A Locally Injected Bradykinin Antagonist for TReatment of OSteoarthritiS

Study Overview
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Brief Summary
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The purpose of this study is to determine whether intra-articular (knee joint) administration of MEN16132 is effective reducing the pain from knee osteoarthritis.

Detailed Description
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MEN16132 is a non-peptide bradykinin B2-receptor antagonist showing analgesic and anti-inflammatory activity in nonclinical osteoarthritis models. This study is being conducted as a dose finding study to determine the safety and efficacy of MEN16132, given as three doses/four treatment regimens in comparison to placebo, as well the time to onset and duration of effect.

Official Title
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Intra-articular Treatment With MEN16132 in Patients With Symptomatic Primary Osteoarthritis of the Knee: A Randomized, Multi-centre, Double Blind, Placebo Controlled, Five Parallel Group, Dose Finding Study

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Drug: MEN16132 - 0.125 mg
* Drug: MEN16132 - 0.25 mg
* Drug: MEN16132 - 0.5 mg
* Drug: MEN16132 - 0.5 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Male or female patients ≥40 years old. Symptomatic primary knee osteoarthritis (ACR criteria) since ≥6 months prior to screening, Kellgren Lawrence Grade 2 or 3, and representing an indication for intra-articular drug injection. >50 mm VAS pain score assigned to the index knee at WOMAC VA 3.1-A1 (pain while walking on a flat surface). >125 mm VAS pain score assigned to the index knee at WOMAC VA 3.1 A subscore (total pain). Pain in the index knee on at least 50% of the days in the month preceding the screening. Main Exclusion Criteria: Patients with Kellgren & Lawrence Grade I or IV (doubtful or severe) osteoarthritis of the knee. Knee condition representing an indication for surgery Patients with Inflammatory or crystal arthropathies, acute fractures, severe loss of bone density, bone necrosis. Patients with isolated patella-femoral syndrome or chondromalacia. Patients with OA predominant in the lateral compartment or any significant valgus deformity. Patients with any other disease or condition interfering with the free use and evaluation of the index knee for the 3 month duration of the trial (e.g. cancer, congenital defects, spine osteoarthritis). Major injury or surgery to the index knee within the previous 12 months prior to screening. Severe hip osteoarthritis ipsilateral to index knee. Any pain >30 mm VAS that could interfere with the assessment of index knee pain (e.g. pain in any other part of the lower extremities, pain radiating to the knee). Any pharmacological or non-pharmacological treatment started or changed during 4 weeks prior to randomisation or likely to be changed during the duration of the study Use of systemic or topical corticosteroids >10 mg prednisolone equivalent per day during 30 days prior to randomisation. Use of any pain or OA medication (e.g. NSAIDs, COX-2 inhibitors, analgesics) during 1 or 2 weeks prior to randomisation. Any intra-articular or local periarticular punction, injection or surgery to the index knee during the 6 months prior to screening.

Ages Eligible for Study
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Minimum Age: 40 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double dose MEN16132 0.125 mg<br>Intra-articular administration of two 0.125 mg doses of MEN16132 at 2-week interval. | Drug: MEN16132 - 0.125 mg<br>* Intra-articular administration of two low doses of MEN16132 at 2-week interval.<br>* Other names: fasitibant 0.125 mg;|
| Experimental: Double dose MEN16132 0.25 mg<br>Intra-articular administration of two 0.25 mg doses of MEN16132 at 2-week interval. | Drug: MEN16132 - 0.25 mg<br>* Intra-articular injection of two intermediate doses of MEN16132 at 2-week interval<br>* Other names: fasitibant 0.25 mg;|
| Experimental: Double dose MEN16132 0.5 mg<br>Intra-articular administration of two 0.5 mg doses of MEN16132 at 2-week interval. | Drug: MEN16132 - 0.5 mg<br>* Intra-articular injection of two high doses of MEN16132 at 2-week interval<br>* Other names: fasitibant 0.5 mg;|
| Experimental: Single dose MEN16132 0.5 mg<br>Intra-articular administration of one 0.5 mg dose of MEN16132 followed by one intra-articular injection of placebo at 2-week interval. | Drug: MEN16132 - 0.5 mg<br>* Single intra-articular injection of one high dose of MEN16132, followed by one dose of placebo at 2-week interval<br>* Other names: fasitibant 0.5 mg;|
| Placebo Comparator: Placebo<br>Intra-articular administration of two doses of Placebo at 2-week interval. | Drug: Placebo<br>* Intra-articular injection of 2 doses of Placebo control at 2-week interval<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WOMAC VA 3.1 A Score (Total Pain) | Western Ontario and McMaster Universities osteoarthritis index (WOMAC). The WOMAC VA 3.1 A score (total pain , range 0-500 mm) is the sum of VAS scores (0-100 mm) attributed by the patient to each of the 5 questions referring to osteoarthritic pain experienced during the preceding 48 hours. The higher is the WOMAC VA 3.1 A score, the higher is the intensity of pain symptoms (0 = no pain ; 500 = extreme pain). A decrease of the WOMAC VA 3.1 A score following treatment administration indicates a reduction of pain symptom. The change from baseline was assessed along 3 weeks after first drug administrations. | over the 3 weeks after the first administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WOMAC VA 3.1.B Score (Knee Stiffness) | WOMAC VA 3.1.B score(range 0-200) is the sum of VAS scores (0-100 mm)attributed by the patient to each of the 2 questions referring to joint stiffness experienced during the preceding 48 hours. The higher is the WOMAC VA 3.1 B score, the higher is joint stiffness (0 = no stiffness ; 200 = extreme stiffness). A decrease of the WOMAC VA 3.1 B score following treatment administration indicates a reduction of joint stiffness. The change at Week 13 from baseline is reported. | up to 3 months after first dose | 
| WOMAC VA 3.1. C Score (Function) | Knee function evaluated by WOMAC VA 3.1 C score (range 0-1700) is the sum of VAS scores (range 0-100 mm) attributed by the patient to each of 17 questions referring to difficulty in performing daily activities experienced during the preceding 48 hours. The higher is the WOMAC VA 3.1 C score, the higher is functional impairment in daily activities (0 = no difficulty ; 1700 = extreme difficulty). A decrease of the WOMAC VA 3.1 C score following treatment administration indicates an improvement in performing daily activities. WOMAC VA 3.1.C scores at baseline and at Week 13 are reported. | up to 3 months after first dose | 
| Percentage of Treatment Responders According to OMERACT-OARSI Responder Criteria | Osteoarthritis Research Society International (OARSI). Response defined as: a decrease in WOMAC pain or physical-function score by 50% or more and by 20 or more points on the visual analogue scale OR if two of the following three findings are recorded: a decrease in the WOMAC pain score by 20% or more and by 10 or more points on the visual analogue scale; a decrease in the WOMAC physical-function score by 20% or more and by 10 or more points on the scale; an improvement in the score on the patient's global assessment by 20% or more and by 10 or more points on the scale. | up to 3 months after first dose | 
| Patient Global Assessment | Patient global assessment evaluated using a VAS scale score attributed by the patient (range 0-100 mm). Efficacy assessed as change at each time-point post-dosing (week 1, 2 ,3, 13) versus baseline (week 0). A decrease of patient global assessment score indicates an improvement of osteoarthritis symptoms. | up to 3 months after first dose | 
| WOMAC VA 3.1A - Total Pain Score by Body Mass Index [BMI <= 25] | Analysis in normal-weight population (BMI <= 25) of the WOMAC VA 3.1A score (range 0-500 mm) is reported. A decrease of the WOMAC VA 3.1 A score following treatment administration indicates a reduction of pain symptom. | over the 3 weeks after the first administration | 
| WOMAC VA 3.1A - Total Pain Score by Body Mass Index -[BMI > 25] | Analysis in over-weight population (BMI > 25) of the WOMAC VA 3.1A score (range 0-500 mm) is reported. A decrease of the WOMAC VA 3.1 A score following treatment administration indicates a reduction of pain symptom. | over the 3 weeks after the first administration | 
| Adverse Event Reports | Incidence of spontaneously reported adverse events | up to 4 months after screening | 
| Clinically Significant Abnormal Laboratory Tests | Percentage of patients with Abnormal Laboratory Tests judged Clinically Significant by Investigators. The following hematochemical and urinary parameters were analysed: Red Blood Cells Count, Haematocrit, Haemoglobin, Platelets, MCV, MCH, MCHC, White Blood Cells, Sodium, Chloride, Potassium, Total calcium, AST (SGOT), ALT (SGPT), GGT, Alkaline phosphatase, Total Bilirubin, Direct Bilirubin, Creatinine, BUN, CPK, LDH, Glucose, Total proteins, Albumin. | up to 4 months from screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Injections, Intra-Articular