Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.	Total of all reporting groups
Overall Participants	1603	1604	3207
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.9 (9.03)	63.4 (9.20)	63.7 (9.12)
Age, Customized (participants) [Number]
Less than (<) 65 years	794 49.5%	851 53.1%	1645 51.3%
Greater than or equal to (>=) 65 years	809 50.5%	753 46.9%	1562 48.7%
Sex: Female, Male (Count of Participants)
Female	543 33.9%	563 35.1%	1106 34.5%
Male	1060 66.1%	1041 64.9%	2101 65.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	150 9.4%	119 7.4%	269 8.4%
Not Hispanic or Latino	446 27.8%	477 29.7%	923 28.8%
Unknown or Not Reported	1007 62.8%	1008 62.8%	2015 62.8%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	47 2.9%	41 2.6%	88 2.7%
Asian	199 12.4%	205 12.8%	404 12.6%
Native Hawaiian or Other Pacific Islander	6 0.4%	7 0.4%	13 0.4%
Black or African American	79 4.9%	95 5.9%	174 5.4%
White	1265 78.9%	1246 77.7%	2511 78.3%
Multiracial/More than 1 race	7 0.4%	10 0.6%	17 0.5%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	168.1 (9.84)	167.6 (10.54)	167.8 (10.20)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	91.14 (19.832)	91.40 (21.319)	91.27 (20.586)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	32.14 (6.107)	32.45 (7.497)	32.30 (6.838)
Glycosylated Hemoglobin (HbA1c) Category (participants) [Number]
<8.5 percent (%)	988 61.6%	936 58.4%	1924 60%
>=8.5%	615 38.4%	668 41.6%	1283 40%
Smoking Classification (participants) [Number]
Never smoked	667 41.6%	668 41.6%	1335 41.6%
Current smoker	330 20.6%	328 20.4%	658 20.5%
Ex-smoker	606 37.8%	608 37.9%	1214 37.9%
Duration of Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.583 (8.409)	13.333 (8.321)	13.458 (8.365)
Region of Enrollment (participants) [Number]
Argentina	121 7.5%	121 7.5%	242 7.5%
Australia	34 2.1%	35 2.2%	69 2.2%
Bulgaria	21 1.3%	22 1.4%	43 1.3%
Canada	104 6.5%	107 6.7%	211 6.6%
Croatia	16 1%	17 1.1%	33 1%
Czech Republic	56 3.5%	56 3.5%	112 3.5%
Estonia	13 0.8%	11 0.7%	24 0.7%
France	3 0.2%	4 0.2%	7 0.2%
Germany	30 1.9%	30 1.9%	60 1.9%
Hong Kong	29 1.8%	29 1.8%	58 1.8%
Hungary	74 4.6%	72 4.5%	146 4.6%
Israel	25 1.6%	26 1.6%	51 1.6%
Italy	3 0.2%	3 0.2%	6 0.2%
Korea, Republic of	29 1.8%	27 1.7%	56 1.7%
Latvia	11 0.7%	11 0.7%	22 0.7%
Lithuania	15 0.9%	15 0.9%	30 0.9%
Malaysia	30 1.9%	31 1.9%	61 1.9%
Mexico	26 1.6%	26 1.6%	52 1.6%
New Zealand	20 1.2%	20 1.2%	40 1.2%
Peru	18 1.1%	17 1.1%	35 1.1%
Philippines	25 1.6%	24 1.5%	49 1.5%
Poland	118 7.4%	118 7.4%	236 7.4%
Romania	5 0.3%	4 0.2%	9 0.3%
Russian Federation	25 1.6%	23 1.4%	48 1.5%
Slovakia	31 1.9%	31 1.9%	62 1.9%
South Africa	10 0.6%	10 0.6%	20 0.6%
Taiwan, Province of China	31 1.9%	31 1.9%	62 1.9%
Thailand	29 1.8%	32 2%	61 1.9%
Ukraine	76 4.7%	76 4.7%	152 4.7%
United Kingdom	16 1%	16 1%	32 1%
United States	559 34.9%	559 34.9%	1118 34.9%

Outcome Measures

1. Primary Outcome

Title	Time to First Occurrence of Any Component of Primary Major Adverse Cardiovascular Event (MACE) Composite
Description	The time from randomization to the first occurrences of any event in the primary MACE composite was evaluated using Kaplan-Meier analysis. The primary MACE composite comprised cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, and hospitalization for unstable angina (with or without revascularization).
Time Frame	Baseline up to end of study (up to Day 588)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all randomized participants who had baseline and at least 1 post-baseline assessment.

Arm/Group Title	Placebo	Fasiglifam 50 mg
Arm/Group Description	Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.	Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.
Measure Participants	1603	1604
Median (95% Confidence Interval) [days]	NA	NA

2. Secondary Outcome

Title	Time to First Occurrence of Any Component of Secondary Major Adverse Cardiovascular Event (MACE) Composite
Description	The time from randomization to the first occurrences of any event in the secondary MACE composite was evaluated using Kaplan-Meier analysis. The secondary MACE composite comprised CV death, nonfatal MI, and nonfatal stroke.
Time Frame	Baseline up to end of study (up to Day 588)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all randomized participants who had baseline and at least 1 post-baseline assessment.

Arm/Group Title	Placebo	Fasiglifam 50 mg
Arm/Group Description	Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.	Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.
Measure Participants	1603	1604
Median (95% Confidence Interval) [days]	NA	NA

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 30 days after the last dose of double-blind study drug.
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Placebo		Fasiglifam 50 mg
Arm/Group Description	Fasiglifam placebo-matching tablet, orally, once daily for up to 588 days.		Fasiglifam 50 mg, tablet, orally, once daily for up to 582 days.
All Cause Mortality
	Placebo		Fasiglifam 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Fasiglifam 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	197/1603 (12.3%)		201/1601 (12.6%)
Blood and lymphatic system disorders
Anaemia	1/1603 (0.1%)		3/1601 (0.2%)
Cardiac disorders
Atrioventricular block first degree	3/1603 (0.2%)		3/1601 (0.2%)
Atrioventricular block	0/1603 (0%)		1/1601 (0.1%)
Atrioventricular block complete	1/1603 (0.1%)		0/1601 (0%)
Cardiac disorder	1/1603 (0.1%)		0/1601 (0%)
Intracardiac thrombus	0/1603 (0%)		1/1601 (0.1%)
Ischaemic cardiomyopathy	0/1603 (0%)		1/1601 (0.1%)
Coronary artery disease	7/1603 (0.4%)		6/1601 (0.4%)
Coronary artery occlusion	0/1603 (0%)		2/1601 (0.1%)
Cardiac failure congestive	7/1603 (0.4%)		12/1601 (0.7%)
Cardiac failure chronic	0/1603 (0%)		1/1601 (0.1%)
Acute myocardial infarction	9/1603 (0.6%)		12/1601 (0.7%)
Arteriosclerosis coronary artery	1/1603 (0.1%)		0/1601 (0%)
Cardiac failure	2/1603 (0.1%)		4/1601 (0.2%)
Cardiogenic shock	0/1603 (0%)		1/1601 (0.1%)
Angina pectoris	7/1603 (0.4%)		9/1601 (0.6%)
Angina unstable	5/1603 (0.3%)		7/1601 (0.4%)
Myocardial infarction	5/1603 (0.3%)		4/1601 (0.2%)
Acute coronary syndrome	3/1603 (0.2%)		3/1601 (0.2%)
Myocardial ischaemia	4/1603 (0.2%)		1/1601 (0.1%)
Left ventricular failure	1/1603 (0.1%)		0/1601 (0%)
Mitral valve incompetence	1/1603 (0.1%)		0/1601 (0%)
Arrhythmia	0/1603 (0%)		3/1601 (0.2%)
Right ventricular failure	1/1603 (0.1%)		0/1601 (0%)
Atrial fibrillation	4/1603 (0.2%)		1/1601 (0.1%)
Sinus bradycardia	1/1603 (0.1%)		0/1601 (0%)
Cardiac arrest	1/1603 (0.1%)		4/1601 (0.2%)
Cardio-respiratory arrest	2/1603 (0.1%)		1/1601 (0.1%)
Ear and labyrinth disorders
Vertigo	0/1603 (0%)		2/1601 (0.1%)
Endocrine disorders
Pituitary haemorrhage	1/1603 (0.1%)		0/1601 (0%)
Eye disorders
Cataract	1/1603 (0.1%)		0/1601 (0%)
Retinal haemorrhage	1/1603 (0.1%)		0/1601 (0%)
Diabetic retinopathy	1/1603 (0.1%)		0/1601 (0%)
Gastrointestinal disorders
Abdominal hernia	0/1603 (0%)		1/1601 (0.1%)
Pancreatitis	2/1603 (0.1%)		0/1601 (0%)
Pancreatitis acute	0/1603 (0%)		1/1601 (0.1%)
Large intestine polyp	1/1603 (0.1%)		2/1601 (0.1%)
Colitis	1/1603 (0.1%)		0/1601 (0%)
Diarrhoea	1/1603 (0.1%)		0/1601 (0%)
Diverticulum	1/1603 (0.1%)		0/1601 (0%)
Small intestinal obstruction	1/1603 (0.1%)		2/1601 (0.1%)
Duodenal ulcer	0/1603 (0%)		2/1601 (0.1%)
Obstruction gastric	0/1603 (0%)		1/1601 (0.1%)
Gastritis	0/1603 (0%)		1/1601 (0.1%)
Gastroduodenitis	0/1603 (0%)		1/1601 (0.1%)
Abdominal pain	1/1603 (0.1%)		1/1601 (0.1%)
Abdominal pain upper	0/1603 (0%)		1/1601 (0.1%)
Constipation	0/1603 (0%)		1/1601 (0.1%)
Duodenitis	0/1603 (0%)		1/1601 (0.1%)
Abdominal discomfort	0/1603 (0%)		1/1601 (0.1%)
Haemorrhoids	1/1603 (0.1%)		1/1601 (0.1%)
Rectal haemorrhage	1/1603 (0.1%)		1/1601 (0.1%)
Anal haemorrhage	1/1603 (0.1%)		0/1601 (0%)
Nausea	0/1603 (0%)		1/1601 (0.1%)
Gastrointestinal haemorrhage	2/1603 (0.1%)		3/1601 (0.2%)
Haematemesis	1/1603 (0.1%)		0/1601 (0%)
Haematochezia	1/1603 (0.1%)		0/1601 (0%)
Oesophageal stenosis	0/1603 (0%)		1/1601 (0.1%)
Pancreatic calcification	1/1603 (0.1%)		0/1601 (0%)
General disorders
Medical device pain	1/1603 (0.1%)		0/1601 (0%)
Death	1/1603 (0.1%)		0/1601 (0%)
Sudden death	1/1603 (0.1%)		0/1601 (0%)
Device malfunction	0/1603 (0%)		2/1601 (0.1%)
Local swelling	0/1603 (0%)		1/1601 (0.1%)
Oedema peripheral	1/1603 (0.1%)		0/1601 (0%)
Chest pain	6/1603 (0.4%)		8/1601 (0.5%)
Non-cardiac chest pain	3/1603 (0.2%)		4/1601 (0.2%)
Chest discomfort	1/1603 (0.1%)		0/1601 (0%)
Hepatobiliary disorders
Cholecystitis	1/1603 (0.1%)		3/1601 (0.2%)
Cholelithiasis	2/1603 (0.1%)		2/1601 (0.1%)
Cholecystitis acute	2/1603 (0.1%)		0/1601 (0%)
Jaundice cholestatic	0/1603 (0%)		1/1601 (0.1%)
Hepatic mass	1/1603 (0.1%)		0/1601 (0%)
Infections and infestations
Gastroenteritis	1/1603 (0.1%)		4/1601 (0.2%)
Appendicitis	1/1603 (0.1%)		1/1601 (0.1%)
Diverticulitis	1/1603 (0.1%)		0/1601 (0%)
Cellulitis	2/1603 (0.1%)		6/1601 (0.4%)
Gangrene	1/1603 (0.1%)		2/1601 (0.1%)
Diabetic gangrene	1/1603 (0.1%)		2/1601 (0.1%)
Osteomyelitis	1/1603 (0.1%)		1/1601 (0.1%)
Intervertebral discitis	0/1603 (0%)		1/1601 (0.1%)
Extradural abscess	1/1603 (0.1%)		0/1601 (0%)
Clostridium difficile colitis	0/1603 (0%)		1/1601 (0.1%)
Abscess	0/1603 (0%)		1/1601 (0.1%)
Abscess limb	1/1603 (0.1%)		0/1601 (0%)
Wound infection	1/1603 (0.1%)		0/1601 (0%)
Influenza	1/1603 (0.1%)		0/1601 (0%)
Pneumonia	5/1603 (0.3%)		7/1601 (0.4%)
Bronchitis	1/1603 (0.1%)		3/1601 (0.2%)
Lung infection	0/1603 (0%)		1/1601 (0.1%)
Sepsis	2/1603 (0.1%)		3/1601 (0.2%)
Urosepsis	1/1603 (0.1%)		1/1601 (0.1%)
Diabetic foot infection	1/1603 (0.1%)		0/1601 (0%)
Infected skin ulcer	1/1603 (0.1%)		0/1601 (0%)
Paronychia	0/1603 (0%)		1/1601 (0.1%)
Staphylococcal bacteraemia	1/1603 (0.1%)		0/1601 (0%)
Staphylococcal infection	0/1603 (0%)		1/1601 (0.1%)
Erysipelas	0/1603 (0%)		1/1601 (0.1%)
Streptococcal infection	1/1603 (0.1%)		0/1601 (0%)
Streptococcal urinary tract infection	1/1603 (0.1%)		0/1601 (0%)
Pulmonary tuberculosis	0/1603 (0%)		1/1601 (0.1%)
Laryngitis	0/1603 (0%)		1/1601 (0.1%)
Upper respiratory tract infection	0/1603 (0%)		1/1601 (0.1%)
Urinary tract infection	1/1603 (0.1%)		2/1601 (0.1%)
Gastrointestinal viral infection	0/1603 (0%)		1/1601 (0.1%)
Pneumonia viral	1/1603 (0.1%)		0/1601 (0%)
Injury, poisoning and procedural complications
Postpericardiotomy syndrome	1/1603 (0.1%)		0/1601 (0%)
Vascular pseudoaneurysm	1/1603 (0.1%)		0/1601 (0%)
Subdural haematoma	1/1603 (0.1%)		1/1601 (0.1%)
Joint dislocation	1/1603 (0.1%)		0/1601 (0%)
Traumatic fracture	0/1603 (0%)		1/1601 (0.1%)
Ankle fracture	2/1603 (0.1%)		2/1601 (0.1%)
Hip fracture	1/1603 (0.1%)		1/1601 (0.1%)
Femur fracture	1/1603 (0.1%)		0/1601 (0%)
Foot fracture	1/1603 (0.1%)		0/1601 (0%)
Tibia fracture	0/1603 (0%)		1/1601 (0.1%)
Tendon injury	1/1603 (0.1%)		0/1601 (0%)
Fall	1/1603 (0.1%)		2/1601 (0.1%)
Incisional hernia	0/1603 (0%)		1/1601 (0.1%)
Post procedural complication	1/1603 (0.1%)		0/1601 (0%)
Wound dehiscence	1/1603 (0.1%)		0/1601 (0%)
Accidental overdose	1/1603 (0.1%)		0/1601 (0%)
Contusion	1/1603 (0.1%)		1/1601 (0.1%)
Laceration	1/1603 (0.1%)		0/1601 (0%)
Lumbar vertebral fracture	0/1603 (0%)		1/1601 (0.1%)
Humerus fracture	1/1603 (0.1%)		0/1601 (0%)
Wrist fracture	1/1603 (0.1%)		0/1601 (0%)
Investigations
Blood glucose increased	1/1603 (0.1%)		0/1601 (0%)
International normalised ratio increased	0/1603 (0%)		1/1601 (0.1%)
Electrocardiogram ST segment elevation	1/1603 (0.1%)		0/1601 (0%)
Angiogram	0/1603 (0%)		1/1601 (0.1%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	2/1603 (0.1%)		1/1601 (0.1%)
Type 2 diabetes mellitus	0/1603 (0%)		1/1601 (0.1%)
Diabetic ketoacidosis	2/1603 (0.1%)		0/1601 (0%)
Hyperglycaemia	4/1603 (0.2%)		1/1601 (0.1%)
Hypoglycaemia	4/1603 (0.2%)		5/1601 (0.3%)
Fluid overload	0/1603 (0%)		1/1601 (0.1%)
Musculoskeletal and connective tissue disorders
Bursitis	1/1603 (0.1%)		0/1601 (0%)
Polymyalgia rheumatica	0/1603 (0%)		1/1601 (0.1%)
Gouty arthritis	0/1603 (0%)		1/1601 (0.1%)
Intervertebral disc degeneration	1/1603 (0.1%)		0/1601 (0%)
Intervertebral disc protrusion	1/1603 (0.1%)		0/1601 (0%)
Back pain	1/1603 (0.1%)		1/1601 (0.1%)
Neck pain	0/1603 (0%)		1/1601 (0.1%)
Spinal pain	1/1603 (0.1%)		0/1601 (0%)
Osteoarthritis	1/1603 (0.1%)		1/1601 (0.1%)
Spinal osteoarthritis	0/1603 (0%)		1/1601 (0.1%)
Spinal column stenosis	0/1603 (0%)		2/1601 (0.1%)
Spondylolisthesis	1/1603 (0.1%)		0/1601 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cholangiocarcinoma	1/1603 (0.1%)		1/1601 (0.1%)
Bone cancer metastatic	1/1603 (0.1%)		0/1601 (0%)
Invasive ductal breast carcinoma	1/1603 (0.1%)		0/1601 (0%)
Adenocarcinoma gastric	1/1603 (0.1%)		0/1601 (0%)
Gastric cancer stage IV	0/1603 (0%)		1/1601 (0.1%)
Large intestine benign neoplasm	1/1603 (0.1%)		0/1601 (0%)
Hepatic cancer	1/1603 (0.1%)		0/1601 (0%)
Hepatocellular carcinoma	1/1603 (0.1%)		0/1601 (0%)
Metastatic neoplasm	0/1603 (0%)		1/1601 (0.1%)
Metastatic squamous cell carcinoma	0/1603 (0%)		1/1601 (0.1%)
Brain neoplasm	0/1603 (0%)		1/1601 (0.1%)
Non-small cell lung cancer	1/1603 (0.1%)		0/1601 (0%)
Squamous cell carcinoma of lung	0/1603 (0%)		1/1601 (0.1%)
Pancreatic carcinoma	1/1603 (0.1%)		0/1601 (0%)
Prostate cancer	1/1603 (0.1%)		1/1601 (0.1%)
Rectosigmoid cancer	0/1603 (0%)		1/1601 (0.1%)
Lung neoplasm malignant	1/1603 (0.1%)		1/1601 (0.1%)
Malignant melanoma	0/1603 (0%)		1/1601 (0.1%)
Metastatic malignant melanoma	0/1603 (0%)		1/1601 (0.1%)
Transitional cell carcinoma	1/1603 (0.1%)		0/1601 (0%)
Bladder neoplasm	0/1603 (0%)		1/1601 (0.1%)
Uterine cancer	0/1603 (0%)		1/1601 (0.1%)
Nervous system disorders
Dementia Alzheimer's type	0/1603 (0%)		1/1601 (0.1%)
Cerebrovascular accident	7/1603 (0.4%)		1/1601 (0.1%)
Ischaemic stroke	1/1603 (0.1%)		2/1601 (0.1%)
Cerebral infarction	0/1603 (0%)		1/1601 (0.1%)
Embolic stroke	1/1603 (0.1%)		0/1601 (0%)
Haemorrhagic stroke	1/1603 (0.1%)		0/1601 (0%)
Carotid arteriosclerosis	1/1603 (0.1%)		0/1601 (0%)
Syncope	5/1603 (0.3%)		3/1601 (0.2%)
Encephalopathy	0/1603 (0%)		1/1601 (0.1%)
VIIth nerve paralysis	0/1603 (0%)		2/1601 (0.1%)
Carpal tunnel syndrome	1/1603 (0.1%)		0/1601 (0%)
Dizziness	1/1603 (0.1%)		1/1601 (0.1%)
Epilepsy	1/1603 (0.1%)		1/1601 (0.1%)
Central pain syndrome	1/1603 (0.1%)		0/1601 (0%)
Transient ischaemic attack	1/1603 (0.1%)		3/1601 (0.2%)
Psychiatric disorders
Delusion	1/1603 (0.1%)		0/1601 (0%)
Depression	1/1603 (0.1%)		0/1601 (0%)
Mental status changes	0/1603 (0%)		1/1601 (0.1%)
Psychogenic seizure	0/1603 (0%)		1/1601 (0.1%)
Suicidal ideation	0/1603 (0%)		1/1601 (0.1%)
Renal and urinary disorders
Urinary retention	0/1603 (0%)		1/1601 (0.1%)
Bladder prolapse	0/1603 (0%)		1/1601 (0.1%)
Renal failure acute	6/1603 (0.4%)		11/1601 (0.7%)
Renal failure	4/1603 (0.2%)		6/1601 (0.4%)
Renal failure chronic	2/1603 (0.1%)		1/1601 (0.1%)
Prerenal failure	1/1603 (0.1%)		0/1601 (0%)
Nephrolithiasis	1/1603 (0.1%)		0/1601 (0%)
Renal infarct	0/1603 (0%)		1/1601 (0.1%)
Calculus ureteric	1/1603 (0.1%)		1/1601 (0.1%)
Reproductive system and breast disorders
Prostatitis	0/1603 (0%)		1/1601 (0.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/1603 (0%)		2/1601 (0.1%)
Respiratory distress	1/1603 (0.1%)		0/1601 (0%)
Sleep apnoea syndrome	1/1603 (0.1%)		0/1601 (0%)
Chronic obstructive pulmonary disease	2/1603 (0.1%)		2/1601 (0.1%)
Asthma	0/1603 (0%)		1/1601 (0.1%)
Pneumonia aspiration	0/1603 (0%)		1/1601 (0.1%)
Pleuritic pain	1/1603 (0.1%)		0/1601 (0%)
Hypoxia	1/1603 (0.1%)		0/1601 (0%)
Interstitial lung disease	1/1603 (0.1%)		0/1601 (0%)
Pulmonary fibrosis	0/1603 (0%)		1/1601 (0.1%)
Pleural effusion	0/1603 (0%)		1/1601 (0.1%)
Pulmonary hypertension	1/1603 (0.1%)		1/1601 (0.1%)
Pulmonary oedema	1/1603 (0.1%)		0/1601 (0%)
Pulmonary embolism	0/1603 (0%)		1/1601 (0.1%)
Acute respiratory failure	1/1603 (0.1%)		3/1601 (0.2%)
Respiratory failure	2/1603 (0.1%)		1/1601 (0.1%)
Skin and subcutaneous tissue disorders
Blister	0/1603 (0%)		1/1601 (0.1%)
Nail bed inflammation	0/1603 (0%)		1/1601 (0.1%)
Diabetic foot	3/1603 (0.2%)		1/1601 (0.1%)
Skin ulcer	1/1603 (0.1%)		1/1601 (0.1%)
Surgical and medical procedures
Coronary arterial stent insertion	1/1603 (0.1%)		0/1601 (0%)
Coronary revascularisation	1/1603 (0.1%)		0/1601 (0%)
Foot amputation	1/1603 (0.1%)		0/1601 (0%)
Vascular disorders
Hypertensive crisis	0/1603 (0%)		3/1601 (0.2%)
Accelerated hypertension	0/1603 (0%)		1/1601 (0.1%)
Aortic stenosis	2/1603 (0.1%)		0/1601 (0%)
Circulatory collapse	1/1603 (0.1%)		1/1601 (0.1%)
Haematoma	1/1603 (0.1%)		0/1601 (0%)
Arteriosclerosis	0/1603 (0%)		1/1601 (0.1%)
Venous occlusion	0/1603 (0%)		1/1601 (0.1%)
Peripheral vascular disorder	1/1603 (0.1%)		1/1601 (0.1%)
Peripheral ischaemia	3/1603 (0.2%)		3/1601 (0.2%)
Peripheral arterial occlusive disease	1/1603 (0.1%)		2/1601 (0.1%)
Femoral artery occlusion	0/1603 (0%)		2/1601 (0.1%)
Intermittent claudication	1/1603 (0.1%)		0/1601 (0%)
Peripheral artery stenosis	0/1603 (0%)		1/1601 (0.1%)
Hypertension	1/1603 (0.1%)		5/1601 (0.3%)
Hypotension	2/1603 (0.1%)		0/1601 (0%)
Arteriovenous fistula	0/1603 (0%)		1/1601 (0.1%)
Vasculitis	0/1603 (0%)		1/1601 (0.1%)
Other (Not Including Serious) Adverse Events
	Placebo		Fasiglifam 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	427/1603 (26.6%)		415/1601 (25.9%)
Blood and lymphatic system disorders
Anaemia	26/1603 (1.6%)		33/1601 (2.1%)
Gastrointestinal disorders
Diarrhoea	48/1603 (3%)		44/1601 (2.7%)
Nausea	35/1603 (2.2%)		33/1601 (2.1%)
Infections and infestations
Upper respiratory tract infection	87/1603 (5.4%)		75/1601 (4.7%)
Bronchitis	45/1603 (2.8%)		49/1601 (3.1%)
Urinary tract infection	43/1603 (2.7%)		35/1601 (2.2%)
Nasopharyngitis	55/1603 (3.4%)		61/1601 (3.8%)
Influenza	37/1603 (2.3%)		34/1601 (2.1%)
Sinusitis	36/1603 (2.2%)		22/1601 (1.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	36/1603 (2.2%)		41/1601 (2.6%)
Nervous system disorders
Dizziness	30/1603 (1.9%)		39/1601 (2.4%)
Headache	32/1603 (2%)		41/1601 (2.6%)
Respiratory, thoracic and mediastinal disorders
Cough	30/1603 (1.9%)		40/1601 (2.5%)
Vascular disorders
Hypertension	40/1603 (2.5%)		42/1601 (2.6%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.