Trial Outcomes & Findings for Efficacy and Safety of Repeated Intraarticular Injections of Hyaluronic Acid in Patients With OA of the Knee (NCT NCT00669032)

NCT ID: NCT00669032

Last Updated: 2023-08-28

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 446 participants
• Primary outcome timeframe: 40 months
• Results posted on: 2023-08-28

Participant Flow

Recruiting started in October 2003 and the last follow-up was performed on July 2009. This study enrolled patients from the Rheumatology Departments belonging to 19 centres located in Spain.

A total of 446 patients were screened, of whom 140 (31,4%) were screening failures. At the screening visit the patients were assessed by the blinded physician for fulfilment of the selection criteria, demographic characteristics and medical history. Knee radiographs were also obtained.

Participant milestones

Measure	Hyaluronic Acid (Adant) Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Overall Study STARTED	153	153
Overall Study COMPLETED	109	94
Overall Study NOT COMPLETED	44	59

Reasons for withdrawal

Measure	Hyaluronic Acid (Adant) Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Overall Study Lost to Follow-up	6	5
Overall Study Lack of Efficacy	8	19
Overall Study Withdrawal by Subject	12	13
Overall Study Adverse Event	12	16
Overall Study Physician Decision	1	1
Overall Study No fulfilment of the selection criteria	5	5

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Hyaluronic Acid (Adant) n=153 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=153 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Total n=306 Participants Total of all reporting groups
Age, Continuous	63 years STANDARD_DEVIATION 8.2 • n=5 Participants	63.9 years STANDARD_DEVIATION 8.9 • n=7 Participants	63.4 years STANDARD_DEVIATION 8.6 • n=5 Participants
Sex: Female, Male Female	128 Participants n=5 Participants	128 Participants n=7 Participants	256 Participants n=5 Participants
Sex: Female, Male Male	25 Participants n=5 Participants	25 Participants n=7 Participants	50 Participants n=5 Participants
Body Mass Index (BMI)	28.4 kg/m^2 STANDARD_DEVIATION 2.7 • n=5 Participants	28.7 kg/m^2 STANDARD_DEVIATION 2.6 • n=7 Participants	28.6 kg/m^2 STANDARD_DEVIATION 2.7 • n=5 Participants
Duration knee osteoarthritis	6.9 years STANDARD_DEVIATION 6.8 • n=5 Participants	8.1 years STANDARD_DEVIATION 8.4 • n=7 Participants	7.5 years STANDARD_DEVIATION 7.6 • n=5 Participants

PRIMARY outcome

Timeframe: 40 months

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Responders OARSI 2004 at the End of Follow-up	80.5 percentage of responders	65.8 percentage of responders

SECONDARY outcome

Timeframe: 7 months (6 months after first cycle)

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Responders OARSI 2004 at 7 Months Follow-up Visit	71.1 percentage of responders	67.8 percentage of responders

SECONDARY outcome

Timeframe: 14 months (6 months after second cycle)

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Responders OARSI 2004 at 14 Months Follow-up Visit	76.5 percentage of responders	65.1 percentage of responders

SECONDARY outcome

Timeframe: 21 months (6 months after third cycle)

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Responders OARSI 2004 at 21 Months Follow-up Visit	77.9 percentage of responders	67.8 percentage of responders

SECONDARY outcome

Timeframe: 27 months (12 months after third cycle)

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Responders OARSI 2004 at 27 Months Follow-up Visit	77.9 percentage of responders	67.8 percentage of responders

SECONDARY outcome

Timeframe: 34 months (6 months after fourth cycle)

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Responders OARSI 2004 at 34 Months Follow-up Visit	81.2 percentage of responders	65.1 percentage of responders

SECONDARY outcome

Timeframe: 40 months

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Pain or Function Scores Reduction 50% (20mm) at the End of Follow-up	65.1 percentage of patients	52.0 percentage of patients

SECONDARY outcome

Timeframe: 40 months

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Overall Pain Reduction 20% (10mm) at the End of Follow-up	79.2 percentage of patients	67.8 percentage of patients

SECONDARY outcome

Timeframe: 40 months

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Function Improvement 20% (10mm) at the End of Follow-up	70.5 percentage of patients	57.9 percentage of patients

SECONDARY outcome

Timeframe: 40 months

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

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.

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Patient's Global Assessment Increase 20% (10mm) at the End of Follow-up	74.5 percentage of patients	57.9 percentage of patients

SECONDARY outcome

Timeframe: Throughout the study, an average of 40 months

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

Consumption of rescue medication (paracetamol/NSAID) for osteoarthritis throughout the study, an average of 40 months

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Percentage of Patients Who Consumed Rescue Medication for Osteoarthritis	71.1 percentage of patients	71.7 percentage of patients

SECONDARY outcome

Timeframe: Throughout the study, an average of 40 months

Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

Mean daily dose of paracetamol consumption throughout the study, an average of 40 months

Outcome measures

Measure	Hyaluronic Acid (Adant) n=149 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=152 Participants Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Mean Daily Dose of Paracetamol Consumption	408.8 mg/day Standard Deviation 644.2	451.4 mg/day Standard Deviation 925.8

Adverse Events

Hyaluronic Acid (Adant)

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Hyaluronic Acid (Adant) n=153 participants at risk Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.	Placebo n=153 participants at risk Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles.
Immune system disorders Allergic reaction	2.0% 3/153 • Number of events 3 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).	2.0% 3/153 • Number of events 3 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).
General disorders Pain at injection site	3.9% 6/153 • Number of events 6 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).	1.3% 2/153 • Number of events 2 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).
General disorders Bleeding at injection site	1.3% 2/153 • Number of events 2 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).	3.9% 6/153 • Number of events 6 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).
Musculoskeletal and connective tissue disorders Arthralgia	1.3% 2/153 • Number of events 2 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).	1.3% 2/153 • Number of events 2 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/153 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).	0.65% 1/153 • Number of events 1 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).
Musculoskeletal and connective tissue disorders Heaviness feeling	0.65% 1/153 • Number of events 1 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).	0.00% 0/153 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).
Vascular disorders Bleeding	0.65% 1/153 • Number of events 1 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).	0.00% 0/153 • 40 months Treatment safety and tolerability was evaluated based on the incidence and type of adverse events and the results of blood laboratory tests and physical examinations throughout the duration of the study. Safety analyses were performed in those patients who received at least one intra-articular injection (safety population).

Additional Information

R&D Director

Tedec-Meiji Farma, S.A.

Phone: 918870980

Email: m.gimeno@tedecmeiji.com

Results disclosure agreements

• Principal investigator is a sponsor employee The only disclosure restriction on the PIs is that the study results will be presented during scientific meetings or published in scientific journals with prior agreement with the sponsor.
• Publication restrictions are in place

Restriction type: OTHER