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    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase II trial to investigate the efficacy and safety of 30 mcg and 100 mcg AS902330 given as one cycle of three intra-articular knee injections once a week for three weeks as an adjunct treatment to patients following microfracture surgery for cartilage injury of the knee.

    Summary
    EudraCT number
    2012-001431-31
    Trial protocol
    BE  
    Global end of trial date
    10 Sep 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    04 Jul 2016
    First version publication date
    04 Jul 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Update in population of trial subjects section

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR700692-007
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01689337
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.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
    10 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The trial’s primary objectives were as follows: To evaluate the effect of AS902330 intra-articular (i.a.) knee injections as adjunct to microfracture (MFx) surgery on the composition of the refilled cartilage in the target knee, as measured by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) T1 relaxation time at 6 months after MFx surgery. To evaluate the safety profile of AS902330 when administered i.a into the knee as adjunct to MFx surgery in subjects with cartilage injury of the knee.
    Protection of trial subjects
    Patient protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Apr 2013
    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
    United States: 1
    Worldwide total number of subjects
    1
    EEA total number of subjects
    0
    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)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    First/last subject (informed consent): Apr 2013/Aug 2013; Study completion date: September 2013.

    Pre-assignment
    Screening details
    A total of 4 subjects were screened and gave signed informed consent to participate in the study. Three subjects were screen failure, therefore only one subject was randomized.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Arm title
    Sprifermin (AS902330), 100 mcg
    Arm description
    Sprifermin (AS902330) was administered at a dose of 100 microgram (mcg) as intra-articular injection once every week for 3 weeks, starting from 2 weeks after microfracture (MFx) surgery.
    Arm type
    Experimental

    Investigational medicinal product name
    Sprifermin
    Investigational medicinal product code
    Other name
    AS902330, recombinant human FGF-18, rhFGF-18
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Sprifermin (AS902330) was administered at a dose of 100 microgram (mcg) as intra-articular injection once every week for 3 weeks, starting from 2 weeks after microfracture (MFx) surgery.

    Number of subjects in period 1
    Sprifermin (AS902330), 100 mcg
    Started
    1
    Completed
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall
    Reporting group description
    -

    Reporting group values
    Overall Total
    Number of subjects
    1 1
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    1 1
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Sprifermin (AS902330), 100 mcg
    Reporting group description
    Sprifermin (AS902330) was administered at a dose of 100 microgram (mcg) as intra-articular injection once every week for 3 weeks, starting from 2 weeks after microfracture (MFx) surgery.

    Primary: Composition of the Refilled Cartilage Measured by Delayed Gadolinium-Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC) Using T1 Relaxation Time at Month 6 Post-MFx Surgery

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    End point title
    Composition of the Refilled Cartilage Measured by Delayed Gadolinium-Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC) Using T1 Relaxation Time at Month 6 Post-MFx Surgery [1]
    End point description
    The dGEMRIC is an imaging technique that estimates the proteoglycan (and glycosaminoglycan) content of joint cartilage using spin-lattice relaxation time T1 after penetration of gadolinium contrast agent. Composition of the refilled cartilage was to be reported.
    End point type
    Primary
    End point timeframe
    6 months post-MFx surgery
    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: Efficacy analysis was not performed as only one subject was enrolled in the study.
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [2]
    Units: Subjects
    Notes
    [2] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Composition of the Refilled Cartilage Measured by dGEMRIC Using T1 Relaxation Time Beyond Month 6 Post-MFx Surgery

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    End point title
    Composition of the Refilled Cartilage Measured by dGEMRIC Using T1 Relaxation Time Beyond Month 6 Post-MFx Surgery
    End point description
    The dGEMRIC is an imaging technique that estimates the proteoglycan (and glycosaminoglycan) content of joint cartilage using spin-lattice relaxation time T1 after penetration of gadolinium contrast agent. Composition of the refilled cartilage was to be reported.
    End point type
    Secondary
    End point timeframe
    Every 6 months up to 5 years beyond 6 months post-MFx surgery
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [3]
    Units: Subjects
    Notes
    [3] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Subject-reported Outcome Measure: Knee Injury and Osteoarthritis Outcome Score (KOOS) Sub-scores for Pain and Activities of Daily Living (ADL)

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    End point title
    Change From Baseline in Subject-reported Outcome Measure: Knee Injury and Osteoarthritis Outcome Score (KOOS) Sub-scores for Pain and Activities of Daily Living (ADL)
    End point description
    The KOOS Version LK1.0 is a knee-specific self-administered questionnaire used to assess pain, function, quality of life, and ADL. It consists of 42 items grouped into 5 subscales: pain, other symptoms (including swelling, restricted range of motion, and mechanical symptoms), function in ADL, function in sport and recreation (FSR), and impact on quality of life (QOL) (knee-related QOL, including awareness of the knee condition and changes in lifestyle). The subscales are scored separately; each yields a score between 0 and 100, with 0 representing extreme knee problems and 100 representing absence of problems. Total KOOS score is the average of all 5 subscale scores; ranging from 0 to 100; where 0 represents extreme knee problems and 100 represents absence of knee problems. Change from baseline in pain and ADL sub-scores was to be calculated by the respective scores at the specific time point minus the scores at baseline.
    End point type
    Secondary
    End point timeframe
    Every 6 months up to 5 years
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [4]
    Units: Subjects
    Notes
    [4] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Subject-reported Outcome Measure: Total KOOS Score, Three KOOS Sub-scores and Total KOOS Minus FSR Sub-score

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    End point title
    Change From Baseline in Subject-reported Outcome Measure: Total KOOS Score, Three KOOS Sub-scores and Total KOOS Minus FSR Sub-score
    End point description
    The KOOS Version LK1.0 is a knee-specific self-administered questionnaire used to assess pain, function, quality of life, and ADL. It consists of 42 items grouped into 5 subscales: pain, other symptoms (including swelling, restricted range of motion, and mechanical symptoms), function in ADL, FSR, and impact on QOL (knee-related QOL, including awareness of the knee condition and changes in lifestyle). The subscales are scored separately; each yields a score between 0 and 100, with 0 representing extreme knee problems and 100 representing absence of problems. Total KOOS score is the average of all 5 subscale scores; ranging from 0 to 100; where 0 represents extreme knee problems and 100 represents absence of knee problems. Change from baseline in total KOOS score; other symptoms, knee-related QOL, and FSR sub-scores; and total KOOS minus FSR sub-score was to be calculated by the respective scores at the specific time point minus the scores at baseline.
    End point type
    Secondary
    End point timeframe
    Every 6 months up to 5 years
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [5]
    Units: Subjects
    Notes
    [5] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Composition of the Refilled Cartilage Using T2 Mapping

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    End point title
    Composition of the Refilled Cartilage Using T2 Mapping
    End point description
    The transverse relaxation time T2 mapping is an MRI technique that is able to evaluate collagen organization and orientation within cartilage. Composition of the refilled cartilage was to be reported.
    End point type
    Secondary
    End point timeframe
    Every 6 months up to 5 years
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [6]
    Units: Subjects
    Notes
    [6] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Volume of the Refilled Cartilage

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    End point title
    Volume of the Refilled Cartilage
    End point description
    Volume of the refilled cartilage was to be measured by MRI.
    End point type
    Secondary
    End point timeframe
    Every 6 months up to 5 years
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [7]
    Units: Subjects
    Notes
    [7] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) Score

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    End point title
    Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) Score
    End point description
    The MOCART score is used to describe the constitution of the cartilage repair tissue and the surrounding structures.
    End point type
    Secondary
    End point timeframe
    Every 6 months up to 5 years
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [8]
    Units: Subjects
    Notes
    [8] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Six-minute Walk Test

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    End point title
    Six-minute Walk Test
    End point description
    Six (6)-minute walk test is used to measure gait function and for pre- and post-operative evaluation in cartilage injury repair. Maximum comfortable distance (in meters) that a subject can walk in 6 minutes was to be reported.
    End point type
    Secondary
    End point timeframe
    Every 3 months up to 5 years beyond Month 6 post-MFx surgery
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [9]
    Units: Subjects
    Notes
    [9] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE is an AE that results in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 60
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    1
    Units: Subjects
        SAEs
    0
        AEs
    6
    No statistical analyses for this end point

    Secondary: Change From Baseline in Subject-reported Outcome Measure: Numeric Rating Scale (NRS) Score

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    End point title
    Change From Baseline in Subject-reported Outcome Measure: Numeric Rating Scale (NRS) Score
    End point description
    Knee pain was to be rated by the subject using an 11-point NRS of pain intensity. The NRS is scaled from 0 (no pain) to 10 (worst possible pain). Change from baseline in NRS score was to be calculated by the score at the specific time point minus the score at baseline.
    End point type
    Secondary
    End point timeframe
    Every 6 months up to 5 years
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [10]
    Units: Units on scale
    Notes
    [10] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Subject-reported Outcome Measure: Lower Extremity Activity Scale (LEAS) Score

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    End point title
    Change From Baseline in Subject-reported Outcome Measure: Lower Extremity Activity Scale (LEAS) Score
    End point description
    The LEAS is an 18-level single-question self-administered scale that has been validated as a clinical outcome measure for the assessment of subjects' actual activity levels. The LEAS is scaled from 1 to 18, with 18 indicating levels of highest activity. Change from baseline in LEAS score was to be calculated by the score at the specific time point minus the score at baseline.
    End point type
    Secondary
    End point timeframe
    Every 6 months up to 5 years
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [11]
    Units: Units on scale
    Notes
    [11] - Efficacy analysis was not performed as only one subject was enrolled in the study.
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Physician-reported Outcome Measure: Lysholm Knee Scale Score

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    End point title
    Change From Baseline in the Physician-reported Outcome Measure: Lysholm Knee Scale Score
    End point description
    The Lysholm knee scale is a physician-reported outcome measure to assess knee function after ligament injury. It is scaled from 0 to 100 with higher scores representing better function. Change from baseline in Lysholm knee scale score was to be calculated by the score at the specific time point minus the score at baseline.
    End point type
    Secondary
    End point timeframe
    Every 6 months up to 5 years
    End point values
    Sprifermin (AS902330), 100 mcg
    Number of subjects analysed
    0 [12]
    Units: Units on scale
        number (not applicable)
    Notes
    [12] - Efficacy analysis was not performed as only one subject was enrolled in the study
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 6 months
    Adverse event reporting additional description
    An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Sprifermin (AS902330), 100 mcg
    Reporting group description
    Sprifermin (AS902330) will be administered at a dose of 100 microgram (mcg) as intra-articular injection once every week for 3 weeks, starting from 2 weeks after MFx surgery.

    Serious adverse events
    Sprifermin (AS902330), 100 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Sprifermin (AS902330), 100 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Infections and infestations
    Pyrexia
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Streptococcal pharyngitis
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1

    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.
    Efficacy analysis was not performed as only one subject was enrolled in the study. The study was terminated due to low recruitment.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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