A Study of Daily Oral Orforglipron (LY3502970) Compared With Insulin Glargine in Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk (ACHIEVE-4)

• ClinicalTrials.gov Identifier: NCT05803421
• Recruitment Status: Recruiting
• First Posted: April 7, 2023
• Last Update Posted: March 13, 2024
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: March 27, 2023
• First Posted Date: April 7, 2023
• Last Update Posted Date: March 13, 2024
• Actual Study Start Date: April 3, 2023
• Estimated Primary Completion Date: April 24, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 27, 2023)

Time to First Occurrence of Any Major Adverse Cardiovascular Event (MACE-4) [Myocardial Infarction (MI), Stroke, Hospitalization for Unstable Angina, or Cardiovascular (CV) Death] [ Time Frame: Baseline to End of the Study (Approximate Maximum 104 Weeks) ]

Time to First Occurrence of Any MACE-4 (Myocardial Infarction (MI), Stroke, Hospitalization for Unstable Angina, or Cardiovascular [CV] Death)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 27, 2023)

• Time to First Occurrence of Any MACE-3 Event (MI, Stroke, or CV death) [ Time Frame: Baseline to End of the Study (Approximately 104 Weeks) ]
  Time to First Occurrence of Any MACE-3 Event (MI, Stroke, or CV death)
• Change from Baseline in Hemoglobin A1c (HbA1c) [ Time Frame: Baseline, Week 52 ]
  Change from Baseline in HbA1c
• Change from Baseline in Fasting Serum Glucose [ Time Frame: Baseline, Week 52 ]
  Change from Baseline in Fasting Serum Glucose
• Change from Baseline in Daily Average 7-point Self-monitoring Blood Glucose (SMBG) Profile [ Time Frame: Baseline, Week 52 ]
  Change from Baseline in Daily Average 7-point SMBG
• Percentage of Participants with HbA1c Target Values Less Than (<)7.0% (53 mmol/mol) [ Time Frame: Week 52 ]
  Percentage of Participants with HbA1c Target Values <7.0% (53 mmol/mol)
• Change from Baseline in Body Weight [ Time Frame: Baseline, Week 52 ]
  Change from Baseline in Body Weight
• Percent Change from Baseline Body Weight [ Time Frame: Week 52 ]
  Percent Change from Baseline Body Weight
• Change from Baseline in Short Form 36 Version 2 (SF-36v2) Acute Form Domain Score [ Time Frame: Baseline, Week 52 ]
  The SF-36v2 acute form is a 36-item generic, participant completed measure designed to assess 8 domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Scores of each domain are measured by T-scores, with a mean of 50 and standard deviation of 10; higher scores indicate better levels of function and/or better health.
• Pharmacokinetics (PK): Plasma Serum Concentrations of Orforglipron [ Time Frame: Baseline through Week 52 ]
  PK will be estimated based on the population PK model.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Daily Oral Orforglipron (LY3502970) Compared With Insulin Glargine in Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk
• Official Title: A Phase 3, Open-Label Study of Once Daily LY3502970 Compared With Insulin Glargine in Adult Participants With Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk
• Brief Summary: The main purpose of this study is to determine safety and efficacy of orforglipron compared with insulin glargine in participants with type 2 diabetes and obesity or overweight at increased cardiovascular risk. The study will last approximately 2 years may include up to 27 visits.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Type 2 Diabetes
• Obesity
• Overweight or Obesity
• Overweight
• Cardiovascular Diseases
• Chronic Kidney Disease

Intervention

• Drug: Orforglipron
  Administered orally once daily
  Other Name: LY3502970
• Drug: Insulin Glargine
  Administered SC once daily

Study Arms

• Experimental: Orforglipron
  Participants will receive escalated doses of orforglipron orally.
  Intervention: Drug: Orforglipron
• Active Comparator: Insulin Glargine
  Participants will receive insulin glargine subcutaneously (SC). Doses will be individualized and titrated according to a treat-to-target algorithm.
  Intervention: Drug: Insulin Glargine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 27, 2023): 2620
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 17, 2025
• Estimated Primary Completion Date: April 24, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Have been diagnosed with type 2 diabetes mellitus (T2DM)
• Are at least 18 years of age or legal age of consent in the jurisdiction in which the study is taking place, whichever is older.

• Have HbA1c at screening

  • ≥7.0% and ≤10.5% if background diabetes medication does not include a sulfonylurea, or
  • ≥7.5% and ≤10.5% if background diabetes medication includes a sulfonylurea.
• Are on stable treatment of at least 1 and no more than 3 oral antihyperglycemic drugs for at least 90 days before screening. Antihyperglycemic drugs may include metformin, SGLT-2 inhibitors, and/or sulfonylureas

• Have increased risk for cardiovascular (CV) events due to:

  • Coronary heart disease
  • Peripheral arterial disease, presumed to be of atherosclerotic origin
  • Cerebrovascular disease, presumed to be of atherosclerotic origin
  • Chronic kidney disease (CKD)
  • Congestive heart failure (CHF) New York Heart Association (NYHA) functional classification II to III
• Are of stable weight (± 5%) for at least 90 days prior to screening
• Have a BMI ≥25 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 screening
• Currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema (e.g. laster photocoagulation or intravitreal injections of anty-VEGF inhibitors
• Have a known clinically significant gastric emptying abnormality
• Have acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood alanine transaminase (ALT) or aspartate aminotransferase (AST) enzyme level ≥5.0 times the upper limit of normal (ULN) for the reference range, as determined by the central laboratory
• Have had any of the following within 60 days prior to screening: acute myocardial infarction, cerebrovascular accident (stroke), or hospitalization for congestive heart failure
• Have an eGFR <15 mL/min/1.73 m2 as determined at screening
• Have a family (first-degree relative) or personal history of medullary thyroid carcinoma or 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 90 days
• Have used any weight loss drugs, including herbal or nutritional supplements, within 90 days of screening

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or; 1-317-615-4559; ClinicalTrials.gov@lilly.com

• Listed Location Countries: Argentina, Austria, Brazil, Czechia, Germany, Greece, India, Italy, Korea, Republic of, Mexico, Puerto Rico, Romania, Slovakia, Spain, Turkey, United States

Administrative Information

• NCT Number: NCT05803421
• Other Study ID Numbers: 18563; J2A-MC-GZGS ( Other Identifier: Eli Lilly and Company ); 2022-502833-25-00 ( Other Identifier: EU Trial Number ); U1111-1285-6821 ( Other Identifier: Universal Trial Number (UTN) )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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 European Union (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://vivli.org/

• 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: March 2024