Evaluation of the Structural Modification Effect of Diacerein (Artrodar®) in Knee Osteoarthritic Patients

Study Overview
=================
Brief Summary
-----------------
This study evaluates the structure-modifying effect of Diacerein (Artrodar ®) in knee osteoarthritic (OA) patients by measuring total cartilage volume from magnetic resonance imaging (MRI) of the knee. Half of participants will receive Diacerein (Artrodar ®), while the other half will receive a placebo.

Detailed Description
-----------------
Diacerein (Artrodar ®) participants take 1x1 with evening meal for 1 month (D1-D28) then 1x2 with morning and evening meal for 23 months (D29-end of study). Placebo participants take 1x1 with evening meal for 1 month (D1-D28) then 1x2 with morning and evening meal for 23 months (D29-end of study).

Official Title
-----------------
Evaluation of the Structural Modification Effect of Diacerein (Artrodar®) in Knee Osteoarthritic Patients

Conditions
-----------------
Knee Osteoarthritis

Intervention / Treatment
-----------------
* Drug: Artrodar
* Drug: Placebos


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients aged between 40 and 65 years who diagnosed with primary OA knee (medial tibiofemoral compartment) according to ACR criteria Grade II-III OA severity that classified by the Kellgren-Lawrence classification Varus malalignment ≤ 15° Body mass index (BMI) ≤ 30 kg/m2 Pain on walking at 15 metres ≥ 30 mm using 100 mm visual analogue pain score (VAPS) Evidence of adequate contraceptive methods in women of childbearing age Exclusion Criteria: Accompanying osteoarthritis of the hip of sufficient severity to interfere with the functional assessment of the knee Intra-articular treatment with any product (corticosteroids in the last 3 months, glycosaminoglycans, hyaluronic acid in the last 6 months, etc.), joint lavage or arthroscopic procedures within 6 months before the start of the study Oral corticosteroids, oral symptomatic slow acting drug for OA (SYSADOA) treatment (chondroitin sulfate, glucosamine sulfate, piascledin, diacerein) within last 3 months Current treatment with anti-depressants, tranquilisers, antacids or antibiotics Poor general health or other conditions which would make regular hospital attendance difficult Primary inflammatory painful conditions of the knee (e.g. rheumatoid arthritis, psoriatic arthropathy, pseudo-gout) Painful knee conditions other than osteoarthritis (e.g. Sudeck's atrophy, intra-articular neoplasm, villonodular synovitis) Evolving arthritis requiring surgery within the coming year; Persistent diarrhoea (> 3 stools /24 h) or laxative use (any laxative use is to be stopped before inclusion in the trial) Severe gastrointestinal disorders, indications or history of severe gastrointestinal disorders (e.g. gastric or duodenal ulcers, ulcerative colitis, Crohn's syndrome, diverticulitis, recurrent pancreatitis) Renal insufficiency (estimate glomerular filtration rate ≤ 60 ml/min/1.73 m2) Hepatic disease (transaminases > 2.5 x upper limit of normal values (ULN) or total bilirubin > 2 x ULN) or history of alcoholism and liver disease Severe parenchymal organ disease History of heart attack or stroke, or have had serious diseases of the heart such as congestive heart failure, or taking clopidogrel. Patient with diabetes mellitus (DM) who has heamoglobin A1c level > 8% Patient with hypertension who has systolic blood pressure > 150 mmHg or diastolic Blood pressure > 95 mmHg Pregnancy or lactation Participation in a drug clinical trial within the 3 months before the start of the study; Ascertained hypersensitivity to the active ingredient diacerein, to similar compounds, to the excipients or to paracetamol, naproxen, and omeprazole Contraindications for magnetic resonance imaging (MRI) assessment such as heart pacemaker, aneurysm clip or claustrophobia Knee size measured at lower thigh > 50 cm

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: diacerein (Artrodar)<br> | Drug: Artrodar<br>* Diacerein (Artrodar): D1-D28 (1 month): Artrodar (50 mg) 1 x 1 with evening meal D29-end of study (23 months): Artrodar (50 mg) 1 x 2 with meal<br>|
| Placebo Comparator: placebo<br> | Drug: Placebos<br>* Placebo: D1-D28 (1 month): Placebo 1 x 1 with evening meal D29-end of study (23 months) Placebo 1 x 2 with meal<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cartilage volume measured by MRI of the affected knee. | Cartilage volume in cc | Change from Day 0 cartilage volume at Day 336, Day 672 | 
| Bone marrow lesions measured by MRI of the affected knee. | Bone marrow lesions in mm3 | Change from Day 0 Bone marrow lesions at Day 336, Day 672 | 
| Synovitis measured by MRI of the affected knee. | Synovial tissue volume in mm3 | Change from Day 0 Synovial tissue volume at Day 336, Day 672 | 
| Joint space width at narrowest point at medial compartment measured by X-ray (Full extension, weight-bearing position) | Joint space width in mm | Change from Day -7 to -30 Joint space width at Day 168, Day 336, Day 504, Day 672 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain at rest | Visual analogue scale (VAS) 0-100 mm. 0 is no pain, 100 is extreme pain. | Day 0, Day 28, Day 84, Day 168, Day 252, Day 336, Day 420, Day 504, Day 588, Day 672 | 
| Pain on walking at 15 meters | Visual analogue scale (VAS) 0-100 mm. 0 is no pain, 100 is extreme pain. | Day -7 to -30, Day 0, Day 28, Day 84, Day 168, Day 252, Day 336, Day 420, Day 504, Day 588, Day 672 | 
| KOOs | Knee and Osteoarthritis Outcome Score from 1-5 Likert scale score with higher scores denoting worse pain and disability. | Day 0, Day 28, Day 84, Day 168, Day 252, Day 336, Day 420, Day 504, Day 588, Day 672 | 
| EQ5D5L | EQ5D5L is a standardized instrument for measuring generic health status | Day 0, Day 28, Day 84, Day 168, Day 252, Day 336, Day 420, Day 504, Day 588, Day 672 | 
| Time up-and-go test |  | Day 0, Day 28, Day 84, Day 168, Day 252, Day 336, Day 420, Day 504, Day 588, Day 672 | 
| Physician and Patient's global assessment | Visual analogue scale (VAS) 0-100 mm to assess efficacy and tolerability by physician and patient. 0 is not effective/ no tolerate, 100 is very effective/ very good. | Day 168, Day 336, Day 672 | 
| Rescued medicine consumption |  | Day 28, Day 84, Day 168, Day 252, Day 336, Day 420, Day 504, Day 588, Day 672 | 
| Oxford Knee Questionnaire | 1-5 Likert scale score with higher scores denoting worse pain and disability. | Day 0, Day 28, Day 84, Day 168, Day 252, Day 336, Day 420, Day 504, Day 588, Day 672 |