A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk

Type 2 Diabetes Mellitus Clinical Trial

— SURPASS-4  

Official title:

Efficacy and Safety of LY3298176 Once Weekly Versus Insulin Glargine in Patients With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03730662
• Other study ID #: 17072
• Secondary ID: I8F-MC-GPGM2018-
• Status: Completed
• Phase: Phase 3
• Start date: November 20, 2018
• Est. completion date: April 22, 2021

Study information

• Verified date: January 2022
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the trial is to assess the efficacy and safety of tirzepatide taken once a week to insulin glargine taken once daily in participants with type 2 diabetes and increased cardiovascular risk. The study will last about 108 weeks and may include up to 30 visits.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2002
• Est. completion date: April 22, 2021
• Est. primary completion date: January 22, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Participants must:

• Have been diagnosed with type 2 diabetes mellitus (T2DM)

• Have HbA1c between =7.5% and =10.5%

• Be on stable treatment with unchanged dose of at least 1 and no more than 3 types of oral antihyperglycemic drugs, which may only include metformin, SGLT-2 inhibitors, and/or sulfonylureas for at least 3 months before screening

• Have increased risk for cardiovascular (CV) events

• Be of stable weight (± 5%)

• Have a BMI =25 kilograms per meter squared (kg/m2) at screening

Exclusion Criteria

Participants must not:

• Have type 1 diabetes mellitus

• Have had chronic or acute pancreatitis any time prior to study entry

• Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring immediate or urgent treatment

• Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss

• Have acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood alanine transaminase (ALT) enzyme level >3.0 times the upper limit of normal (ULN) for the reference range, as determined by the central laboratory. Participants with nonalcoholic fatty liver disease (NAFLD) are eligible for participation in this trial only if there ALT level is =3.0 the ULN for the reference range

• Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months

• Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2

• Have been taking any other diabetes medicines other than metformin, SGLT-2 inhibitors, and/or sulfonylureas during the last 3 months

• Have been taking weight loss drugs, including over-the-counter medications during the last 3 months

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Tirzepatide
Administered SC.
• Insulin Glargine
Administered SC

Locations

Country	Name	City	State
Argentina	AXISMED SRL - Bioclinica Research Network	Buenos Aires
Argentina	CEDIC-Centro de Investigaciones Clinicas	Caba	Buenos Aires
Argentina	CEMEDIC	Caba	Buenos Aires
Argentina	Centro de Investigaciones Metabólicas (CINME)	Caba	Buenos Aires
Argentina	Investigaciones Medicas IMOBA S.R.L.	Caba	Buenos Aires
Argentina	Mautalen Salud e Investigación - Servicio de Endocrinología	Caba	Buenos Aires
Argentina	Centro de Investigacion y Prevencion Cardiovascular (CIPREC)	Ciudad Autonoma de	Buenos Aires
Argentina	Cemediab - Centro Médico Diabetológico Dr. Alejandro Chertkoff	Ciudad Autonoma de Buenos Aire
Argentina	Centro Medico Dr Laura Maffei Investigacion Clinica Aplicada	Ciudad Autonoma de Buenos Aire	Buenos Aires
Argentina	Centro Médico Viamonte	Ciudad Autonoma de Buenos Aire
Argentina	Instituto Centenario	Ciudad Autonoma de Buenos Aire
Argentina	Cent Priva Especiali Médicas Ambulatorias Inve Clin CEMAIC	Cordoba
Argentina	Centro Diabetologico Dr Waitman	Cordoba
Argentina	Centro Medico Privado San Vicente Diabetes	Cordoba
Argentina	CIPADI	Godoy Cruz	Mendoza
Australia	Paratus Clinical Blacktown Clinic	Blacktown	New South Wales
Australia	Eastern Clinical Research Unit	Box Hill	Victoria
Australia	CORE Research Group Pty Ltd	Brisbane	Queensland
Australia	Campbelltown Medical & Dental Centre	Campbelltown	New South Wales
Australia	Forest Hill Medical and Dental Centre	Forest Hill	Victoria
Australia	Fremantle Hospital	Fremantle	Western Australia
Australia	Barwon Health - The Geelong Hospital	Geelong	Victoria
Australia	Paratus Clinical Kanwal Clinic	Kanwal	New South Wales
Australia	The AIM Centre	Merewether	New South Wales
Australia	Morayfield Medical and Dental Centre	Morayfield	Queensland
Australia	GP Plus Marion	Oaklands Park	South Australia
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	AusTrials Pty Ltd	Sherwood	Queensland
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Australia	Victoria Point Medical and Dental Centre	Victoria Point	Queensland
Brazil	Centro de Pesquisa Clinica do Brasil	Brasilia	Distrito Federal
Brazil	Centro de Diabetes Curitiba	Curitiba	Parana
Brazil	Centro de Pesq. em Diabetes e Doencas Endocrino Metabol.	Fortaleza
Brazil	Instituto de Ensino e Pesquisa Clinica do Ceara	Fortaleza	Ceara
Brazil	CCBR Brasil Centro de Analises e Pesquisas Clínicas LTDA	Rio de Janeiro	RJ
Brazil	Cpclin Centro de Pesquisas Clinicas	São Paulo	SP
Brazil	CPQuali Pesquisa Clínica Ltda.	São Paulo	SP
Brazil	Dr. Consulta Clínica Médica LTDA	São Paulo
Brazil	Cedoes Centro Diagnostico Pequisa Osteoporose E Santo Ltd	Vitoria	ES
Canada	LMC Endocrinology Centres Ltd.	Barrie	Ontario
Canada	Aggarwal and Associates Ltd	Brampton	Ontario
Canada	LMC Endocrinology Centers Brampton	Brampton	Ontario
Canada	C-Health Diabetes and Endocrinology Clinic Calgary	Calgary	Alberta
Canada	LMC Manna Research	Calgary	Alberta
Canada	LMC Endocrinology Centres Ltd.	Concord	Ontario
Canada	Q & T Research Outaouais	Gatineau	Quebec
Canada	Centre De Recherche Clinique De Laval	Laval	Quebec
Canada	Manna Research (Quebec)	Levis	Quebec
Canada	Milestone Research Inc.	London	Ontario
Canada	LMC Endocrinology Centres Ltd.	Nepean	Ontario
Canada	Bluewater Clinical Research Group Inc	Sarnia	Ontario
Canada	Synergy Medical Research	Sherwood Park	Alberta
Canada	Canadian Centre for Research on Diabetes	Smiths Falls	Ontario
Canada	Manna Research, Inc.	Stoney Creek	Ontario
Canada	Medicor Research Inc	Sudbury	Ontario
Canada	LMC Endocrinology Centres Ltd.	Toronto	Ontario
Canada	LMC Endocrinology Centres Ltd.	Ville St-Laurent	Quebec
Canada	Sameh Fikry Medicine Professional Corporation	Waterloo	Ontario
Greece	University General Hospital of Larissa	Larissa
Greece	Iatriko Palaiou Falirou, Medical Center	Palaio Faliro	Athens
Greece	Thermi Clinic	Thermi	Thessaloniki
Greece	AHEPA Hospital	Thessaloniki
Greece	Euromedica - General Clinic of Thessaloniki	Thessaloniki
Israel	Ha'Emek Medical Center	Afula
Israel	Soroka Medical Center	Beer Sheva
Israel	Rambam Medical Center	Haifa
Israel	Wolfson Medical Center	Holon
Israel	Hadassah Medical Center	Jerusalem
Israel	Rabin Medical Center	Petach Tikva
Israel	Sheba Medical Center	Ramat Gan
Israel	Sakhnin Community Clinic, Clalit Health Services	Sakhnin
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv Jaffa
Mexico	Investigacion en Salud y Metabolismo S.C	Chihuahua
Mexico	Diseno y Planeacion en Investigacion Medica S.C.	Guadalajara	Jalisco
Mexico	Instituto Jalisciense de Investigacion en Diabetes y Obesida	Guadalajara	Jalisco
Mexico	St. Lucas Clinical Research Center	Merida	Mexico State
Mexico	Unidad Medica para la Salud Integral (UMSI)	Monterrey	Nuevo León
Mexico	Centro de Estudios de Investigacion Metabolicos y Cardiovasc	Tampico	Tamaulipas
Poland	Poradnia Diabetologiczna SN ZOZ Lege Artis	Bialystok
Poland	NZOZ Diab-Endo-Met	Krakow
Poland	Centrum Terapii Wspolczesnej J.M. Jasnorzewska S.K.A.	Lodz
Poland	Gabinety Terpa	Lublin
Poland	NZOZ CenterMed Lublin	Lublin
Poland	NZOZ Przychodnia Specjalistyczna MEDICA	Lublin
Poland	Nzoz Neuro - Kard	Poznan
Poland	Praktyka Lekarska	Poznan
Poland	NZOZ Przychodnia Specjalistyczna Henryk RudzkiAndrzej Wittek	Ruda Slaska
Poland	Centralny Szpital Kliniczny MSWiA Klinika Dermatologiczna	Warszawa	Mazowieckie
Poland	Woj. Zesp. Spec. Opieki Zdrowotnej	Wroclaw
Puerto Rico	Emanuelli Research & Development Center, LLC	Arecibo
Puerto Rico	Manati Center for Clinical Research Inc	Manati
Puerto Rico	Ponce School of Medicine CAIMED Center	Ponce
Puerto Rico	Research and Cardiovascular Corp.	Ponce
Puerto Rico	University Of Puerto Rico	Rio Pedras
Puerto Rico	Consultorio Medico	San Juan
Puerto Rico	GCM Medical Group PSC	San Juan
Romania	CMI DNBM Dr. Pop Lavinia	Baia Mare	Maramures
Romania	Centrul Medical de Diagnostic si Tratament Ambulatoriu Neomed SRL	Brasov
Romania	Cabinetul Medical Nicodiab SRL	Bucharest
Romania	SC Nutrilife SRL	Bucuresti
Romania	Milena Sante SRL	Galati
Romania	SC Gama Diamed SRL	Mangalia	Constanta
Romania	Spitalul Judetean de Urgenta Satu Mare	Satu-Mare	Jud Satu-Mare
Romania	Cosamext SRL	Targu Mures	Mures
Romania	Centrul Medical Dr. Negrisanu	Timisoara	Timis
Russian Federation	Arkhangelsk the first city clinical hospital	Arkhangelsk
Russian Federation	FSBI Endocrinological Research Center of the MOH of the ROF	Moscow
Russian Federation	Novosibirsk Regional Clinical Hospital	Novosibirsk
Russian Federation	Ryazan Regional Clinincal Cardiology Dispensary	Ryazan
Russian Federation	City Hospital of Saint Martyr Elizabeth	Saint Petersburg
Russian Federation	Medical Military Academy	Saint Petersburg
Russian Federation	SPb GUZ "Diagnostic Center #85"	Saint Petersburg
Russian Federation	City Consultative and Diagnostic Center	Saint-Petersburg
Russian Federation	Regional Clinical Hospital	Saratov
Russian Federation	Research & Practice Ltd	Yaroslavl
Slovakia	Human care s.r.o.	Kosice	Slovak Republic
Slovakia	MediVet s.r.o.	Malacky	Slovak Republic
Slovakia	DIA-MED CENTRUM s.r.o.	Puchov
Slovakia	Tatratrial s.r.o.	Roznava
Slovakia	MEDI-DIA s.r.o.	Sabinov
Slovakia	Areteus s.r.o.	Trebisov	Slovak Republic
Spain	Hospital de la Ribera	Alcira	Valencia
Spain	Instituto de Ciencias medicas	Alicante
Spain	Centro Periférico de Especialidades Bola Azul	Almeria
Spain	Hospital Quironsalud Barcelona- END	Barcelona
Spain	Hospital Clinico Universitario San Cecilio	Granada
Spain	Complexo Hospitalario Universitario A Coruña, CHUAC	La Coruña
Spain	Centro Especialidades San Jose Obrero (Barbarela)	Malaga
Spain	Clinica Juaneda	Palma de Mallorca
Spain	Hospital Universitario Quiron Madrid	Pozuelo de Alarcon	Madrid
Spain	Hospital Universitario Marques De Valdecilla	Santander	Cantabria
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Clinica Nuevas Tecnologias en Diabetes y Endocrinologia	Seville
Taiwan	Chang Gung Memorial Hospital - Kaohsiung	Kaohsiung City
Taiwan	Cardinal Tien Hospital	Sindian City	Taipei County
Taiwan	China Medical University Hospital	Taichung
Taiwan	Chung Shan Medical University Hospital	Taichung City
Taiwan	Kuang Tien General Hospital	Taichung County
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Chi-Mei Medical Center	Tainan City
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei City
United States	Advanced Research Center	Anaheim	California
United States	Primary Care Specialists, LLC	Atlanta	Georgia
United States	Heritage Valley Medical Group, Inc.	Beaver	Pennsylvania
United States	Burke Internal Medicine & Research	Burke	Virginia
United States	Capital Area Research	Camp Hill	Pennsylvania
United States	Clinical Research Professionals	Chesterfield	Missouri
United States	Northwestern Feinberg School of Medicine	Chicago	Illinois
United States	Rapid Medical Research Inc	Cleveland	Ohio
United States	Aventiv Research	Columbus	Ohio
United States	Ohio State Univ College Of Medicine	Columbus	Ohio
United States	ALL Medical Research, LLC	Cooper City	Florida
United States	The Corvallis Clinic P.C.	Corvallis	Oregon
United States	Valley Clinical Trials, Inc.	Covina	California
United States	Advanced Pharma Research	Cutler Bay	Florida
United States	Dallas Diabetes Endocrine Center	Dallas	Texas
United States	NECCR PrimaCare Research, LLC	Fall River	Massachusetts
United States	Lillestol Research LLC	Fargo	North Dakota
United States	Alpine Research Organization	Farmington	Utah
United States	Private: Dr. Larry Stonesifer	Federal Way	Washington
United States	AA Medical Research Center	Flint	Michigan
United States	Marin Endocrine Associates	Greenbrae	California
United States	PharmQuest	Greensboro	North Carolina
United States	Mountain View Clinical Research, Inc.	Greer	South Carolina
United States	PCP for Life	Houston	Texas
United States	National Research Institute	Huntington Park	California
United States	Rocky Mountain Diabetes and Osteoporosis Center	Idaho Falls	Idaho
United States	University of Iowa Hospital & Clinic	Iowa City	Iowa
United States	Glacier View Research Institute	Kalispell	Montana
United States	Holston Medical Group Clinical Research	Kingsport	Tennessee
United States	New Phase Research & Development	Knoxville	Tennessee
United States	Scripps Whittier Diabetes Institute	La Jolla	California
United States	First Valley Medical Group	Lancaster	California
United States	Detweiler Family Medicine	Lansdale	Pennsylvania
United States	Palm Research Center	Las Vegas	Nevada
United States	Palm Research Center	Las Vegas	Nevada
United States	National Research Institute	Los Angeles	California
United States	Robley Rex VAMC	Louisville	Kentucky
United States	South Florida Wellness & Clinical Research Institute	Margate	Florida
United States	The Research Center of the Upstate	Mauldin	South Carolina
United States	Solaris Clinical Research	Meridian	Idaho
United States	New Horizon Research Center	Miami	Florida
United States	Suncoast Research Group, LLC	Miami	Florida
United States	Montana Medical Research, Inc	Missoula	Montana
United States	Catalina Research Institute, LLC	Montclair	California
United States	Monterey Endocrine & Diabetes Institute, Inc.	Monterey	California
United States	Saltzer Medical Group. P.A.	Nampa	Idaho
United States	Southern New Hampshire Diabetes and Endocrinology	Nashua	New Hampshire
United States	Capital Area Research	Newport	Pennsylvania
United States	Intend Research	Norman	Oklahoma
United States	Valley Clinical Trials, Inc.	Northridge	California
United States	Capital Clinical Research Center	Olympia	Washington
United States	Clinical Neuroscience Solutions Inc	Orlando	Florida
United States	Desert Medical Group Inc	Palm Springs	California
United States	Havana Research Institute	Pasadena	California
United States	Parkside Family Medical	Philadelphia	Pennsylvania
United States	Preferred Primary Care Physicians- Bower Hill	Pittsburgh	Pennsylvania
United States	Western University of Health Sciences	Pomona	California
United States	Progressive Medical Research	Port Orange	Florida
United States	Oregon Health and Science University	Portland	Oregon
United States	BFHC Research	San Antonio	Texas
United States	LCGK Research	San Carlos	California
United States	Consano Clinical Research	Shavano Park	Texas
United States	NorthShore University HealthSystem	Skokie	Illinois
United States	Olive View Medical Center	Sylmar	California
United States	Martin Diagnostic Clinic	Tomball	Texas
United States	Cotton O'Neil Diabetes and Endocrinology Center	Topeka	Kansas
United States	Troy Internal Medicine, PC	Troy	Michigan
United States	University Clinical Investigators, Inc.	Tustin	California
United States	Touro University	Vallejo	California
United States	Coastal Metabolic Research Centre	Ventura	California
United States	Walla Walla Clinic	Walla Walla	Washington
United States	Diablo Clinical Research	Walnut Creek	California
United States	Chase Medical Research, LLC	Waterbury	Connecticut
United States	Iowa Diabetes Research	West Des Moines	Iowa

Sponsors (1)

Lead Sponsor	Collaborator
Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Greece,  Israel,  Mexico,  Poland,  Puerto Rico,  Romania,  Russian Federation,  Slovakia,  Spain,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg)	HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Secondary	Change From Baseline in HbA1c (5 mg)	HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Secondary	Change From Baseline in Body Weight	LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Secondary	Percentage of Participants With HbA1c of <7.0%	HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Imputed data includes observed value and imputed value if endpoint measure is missing.	Week 52
Secondary	Change From Baseline in Fasting Serum Glucose	LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Secondary	Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values	The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Postmeal, Midday Premeal, Midday 2-hour Postmeal, Evening Premeal, Evening 2-hour Postmeal and Bedtime. LS mean was determined by mixed-model repeated measures (MMRM) model with variables Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 52
Secondary	Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide	Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide	1 to 24 hours, 24 to 96 hours, or 120 to 168 hours post dose of Week 7, 15, 23, 35
Secondary	Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 (Millimole/Liter (mmol/L))] or Severe Hypoglycemia	The hypoglycemia events were defined by participant reported events with blood glucose <54mg/dL (<3.0 mmol/L) or severe hypoglycemia. Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Post-baseline comparisons between treatment and control group was evaluated using negative binomial model with variables : Number of episodes = Baseline HbA1c Group (<=8.5%, >8.5%) + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment, with log (exposure in days/365.25) as an offset variable	Baseline through Week 52

External Links

•   A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk