Effect Of Plasma Rich In Growth Factors In Knee Osteoarthritis
Condition: Knee Osteoarthritis
MeSH terms: Osteoarthritis; Osteoarthritis, Knee
Study type: Interventional
Phase: Phase 3

Summary: 
      HYPOTHESIS:

      The application of plasma rich in growth factors (PRGF) will improve the quality of life and
      functional capacity of patients diagnosed with knee osteoarthritis, providing better
      functional results than conventional treatment with viscosupplementation.

      OPERATING ASSUMPTIONS

      Following the initial administration of three doses of PRGF interspersed every 15 days,
      applied via intraarticular, patients will present an improvement in functional test (WOMAC
      and Lequesne scales) of 15% or more after 6 and 12 months compared to the control group with
      patients treated with hyaluronic acid.
    

Detailed description: 
      OBJECTIVES

      The overall objective of the study is to assess the effectiveness of the treatment with PRGF
      in the osteoarthritis of the knee.

      Main objective:

      - To show more effectiveness after 6 months of the treatment with PRGF, with an improvement
      in the reference test (WOMAC and Lequesne) of 15 % or more compared to the treatment with
      hyaluronic acid in patients with osteoarthritis of the knee.

      Secondary objectives:

        -  To assess the effectiveness after 12 months of the treatment with PRGF compared to the
           treatment with hyaluronic acid.

        -  To assess the effectiveness after 12 months of the two cycles re-treatment with PRGF
           (second phase of the study), compared to the effect of a single cycle with PRGF (first
           phase of the study ).

        -  Quantifying platelet growth factors blood concentration in patients treated with PRGF
           and its correlation with the intraarticular effect.

      METHODOLOGY.STUDY DESIGN:

      First Phase:

      A randomized, single-blind, clinical trial will be performed to compare the effectiveness of
      2 different treatment strategies (PRGF and hyaluronic acid) in patients with knee
      osteoarthritis.

      Patients will be divided into two homogeneous groups using a randomization procedure by
      permuted blocks system.

      The first group (experimental) will receive the treatment with PRGF; one cycle of three
      intraarticular doses every 15 days.

      The control group, will receive viscosupplementation wih hyaluronic acid of high molecular
      weight (Durolane®). Its administration is performed in a one cycle of a single intraarticular
      dose.

      Second phase :

      An interim analysis of the main objective in the first phase at 6 months will be performed.
      If the clinical data indicate that the PRGF is more effective than hyaluronic acid and no
      serious adverse events were described, the investigators will carry out a second phase of
      extension, exploratory, open label, non randomized, starting-up after 12 months of the finish
      of the first phase (in order to wash out the effects of the treatment in the first phase).
      Patients who were treated with hyaluronic acid in the first phase will be offered to be
      treated with PRGF in two cycles of administration (the first one at the begining and the
      second one after 6 months) in order to know whether a two-cycles-based-treatment improves the
      results of a single-cycle-based-treatment.

      STUDY VARIABLES

      Within the study the investigators will analyze different variables:

      Predicting Variables:

        -  sex

        -  age

        -  BMI,

        -  Grade of chondropathy by classification of Kellgren and Lawrence scale

        -  laterality

        -  employment status (Working, unemployed or retired)

        -  presence of complications.

        -  quantification of platelet blood concentration in all patients in the study group.

      Outcome Variables :

      The investigators will use specific tests to evaluate Osteoarthritis of the knee:

        -  WOMAC scale (Western Ontario and McMaster Universities ).

        -  Severity index of Lequesne in knee osteoarthritis. Both are tests internationally
           validated for clinical and functional health assessment in patients with osteoarthritis
           of the knee. All are translated into spanish and validated by the scientific community
           for its use in clinical research.

        -  Visual Analogue Scale (VAS) and SF-363 Health Questionnaire.

      The results of the study questionnaires will be measured after 3, 6 and 12 months in both
      phases.

      The WOMAC questionnaire assesses pain intensity in 5 different situations, the joint
      stiffness in 2 different situations and the functional capacity in 17 everyday situations.
      Each item is scored from 0 ( "no pain, or without stiffness or no difficulty" ) to 4 ( " Very
      much " ) . The total score ranges as follows : Pain 0-20 , stiffness 0-8 and Functional
      Capacity 0-68 .

      The severity index of Lequesne for knee osteoarthritis quantifies the severity of disability
      or severity of osteoarthritis. The pain is measured in 3 items, the maximum distance walked
      and activities of daily living are measured in 4 situations. Scores ranges from 1-4 (mild
      inability) to >14 (where the failure is extremely serious).

      The SF -36 is a health questionnaire . It is used in medical research. It provides an
      overview of the state of health of the person. Contains 36 questions addressing different
      aspects of the daily life of the person.

      COLLECTION AND ANALYSIS .

      At baseline patients before receiving the first infiltration, regardless of the study group,
      must complete the tests described earlier. Then, at 3, 6 and 12 months the patients will
      perform the same tests.

      Analysis:

        -  Description of variables : qualitative variables are summarized by their absolute and
           relative frequencies. Quantitative variables by its mean and standard deviation, or
           alternatively, by the median and interquartile range, in case they do not follow normal
           distribution.

        -  Comparison of means between the two groups by Student t-test or , alternatively by the U
           of Mann - Whitney, in case they do not follow normal distribution.

        -  Qualitative variables will be analyzed using the chi2 test and calculation of relative
           risk ( RR ) with a 95% of confidence interval.

        -  Linear regression and correlation between the blood concentration of platelets in the
           PRGF obtained and injected . These tests will also be conducted to correlate plasma
           concentrations with these outcome variables.

        -  Level of statistical significance was set at P < 0.05 .

        -  The analysis is carried out by intention to treat.

      ETHICS

      All patients must sign the informed consent before their inclusion. The study was approved by
      the ethics committee of the Principe de Asturias University Hospital.

      The investigators are responsible to ensure the confidentiality of patient's data, and to act
      according to the Spanish Law of Protection of Personal Data (LO 15/ 1999).

      STUDY LIMITATIONS .

      Limitations of the study include the lack of control group treated with placebo. In this
      study a placebo-controlled group is not ethically acceptable, because the patient must
      undergo invasive procedures with associated risks and discomfort involved. Therefore, in our
      case we will use as a control group the patients treated with hyaluronic acid, considered as
      an alternative to surgical treatment of osteoarthritis of the knee .

      Another bias that may occur is the loss of patients by different reasons. To prevent this
      problem, we will contact every month with patients by telephone to remind them the
      appointments at 3,6 and 12 months.

      In the second phase all patients that had completed the first phase in the control group will
      have the possibility of treatment with two cycles with PRGF. Because it is considered to be
      very unlikely to remain a residual effect of hyaluronic acid after 12 months of receiving the
      first infiltration, homogeneity achieved by the randomization in the first phase is expected
      to be maintained in the second phase. It is considered that 12 months is a relatively short
      time interval in a longstanding chronic disease such as osteoarthritis of the knee. Just in
      case, a comparative analysis of the baseline characteristics will be performed and adjusted
      for differences that may be found. Finally, due to the sample size was estimated to detect a
      difference between a one cycle treatment with PRGF and hyaluronic acid in the first phase, it
      is possible that it could be insufficient for comparison in the second phase. Thus, the
      second phase is considered as exploratory.
    

Intervention name(s): Plasma rich in growth factors; Hyaluronic Acid
Intervention type(s): Biological; Drug
Other intervention name(s): Durolane
Intervention MeSH terms: Mitogens; Hyaluronic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Knee; osteoarthritis; plasma rich in growth factors; platelet rich plasma; hyaluronic acid