Subcutaneous Tirzepatide Once-weekly in Patients With Obesity and Knee Osteoarthritis (STOP KNEE-OA)

Inclusion Criteria:

• Have a body mass index of ≥ to 30 kg/m2.

• Report one or more previous unsuccessful attempt to lose body weight via lifestylemodification.

• Have been deemed eligible to enter the waiting list for primary knee replacement forthe treatment of osteoarthritis in the target joint by an orthopaedic surgeon at oneof the participating study sites.

• Have moderate-to-severe knee osteoarthritis in the target joint, defined as aKellgren-Lawrence grade two or greater.

• Be willing to and capable of learning how to self-inject the study drug and followstudy procedures for the duration of the trial.

• Provide informed consent to study participation in line with the requirements of thehuman research ethics committee of the study site.

Female participants must:

• Not be currently pregnant or breastfeeding AND

• Not be of reproductive potential, defined as:

• Infertile due to surgical sterilization or congenital anomaly, OR

• Post-menopausal defined as:

• A woman over the age of 40 years with spontaneous cessation of menses for at least 12 consecutive months (in the absence of medications known to induce amenorrhea),with a follicle-stimulating hormone ≥40mIU/mL, and a negative pregnancy test priorto study entry, OR

• A woman over the age of 55 years with cessation of menses for at least 12consecutive months (in the absence of medications known to induce amenorrhea), OR

• A woman over the age of 55 years that has commenced hormone replacement therapyafter a documented diagnosis of menopause.

Exclusion Criteria:

Participant will be ineligible for inclusion if they meet any of the following criteria:

• Have been deemed eligible to enter the waiting list for knee replacement in thecontralateral knee by an orthopaedic surgeon at one of the participating studysites.

• Have used any prescription medications intended to promote weight loss (e.g.,tirzepatide, liraglutide, semaglutide) in the three months prior to screening.

• Have previously undergone any surgical or endoscopic procedure intended to promoteweight loss.

• Have been diagnosed with type 1 diabetes mellitus (T1DM) or T2DM

• Have laboratory evidence indicative of diabetes mellitus during screening.

• Have personal or family history of medullary thyroid carcinoma (MTC) or MultipleEndocrine Neoplasia syndrome type 2 (MEN 2)

• Have an active malignancy (excluding basal or squamous cell skin cancer).

• Have had a transplanted organ or awaiting an organ transplant

• Have received chronic systemic glucocorticoid therapy (for more than 14 days) inprior 3 months or have a significant, active autoimmune abnormality (e.g., lupus orrheumatoid arthritis) that the study doctor deems likely to require systemicglucocorticoid therapy during the next 18 months.

• Have any other medical conditions, abnormal laboratory tests or concomitantmedications that make them unsuitable for participation:

• Have a clinically significant gastric emptying abnormality.

• Have had a history of acute or chronic pancreatitis.

• Have obesity induced by other endocrinologic disorders

• Have an unstable psychiatric disorder

• Have a Patient Health Questionnaire (PHQ-9) score of >15 during screening

• Have been deemed by the study doctor to be actively suicidal,

• Have answered "yes" to questions 4 or 5 on the "Suicidal Ideation" section of theColumbia-Suicide Severity Rating Scale (C-SSRS) during screening, OR

• Have answered yes to any questions in the "Suicidal Behaviour" section of the C-SSRSduring screening. AND

• The behaviour or ideation occurred in the last month

• Have uncontrolled hypertension (systolic blood pressure above or equal to 160mmHg and/or diastolic blood pressure above or equal to 100 mmHg)

• Have had within the past 6 months prior to randomisation any of the following:acute myocardial infarction, cerebrovascular accident, unstable angina, orhospitalisation due to congestive cardiac failure (are also exclusion criteriafor elective knee replacement)

• Have severe renal impairment defined as an eGFR <30 mL/min/1.73 m2 at screeningvisit.

• Have thyroid-stimulating hormone outside of the range of 0.4 to 6.0 mIU/L atscreening visit

• Have acute or chronic hepatitis or abnormal liver function tests as measured byeither alanine aminotransferase or alkaline phosphatase >200 IU.

• Have any other known contraindication to any glucagon-like peptide-1 receptoragonists.

• Are study site personnel, or immediate family of a member of the study site.

• Have been enrolled in any other study of an investigational product within the pastninety days or are currently enrolled in such a study.