A Double-blind, Placebo-controlled, Randomized Study to Evaluate the Efficacy and Safety of KBP-336 as an Adjunct to Diet and Exercise in Obese Individuals with Osteoarthritis of the Knee

Prior treatment

• Participation in any previous DACRA/amylin study
• Intra-articular injection of corticosteroids within 3 months or hyaluronic acid within 6 months of screening in the target knee or into any other major joint within 30 days prior to screening (for extended-release corticosteroid injections: within 6 months in target knee and 3 months into any other major joint)
• Systemic corticosteroid treatment for the treatment of musculoskeletal conditions of more than 14 days during the past 6 months prior to screening
• Any pharmacological or non-pharmacological treatment primarily targeting OA started or changed during the 4 weeks prior to randomization or likely to be changed during the duration of the study
• Target knee surgery or arthroscopy within 1 year prior to screening
• Treatment with medication for obesity, including GLP-1 analogues, unless the dose of use has been stable for at least six months prior to screening
• History of alcohol or drug abuse within 5 years prior to screening, in the opinion of the Investigator
• Use of an investigational drug within 90 days prior to screening
• Planned major surgery within the next 6 months
• Bariatric surgery within the last 12 months of the screening visit

Other illness

• Conditions significantly affecting joint and bone health, in the opinion of the Investigator should be excluded (including but not limited to atrophic or hypotrophic OA, subchondral insufficiency fracture, osteonecrosis, osteoporotic fractures, excessive malalignment of the knee or severe chondrocalcinosis)
• Active comorbid condition other than OA (e.g radicular back pain, bursitis, tendinitis) significantly affecting target knee pain reporting in the opinion of the investigator
• History of gout, or pseudogout, with high likelihood of flare up during trial participation that would require NSAID treatment, in the opinion of the investigator
• Hip dislocation and congenital hip dysplasia with degenerative joint disease should be excluded
• History or presence of clinically significant neurological disease or psychiatric disorder in the opinion of the investigator
• Presence or history of clinically significant allergies, including relevant drug hypersensitivity or allergy
• Current malignancy or treatment for malignancy within the past five years, apart from resected basal cell carcinoma, squamous skin cell carcinoma, or resected cervical atypia or carcinoma in situ, unless affecting the target knee area
• For sexually active men with a female partner of childbearing potential: a. Failure to agree to ensure that their female partners use a highly effective method of contraception (see Appendix A) from enrolment up to at least 3 months after the study end b. Failure to agree not to donate sperm throughout the study and at least 3 months after the study end
• Current comorbid condition, other than OA, affecting target knee or systemic illness known to be significantly associated with arthritis or joint pathology affecting any joint, including but not necessarily limited to endocrinopathies, inflammatory, or autoimmune disease with significant joint involvement (e.g., Rheumatoid Arthritis); Seronegative Spondyloarthropathies (e.g. Ankylosing Spondylitis, Psoriasis arthritis, Reactive arthritis)

Lab values

• For women of childbearing potential: a. Pregnancy (i.e. positive serum pregnancy test at screening) or breastfeeding b. Failure to agree to practice a highly effective method of contraception (see Appendix A), from enrolment up to at least 3 months after the study end
• Uncontrolled thyroid disease in the opinion of the Investigator based on medical history and laboratory results collected in screening

Other

• Partial or complete joint replacement of either knee
• A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15 at screening
• Vitamin D deficiency defined as blood 25-OH D3 concentration ≤25 nmol/L. Vitamin D supplementation and subsequent rescreening is allowed
• Unsuitable for study participation for any reason in the opinion of the Investigator
• Diagnosis of OA resulting from trauma within the last 5 years
• Pain of the contralateral knee exceeding that of the target knee at the baseline visit, as measured by the WOMAC pain subscale
• Participant-reported weight loss >5% of body weight within the last 6 months of the screening visit

• The participant is able to read and understand the language and content of the study material and provide written Informed Consent
• Willing to withdraw from any pain medication including, but not limited to, Opioids (including semisynthetic opioids), Non-Steroidal Anti-inflammatories (NSAIDs, with the exception of low-dose aspirin for thromboprophylaxis), COX-2 inhibitors, Topical medication, and Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs e.g. Duloxetine) and only use the allowed Rescue Medications from baseline to Visit11/ET (maximum 4000 mg paracetamol per day)
• Willing and able to comply with study requirements and instructions
• A diagnosis of OA of the target knee based on American College of Rheumatology (ACR) clinical and radiographic criteria(31), with OA symptoms (as reported by the participant) that have been present for at least 3 months prior to screening
• Radiological OA grade 2 or 3 of the target knee, using the Kellgren-Lawrence method as graded by a central reader on a Fixed-Flexion X-ray obtained during screening, or on a recent (within 6 months) Xray which fulfills the protocol specifications for reading
• Age ≥ 45 years of either sex
• Body Mass Index (BMI) ≥ 30 kg/m2
• Good health, defined as no significantly relevant medical history or findings on physical examination, vital signs, ECG, and laboratory results in the opinion of the investigator
• Intolerance or insufficient pain relief with standard of care (e.g. physiotherapy, paracetamol, local or systemic NSAID, short term opioid use, injec-tions of hyaluronic acid, or corticosteroids) for symptomatic OA in the index knee in the opinion of the investigator.
• WOMAC pain subscale score in target knee at screening AND baseline ≥20 (0-50 scale)