Dose-Response Effect of Intra-Articular Ozone in Knee Osteoarthritis

Official title

Dose-Response Effect of Intra-Articular Ozone in Knee Osteoarthritis: A Randomized Controlled Single-Blind Clinical Study

Overview

The goal of this clinical trial is to evaluate the clinical efficacy of different doses of intra-articular ozone injections combined with exercise in patients aged 40-75 diagnosed with Grade 2-3 knee osteoarthritis. The main questions it aims to answer are: * Which intra-articular ozone doses (10 µg/mL, 15 µg/mL, or 20 µg/mL) is most effective in improving pain and physical function in knee osteoarthritis? * Do combined ozone and exercise therapies provide superior clinical outcomes compared to exercise therapy alone? Researchers will compare four groups (Ozone 10 µg/mL + Exercise, Ozone 15 µg/mL + Exercise, Ozone 20 µg/mL + Exercise and Exercise Alone) to see the dose-dependent effects of ozone therapy. Participants will: * Complete a structured home exercise program for the duration of the study. * Receive 3 sessions of intra-articular ozone injections (for patients allocated to the ozone groups). * Participate follow-up visits for clinical and functional assessments at baseline (before the procedure), immediately after the 3rd injection session, at 1 month after the last ozone injection, and at 3 months after the last ozone injection.

Detailed description

This clinical trial is designed as a prospective, randomized, controlled study to investigate the dose-dependent therapeutic effects of intra-articular ozone therapy in patients with Grade 2-3 knee osteoarthritis.

Eligible participants aged 40-75 with a confirmed diagnosis of knee osteoarthritis (Kellgren-Lawrence Grade 2 or 3) will be recruited. Participants will be allocated into one of four parallel groups by computerized randomization.

All patients allocated to the ozone intervention groups will receive a total of 3 sessions of intra-articular ozone injections, administered once a week for three consecutive weeks. For all three treatment groups, the injection volume will be at 10 mL per session, while the ozone concentrations will vary according to the assigned group as follows:

Ozone 10 µg + Exercise: 10 mL of ozone injection at a concentration of 10 µg/mL + Home exercise program.

Ozone 15 µg + Exercise: 10 mL of ozone injection at a concentration of 15 µg/mL + Home exercise program.

Ozone 20 µg + Exercise: 10 mL of ozone injection at a concentration of 20 µg/mL + Home exercise program.

Exercise Alone (Control): Home exercise program alone.

All participants across all four groups will be prescribed a structured home exercise program. This program includes joint range of motion (ROM) exercises; strengthening exercises and flexibility exercises.

The home program will be performed for 30 minutes per day, 5 days a week, throughout the 3-month study period. To improve patient adherence to exercise, patients will be provided with an exercise diary and also an analgesic diary to track analgesic use.

Clinical and functional evaluations will be performed at four distinct time points: baseline (pre-treatment), immediately after the 3rd injection session (post-treatment), 1 month after the last ozone injection, and 3 months after the last ozone injection. The clinical and functional status of the participants will be evaluated using the Numerical Rating Scale (NRS) for pain severity, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for knee-specific symptoms and physical function, the Lequesne Algofunctional Index for osteoarthritis severity and physical disability, and the EuroQol 5-Dimension (EQ-5D) questionnaire for overall health-related quality of life. Additionally, objective functional capacity, dynamic balance, and mobility will be assessed using the 6-Minute Walk Test (6MWT) and the Timed Up and Go (TUG) test.

Interventions

• Other ozone injection
  All patients allocated to the ozone intervention groups will receive a total of 3 sessions of intra-articular ozone injections, administered once a week for three consecutive weeks. For all three treatment groups, the injection volume will be 10 mL per session, while the ozone concentrations will vary according to the assigned group as Ozone 10 µg/mL + Exercise, Ozone 15 µg/mL + Exercise, and Ozone 20 µg/mL + Exercise.
• Behavioral Exercise
  All participants across all four groups will be prescribed a structured home exercise program. This program includes joint range of motion (ROM) exercises; strengthening exercises (including quadriceps strengthening, hamstring strengthening, hip abductor strengthening, and seated calf raises); and flexibility exercises (including hamstring stretching, gastrocnemius-soleus stretching, and quadriceps stretching). The home program will be performed for 30 minutes per day, 5 days a week, throughout

Primary outcome measures

• Numerical Rating Scale at Third Month after the last ozone injection [Time frame: Baseline, Week 2 (immediately after the 3rd injection session), 1 month after the last ozone injection, and 3 months after the last ozone injection.]

Secondary outcome measures (5)

• Knee-specific symptoms and physical function-WOMAC [Time frame: Baseline, Week 2 (immediately after the 3rd injection session), 1 month after the last ozone injection, and 3 months after the last ozone injection.]
• Osteoarthritis severity and physical disability- Lequesne Algofunctional Index [Time frame: Baseline, Week 2 (immediately after the 3rd injection session), 1 month after the last ozone injection, and 3 months after the last ozone injection.]
• Overall health-related quality of life- EuroQol 5-Dimension (EQ-5D) questionnaire [Time frame: Baseline, Week 2 (immediately after the 3rd injection session), 1 month after the last ozone injection, and 3 months after the last ozone injection.]
• 6-Minute Walk Test (6MWT) [Time frame: Baseline, Week 2 (immediately after the 3rd injection session), 1 month after the last ozone injection, and 3 months after the last ozone injection.]
• Timed Up and Go (TUG) Test [Time frame: Baseline, Week 2 (immediately after the 3rd injection session), 1 month after the last ozone injection, and 3 months after the last ozone injection.]

Eligibility criteria

Inclusion criteria

• Patients aged 40-75 years diagnosed with knee osteoarthritis according to the American College of Rheumatology 2019 criteria
• Grade 2 or 3 knee osteoarthritis based on the Kellgren-Lawrence radiological classification system.
• Presence of chronic knee pain lasting for more than 6 months.
• Numerical Rating Scale score of 3 or higher during knee-loading activities

Exclusion criteria

• Presence or history of acute knee infection, major knee trauma, or inflammatory arthritis
• History of knee fracture or surgical intervention involving the affected knee joint within the last 6 months.
• History of intra-articular injections (e.g., corticosteroids, hyaluronic acid, PRP) into the affected knee joint within the last 6 months.
• History of physical therapy or rehabilitation in the knee region within the last 6 months
• Presence of osteomyelitis adjacent to the knee joint, bacteremia, or hemarthrosis.
• History of malignancy involving the lower extremity.
• Known hypersensitivity or allergy to medical ozone.
• Severe anemia, thrombocytopenia, active bleeding disorders, or ongoing anticoagulant therapy.
• Pregnancy or lactation
• Active infection
• Severe systemic diseases (e.g., advanced cardiopulmonary disease, uncontrolled diabetes mellitus).
• Hyperthyroidism or progressive neuromuscular disorders.
• Cognitive impairment or inability to cooperate with the assessment tools and study protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Turkey (Türkiye) · 1 center

• Kayseri City Hospital — Kayseri

Identifiers

NCT: NCT07678996 · Kayseri-GETAT-2025-102

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗