A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin (SURPASS-5)

Randomized, Phase 3, Double-blind Trial Comparing the Effect of the Addition of Tirzepatide Versus Placebo in Patients With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin

The purpose of this study is to compare the safety and efficacy of the study drug tirzepatide to placebo in participants with type 2 diabetes that are already on insulin glargine, with or without metformin. Participants will administer tirzepatide or placebo along with their previous glucose lowering medications. The study will last approximately 47 weeks and may include about 23 visits.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Tirzepatide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 475
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czechia
  • Brandys Nad Labem-Stara Bolesl, Czechia, 25001
    • Diacentrum Brandys n.L. s.r.o.
  • Krnov, Czechia, 79401
    • Diabetologicka ordinace pro dospele
  • Pardubice, Czechia, 53002
    • Diahelp s.r.o., Interni a diabetologicka ambulance
  • Praha 1, Czechia, 11000
    • Lekarna Dr. Max
  • Praha 4, Czechia, 149 00
    • MILAN KVAPIL s.r.o.
  • Praha 8, Czechia, 181 00
    • ResTrial s.r.o.
  • Středočeský Kraj
    • Pribram, Středočeský Kraj, Czechia, 26201
      • MILAN KVAPIL s.r.o.
• Germany
  • Hamburg, Germany, 21073
    • Diabetologische Schwerpunktpraxis B. Scholz/Dr. B. Paschen
  • Hamburg, Germany, 22607
    • Gemeinschaftspraxis für innere Medizin und Diabetologie
  • Brandenburg
    • Falkensee, Brandenburg, Germany, 14612
      • Praxis Dr. Jörg Lüdemann
  • Hessen
    • Pohlheim, Hessen, Germany, 35415
      • Arztpraxis Dr. Cornelia Marck
  • Nordrhein-Westfalen
    • Essen, Nordrhein-Westfalen, Germany, 45136
      • InnoDiab Forschung GmbH
    • Münster, Nordrhein-Westfalen, Germany, 48145
      • Institut für Diabetesforschung Münster GmbH
  • Rheinland-Pfalz
    • Ludwigshafen am Rhein, Rheinland-Pfalz, Germany, 67059
      • Praxis Dr. Kempe - Dr. Stemler
  • Saarland
    • Saint Ingbert-Oberwürzbach, Saarland, Germany, 66386
      • Schwerpunktpraxis Diabetes
  • Sachsen-Anhalt
    • Magdeburg, Sachsen-Anhalt, Germany, 39112
      • SMO.MD GmbH
  • Schleswig Holstein
    • Oldenburg in Holstein, Schleswig Holstein, Germany, 23758
      • RED-Institut GmbH
• Japan
  • Kumamoto, Japan, 862-0976
    • Jinnouchi Hospital
  • Chiba
    • Kashiwa, Chiba, Japan, 277-0825
      • Kashiwa hospital
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-0062
      • Manda Hospital
  • Kanagawa
    • Kamakura, Kanagawa, Japan, 247-0056
      • Takai Naika Clinic
  • Osaka
    • Takatsuki, Osaka, Japan, 569-1096
      • Takatsuki Red Cross Hospital
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 103-0027
      • Tokyo-Eki Center-building Clinic
    • Chuo-ku, Tokyo, Japan, 103-0028
      • Tokyo Center Clinic
    • Chuo-ku, Tokyo, Japan, 104-0031
      • Tokyo Clinical Trial Centre Fukuwa Clinic
    • Chuou-ku, Tokyo, Japan, 1030002
      • The Institute for Adult Diseases, Asahi Life Foundation
    • Ota-ku, Tokyo, Japan, 143-0015
      • Sato Naika Clinic
• Poland
  • Lublin, Poland, 20-538
    • NZOZ Przychodnia Specjalistyczna Medica
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 01-518
      • Centrum Medyczne AMED
  • Podlaskie
    • Bialystok, Podlaskie, Poland, 15-351
      • Nzoz Zdrowie Osteo-Medic
  • Pomorskie
    • Gdansk, Pomorskie, Poland, 80-546
      • Centrum Badan Klinicznych, PI House
• Puerto Rico
  • Caguas, Puerto Rico, 00725
    • Centro de Endocrinologia y Nutricion del Turabo
  • Manati, Puerto Rico, 00674
    • Manati Center for Clinical Research Inc
• Slovakia
  • Hnusta, Slovakia, 98101
    • Ambulancia vnútorného lekárstva Hnúša (Diabetes care)
  • Malacky, Slovakia, 901 01
    • Sin Azucar
  • Prievidza, Slovakia, 971 01
    • Dia-Clarus.s.r.o.
  • Trnava, Slovakia, 917 01
    • JAL
  • Zilina, Slovakia, 01001
    • MEDIVASA, s.r.o.
• Spain
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Sevilla, Spain, 41010
    • Hospital Infanta Luisa
  • València, Spain, 46026
    • Hospital Universitari i Politecnic La Fe-ENDO
  • Andalucia
    • Malaga, Andalucia, Spain, 29010
      • Hospital Clinico Universitario Virgen de la Victoria
  • Valencia
    • Alcira, Valencia, Spain, 46600
      • Hospital de la Ribera
• United States
  • California
    • Fresno, California, United States, 93720
      • Valley Endocrine, Fresno
  • Florida
    • New Port Richey, Florida, United States, 34652
      • Sun Coast Clinical Research, Inc
  • New Hampshire
    • Nashua, New Hampshire, United States, 03063
      • Southern New Hampshire Diabetes and Endocrinology
  • New York
    • New York, New York, United States, 10016
      • Manhattan Medical Research
  • Oklahoma
    • Norman, Oklahoma, United States, 73069
      • Intend Research

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:

• Have been diagnosed with type 2 diabetes mellitus (T2DM) and have been treated with insulin glargine (U100), once daily with or without metformin ≥3 months prior to screening visit.
• Have HbA1c between ≥7.0% and ≤10.5%.
• Have a stable weight (± 5%) for at least 3 months before screening.
• Have a body mass index (BMI) ≥23 kilograms per meter squared (kg/m²) at screening.

Exclusion Criteria:

• 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 acute treatment.
• Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss.
• Have an estimated glomerular filtration rate <30 mL/minute/1.73 m² [for participants on metformin, estimated glomerular filtration rate <45 mL/min/1.73 m2 (or lower than the country-specific threshold for using the protocol-required dose of metformin per local label)]
• 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 weight loss drugs, including over-the-counter medications during the last 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 5 mg Tirzepatide; 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	Drug: Tirzepatide; Administered SC as add-on to the pre-trial background medication.; Other Names: LY3298176
Experimental: 10 mg Tirzepatide; 10 mg tirzepatide administered SC once a week.	Drug: Tirzepatide; Administered SC as add-on to the pre-trial background medication.; Other Names: LY3298176
Experimental: 15 mg Tirzepatide; 15 mg tirzepatide administered SC once a week.	Drug: Tirzepatide; Administered SC as add-on to the pre-trial background medication.; Other Names: LY3298176
Placebo Comparator: Placebo; Placebo administered SC once a week.	Drug: Placebo; Administered SC as add-on to the pre-trial background medication.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 with Baseline + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 40

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 40
Change From Baseline in Body Weight	Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Baseline HbA1c Group (<= 8.0%, >8.0%) + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment + Time + Treatment*Time (Type III sum of squares).	Baseline, Week 40
Percentage of Participants Achieving an HbA1c Target Value of <7%	Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A.HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.	Week 40
Change From Baseline in Fasting Serum Glucose	Fasting serum glucose (FSG) is a test to determine sugar levels in serum sample after an overnight fast. LS Mean was determined by MMRM model with Baseline + Pooled Country + Baseline Metformin Use (Yes, No) + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.	Baseline, Week 40
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. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with Baseline + Baseline HbA1c Group (<= 8.0%, >8.0%) + Baseline Metformin Use (Yes, No) + Pooled Country + Treatment (Type III sum of squares).	Baseline, Week 40
Percentage of Participants Who Achieved Weight Loss ≥5%	Percentage of Participants who Achieved Weight Loss ≥5%.	Week 40
Percentage Change From Baseline in Daily Mean Insulin Glargine Dose	LS mean was calculated using MMRM model with log (Baseline) + Baseline Metformin Use (Yes, No) + Pooled Country + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.	Baseline, Week 40
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. The rate of postbaseline hypoglycemia was estimated by negative binomial model: number of episodes = Pooled Country + Baseline Metformin Use (Yes, No) + Baseline HbA1c Group (<= 8.0%, >8.0%) + Treatment, with log (exposure in days/365.25) as an offset variable.	Baseline through Safety Follow-Up (Up to Week 44)
Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve (AUC) of Tirzepatide	AUC is a combined measure obtained from Week 7, 15, 23 and 39 and a single averaged measure of AUC was reported.	Week 7, 15, 23 and 39 post dose
Percentage of Participants Achieving an HbA1c Target Value of <5.7%	Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.	Week 40

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General Publications

• Sattar N, McGuire DK, Pavo I, Weerakkody GJ, Nishiyama H, Wiese RJ, Zoungas S. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat Med. 2022 Mar;28(3):591-598. doi: 10.1038/s41591-022-01707-4. Epub 2022 Feb 24.
• Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodriguez A. Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial. JAMA. 2022 Feb 8;327(6):534-545. doi: 10.1001/jama.2022.0078.

Helpful Links

• A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2019
• Primary Completion (Actual): December 22, 2020
• Study Completion (Actual): January 13, 2021

Study Registration Dates

• First Submitted: July 30, 2019
• First Submitted That Met QC Criteria: July 30, 2019
• First Posted (Actual): July 31, 2019

Study Record Updates

• Last Update Posted (Actual): January 12, 2022
• Last Update Submitted That Met QC Criteria: December 12, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: T2DM; glucagon-like peptide-1 (GLP-1); GIP/GLP-1 dual receptor agonist; glucose-dependent insulinotropic polypeptide (GIP)
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Tirzepatide
• Other Study ID Numbers: 16998; I8F-MC-GPGI (Other Identifier: Eli Lilly and Company); 2019-000860-99 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• IPD Sharing Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No