Platelet-rich Plasma vs Viscosupplementation in the Treatment of Knee Articular Degenerative Pathology
Condition: Knee Chondropathy; Osteoarthritis, Knee
MeSH terms: Osteoarthritis; Osteoarthritis, Knee
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): PRP; Hyaluronic acid
Intervention type(s): Biological; Device
Other intervention name(s): Hyalubrix fl. 30 mg/2ml, Fidia farmaceutici Spa, Italy
Intervention MeSH terms: Hyaluronic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: P.R.P.; viscosupplementation; double-blind randomized; intra-articular injections; knee degenerative pathology; early osteoarthritis