<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/NCT01670578</url>
  </required_header>
  <id_info>
    <org_study_id>KNEEJECT</org_study_id>
    <nct_id>NCT01670578</nct_id>
  </id_info>
  <brief_title>Platelet-rich Plasma vs Viscosupplementation in the Treatment of Knee Articular Degenerative Pathology</brief_title>
  <acronym>PRP2009</acronym>
  <official_title>Platelet-rich Plasma (PRP) vs Viscosupplementation in the Treatment of Knee Articular Degenerative Pathology: a Randomized Double-blind Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Istituto Ortopedico Rizzoli</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Istituto Ortopedico Rizzoli</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators hypothesized that intra-articular injections of Platelet-rich Plasma (PRP)&#xD;
      to treat knee degenerative articular cartilage pathology could determine pain relief and&#xD;
      recovery of knee function with overall clinical outcome comparable or even better than&#xD;
      viscosupplementation, which is a common injective approach applied in this kind of pathology.&#xD;
      To this purpose the investigators designed a double blind randomized controlled trial&#xD;
      comparing PRP vs viscosupplementation.&#xD;
&#xD;
      A power analysis has been performed for the primary endpoint of IKDC (International Knee&#xD;
      Documentation Committee) subjective score improvement at the 12-month follow-up for PRP. From&#xD;
      a pilot study, a standard deviation of 15.2 points was found. With an alpha error of 0.05, a&#xD;
      beta error of 0.2 and a minimal clinically significant difference of 6.7 points corresponding&#xD;
      at 1/3 of the documented mean improvement, the minimum sample size was 83 for each group.&#xD;
      Considering a possible drop out of 15%, 96 patients per group are required for total 192&#xD;
      patients, selected according to well-defined inclusion criteria (see 'Eligibility criteria'&#xD;
      section). Patients are then assigned to two different treatment groups, according to a&#xD;
      randomization list. The first group of treatment consists of three weekly intra-articular&#xD;
      injections of autologous PRP obtained with the following procedure: a 150-ml autologous&#xD;
      venous blood sample undergoes 2 centrifugations (the first at 1480 rpm for 6 minutes to&#xD;
      separate erythrocytes, and a second at 3400 rpm for 15 minutes to concentrate platelets) to&#xD;
      produced 20 ml of PRP. This unit of PRP is then divided into 4 small units of 5 ml each. One&#xD;
      unit is sent to the laboratory for analysis of platelet concentration and for a quality test,&#xD;
      3 units are stored at -30° C.&#xD;
&#xD;
      The second treatment group consists of patients receiving three weekly injections of&#xD;
      hyaluronic acid (Hyalubrix 30 mg/2ml, Fidia Farmaceutici Spa, Italy;Molecular Weight: 1500&#xD;
      kDa).&#xD;
&#xD;
      To guarantee the blinding of the patients, all of them undergo blood harvesting to obtain&#xD;
      autologous PRP which will be used only in half of them, according to the aforementioned&#xD;
      randomization list. One week after the PRP production, the injective treatment starts, with 3&#xD;
      weekly injections of PRP or HA. At the moment of the injection the syringe is properly&#xD;
      covered to prevent the patient from discovering the substance he was receiving. After the&#xD;
      injection, patients are sent home with instructions to limit the use of the leg for at least&#xD;
      24 h and to use cold therapy/ice on the affected area to relieve pain. During this period,&#xD;
      the use of non-steroidal medication is forbidden.&#xD;
&#xD;
      Patients are prospectively evaluated basally and at 2, 6, and 12 months of follow-up using&#xD;
      clinical subjective scores and objective parameters to determine clinical outcome (see&#xD;
      'Outcome measure' section). Patient satisfaction and adverse events will be also reported.&#xD;
      All the clinical evaluations are performed by a medical staff not involved in the injective&#xD;
      procedure, in order to keep the study double blinded. At the end of the study, the nature of&#xD;
      the injected substance is revealed to the patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Current research is investigating new methods for stimulating repair or replacing damaged&#xD;
      cartilage. In particular, the most recent knowledge regarding tissue biology highlights a&#xD;
      complex regulation of growth factors (GFs) for the normal tissue structure and the reaction&#xD;
      to tissue damage. The influence of GFs on cartilage repair is now widely investigated in&#xD;
      vitro and in vivo. Platelet Rich Plasma (PRP) is a simple, low- cost and minimally- invasive&#xD;
      method that allows one to obtain a natural concentrate of autologous GFs from the blood, and&#xD;
      it is increasingly applied in the clinical practice to treat knee degenerative pathology,&#xD;
      such as chondropathy and early osteoarthritis (OA). The biological rational of PRP is that&#xD;
      platelets contain storage pools of GFs, cytokines, chemokines and many other&#xD;
      mediators.Although its widespread application, there are no high level studies in the&#xD;
      literature to demonstrate the real efficacy of PRP. In fact, at the present moment, to our&#xD;
      knowledge there is no published randomized controlled trial comparing PRP with other&#xD;
      conservative treatments commonly used for knee OA.&#xD;
&#xD;
      The investigators hypothesized that intra-articular injections of PRP to treat knee&#xD;
      degenerative articular cartilage pathology could determine pain relief and recovery of knee&#xD;
      function with overall clinical outcome comparable or even better than viscosupplementation,&#xD;
      which is a common injective approach applied in this kind of pathology. To this purpose the&#xD;
      investigators designed a double blind randomized controlled trial comparing PRP vs&#xD;
      viscosupplementation.&#xD;
&#xD;
      A power analysis has been performed for the primary endpoint of IKDC subjective score&#xD;
      improvement at the 12-month follow-up for PRP. From a pilot study, a standard deviation of&#xD;
      15.2 points was found. With an alpha error of 0.05, a beta error of 0.2 and a minimal&#xD;
      clinically significant difference of 6.7 points corresponding at 1/3 of the documented mean&#xD;
      improvement, the minimum sample size was 83 for each group. Considering a possible drop out&#xD;
      of 15%, 96 patients per group are required for total 192 patients. Patients are then assigned&#xD;
      to two different treatment groups, according to a randomization list. The first group of&#xD;
      treatment consists of three weekly intra-articular injections of autologous PRP obtained with&#xD;
      the following procedure: a 150-ml autologous venous blood sample undergoes 2 centrifugations&#xD;
      (the first at 1480 rpm for 6 minutes to separate erythrocytes, and a second at 3400 rpm for&#xD;
      15 minutes to concentrate platelets) to produced 20 ml of PRP. This unit of PRP is then&#xD;
      divided into 4 small units of 5 ml each. One unit is sent to the laboratory for analysis of&#xD;
      platelet concentration and for a quality test, 3 units are stored at -30° C.&#xD;
&#xD;
      The second treatment group consists of patients receiving three weekly injections of&#xD;
      hyaluronic acid (Hyalubrix 30 mg/2ml, Fidia Farmaceutici Spa, Italy;Molecular Weight: 1500&#xD;
      kDa).&#xD;
&#xD;
      To guarantee the blinding of the patients, all of them undergo blood harvesting to obtain&#xD;
      autologous PRP which will be used only in half of them, according to the aforementioned&#xD;
      randomization list. One week after the PRP production, the injective treatment starts, with 3&#xD;
      weekly injections of PRP or HA. At the moment of the injection the syringe is properly&#xD;
      covered to prevent the patient from discovering the substance he was receiving. After the&#xD;
      injection, patients are sent home with instructions to limit the use of the leg for at least&#xD;
      24 h and to use cold therapy/ice on the affected area to relieve pain. During this period,&#xD;
      the use of non-steroidal medication is forbidden.&#xD;
&#xD;
      Furthermore, at the moment of each weekly injection, before injecting the substance, an&#xD;
      attempt of harvesting synovial fluid is performed. During the same visit, also a peripheral&#xD;
      blood sample (3 ml) is taken. These samples are then sent to a dedicated Laboratory in order&#xD;
      to test the concentration of some GFs, pro and anti-inflammatory cytokines, both at local&#xD;
      (synovial fluid) and systemic level (peripheral blood). The aim is to evaluate the trend in&#xD;
      the concentration rate of these molecules over the period of the injective treatment.&#xD;
&#xD;
      Patients are prospectively evaluated basally and at 2, 6, and 12 months of follow-up using&#xD;
      IKDC, KOOS (Knee Injury and Osteoarthritis Outcome Score), EQ-VAS (Visual Analogue Scale) for&#xD;
      general health status, and Tegner scores. Furthermore at basal evaluation and at every&#xD;
      follow-up the ROM (Range of Motion) and the transpatellar circumference of both the index&#xD;
      knee and the contralateral one are measured to check if any changes occurred over time.&#xD;
      Patient satisfaction and adverse events will be also reported.&#xD;
&#xD;
      During follow-up evaluations, also a peripheral blood sample is harvested (as described&#xD;
      before) in order to assess any eventual variation in the concentration of same GFs, pro and&#xD;
      anti-inflammatory cytokines previously evaluated. All the clinical evaluations are performed&#xD;
      by a medical staff not involved in the injective procedure, in order to keep the study double&#xD;
      blinded. At the end of the study, the nature of the injected substance is revealed to the&#xD;
      patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>February 2009</start_date>
  <completion_date type="Actual">May 2014</completion_date>
  <primary_completion_date type="Actual">August 2013</primary_completion_date>
  <phase>Phase 4</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>IKDC (International Knee Documentation Committee) subjective score variation for both groups of treatment at 12 months of follow-up (f-up)</measure>
    <time_frame>baseline and 12 months of follow-up</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>IKDC (International Knee Documentation Committee) subjective score variation for both groups of treatment at 6 months of follow-up (f-up)</measure>
    <time_frame>baseline and 6 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IKDC (International Knee Documentation Committee) subjective score variation for both groups of treatment at 2 months of follow-up (f-up)</measure>
    <time_frame>baseline and 2 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IKDC (International Knee Documentation Committee) objective score variation for both groups of treatment at 12 months of follow-up (f-up)</measure>
    <time_frame>baseline and 12 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IKDC (International Knee Documentation Committee) objective score variation for both groups of treatment at 6 months of follow-up (f-up)</measure>
    <time_frame>baseline and 6 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IKDC (International Knee Documentation Committee) objective score variation for both groups of treatment at 2 months of follow-up (f-up)</measure>
    <time_frame>baseline and 2 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VAS (Visual Analogue scale) for General Health Status variation for both groups of treatment at 12 months of follow-up (f-up)</measure>
    <time_frame>baseline and 12 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VAS (Visual Analogue scale) for General Health Status variation for both groups of treatment at 6 months of follow-up (f-up)</measure>
    <time_frame>baseline and 6 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VAS (Visual Analogue scale) for General Health Status variation for both groups of treatment at 2 months of follow-up (f-up)</measure>
    <time_frame>baseline and 2 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tegner score variation for both groups of treatment at 12 months of follow-up (f-up)</measure>
    <time_frame>baseline and 12 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tegner score variation for both groups of treatment at 6 months of follow-up (f-up)</measure>
    <time_frame>baseline and 6 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tegner score variation for both groups of treatment at 2 months of follow-up (f-up)</measure>
    <time_frame>baseline and 2 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>KOOS (Knee injury and Osteoarthritis Outcome Score) variation for both groups of treatment at 12 months of follow-up (f-up)</measure>
    <time_frame>baseline and 12 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>KOOS (Knee injury and Osteoarthritis Outcome Score) variation for both groups of treatment at 6 months of follow-up (f-up)</measure>
    <time_frame>baseline and 6 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>KOOS (Knee injury and Osteoarthritis Outcome Score) variation for both groups of treatment at 2 months of follow-up (f-up)</measure>
    <time_frame>baseline and 2 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Knee Range of Motion (ROM) variation for both groups of treatment at 12 months of follow-up (f-up)</measure>
    <time_frame>baseline and 12 months of follow-up</time_frame>
    <description>Every patient had both knees' ROM measured to eventually assess any variation between the treated and un-treated knee during the follow-up evaluation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Knee Range of Motion variation for both groups of treatment at 6 months of follow-up (f-up)</measure>
    <time_frame>baseline and 6 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Knee Range of Motion variation for both groups of treatment at 2 months of follow-up (f-up)</measure>
    <time_frame>baseline and 2 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Knee Trans patellar and distal quadriceps circumference variation for both groups of treatment at 12 months of follow-up (f-up)</measure>
    <time_frame>baseline and 12 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Knee Trans patellar and distal quadriceps circumference variation for both groups of treatment at 6 months of follow-up (f-up)</measure>
    <time_frame>baseline and 6 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Knee Trans patellar and distal quadriceps circumference variation for both groups of treatment at 2 months of follow-up (f-up)</measure>
    <time_frame>baseline and 2 months of follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient global satisfaction for the treatment</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Level on a Visual Analogue Score after each intra-articular injection</measure>
    <time_frame>7 days after each injection</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Swelling Level on a Visual Analogue Score after each injection</measure>
    <time_frame>7 days after each injection</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Adverse Events</measure>
    <time_frame>2, 6, 12 months of follow up</time_frame>
    <description>Type, duration and trend of every adverse event for each patient will be reported</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Duration after each intra-articular injection</measure>
    <time_frame>7 days after each injection</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Swelling Duration after each injection</measure>
    <time_frame>7 days after each injection</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trend in the concentration of GFs and cytokines in synovial fluid</measure>
    <time_frame>Baseline, day 7 (second injection), day 14 (third injection)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trend in the concentration of GFs and cytokines in peripheral blood</measure>
    <time_frame>Baseline, day 7 (second injection), day 14 (third injection), 2 months, 6 months, 12 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">192</enrollment>
  <condition>Knee Chondropathy</condition>
  <condition>Osteoarthritis, Knee</condition>
  <arm_group>
    <arm_group_label>PRP Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients (n=96) randomized to this group of treatment will receive 3 blinded knee intra-articular injections of autologous Platelet-Rich Plasma one week apart each other.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hyaluronan Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients (n=96) randomized to this group of treatment will receive 3 blinded knee intra-articular injections of hyaluronic acid ( Hyalubrix 30 mg/2ml, Fidia Farmaceutici Spa, Italy) one week apart each other.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>PRP</intervention_name>
    <arm_group_label>PRP Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Hyaluronic acid</intervention_name>
    <arm_group_label>Hyaluronan Group</arm_group_label>
    <other_name>Hyalubrix fl. 30 mg/2ml, Fidia farmaceutici Spa, Italy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients affected by knee articular degenerative pathology with history of chronic&#xD;
             (for at least 4 months) pain or swelling;&#xD;
&#xD;
          -  imaging findings of degenerative changes of the joint (Kellgren Lawrence 0 to III at&#xD;
             X-ray evaluation).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  age &gt; 80 years;&#xD;
&#xD;
          -  Kellgren-Lawrence score at X-ray evaluation &gt; 3;&#xD;
&#xD;
          -  major axial deviation (varus &gt;5° , valgus &gt; 5°),&#xD;
&#xD;
          -  systemic disorders such as diabetes, rheumatoid arthritis, haematological diseases&#xD;
             (coagulopathy), severe cardiovascular diseases, infections, immunodepression;&#xD;
&#xD;
          -  patients in therapy with anticoagulants or antiaggregants;&#xD;
&#xD;
          -  use of NSAIDs in the 5 days before blood donation;&#xD;
&#xD;
          -  patients with Hb values &lt; 11 g/dl and platelet values &lt; 150,000/mmc.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizaveta Kon, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>III Orthopaedic Clinic and Nano-biotechnology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>III Orthopaedic Clinic and Nano-biotechnology Lab, Rizzoli Orthopaedic Institute</name>
      <address>
        <city>Bologna</city>
        <state>Emilia Romagna</state>
        <zip>40136</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Sanchez M, Azofra J, Anitua E, Andia I, Padilla S, Santisteban J, Mujika I. Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. Med Sci Sports Exerc. 2003 Oct;35(10):1648-52. doi: 10.1249/01.MSS.0000089344.44434.50.</citation>
    <PMID>14523300</PMID>
  </reference>
  <reference>
    <citation>Everts PA, Knape JT, Weibrich G, Schonberger JP, Hoffmann J, Overdevest EP, Box HA, van Zundert A. Platelet-rich plasma and platelet gel: a review. J Extra Corpor Technol. 2006 Jun;38(2):174-87.</citation>
    <PMID>16921694</PMID>
  </reference>
  <reference>
    <citation>Tschon M, Fini M, Giardino R, Filardo G, Dallari D, Torricelli P, Martini L, Giavaresi G, Kon E, Maltarello MC, Nicolini A, Carpi A. Lights and shadows concerning platelet products for musculoskeletal regeneration. Front Biosci (Elite Ed). 2011 Jan 1;3(1):96-107. doi: 10.2741/e224.</citation>
    <PMID>21196289</PMID>
  </reference>
  <reference>
    <citation>Grimaud E, Heymann D, Redini F. Recent advances in TGF-beta effects on chondrocyte metabolism. Potential therapeutic roles of TGF-beta in cartilage disorders. Cytokine Growth Factor Rev. 2002 Jun;13(3):241-57. doi: 10.1016/s1359-6101(02)00004-7.</citation>
    <PMID>12486877</PMID>
  </reference>
  <reference>
    <citation>Sanchez AR, Sheridan PJ, Kupp LI. Is platelet-rich plasma the perfect enhancement factor? A current review. Int J Oral Maxillofac Implants. 2003 Jan-Feb;18(1):93-103.</citation>
    <PMID>12608674</PMID>
  </reference>
  <reference>
    <citation>Hickey DG, Frenkel SR, Di Cesare PE. Clinical applications of growth factors for articular cartilage repair. Am J Orthop (Belle Mead NJ). 2003 Feb;32(2):70-6.</citation>
    <PMID>12602635</PMID>
  </reference>
  <reference>
    <citation>Sampson S, Reed M, Silvers H, Meng M, Mandelbaum B. Injection of platelet-rich plasma in patients with primary and secondary knee osteoarthritis: a pilot study. Am J Phys Med Rehabil. 2010 Dec;89(12):961-9. doi: 10.1097/PHM.0b013e3181fc7edf.</citation>
    <PMID>21403592</PMID>
  </reference>
  <reference>
    <citation>Wang-Saegusa A, Cugat R, Ares O, Seijas R, Cusco X, Garcia-Balletbo M. Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life. Arch Orthop Trauma Surg. 2011 Mar;131(3):311-7. doi: 10.1007/s00402-010-1167-3. Epub 2010 Aug 17.</citation>
    <PMID>20714903</PMID>
  </reference>
  <reference>
    <citation>Kon E, Filardo G, Di Martino A, Marcacci M. Platelet-rich plasma (PRP) to treat sports injuries: evidence to support its use. Knee Surg Sports Traumatol Arthrosc. 2011 Apr;19(4):516-27. doi: 10.1007/s00167-010-1306-y. Epub 2010 Nov 17.</citation>
    <PMID>21082164</PMID>
  </reference>
  <reference>
    <citation>Kon E, Buda R, Filardo G, Di Martino A, Timoncini A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc. 2010 Apr;18(4):472-9. doi: 10.1007/s00167-009-0940-8. Epub 2009 Oct 17.</citation>
    <PMID>19838676</PMID>
  </reference>
  <reference>
    <citation>Filardo G, Kon E, Buda R, Timoncini A, Di Martino A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2011 Apr;19(4):528-35. doi: 10.1007/s00167-010-1238-6. Epub 2010 Aug 26.</citation>
    <PMID>20740273</PMID>
  </reference>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>August 13, 2012</study_first_submitted>
  <study_first_submitted_qc>August 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 22, 2012</study_first_posted>
  <last_update_submitted>October 27, 2017</last_update_submitted>
  <last_update_submitted_qc>October 27, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 30, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>P.R.P.</keyword>
  <keyword>viscosupplementation</keyword>
  <keyword>double-blind randomized</keyword>
  <keyword>intra-articular injections</keyword>
  <keyword>knee degenerative pathology</keyword>
  <keyword>early 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>
  <!-- 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/NCT01670578
org study id: KNEEJECT
nct id: NCT01670578
lead sponsor: 
has dmc: Yes
The investigators hypothesized that intra-articular injections of Platelet-rich Plasma (PRP)
      to treat knee degenerative articular cartilage pathology could determine pain relief and
      recovery of knee function with overall clinical outcome comparable or even better than
      viscosupplementation, which is a common injective approach applied in this kind of pathology.
      To this purpose the investigators designed a double blind randomized controlled trial
      comparing PRP vs viscosupplementation.

      A power analysis has been performed for the primary endpoint of IKDC (International Knee
      Documentation Committee) subjective score improvement at the 12-month follow-up for PRP. From
      a pilot study, a standard deviation of 15.2 points was found. With an alpha error of 0.05, a
      beta error of 0.2 and a minimal clinically significant difference of 6.7 points corresponding
      at 1/3 of the documented mean improvement, the minimum sample size was 83 for each group.
      Considering a possible drop out of 15%, 96 patients per group are required for total 192
      patients, selected according to well-defined inclusion criteria (see 'Eligibility criteria'
      section). Patients are then assigned to two different treatment groups, according to a
      randomization list. The first group of treatment consists of three weekly intra-articular
      injections of autologous PRP obtained with the following procedure: a 150-ml autologous
      venous blood sample undergoes 2 centrifugations (the first at 1480 rpm for 6 minutes to
      separate erythrocytes, and a second at 3400 rpm for 15 minutes to concentrate platelets) to
      produced 20 ml of PRP. This unit of PRP is then divided into 4 small units of 5 ml each. One
      unit is sent to the laboratory for analysis of platelet concentration and for a quality test,
      3 units are stored at -30° C.

      The second treatment group consists of patients receiving three weekly injections of
      hyaluronic acid (Hyalubrix 30 mg/2ml, Fidia Farmaceutici Spa, Italy;Molecular Weight: 1500
      kDa).

      To guarantee the blinding of the patients, all of them undergo blood harvesting to obtain
      autologous PRP which will be used only in half of them, according to the aforementioned
      randomization list. One week after the PRP production, the injective treatment starts, with 3
      weekly injections of PRP or HA. At the moment of the injection the syringe is properly
      covered to prevent the patient from discovering the substance he was receiving. After the
      injection, patients are sent home with instructions to limit the use of the leg for at least
      24 h and to use cold therapy/ice on the affected area to relieve pain. During this period,
      the use of non-steroidal medication is forbidden.

      Patients are prospectively evaluated basally and at 2, 6, and 12 months of follow-up using
      clinical subjective scores and objective parameters to determine clinical outcome (see
      'Outcome measure' section). Patient satisfaction and adverse events will be also reported.
      All the clinical evaluations are performed by a medical staff not involved in the injective
      procedure, in order to keep the study double blinded. At the end of the study, the nature of
      the injected substance is revealed to the patients.
Current research is investigating new methods for stimulating repair or replacing damaged
      cartilage. In particular, the most recent knowledge regarding tissue biology highlights a
      complex regulation of growth factors (GFs) for the normal tissue structure and the reaction
      to tissue damage. The influence of GFs on cartilage repair is now widely investigated in
      vitro and in vivo. Platelet Rich Plasma (PRP) is a simple, low- cost and minimally- invasive
      method that allows one to obtain a natural concentrate of autologous GFs from the blood, and
      it is increasingly applied in the clinical practice to treat knee degenerative pathology,
      such as chondropathy and early osteoarthritis (OA). The biological rational of PRP is that
      platelets contain storage pools of GFs, cytokines, chemokines and many other
      mediators.Although its widespread application, there are no high level studies in the
      literature to demonstrate the real efficacy of PRP. In fact, at the present moment, to our
      knowledge there is no published randomized controlled trial comparing PRP with other
      conservative treatments commonly used for knee OA.

      The investigators hypothesized that intra-articular injections of PRP to treat knee
      degenerative articular cartilage pathology could determine pain relief and recovery of knee
      function with overall clinical outcome comparable or even better than viscosupplementation,
      which is a common injective approach applied in this kind of pathology. To this purpose the
      investigators designed a double blind randomized controlled trial comparing PRP vs
      viscosupplementation.

      A power analysis has been performed for the primary endpoint of IKDC subjective score
      improvement at the 12-month follow-up for PRP. From a pilot study, a standard deviation of
      15.2 points was found. With an alpha error of 0.05, a beta error of 0.2 and a minimal
      clinically significant difference of 6.7 points corresponding at 1/3 of the documented mean
      improvement, the minimum sample size was 83 for each group. Considering a possible drop out
      of 15%, 96 patients per group are required for total 192 patients. Patients are then assigned
      to two different treatment groups, according to a randomization list. The first group of
      treatment consists of three weekly intra-articular injections of autologous PRP obtained with
      the following procedure: a 150-ml autologous venous blood sample undergoes 2 centrifugations
      (the first at 1480 rpm for 6 minutes to separate erythrocytes, and a second at 3400 rpm for
      15 minutes to concentrate platelets) to produced 20 ml of PRP. This unit of PRP is then
      divided into 4 small units of 5 ml each. One unit is sent to the laboratory for analysis of
      platelet concentration and for a quality test, 3 units are stored at -30° C.

      The second treatment group consists of patients receiving three weekly injections of
      hyaluronic acid (Hyalubrix 30 mg/2ml, Fidia Farmaceutici Spa, Italy;Molecular Weight: 1500
      kDa).

      To guarantee the blinding of the patients, all of them undergo blood harvesting to obtain
      autologous PRP which will be used only in half of them, according to the aforementioned
      randomization list. One week after the PRP production, the injective treatment starts, with 3
      weekly injections of PRP or HA. At the moment of the injection the syringe is properly
      covered to prevent the patient from discovering the substance he was receiving. After the
      injection, patients are sent home with instructions to limit the use of the leg for at least
      24 h and to use cold therapy/ice on the affected area to relieve pain. During this period,
      the use of non-steroidal medication is forbidden.

      Furthermore, at the moment of each weekly injection, before injecting the substance, an
      attempt of harvesting synovial fluid is performed. During the same visit, also a peripheral
      blood sample (3 ml) is taken. These samples are then sent to a dedicated Laboratory in order
      to test the concentration of some GFs, pro and anti-inflammatory cytokines, both at local
      (synovial fluid) and systemic level (peripheral blood). The aim is to evaluate the trend in
      the concentration rate of these molecules over the period of the injective treatment.

      Patients are prospectively evaluated basally and at 2, 6, and 12 months of follow-up using
      IKDC, KOOS (Knee Injury and Osteoarthritis Outcome Score), EQ-VAS (Visual Analogue Scale) for
      general health status, and Tegner scores. Furthermore at basal evaluation and at every
      follow-up the ROM (Range of Motion) and the transpatellar circumference of both the index
      knee and the contralateral one are measured to check if any changes occurred over time.
      Patient satisfaction and adverse events will be also reported.

      During follow-up evaluations, also a peripheral blood sample is harvested (as described
      before) in order to assess any eventual variation in the concentration of same GFs, pro and
      anti-inflammatory cytokines previously evaluated. All the clinical evaluations are performed
      by a medical staff not involved in the injective procedure, in order to keep the study double
      blinded. At the end of the study, the nature of the injected substance is revealed to the
      patients.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: IKDC (International Knee Documentation Committee) subjective score variation for both groups of treatment at 12 months of follow-up (f-up)
time frame: baseline and 12 months of follow-up
measure: IKDC (International Knee Documentation Committee) subjective score variation for both groups of treatment at 6 months of follow-up (f-up)
time frame: baseline and 6 months of follow-up
measure: IKDC (International Knee Documentation Committee) subjective score variation for both groups of treatment at 2 months of follow-up (f-up)
time frame: baseline and 2 months of follow-up
measure: IKDC (International Knee Documentation Committee) objective score variation for both groups of treatment at 12 months of follow-up (f-up)
time frame: baseline and 12 months of follow-up
measure: IKDC (International Knee Documentation Committee) objective score variation for both groups of treatment at 6 months of follow-up (f-up)
time frame: baseline and 6 months of follow-up
measure: IKDC (International Knee Documentation Committee) objective score variation for both groups of treatment at 2 months of follow-up (f-up)
time frame: baseline and 2 months of follow-up
measure: VAS (Visual Analogue scale) for General Health Status variation for both groups of treatment at 12 months of follow-up (f-up)
time frame: baseline and 12 months of follow-up
measure: VAS (Visual Analogue scale) for General Health Status variation for both groups of treatment at 6 months of follow-up (f-up)
time frame: baseline and 6 months of follow-up
measure: VAS (Visual Analogue scale) for General Health Status variation for both groups of treatment at 2 months of follow-up (f-up)
time frame: baseline and 2 months of follow-up
measure: Tegner score variation for both groups of treatment at 12 months of follow-up (f-up)
time frame: baseline and 12 months of follow-up
measure: Tegner score variation for both groups of treatment at 6 months of follow-up (f-up)
time frame: baseline and 6 months of follow-up
measure: Tegner score variation for both groups of treatment at 2 months of follow-up (f-up)
time frame: baseline and 2 months of follow-up
measure: KOOS (Knee injury and Osteoarthritis Outcome Score) variation for both groups of treatment at 12 months of follow-up (f-up)
time frame: baseline and 12 months of follow-up
measure: KOOS (Knee injury and Osteoarthritis Outcome Score) variation for both groups of treatment at 6 months of follow-up (f-up)
time frame: baseline and 6 months of follow-up
measure: KOOS (Knee injury and Osteoarthritis Outcome Score) variation for both groups of treatment at 2 months of follow-up (f-up)
time frame: baseline and 2 months of follow-up
measure: Knee Range of Motion (ROM) variation for both groups of treatment at 12 months of follow-up (f-up)
time frame: baseline and 12 months of follow-up
description: Every patient had both knees' ROM measured to eventually assess any variation between the treated and un-treated knee during the follow-up evaluation
measure: Knee Range of Motion variation for both groups of treatment at 6 months of follow-up (f-up)
time frame: baseline and 6 months of follow-up
measure: Knee Range of Motion variation for both groups of treatment at 2 months of follow-up (f-up)
time frame: baseline and 2 months of follow-up
measure: Knee Trans patellar and distal quadriceps circumference variation for both groups of treatment at 12 months of follow-up (f-up)
time frame: baseline and 12 months of follow-up
measure: Knee Trans patellar and distal quadriceps circumference variation for both groups of treatment at 6 months of follow-up (f-up)
time frame: baseline and 6 months of follow-up
measure: Knee Trans patellar and distal quadriceps circumference variation for both groups of treatment at 2 months of follow-up (f-up)
time frame: baseline and 2 months of follow-up
measure: Patient global satisfaction for the treatment
time frame: 12 months
measure: Pain Level on a Visual Analogue Score after each intra-articular injection
time frame: 7 days after each injection
measure: Swelling Level on a Visual Analogue Score after each injection
time frame: 7 days after each injection
measure: Number of Participants with Adverse Events
time frame: 2, 6, 12 months of follow up
description: Type, duration and trend of every adverse event for each patient will be reported
measure: Pain Duration after each intra-articular injection
time frame: 7 days after each injection
measure: Swelling Duration after each injection
time frame: 7 days after each injection
measure: Trend in the concentration of GFs and cytokines in synovial fluid
time frame: Baseline, day 7 (second injection), day 14 (third injection)
measure: Trend in the concentration of GFs and cytokines in peripheral blood
time frame: Baseline, day 7 (second injection), day 14 (third injection), 2 months, 6 months, 12 months
arm group label: PRP Group
arm group type: Experimental
description: Patients (n=96) randomized to this group of treatment will receive 3 blinded knee intra-articular injections of autologous Platelet-Rich Plasma one week apart each other.
arm group label: Hyaluronan Group
arm group type: Active Comparator
description: Patients (n=96) randomized to this group of treatment will receive 3 blinded knee intra-articular injections of hyaluronic acid ( Hyalubrix 30 mg/2ml, Fidia Farmaceutici Spa, Italy) one week apart each other.
intervention type: Biological
intervention name: PRP
arm group label: PRP Group
intervention type: Device
intervention name: Hyaluronic acid
arm group label: Hyaluronan Group
other name: Hyalubrix fl. 30 mg/2ml, Fidia farmaceutici Spa, Italy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Elizaveta Kon, MD
role: Principal Investigator
affiliation: III Orthopaedic Clinic and Nano-biotechnology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy
facility: 
country: Italy
citation: Sanchez M, Azofra J, Anitua E, Andia I, Padilla S, Santisteban J, Mujika I. Plasma rich in growth factors to treat an articular cartilage avulsion: a case report. Med Sci Sports Exerc. 2003 Oct;35(10):1648-52. doi: 10.1249/01.MSS.0000089344.44434.50.
PMID: 14523300
citation: Everts PA, Knape JT, Weibrich G, Schonberger JP, Hoffmann J, Overdevest EP, Box HA, van Zundert A. Platelet-rich plasma and platelet gel: a review. J Extra Corpor Technol. 2006 Jun;38(2):174-87.
PMID: 16921694
citation: Tschon M, Fini M, Giardino R, Filardo G, Dallari D, Torricelli P, Martini L, Giavaresi G, Kon E, Maltarello MC, Nicolini A, Carpi A. Lights and shadows concerning platelet products for musculoskeletal regeneration. Front Biosci (Elite Ed). 2011 Jan 1;3(1):96-107. doi: 10.2741/e224.
PMID: 21196289
citation: Grimaud E, Heymann D, Redini F. Recent advances in TGF-beta effects on chondrocyte metabolism. Potential therapeutic roles of TGF-beta in cartilage disorders. Cytokine Growth Factor Rev. 2002 Jun;13(3):241-57. doi: 10.1016/s1359-6101(02)00004-7.
PMID: 12486877
citation: Sanchez AR, Sheridan PJ, Kupp LI. Is platelet-rich plasma the perfect enhancement factor? A current review. Int J Oral Maxillofac Implants. 2003 Jan-Feb;18(1):93-103.
PMID: 12608674
citation: Hickey DG, Frenkel SR, Di Cesare PE. Clinical applications of growth factors for articular cartilage repair. Am J Orthop (Belle Mead NJ). 2003 Feb;32(2):70-6.
PMID: 12602635
citation: Sampson S, Reed M, Silvers H, Meng M, Mandelbaum B. Injection of platelet-rich plasma in patients with primary and secondary knee osteoarthritis: a pilot study. Am J Phys Med Rehabil. 2010 Dec;89(12):961-9. doi: 10.1097/PHM.0b013e3181fc7edf.
PMID: 21403592
citation: Wang-Saegusa A, Cugat R, Ares O, Seijas R, Cusco X, Garcia-Balletbo M. Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life. Arch Orthop Trauma Surg. 2011 Mar;131(3):311-7. doi: 10.1007/s00402-010-1167-3. Epub 2010 Aug 17.
PMID: 20714903
citation: Kon E, Filardo G, Di Martino A, Marcacci M. Platelet-rich plasma (PRP) to treat sports injuries: evidence to support its use. Knee Surg Sports Traumatol Arthrosc. 2011 Apr;19(4):516-27. doi: 10.1007/s00167-010-1306-y. Epub 2010 Nov 17.
PMID: 21082164
citation: Kon E, Buda R, Filardo G, Di Martino A, Timoncini A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc. 2010 Apr;18(4):472-9. doi: 10.1007/s00167-009-0940-8. Epub 2009 Oct 17.
PMID: 19838676
citation: Filardo G, Kon E, Buda R, Timoncini A, Di Martino A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2011 Apr;19(4):528-35. doi: 10.1007/s00167-010-1238-6. Epub 2010 Aug 26.
PMID: 20740273
responsible party type: Sponsor
mesh term: Osteoarthritis
mesh term: Osteoarthritis, Knee
mesh term: Hyaluronic Acid