<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04426721</url>
  </required_header>
  <id_info>
    <org_study_id>OZKOA1</org_study_id>
    <nct_id>NCT04426721</nct_id>
  </id_info>
  <brief_title>Intra-articular Oxygen-ozone Therapy for the Treatment of Knee Osteoarthritis Compared With Hyaluronic Acid</brief_title>
  <official_title>Intra-articular Oxygen-ozone Therapy for the Treatment of Knee Osteoarthritis: a Randomized, Double-blind, Clinical Trial Compared With Hyaluronic Acid</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Humanitas Clinical and Research Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Humanitas Clinical and Research Center</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Knee osteoarthritis is a very common pathology, characterized by pain, stiffness and&#xD;
      functional deficit. The various therapeutic options used include anti-inflammatory drug&#xD;
      treatment, physiokinesitherapy, minimally invasive procedures and, finally, in non-responsive&#xD;
      cases, surgical treatment. To date, several studies have been conducted on the&#xD;
      intra-articular use of oxygen-ozone in knee osteoarthritis and its potential therapeutic&#xD;
      benefits. However, the methodological quality of the RCTs available in the literature is not&#xD;
      satisfactory, so it is necessary to define a standardized protocol for therapy and&#xD;
      procedures. The aim of this study will be to develop a rigorous protocol to evaluate the&#xD;
      effectiveness of intra-articular oxygen-ozone therapy (OOT) in knee osteoarthritis and&#xD;
      compare it with injection therapy with hyaluronic acid (HA), currently widely used in the&#xD;
      treatment of knee osteoarthritis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Osteoarthritis is a degenerative condition that causes pain, impaired function and affects&#xD;
      daily activities. In knee osteoarthritis, there is destruction of cartilage and subchondral&#xD;
      bone, with the consequent narrowing of articular space. Besides the biomechanical factors,&#xD;
      trauma and obesity; it is believed that inflammation plays an important role. Treatment&#xD;
      options for painful knee osteoarthritis are often unsatisfactory, as represented by 40% of&#xD;
      patients reporting persisting postoperative pain following total knee arthroplasty . There&#xD;
      are no currently approved knee osteoarthritis treatments capable of slowing OA-related&#xD;
      structural progression, so the main goals of the conservative treatment are to provide&#xD;
      symptomatic relief, improve joint function, and delay surgical intervention. One of the main&#xD;
      actions of intra-articular treatments, ranging from corticosteroids to hyaluronic acid (HA)&#xD;
      and biologic products is to reduce inflammatory distress within the joint. In recent years,&#xD;
      there has been a growing interest in the effects of ozone, which can be safely delivered&#xD;
      intra-articularly and whose use is in constant increase in an outpatient setting due to the&#xD;
      ease of preparation methods. From the literature, it is widely accepted that ozone has the&#xD;
      biological properties of inducing analgesia, anti-inflammatory, and antioxidant effects&#xD;
      mediated by activating the cellular metabolism and inhibiting prostaglandin synthesis, reduce&#xD;
      edema and inflammation, and therefore reduce pain and improves function in knee&#xD;
      osteoarthritis. Intra-articular oxygen-ozone has been used in the medical domain for several&#xD;
      decades. Although some articles have reported promising results on the effectiveness of&#xD;
      oxygen-ozone in knee osteoarthritis, the evidence is however low . Currently, few RCTs have&#xD;
      compared the efficacy and safety of ozone therapy versus HA intra-articular injections in&#xD;
      patients affected by knee osteoarthritis. This study will compare the efficacy of OOT&#xD;
      injection to HA in patients with symptomatic OA in one knee, who have failed at least one&#xD;
      prior conservative OA therapy (e.g. physiotherapy, simple analgesics). This will be done&#xD;
      using a double blind, randomized controlled trial with study subjects receiving a cycle of&#xD;
      three injection of OOT or HA. The primary efficacy measure will be pain measured by the WOMAC&#xD;
      LK 3.1 scale; other measures of efficacy will include function, stiffness, and quality of&#xD;
      life. In addition to clinical efficacy measures, safety will be assessed by tracking adverse&#xD;
      events. During screening, potential subjects who provide informed consent will be assessed&#xD;
      for eligibility. Screening will consist in checking the presence of inclusion and exclusion&#xD;
      criteria, including a WOMAC LK 3.1 pain subscale score ≥ 9 and ≤ 19 and by providing&#xD;
      objective physiological evidence of OA using the Kellgren-Lawrence scale (assessed from&#xD;
      radiographs). Subjects will also provide demographic and medication use information. Baseline&#xD;
      X-ray and MRI will be collected.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Anticipated">June 2020</start_date>
  <completion_date type="Anticipated">December 2022</completion_date>
  <primary_completion_date type="Anticipated">December 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Western Ontario and McMaster Universities Osteoarthritis Index using the Likert scale, Version 3.1, Pain subscale (WOMAC LK 3.1)</measure>
    <time_frame>3 months</time_frame>
    <description>Assessment of pain. Score range 0-20. Higher scores indicate worse pain.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The Western Ontario and McMaster Universities Osteoarthritis Index using the Likert scale, Version 3.1(WOMAC LK 3.1)</measure>
    <time_frame>1,3,6,12 months</time_frame>
    <description>Assessment of pain, stiffness and function. Score range 0-20 for Pain, 0-8 for Stiffness, and 0-68 for Physical Function. Higher scores indicate worse pain, stiffness, and functional limitations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Numeric Rating Scale (NRS)</measure>
    <time_frame>1,3,6,12 months</time_frame>
    <description>Assessment of pain. Score range 0-10. Higher scores indicate worse pain.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Knee Injury and Osteoarthritis Outcome Score (KOOS)</measure>
    <time_frame>1,3,6,12 months</time_frame>
    <description>Assessment of Pain, other Symptoms, Function in daily living, Function in Sport and Recreation, and knee-related Quality of Life (QOL). Score range 0-100, with zero representing extreme knee problems and 100 representing no knee problems</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Knee Osteoarthritis</condition>
  <arm_group>
    <arm_group_label>Ozone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participant will receive an intraarticular injection of oxygen-ozone, once a week for three weeks. During procedure a clear ultrasound image is to be taken to document needle placement in the synovial space. The injector may choose the position of the knee (e.g., extended or bent) and the approach for the injection (e.g., medial or lateral).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hyaluronic acid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participant will receive an intraarticular injection of hyaluronic acid, once a week for three weeks. During procedure a clear ultrasound image is to be taken to document needle placement in the synovial space. The injector may choose the position of the knee (e.g., extended or bent) and the approach for the injection (e.g., medial or lateral).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ozone</intervention_name>
    <description>10 cc of oxygen-ozone</description>
    <arm_group_label>Ozone</arm_group_label>
    <other_name>Oxygene-Ozone therapy; O2-O3</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hyaluronic Acid</intervention_name>
    <description>Sinovial forte 32 mg\2ml</description>
    <arm_group_label>Hyaluronic acid</arm_group_label>
    <other_name>Sinovial forte</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female at least 18 years of age at time of screening.&#xD;
&#xD;
          2. Ability to comply with study procedures and visit schedules and able to follow oral&#xD;
             and written instructions.&#xD;
&#xD;
          3. Patients with symptomatic OA in one knee from 3 months&#xD;
&#xD;
          4. A standing knee radiograph showing a K-L grade of 2 to 3 and an absence of severe&#xD;
             osteoarthritis (defined as advanced stage osteoarthritis, including large osteophytes,&#xD;
             chronic fractures or bone remodeling, severe deformity or bone attrition, and/or&#xD;
             bone-on-bone contact indicative of severe osteoarthritis/full thickness cartilage&#xD;
             loss).&#xD;
&#xD;
          5. Body mass index ≤ 40 kg/m2.&#xD;
&#xD;
          6. A WOMAC LK 3.1 pain subscale total score ≥ 9 and ≤ 19.&#xD;
&#xD;
          7. Has undergone at least one prior conservative OA treatment (e.g. physical therapy,&#xD;
             simple analgesics).&#xD;
&#xD;
          8. Signed an ethics committee-reviewed an approved informed consent form.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Presence of clinically observed active infection or severe inflammation in the index&#xD;
             knee joint or skin disease/breakdown or infection in the area of the planned injection&#xD;
             site of the index knee.&#xD;
&#xD;
          2. Presence of symptomatic OA in the non-study knee at screening; if unclear then the&#xD;
             WOMAC LK 3.1 pain subscale for the non-index knee must be ≤ 5.0.&#xD;
&#xD;
          3. Diagnosed with rheumatoid arthritis, Reiter's syndrome, psoriatic arthritis, gout,&#xD;
             ankylosing spondylitis, or arthritis secondary to other inflammatory diseases; Human&#xD;
             Immunodeficiency Virus (HIV), viral hepatitis; chondrocalcinosis, Paget's disease, or&#xD;
             villonodular synovitis.&#xD;
&#xD;
          4. Diagnosed with leukemia, known presence of metastatic malignant cells, or ongoing or&#xD;
             planned chemotherapeutic treatment.&#xD;
&#xD;
          5. Disease of spine, hip or other lower extremity joints judged by the investigator to be&#xD;
             contributing to the pain in the index knee (e.g. sciatica, nerve pain, hip OA). Note:&#xD;
             Patients with contralateral knee replacement, or hip replacement in either hip, may be&#xD;
             enrolled provided there is sufficient pain relief after knee replacement or hip&#xD;
             replacement that analgesics are not required.&#xD;
&#xD;
          6. Untreated symptomatic injury of the index knee (e.g., acute traumatic injury, anterior&#xD;
             cruciate ligament injury, clinically symptomatic meniscus injury characterized by&#xD;
             mechanical issue such as locking or catching).&#xD;
&#xD;
          7. Presence of surgical hardware or other foreign body intended to treat arthritis or&#xD;
             cartilage-related pathology in the index knee. Note: this does not include small&#xD;
             hardware (e.g. screws).&#xD;
&#xD;
          8. Presence of venous or lymphatic stasis in the index leg.&#xD;
&#xD;
          9. Orally administered systemic steroid use within 2 weeks prior to screening&#xD;
&#xD;
         10. Planned/anticipated surgery of the index knee during the study period.&#xD;
&#xD;
         11. Major surgery of the index knee within 12 months prior to screening.&#xD;
&#xD;
         12. Minor surgery (e.g. arthroscopy) of the index knee within 6 months prior to screening.&#xD;
&#xD;
         13. Any documented clinically significant degree of cognitive impairment or other&#xD;
             condition, finding, or psychiatric illness at screening, which, in the opinion of the&#xD;
             investigator, could compromise patient safety or interfere with the assessment of the&#xD;
             safety and treatment effects of the study injection.&#xD;
&#xD;
         14. Pregnant or nursing mothers or women planning to become pregnant during the time they&#xD;
             will be participating in the study.&#xD;
&#xD;
         15. Know hypersensitivity (allergy) to hyaluronan (sodium hyaluronate) preparations.&#xD;
&#xD;
         16. Previously documented failed treatment with OOT or Sinovial&#xD;
&#xD;
         17. Known drug or alcohol dependence currently or within the last year.&#xD;
&#xD;
         18. Use of any investigational drug or device within 30 days prior to screening.&#xD;
&#xD;
         19. Use of any investigational biologics within 60 days prior to screening.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Cristiano Sconza, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Humanitas Clinical and Research Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Berardo Di Matteo, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Humanitas Clinical and Research Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cristiano Sconza, MD</last_name>
    <phone>3332781989</phone>
    <phone_ext>0039</phone_ext>
    <email>cristiano.sconza@humanitas.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Roberta Amenta, MD</last_name>
    <phone>3286935530</phone>
    <phone_ext>0039</phone_ext>
    <email>roberta8928@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Humanitas Clinical and Research Hospital</name>
      <address>
        <city>Rozzano</city>
        <state>Milano</state>
        <zip>20089</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cristiano Sconza, MD</last_name>
      <phone>3332781989</phone>
      <email>cristiano.sconza@humanitas.it</email>
    </contact>
    <contact_backup>
      <last_name>Roberta Amenta, MD</last_name>
      <phone>3286935530</phone>
      <email>roberta8928@gmail.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>June 13, 2020</last_update_submitted>
  <last_update_submitted_qc>June 13, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Humanitas Clinical and Research Center</investigator_affiliation>
    <investigator_full_name>Cristiano Sconza</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Oxygene-Ozone</keyword>
  <keyword>Ozone</keyword>
  <keyword>Hyaluronic acid</keyword>
  <keyword>Osteoarthritis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
    <mesh_term>Osteoarthritis, Knee</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyaluronic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04426721
org study id: OZKOA1
nct id: NCT04426721
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Knee osteoarthritis is a very common pathology, characterized by pain, stiffness and
      functional deficit. The various therapeutic options used include anti-inflammatory drug
      treatment, physiokinesitherapy, minimally invasive procedures and, finally, in non-responsive
      cases, surgical treatment. To date, several studies have been conducted on the
      intra-articular use of oxygen-ozone in knee osteoarthritis and its potential therapeutic
      benefits. However, the methodological quality of the RCTs available in the literature is not
      satisfactory, so it is necessary to define a standardized protocol for therapy and
      procedures. The aim of this study will be to develop a rigorous protocol to evaluate the
      effectiveness of intra-articular oxygen-ozone therapy (OOT) in knee osteoarthritis and
      compare it with injection therapy with hyaluronic acid (HA), currently widely used in the
      treatment of knee osteoarthritis.
Osteoarthritis is a degenerative condition that causes pain, impaired function and affects
      daily activities. In knee osteoarthritis, there is destruction of cartilage and subchondral
      bone, with the consequent narrowing of articular space. Besides the biomechanical factors,
      trauma and obesity; it is believed that inflammation plays an important role. Treatment
      options for painful knee osteoarthritis are often unsatisfactory, as represented by 40% of
      patients reporting persisting postoperative pain following total knee arthroplasty . There
      are no currently approved knee osteoarthritis treatments capable of slowing OA-related
      structural progression, so the main goals of the conservative treatment are to provide
      symptomatic relief, improve joint function, and delay surgical intervention. One of the main
      actions of intra-articular treatments, ranging from corticosteroids to hyaluronic acid (HA)
      and biologic products is to reduce inflammatory distress within the joint. In recent years,
      there has been a growing interest in the effects of ozone, which can be safely delivered
      intra-articularly and whose use is in constant increase in an outpatient setting due to the
      ease of preparation methods. From the literature, it is widely accepted that ozone has the
      biological properties of inducing analgesia, anti-inflammatory, and antioxidant effects
      mediated by activating the cellular metabolism and inhibiting prostaglandin synthesis, reduce
      edema and inflammation, and therefore reduce pain and improves function in knee
      osteoarthritis. Intra-articular oxygen-ozone has been used in the medical domain for several
      decades. Although some articles have reported promising results on the effectiveness of
      oxygen-ozone in knee osteoarthritis, the evidence is however low . Currently, few RCTs have
      compared the efficacy and safety of ozone therapy versus HA intra-articular injections in
      patients affected by knee osteoarthritis. This study will compare the efficacy of OOT
      injection to HA in patients with symptomatic OA in one knee, who have failed at least one
      prior conservative OA therapy (e.g. physiotherapy, simple analgesics). This will be done
      using a double blind, randomized controlled trial with study subjects receiving a cycle of
      three injection of OOT or HA. The primary efficacy measure will be pain measured by the WOMAC
      LK 3.1 scale; other measures of efficacy will include function, stiffness, and quality of
      life. In addition to clinical efficacy measures, safety will be assessed by tracking adverse
      events. During screening, potential subjects who provide informed consent will be assessed
      for eligibility. Screening will consist in checking the presence of inclusion and exclusion
      criteria, including a WOMAC LK 3.1 pain subscale score ≥ 9 and ≤ 19 and by providing
      objective physiological evidence of OA using the Kellgren-Lawrence scale (assessed from
      radiographs). Subjects will also provide demographic and medication use information. Baseline
      X-ray and MRI will be collected.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Western Ontario and McMaster Universities Osteoarthritis Index using the Likert scale, Version 3.1, Pain subscale (WOMAC LK 3.1)
time frame: 3 months
description: Assessment of pain. Score range 0-20. Higher scores indicate worse pain.
measure: The Western Ontario and McMaster Universities Osteoarthritis Index using the Likert scale, Version 3.1(WOMAC LK 3.1)
time frame: 1,3,6,12 months
description: Assessment of pain, stiffness and function. Score range 0-20 for Pain, 0-8 for Stiffness, and 0-68 for Physical Function. Higher scores indicate worse pain, stiffness, and functional limitations.
measure: Numeric Rating Scale (NRS)
time frame: 1,3,6,12 months
description: Assessment of pain. Score range 0-10. Higher scores indicate worse pain.
measure: Knee Injury and Osteoarthritis Outcome Score (KOOS)
time frame: 1,3,6,12 months
description: Assessment of Pain, other Symptoms, Function in daily living, Function in Sport and Recreation, and knee-related Quality of Life (QOL). Score range 0-100, with zero representing extreme knee problems and 100 representing no knee problems
arm group label: Ozone
arm group type: Experimental
description: Participant will receive an intraarticular injection of oxygen-ozone, once a week for three weeks. During procedure a clear ultrasound image is to be taken to document needle placement in the synovial space. The injector may choose the position of the knee (e.g., extended or bent) and the approach for the injection (e.g., medial or lateral).
arm group label: Hyaluronic acid
arm group type: Active Comparator
description: Participant will receive an intraarticular injection of hyaluronic acid, once a week for three weeks. During procedure a clear ultrasound image is to be taken to document needle placement in the synovial space. The injector may choose the position of the knee (e.g., extended or bent) and the approach for the injection (e.g., medial or lateral).
intervention type: Drug
intervention name: Ozone
description: 10 cc of oxygen-ozone
arm group label: Ozone
other name: Oxygene-Ozone therapy; O2-O3
intervention type: Drug
intervention name: Hyaluronic Acid
description: Sinovial forte 32 mg\2ml
arm group label: Hyaluronic acid
other name: Sinovial forte
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Cristiano Sconza, MD
role: Principal Investigator
affiliation: Humanitas Clinical and Research Hospital
last name: Berardo Di Matteo, MD, PhD
role: Study Chair
affiliation: Humanitas Clinical and Research Hospital
last name: Cristiano Sconza, MD
phone: 3332781989
phone ext: 0039
email: cristiano.sconza@humanitas.it
last name: Roberta Amenta, MD
phone: 3286935530
phone ext: 0039
email: roberta8928@gmail.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: Humanitas Clinical and Research Center
investigator full name: Cristiano Sconza
investigator title: Principal Investigator
mesh term: Osteoarthritis
mesh term: Osteoarthritis, Knee
mesh term: Hyaluronic Acid
sharing ipd: Undecided