Efficacy and Safety of Repeated Intraarticular Injections of Hyaluronic Acid in Patients With OA of the Knee

Study Overview
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Brief Summary
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The main objective is the long-term comparison (3 years and 4 months) of the efficacy and safety of repeated intra-articular administration of hyaluronic acid in the treatment of osteoarthritis of the knee.

Detailed Description
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To evaluate the efficacy and safety of repeated injections of hyaluronic acid compared with placebo over a period of 40 months.

Official Title
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Random, Phase IV, Multicentre, Double Blind, Placebo Controlled, Parallel Study to Assess Long-term Efficacy and Safety of Repeated Intraarticular Injections of Hyaluronic Acid (ADANT®) in Patients With Knee OA of the Knee

Conditions
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Osteoarthritis of the Knee

Intervention / Treatment
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* Device: Hyaluronic acid
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient > 45 years of age Out-patient diagnosed with primary osteoarthritis of the femorotibial medial joint of the knee with clinical and radiological (Kellgren grade II-III) ACR diagnosis Joint Space Width (JSW) > 2mm Overall pain greater or equal to 55mm (VAS - Visual Analogue Scale 100mm) recorded in the knee,by the patient at any time during the week prior to the evaluation Exclusion Criteria: Overweight patients (body mass index > 32). Pregnant and lactating women. Women of child-bearinge age not using effective contraception Patients who have received intra-articular hyaluronic acid within the previous year and/or intra-articular steroids or articular lavage in the chosen knee,within the previous 3 months prior to their inclusion in the study. AINE administration within the 14 days prior to their inclusion in the study. Administration of glucosamine sulphate, chondroitin sulphate and diacerein within the 3 months prior to their inclusion in the study. Immunocompromised patients or patients receiving systemic immunosuppressive therapy. Patients with known sensitivity to HA, parcetamol or AINEs permitted as rescue medication. Patients who have received any investigational drug within 30 days prior to visit 1, or who are scheduled for the administration of an investigational drug other than the protocol product during this study. Patients with severely impaired central nervous system. Patients with coagulation alterations, despite receiving treatment. Patients with secondary osteoarthritis of the knee Patients having previously received surgery, including arthroscopy Patients with articular inflammatory disease

Ages Eligible for Study
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Minimum Age: 45 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hyaluronic acid<br>Cycles of 5 injections of hyaluronic acid at specified intervals | Device: Hyaluronic acid<br>* 3 cycles of 5 hyaluronic acid injections, with a 6 month interval between each one. A 4th treatment cycle of five injections will be carried out at the end of one year<br>|
| Placebo Comparator: Placebo<br>Cycles of 5 injections of saline at specified intervals | Other: Placebo<br>* 3 cycles of 5 saline solution injections, with a 6 month interval between each one. A 4th treatment cycle of five injections will be carried out at the end of one year<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responders OARSI 2004 at the End of Follow-up | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at the end of follow-up. Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. | 40 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responders OARSI 2004 at 7 Months Follow-up Visit | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 7 months follow-up visit (6 months after first cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. | 7 months (6 months after first cycle) | 
| Responders OARSI 2004 at 14 Months Follow-up Visit | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 14 months follow-up visit (6 months after second cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. | 14 months (6 months after second cycle) | 
| Responders OARSI 2004 at 21 Months Follow-up Visit | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 21 months follow-up visit (6 months after third cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. | 21 months (6 months after third cycle) | 
| Responders OARSI 2004 at 27 Months Follow-up Visit | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 27 months follow-up visit (12 months after third cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. | 27 months (12 months after third cycle) | 
| Responders OARSI 2004 at 34 Months Follow-up Visit | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 34 months follow-up visit (6 months after fourth cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. | 34 months (6 months after fourth cycle) | 
| Pain or Function Scores Reduction 50% (20mm) at the End of Follow-up | Percentage of patients with a decrease in pain or physical function score of at least 50% and at least 20mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a worse outcome. | 40 months | 
| Overall Pain Reduction 20% (10mm) at the End of Follow-up | Percentage of patients with a decrease in pain score of at least 20% or at least 10mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a worse outcome. | 40 months | 
| Function Improvement 20% (10mm) at the End of Follow-up | Percentage of patients with a decrease in physical function score of at least 20% or at least 10mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a worse outcome. | 40 months | 
| Patient's Global Assessment Increase 20% (10mm) at the End of Follow-up | Percentage of patients with an increase in the score of patient's global assessment by at least 20% and at least 10mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a better outcome. | 40 months | 
| Percentage of Patients Who Consumed Rescue Medication for Osteoarthritis | Consumption of rescue medication (paracetamol/NSAID) for osteoarthritis throughout the study, an average of 40 months | Throughout the study, an average of 40 months | 
| Mean Daily Dose of Paracetamol Consumption | Mean daily dose of paracetamol consumption throughout the study, an average of 40 months | Throughout the study, an average of 40 months |