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    Clinical Trial Results:
    A multicentre study to assess the safety and efficacy of sodium hyaluronate (Hyalgan-F) produced by fermentation in knee psteoarthritis.

    Summary
    EudraCT number
    		 2005-002735-27
    Trial protocol
    		 LV  
    Global end of trial date
    13 Jun 2006

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Jul 2022
    First version publication date
    02 Apr 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    I should add the data from secondary endpoint

    Trial information

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    Trial identification
    Sponsor protocol code
    R30-05-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fidia Farmaceutici S.p.A
    Sponsor organisation address
    Via Ponte della Fabbrica 3/A, Abano Terme, Italy, 35031
    Public contact
    Lucia Beinat, Fidia Farmaceutici S.p.A, +39 049 8232512, lbeinat@fidiapharma.it
    Scientific contact
    Lucia Beinat, Fidia Farmaceutici S.p.A, +39 049 8232512, lbeinat@fidiapharma.it
    Sponsor organisation name
    Fidia Farmaceutici S.p.A
    Sponsor organisation address
    Via Ponte della Fabbrica 3/A, Abano Terme, Italy, 35031
    Public contact
    Evita Zvaigzne, ICON Clinical Research Latvia, +371 7804000, zvaigznee@iconlat.com
    Scientific contact
    Evita Zvaigzne, ICON Clinical Research Latvia, +371 7804000, zvaigznee@iconlat.com
    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
    13 Jun 2006
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jun 2006
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the potential immunogenicity of Hyalgan-F (HA-F) a sodium hyaluronate obtained by fermentation and administered by intra-articular (i.a.) route (5 i.a., once a wek for 5 weeks) in a patients with knee osteoarthritis (OA).
    Protection of trial subjects
    Females of child-bearing potential (i.e. not in menopausal status from at least one year or permanently sterilized) had to have a negative urine pregnancy test prior to the first investigational medicinal product (IMP) administration
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Sep 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 5 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Latvia: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    120
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 • Patients of both genders, ambulant, aged ≥ 40 years, with primary knee OA associated with moderate to severe knee pain. • Diagnosis of OA of the knee according to ACRC. • OA of KL grade II – III • At baseline VAS pain score ≥ 40 mm • Analgesic/NSAID therapy was discontinued if previously taken prior to baseline

    Pre-assignment period milestones
    Number of subjects started
    		 120
    Number of subjects completed
    		 120

    Period 1
    Period 1 title
    Hyalgan-F (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Hyalgan-F (HA-F)
    Arm description
    		 Patients were treated with five i.a. injections of HA-F 2 ml, one injection a week for five weeks, starting from baseline [week 0]) up to six months of follow-up with clinical visits and evaluations.
    Arm type
    		 One arm

    Investigational medicinal product name
    Hyalgan-F
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Hyalgan-F 20mg/2ml Sodium Hyaluronate 20 mg Sodium chloride 17 mg Monobasic sodium phosphate 0.1 mg Dibasic sodium phosphate 1.2 mg Water for injection q.s. to 2 ml

    Number of subjects in period 1
    		Hyalgan-F (HA-F)
    Started
    120
    Completed
    117
    Not completed
    3
         Adverse event, serious fatal
    1
         Did not meet inclusion criteria
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Hyalgan-F
    Reporting group description
    		 -

    Reporting group values
    		 Hyalgan-F Total
    Number of subjects
    		 120 120
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 120 120
    Gender categorical
    Units: Subjects
        Female
    		 103 103
        Male
    		 17 17
    Subject analysis sets

    Subject analysis set title
    mITT 35 days
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Intention to Treat population (ITT) was defined as all patients who received at least one dose of the study drug with at least one post-treatment immunological data, and was used for all the immunological and efficacy analyses.

    Subject analysis set title
    mITT 60 days
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Intention to Treat population (ITT) was defined as all patients who received at least one dose of the study drug with at least one post-treatment immunological data, and was used for all the immunological and efficacy analyses.

    Subject analysis set title
    mITT-120 days
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Modified Intention to Treat population (ITT) was defined as all patients who received at least one dose of the study drug with at least one post-treatment immunological data, and was used for all the immunological and efficacy analyses.

    Subject analysis set title
    mITT-180 days
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Intention to Treat population (ITT) was defined as all patients who received at least one dose of the study drug with at least one post-treatment immunological data, and was used for all the immunological and efficacy analyses.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population was defined as all patients who received at least one dose of study drug and was used for all safety analyses including demographic data, AEs, laboratory data and vital signs.

    Subject analysis sets values
    		 mITT 35 days mITT 60 days mITT-120 days mITT-180 days Safety Population
    Number of subjects
    119
    118
    118
    117
    120
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    119
    118
    118
    117
    120
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Hyalgan-F (HA-F)
    Reporting group description
    		 Patients were treated with five i.a. injections of HA-F 2 ml, one injection a week for five weeks, starting from baseline [week 0]) up to six months of follow-up with clinical visits and evaluations.

    Subject analysis set title
    mITT 35 days
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Intention to Treat population (ITT) was defined as all patients who received at least one dose of the study drug with at least one post-treatment immunological data, and was used for all the immunological and efficacy analyses.

    Subject analysis set title
    mITT 60 days
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Intention to Treat population (ITT) was defined as all patients who received at least one dose of the study drug with at least one post-treatment immunological data, and was used for all the immunological and efficacy analyses.

    Subject analysis set title
    mITT-120 days
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Modified Intention to Treat population (ITT) was defined as all patients who received at least one dose of the study drug with at least one post-treatment immunological data, and was used for all the immunological and efficacy analyses.

    Subject analysis set title
    mITT-180 days
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Intention to Treat population (ITT) was defined as all patients who received at least one dose of the study drug with at least one post-treatment immunological data, and was used for all the immunological and efficacy analyses.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population was defined as all patients who received at least one dose of study drug and was used for all safety analyses including demographic data, AEs, laboratory data and vital signs.

    Primary: Incidence of Immunogenic response of HA-F

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    End point title
    		 Incidence of Immunogenic response of HA-F [1]
    End point description
    End point type
    Primary
    End point timeframe
    The incidence of positive immunogenic response to HA-F calculated at 35 days and 60 days after treatment among patients with a negative immunogenic response at baseline
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were performed
    End point values
    		 mITT 35 days mITT 60 days
    Number of subjects analysed
    118
    117
    Units: percentage protection
        number (confidence interval 95%)
    99.2 (97 to 100)
    98.3 (97 to 100)
    No statistical analyses for this end point

    Secondary: Efficacy measured in VAS scale

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    End point title
    		 Efficacy measured in VAS scale
    End point description
    Results were summarized descriptively for each visit (Day 0, Day 35, Day 60, Day 120, and Day 180). The change from baseline was analyzed and the corresponding 95% CIs were presented. P-values were obtained from a two-sided test of the null-hypothesis that the change from baseline was zero. The time taken to perform the 50 ft walking test was also reported.
    End point type
    Secondary
    End point timeframe
    The VAS was evaluated at baseline, Day 35, Day 60, Day 120 and Day 180.
    End point values
    		 Hyalgan-F (HA-F) mITT 35 days mITT 60 days
    Number of subjects analysed
    119
    119
    118
    Units: millimetre(s)
        median (full range (min-max))
    60.5 (40 to 91)
    -29 (-82 to 14)
    -41.0 (-91 to 19)
    No statistical analyses for this end point

    Secondary: WOMAC index assessment-Pain

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    End point title
    		 WOMAC index assessment-Pain
    End point description
    Results were summarized descriptively for each visit (Day 0, Day 35, Day 60, Day 120, and Day 180). The change from baseline was analyzed and the corresponding 95% CIs were presented. P-values were obtained from a two-sided test of the null-hypothesis that the change from baseline was zero. The time taken to perform the 50 ft walking test was also reported.
    End point type
    Secondary
    End point timeframe
    The WOMAC was measured at baseline, Day 35, Day 60, Day 120, and Day 180.
    End point values
    		 Hyalgan-F (HA-F) mITT 35 days mITT 60 days
    Number of subjects analysed
    119
    119
    118
    Units: millimiter
        median (full range (min-max))
    213.0 (32 to 445)
    122.0 (1 to 335)
    86.5 (0 to 437)
    No statistical analyses for this end point

    Secondary: WOMAC index assessment-Stifness

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    End point title
    		 WOMAC index assessment-Stifness
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0, 35, 60, 120, 180
    End point values
    		 Hyalgan-F (HA-F) mITT 35 days mITT 60 days mITT-120 days mITT-180 days
    Number of subjects analysed
    119
    119
    118
    118
    117
    Units: millimiters
        median (full range (min-max))
    101.0 (2 to 185)
    60.0 (0 to 164)
    44.5 (0 to 177)
    45.0 (0 to 159)
    47.0 (0 to 187)
    No statistical analyses for this end point

    Secondary: WOMAC index assessment-Function

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    End point title
    		 WOMAC index assessment-Function
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0, 35, 60, 120, 180
    End point values
    		 Hyalgan-F (HA-F) mITT 35 days mITT 60 days mITT-120 days mITT-180 days
    Number of subjects analysed
    119
    119
    118
    118
    117
    Units: millimiters
        median (full range (min-max))
    854 (100 to 1529)
    530.0 (10 to 1359)
    384.5 (7 to 1535)
    390 (2 to 1330)
    411.0 (0 to 1405)
    No statistical analyses for this end point

    Secondary: Immunological Parameters-C3

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    End point title
    		 Immunological Parameters-C3
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0, 35 and 60
    End point values
    		 Hyalgan-F (HA-F) mITT 35 days mITT 60 days
    Number of subjects analysed
    119
    119
    118
    Units: mg/dL
        median (full range (min-max))
    124.0 (38 to 180)
    124.0 (71 to 179)
    120.0 (67 to 199)
    No statistical analyses for this end point

    Secondary: Immunological Parameters-C4

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    End point title
    		 Immunological Parameters-C4
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0, 35, 60
    End point values
    		 Hyalgan-F (HA-F) mITT 35 days mITT 60 days
    Number of subjects analysed
    119
    119
    118
    Units: mg/dL
        median (full range (min-max))
    28.0 (7 to 59)
    28 (11 to 57)
    29.0 (15 to 55)
    No statistical analyses for this end point

    Secondary: Immunological Parameters-AH50

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    End point title
    		 Immunological Parameters-AH50
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0, 35, 60
    End point values
    		 Hyalgan-F (HA-F) mITT 35 days mITT 60 days
    Number of subjects analysed
    118
    119
    118
    Units: U/mL
        median (full range (min-max))
    114.0 (70 to 176)
    105.0 (50 to 160)
    108.5 (54 to 177)
    No statistical analyses for this end point

    Secondary: Immunological Parameters-CH50

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    End point title
    		 Immunological Parameters-CH50
    End point description
    End point type
    Secondary
    End point timeframe
    day 0, 35, 60
    End point values
    		 Hyalgan-F (HA-F) mITT 35 days mITT 60 days
    Number of subjects analysed
    118
    119
    118
    Units: U/mL
        median (full range (min-max))
    300 (0 to 453)
    304.0 (0 to 436)
    308.0 (161 to 442)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The time period for recording AE was from Baseline V2 Day 0 to V10 Day 180
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    8.2
    Reporting groups
    Reporting group title
    Hyalgan-F
    Reporting group description
    		 -

    Serious adverse events
    		 Hyalgan-F
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 120 (2.50%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Reproductive system and breast disorders
    Ovarian cyst, Peritonitis, Jejunal perforatio,
         subjects affected / exposed
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    1 / 120 (0.83%)
         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
    		 Hyalgan-F
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 120 (23.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 120 (21.67%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Joint effusion
         subjects affected / exposed
    2 / 120 (1.67%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    2 / 120 (1.67%)
         occurrences all number
    2
    Osteoarthritis
         subjects affected / exposed
    12 / 120 (10.00%)
         occurrences all number
    12
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 120 (1.67%)
         occurrences all number
    2
    Respiratory tract infection
         subjects affected / exposed
    5 / 120 (4.17%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    For support, Contact us.
    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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