Safety, Tolerability and Pharmacokinetics of Intra-articular (IA) Single Ascending Dose of 4P-004 in Patient With Kellgren and Lawrence Grade 2 to 4 Osteoarthritic (OA) Knee

Study Overview
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Brief Summary
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This phase I study is a multicenter, randomized, double-blind, placebo-controlled study to assess the safety and tolerability of single ascending dose of IA 4P-004 at 0.3, 1.0, 3.0 and 6.0 mg in participants, Between 18 and 80 years of age, with target knee OA stage KL 2-4 A total of 32 participants will be enrolled in 4 cohorts, in each cohort participants will receive either 4P-004 or placebo (6:2). 4P-004 dose will increase with cohort 1 to 4.

Official Title
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A Phase I Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of 4P-004 Versus Placebo Injected in the Target Knee Joint of Patients With Grade 2 to 4 Osteoarthritis on the Kellgren and Lawrence Severity Index (KL 2-4)

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Drug: 4P-004
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who have the capacity to give informed consent and who are willing to comply with all study related procedures and assessments (consent via legally authorized representative will not be accepted), Ambulatory participants, agreeing a 24-hour hospitalization, Participants between 18 and 80 years of age, Female participant of childbearing potential (WOCBP), must use contraceptive consistent with local regulations regarding the methods of contraception for those participating in clinical studies (see section 11.4) for at least 5 days following IMP injection, and must have a negative urine pregnancy test done within 24h before randomization, Male participants (whose partners are of childbearing potential) must consent to use methods of contraception consistent with local regulations regarding the methods of contraception for those participating in clinical studies (see section 11.4), for at least 90 days following IMP injection, Participants with knee osteoarthritis, KL 2-4 of their target knee (defined at screening as the knee with greater pain based on the participant's evaluation and the investigator's clinical judgment), X-rays of the target knee within 6 months (if not, to be performed before randomization), ECG within normal range, WBC (white blood cell count) > 3.5/µL, Hemoglobin > 12 g/dL, Platelets > 100,000/ µL, Creatinine clearance (CrCl) > 60 mL/min, Glycemia within normal range, AST, ALT < 1.5 upper limit of normal (ULN), Amylasemia < 1ULN, Negative tests for COVID-19 (if required by the standard practice on site), HIV, HbsAg and hepatitis C Ab (Determination of HIV and hepatitis status can be based on participant-reported medical history, available medical records, and the most recently available laboratory results for the participant). Exclusion Criteria: Breastfeeding women, Treatment with systemic glucocorticoids greater than 10 mg prednisone or the equivalent per day within 4 weeks prior to screening, Any treatment with glucosamine or chondroitin sulfate in the previous 3 months, Any glucagon-like peptide 1 analogue hormones, Anticoagulant treatment (current or within the last 10 days), Treatment of the target knee with any IA injection (steroids, hyaluronic acid derivatives, PRP ….) within 3 months, Knee surgery (of the target knee) performed within the previous 12 months or planned within the next 6 months, Any partial knee replacement of the target knee, Any known active infections or increased predisposition for the development of infections Clinical signs and symptoms of active joint crystal disease, Diabetes type I or II, Congestive Heart Failure stage III or IV of NYHA classification, Inflammatory bowel disease, Any other chronic condition that has not been well controlled for a minimum of 3 months, History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer) within the last 5 years, Any condition, including laboratory findings, that in the opinion of the investigator constitutes a risk or contraindication for participation in the study or that could interfere with the study objectives, conduct or evaluation, (for example, any abnormal reaction to previous IA injection), Hypersensitivity to the active substance liraglutide or to any of the excipients: Disodium phosphate dihydrate, Propylene glycol, Phenol, Participation in an interventional clinical research trial within 12 weeks prior.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A total of 32 participants will be enrolled in 4 cohorts, in each cohort participants will receive either 4P-004 or placebo (6:2). 4P-004 dose will increase with cohort 1 to 4.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4P-004 at 0.3 mg or placebo<br>4P-004 at 0.3 mg or placebo is administered once intraarticularly in the target knee joint | Drug: 4P-004<br>* single intraarticular administration in the knee joint<br>Drug: Placebo<br>* single intraarticular administration in the knee joint<br>|
| Experimental: 4P-004 at 1 mg or placebo<br>4P-004 at 1 mg or placebo is administered once intraarticularly in the target knee joint | Drug: 4P-004<br>* single intraarticular administration in the knee joint<br>Drug: Placebo<br>* single intraarticular administration in the knee joint<br>|
| Experimental: 4P-004 at 3mg or placebo<br>4P-004 at 3 mg or placebo is administered once intraarticularly in the target knee joint | Drug: 4P-004<br>* single intraarticular administration in the knee joint<br>Drug: Placebo<br>* single intraarticular administration in the knee joint<br>|
| Experimental: 4P-004 at 6 mg or placebo<br>4P-004 at 6 mg or placebo is administered once intraarticularly in the target knee joint | Drug: 4P-004<br>* single intraarticular administration in the knee joint<br>Drug: Placebo<br>* single intraarticular administration in the knee joint<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety and tolerability of single IA administration of 4P-004 at escalating doses in participants with knee OA. | Number of participants with Adverse Events, serious AEs (SAEs), with abnormal Vital signs, abnormal ECG reading and abnormal Laboratory test results | Day 1-Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the plasma concentration of liraglutide when administered as single IA doses at escalating dose levels in participants with knee OA | Plasma concentration of liraglutide following a single IA injection at pre-injection (Time 0-15minutes) and 2h, 4h, 8h, 12h, 16h and 24-hours post injection. | Day 1 to Day 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OA, Knee OA, Liraglutide