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    Clinical Trial Results:
    Treatment of Osteoarthritis by intra-articular injection of mesenchymal stem cells from bone marrow and plasma rich in growth factors (PRGF).

    Summary
    EudraCT number
    		 2011-006036-23
    Trial protocol
    		 ES  
    Global end of trial date
    27 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Sep 2021
    First version publication date
    19 Sep 2021
    Other versions
    Summary report(s)
    		 SPANISH REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    CMM-PRGF/ART
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02365142
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Clínica Universidad de Navarra
    Sponsor organisation address
    Avda. Pío XII, 36, Pamplona, Spain, 31008
    Public contact
    UCICEC, Clínica Universidad de Navarra, 34 948 255 400 1144, ucicec@unav.es
    Scientific contact
    UCICEC, Clínica Universidad de Navarra, 34 948 255 400 1144, ucicec@unav.es
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the effectiveness of PRGF versus PRGF + CMM in patients with osteoarthritis of the knee refractory to treatment with hyaluronic acid.
    Protection of trial subjects
    NA
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    48
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patient recruitment will be carried out in each of the centres by the specialists in Orthopaedic Surgery and Traumatology or Rheumatology participating in the project. Once randomised, patients assigned to group 2 undergo a bone marrow extraction to create the autologous mesenchymal stem cell product for intrarticular infusion.

    Pre-assignment
    Screening details
    		 Patients between 18 and 80 years diagnosed by osteoarthritis of the knee according to the criteria f of the ACR and refractory to previous treatment with hyaluronic acid. Joint pain greater than or equal to 2.5 points on the VAS scale, and with radiological classification greater than or equal to 2 on he Kellgren-Lawrence scale.

    Period 1
    Period 1 title
    Treatment and follow-up (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Grupo I
    Arm description
    		 This group receives 3 infiltrations of 8ml (one per week) of plasma rich in growth factors (PRGF).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PRGF
    Investigational medicinal product code
    Other name
    Plasma rich in growth factors
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Three doses of 8ml of PRGF are administered intra-articularly, once a week.

    Arm title
    		 Group II
    Arm description
    		 Patients are administered by three doses of plasma rich in growth factors (PRGF) and one dose of Mesenquimal Stem Cells (MSC). MSC injection is performed on the first day of treatment, followed by the first PRGF injection. The next two PRGF injections are performed at week 2 and week 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Autologous mesenchymal stem cells from bone marrow cultivated ex - vivo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    A single dose of 100 million units is administered intra-articularly on the first day of treatment. PRGF shall be administered after the administration of the cells, using the same intrarticular route.

    Number of subjects in period 1
    		Grupo I Group II
    Started
    30
    30
    Completed
    26
    24
    Not completed
    4
    6
         Physician decision
    -
    1
         Consent withdrawn by subject
    -
    1
         do not like the assigned group
    2
    -
         Lost to follow-up
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment and follow-up
    Reporting group description
    		 -

    Reporting group values
    		 Treatment and follow-up Total
    Number of subjects
    		 60 60
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 48 48
        From 65-84 years
    		 12 12
    Gender categorical
    Units: Subjects
        Female
    		 20 20
        Male
    		 40 40

    End points

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    End points reporting groups
    Reporting group title
    Grupo I
    Reporting group description
    		 This group receives 3 infiltrations of 8ml (one per week) of plasma rich in growth factors (PRGF).

    Reporting group title
    Group II
    Reporting group description
    		 Patients are administered by three doses of plasma rich in growth factors (PRGF) and one dose of Mesenquimal Stem Cells (MSC). MSC injection is performed on the first day of treatment, followed by the first PRGF injection. The next two PRGF injections are performed at week 2 and week 3.

    Primary: Improvement in the rates of clinical and functional assessment

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    End point title
    		 Improvement in the rates of clinical and functional assessment
    End point description
    Improvements in Clinical and Functional Assessment Indices will be evaluated to determine the effectiveness of treatments. The VAS, WOMAC, Lanesque, Euroqol 5D and mobility range scales are used. The most important clinical scales evaluated are the VAS and the WOMAC. On the VAS scale, the evolution of pain showed no statistically significant differences between the two groups. According to the results of the WOMAC scale, there is a clinical improvement in both groups, with a greater improvement in Group II (37.3%) than in Group I (23.4%), but there are no significant differences between the two groups either. There were no notable differences between the two groups in the Lanesque scale, Euroqol 5D and mobility range.
    End point type
    Primary
    End point timeframe
    Evaluation at a week and in 1, 3 and 6 months.
    End point values
    		 Grupo I Group II
    Number of subjects analysed
    26
    24
    Units: NA
    arithmetic mean (standard deviation)
        EVA Baseline
    5 ± 1.8
    5.3 ± 1.9
        EVA 3 months
    3.8 ± 1.6
    3.8 ± 2
        EVA 6 months
    3.5 ± 2
    3.3 ± 2.2
        EVA 12 months
    4.5 ± 2.2
    3.5 ± 2.5
        WOMAC Baseline
    31.9 ± 16.2
    33.4 ± 18.7
        WOMAC 3 months
    21.7 ± 17.1
    24.4 ± 17.4
        WOMAC 6 months
    23 ± 15
    21.3 ± 16.6
        WOMAC 12 months
    22.3 ± 15.8
    23.0 ± 16.6
    Statistical analysis title
    		 Sum of ranks Wilcoxon (U de Mann-Whitney).
    Comparison groups
    Grupo I v Group II
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Radiographic Evaluation

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    End point title
    		 Radiographic Evaluation
    End point description
    Radiographic evaluation is performed to determine the effectiveness of the treatment. A knee X-ray is performed to classify the degree of osteoarthritis and an assessment of the joint interlining, before treatment and at 12 months. Analysis of the interline on radiography showed no clinical change. Magnetic resonance imaging is also performed following the WORMS protocol before treatment and at 12 months. MRI analysis showed no significant change during follow-up.
    End point type
    Primary
    End point timeframe
    Before treatment and in 6 months.
    End point values
    		 Grupo I Group II
    Number of subjects analysed
    26
    24
    Units: mm
    arithmetic mean (standard deviation)
        WORMS Baseline
    73.8 ± 30.9
    74.4 ± 28
        WORMS 12 months
    77.4 ± 31.5
    79.8 ± 29.1
    Statistical analysis title
    		 Comparison between groups
    Comparison groups
    Grupo I v Group II
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs will be collected from the time the patient receives the first dose of the investigational drug until the end of the patient's follow-up.The maximum period for notification of suspected RAGI will be 15 days from the time the promoter become aware.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ND
    Dictionary version
    ND
    Reporting groups
    Reporting group title
    All the patients
    Reporting group description
    		 -

    Serious adverse events
    		 All the patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 60 (5.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Social circumstances
    disorientation
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Ovarian cystectomy and endometrial ablation
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 All the patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 60 (20.00%)
    Vascular disorders
    Venous thrombosis superficial
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Nervous system disorders
    Cluster headache
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Shoulder pain
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Left knee pain
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Pain at the point of extraction of bone marrow
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Eye disorders
    Blepharoplasty
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    cold
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Removal of benign neck cyst
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Ruptured extensor ligament of the 4th finger of the right hand
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Monoarthritis of the left knee
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Joint inflammation
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Infections and infestations
    pharyngitis
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1
    Flu
         subjects affected / exposed
    1 / 60 (1.67%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jun 2013
    New version of protocol (v5)
    05 Sep 2013
    New version of protocol (v6)
    20 Dec 2013
    New version of protocol (v7)
    03 Jul 2015
    New version of protocol (v8)

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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