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

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

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.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis of the Knee
• Intervention / Treatment: Device: Hyaluronic acid; Other: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 446
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: hyaluronic acid; Cycles of 5 injections of hyaluronic acid at specified intervals	Device: Hyaluronic acid; 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
Placebo Comparator: Placebo; Cycles of 5 injections of saline at specified intervals	Other: Placebo; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Tedec-Meiji Farma, S.A.
• Investigators: Principal Investigator: Federico Navarro Sarabia

Publications and helpful links

General Publications

• Navarro-Sarabia F, Coronel P, Collantes E, Navarro FJ, de la Serna AR, Naranjo A, Gimeno M, Herrero-Beaumont G; AMELIA study group. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis. 2011 Nov;70(11):1957-62. doi: 10.1136/ard.2011.152017. Epub 2011 Aug 17.

Study record dates

Study Major Dates

• Study Start: October 1, 2003
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: April 25, 2008
• First Submitted That Met QC Criteria: April 25, 2008
• First Posted (Estimated): April 29, 2008

Study Record Updates

• Last Update Posted (Actual): August 28, 2023
• Last Update Submitted That Met QC Criteria: August 2, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee; Physiological Effects of Drugs; Immunologic Factors; Protective Agents; Adjuvants, Immunologic; Viscosupplements; Hyaluronic Acid
• Other Study ID Numbers: TM-ME3710/304; 2006-001854-28 (EudraCT Number)