A Study of Tirzepatide (LY3298176) Compared to Dulaglutide in Participants With Type 2 Diabetes (SURPASS J-mono)

• ClinicalTrials.gov Identifier: NCT03861052
• Recruitment Status: Completed
• First Posted: March 4, 2019
• Results First Posted: April 14, 2022
• Last Update Posted: April 14, 2022
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: March 1, 2019
• First Posted Date: March 4, 2019
• Results First Submitted Date: March 4, 2022
• Results First Posted Date: April 14, 2022
• Last Update Posted Date: April 14, 2022
• Actual Study Start Date: May 7, 2019
• Actual Primary Completion Date: March 10, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 4, 2022)

Change From Baseline in Hemoglobin A1c (HbA1c) [ Time Frame: Baseline, Week 52 ]

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 + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).

Original Primary Outcome Measures (submitted: March 1, 2019)

Change from Baseline in Hemoglobin A1c (HbA1c) [ Time Frame: Baseline, Week 52 ]

Change from baseline in HbA1c

Current Secondary Outcome Measures (submitted: April 13, 2022)

• Percentage of Participants With HbA1c of <7.0% [ Time Frame: Week 52 ]
  HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.
• Change From Baseline in Fasting Serum Glucose [ Time Frame: Baseline, Week 52 ]
  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 for post-baseline measures: Variable = Baseline + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).
• Change From Baseline in Average 7-Point Self-Monitored Blood Glucose (SMBG) Values [ Time Frame: Baseline, Week 52 ]
  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 analysis of covariance (ANCOVA) model for with Baseline + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment (Type III sum of squares) as variables.
• Change From Baseline in Body Weight [ Time Frame: Baseline, Week 52 ]
  Change from baseline in body weight. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Baseline HbA1c Group (<=8.5%, >8.5%) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).
• Percentage of Participants Who Achieve Weight Loss ≥5% From Baseline [ Time Frame: Week 52 ]
  Percentage of participants who achieve weight loss ≥5% from baseline.
• Change From Baseline in Fasting Insulin [ Time Frame: Baseline, Week 52 ]
  Fasting Insulin is a test used to measure the amount of insulin in the body. LS mean was determined by MMRM model for post-baseline measures with log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares) as variables.
• Change From Baseline in Fasting C-Peptide [ Time Frame: Baseline, Week 52 ]
  Fasting C-peptide is a test used to measure the amount of C-peptide in the body. A high level of C-peptide can mean that body is making too much insulin. LS mean was determined by MMRM model for post-baseline measures: log (Actual Measurement) = log (Baseline) + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).
• Change From Baseline in Homeostasis Model Assessment B (HOMA-2B, Insulin) [ Time Frame: Baseline, Week 52 ]
  HOMA-2B is an estimated steady state beta cell function based on updated HOMA2 model. The HOMA2 model estimates steady state pancreatic beta cell function (%B) as a percentage of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement/Baseline) = log(Baseline) + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).
• Change From Baseline in HOMA-2S (Insluin) [ Time Frame: Baseline, Week 52 ]
  HOMA2-S is an estimated insulin sensitivity based on updated HOMA2 model. The HOMA2 model is a computer model that estimates insulin sensitivity (%S) as percentages of a normal reference population using simultaneously measured fasting plasma glucose and fasting insulin. LS mean was determined by MMRM model for post-baseline measures: log(Actual Measurement) = log(Baseline) + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline BMI Group (<25 or >=25 kg/m^2) + Washout of Antidiabetic Medication + Treatment + Time + Treatment*Time (Type III sum of squares).
• Rate of Hypoglycemia With Glucose < 54 mg/dL or Severe Hypoglycemia [ Time Frame: Baseline through Week 52 ]
  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 for post-baseline comparisons between treatment and control group: number of episodes = baseline hypoglycemia incidence + baseline BMI Group (<25 or >=25 kg/m^2) + washout of antidiabetic medication + baseline hemoglobin A1C (%) + treatment, with log (exposure in days/365.25) as an offset variable.
• Number of Participants With Anti-Tirzepatide Antibodies [ Time Frame: Baseline through Week 52 ]
  Number of participants with anti-tirzepatide antibodies. A participant is treatment emergent (TE) anti-drug antibody (ADA) evaluable if there is at least one non-missing test result for tirzepatide ADA for each of the baseline period and the postbaseline period. All percentages are relative to the total number of TE ADA evaluable participants in each treatment group. A TE ADA evaluable participant is considered to be TE ADA+ if the participant has at least one postbaseline titer that is a 4-fold or greater increase in titer from baseline measurement.

Original Secondary Outcome Measures (submitted: March 1, 2019)

• Percentage of Participants with HbA1c of <7.0% [ Time Frame: Week 52 ]
  Percentage of participants with HbA1c of <7.0%
• Change from Baseline in Fasting Serum Glucose [ Time Frame: Baseline, Week 52 ]
  Change from baseline in fasting serum glucose
• Change from Baseline in Average 7-Point Self-Monitored Blood Glucose (SMBG) Values [ Time Frame: Baseline, Week 52 ]
  Change from baseline in average 7-point SMBG values
• Change from Baseline in Body Weight [ Time Frame: Baseline, Week 52 ]
  Change from baseline in body weight
• Percentage of Participants who Achieve Weight Loss ≥5% from Baseline [ Time Frame: Week 52 ]
  Percentage of participants who achieve weight loss ≥5% from baseline
• Change from Baseline in Fasting Insulin [ Time Frame: Baseline, Week 52 ]
  Change from baseline in fasting insulin
• Change from Baseline in Fasting C-Peptide [ Time Frame: Baseline, Week 52 ]
  Change from baseline in fasting C-peptide
• Change from Baseline in Homeostasis Model Assessment B (HOMA-2B) [ Time Frame: Baseline, Week 52 ]
  Change from baseline in HOMA-2B
• Change from Baseline in HOMA-2S [ Time Frame: Baseline, Week 52 ]
  Change from baseline in HOMA-2S
• Rate of Total Hypoglycemia [ Time Frame: Baseline through Week 52 ]
  Rate of total hypoglycemia
• Number of Participants with Anti-Tirzepatide Antibodies [ Time Frame: Baseline through Week 52 ]
  Number of participants with anti-tirzepatide antibodies

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Tirzepatide (LY3298176) Compared to Dulaglutide in Participants With Type 2 Diabetes
• Official Title: A Phase 3 Study of Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in Patients With Type 2 Diabetes Mellitus
• Brief Summary: The reason for this study is to see if the study drug tirzepatide (LY3298176) is effective and safe compared to dulaglutide in participants with type 2 diabetes in Japan.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Type 2 Diabetes

Intervention

• Drug: Tirzepatide
  Administered SC
  Other Name: LY3298176
• Drug: Dulaglutide
  Administered SC
  Other Name: LY2189265

Study Arms

• Experimental: 5 mg Tirzepatide
  Participants received 5 milligram (mg) tirzepatide administered subcutaneously (SC) once weekly for 52 weeks.
  Intervention: Drug: Tirzepatide
• Experimental: 10 mg Tirzepatide
  Participants received 10 mg tirzepatide administered SC once weekly for 52 weeks.
  Intervention: Drug: Tirzepatide
• Experimental: 15 mg Tirzepatide
  Participants received 15 mg tirzepatide administered SC once weekly for 52 weeks.
  Intervention: Drug: Tirzepatide
• Active Comparator: 0.75 mg Dulaglutide
  Participants received 0.75 mg dulaglutide administered SC once weekly for 52 weeks.
  Intervention: Drug: Dulaglutide

Publications *

• Inagaki N, Takeuchi M, Oura T, Imaoka T, Seino Y. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022 Sep;10(9):623-633. doi: 10.1016/S2213-8587(22)00188-7. Epub 2022 Jul 30.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 1, 2019): 636
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: March 31, 2021
• Actual Primary Completion Date: March 10, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Participant must:

• Have been diagnosed with type 2 diabetes mellitus based on the World Health Organization classification before the screening visit.

• Have HbA1c meeting the following criteria, as determined by the central laboratory at screening and baseline:

  • for participants who are oral antihyperglycemic medication (OAM)-naïve at screening, ≥7.0% to ≤10.0% at both screening and baseline.
  • for participants who have been taking OAM monotherapy at screening, ≥6.5% to ≤9.0% at screening, and ≥7.0% to ≤10.0% at baseline.
• Have body mass index (BMI) of ≥23 kilograms per meter squared at screening.
• Be of stable weight (±5%) during 3 months preceding screening; and agree to not initiate an intensive diet and/or exercise program during the study with the intent of reducing body weight other than the lifestyle and dietary measures for diabetes treatment.

Exclusion Criteria:

Participant 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 weight loss drugs, including over-the-counter medications during the last 3 months.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan

Administrative Information

• NCT Number: NCT03861052
• Other Study ID Numbers: 17077; I8F-JE-GPGO ( Other Identifier: Eli Lilly and Company )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• 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.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: http://www.clinicalstudydatarequest.com

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: April 2022