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    Clinical Trial Results:
    Phase III comparative clinical trial to evaluate the efficacy of amniotic membrane extract for the treatment of severe dry eye disease, in comparison with autologous serum eyedrops.

    Summary
    EudraCT number
    		 2011-006287-50
    Trial protocol
    		 ES  
    Global end of trial date
    11 Feb 2019

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

    Trial information

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    Trial identification
    Sponsor protocol code
    EMAOS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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 2725, ucicec@unav.es
    Scientific contact
    UCICEC, Clínica Universidad de Navarra, 34 948 255 400 2725, 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
    26 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish the efficacy of topical amniotic membrane extract to treat symptoms of severe dry eye disease.
    Protection of trial subjects
    The study was conducted in accordance with the International Conference on Harmonisation (ICH) in relation to good clinical practice and related regulatory requirements. The investigator was familiar with and correctly handled the study drug as described in the protocol dossier. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki in its latest revision and with current legislation. The ethics committee reviewed all study documentation in order to protect the rights, safety and welfare of patients. The investigator provided the ethics committee with the protocol, informed consent, written information provided to patients, safety updates, annual progress reports and any amendments to these documents. The ethics committee, after review, gave its approval for the study to be carried out.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Mar 2016
    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: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    11
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patient recruitment period took place from 04/12/2015 to 20/12/2018. 12 patients were recruited, 6 of whom were assigned to the control arm and 6 to the experimental treatment arm. One patient discontinued for personal reasons and another for non-drug related discomfort. A third was a screening failure.

    Pre-assignment
    Screening details
    		 Patients between 18 and 80 years old, diagnosed by severe or very severe dry eye according to Dry Eye WorkShop (DEWS) classification.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    The study was conducted with a blinded evaluator. The patient was aware of the treatment, as in order to obtain the autologous serum, blood had to be drawn from the patient. In addition, the person who dispensed the eye drops to the patient was also aware of the treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Arm
    Arm description
    		 Patients in this arm are treated with amniotic membrane extract.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amniotic membrane extract
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, suspension
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    The patient will be administered 1 drop (concentration of 50 micrograms/millilitre) in both eyes 4 times a day for 12 weeks.

    Arm title
    		 Control arm
    Arm description
    		 Patients in this arm are treated with autologous serum.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    autologous serum
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Eye drops, suspension
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    The patient will be administered 1 drop 4 times a day for 12 weeks.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Because of the trial design, the patient and the investigator could not be blinded to the treatment. However, the assessor/evaluator was blinded to the treatment.
    Number of subjects in period 1
    		Treatment Arm Control arm
    Started
    6
    6
    Completed
    5
    4
    Not completed
    1
    2
         screening failure
    -
    1
         personal problems
    -
    1
         Discomfort not related to treatment.
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    		 -

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 11 11
        From 65-84 years
    		 1 1
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Treatment Arm
    Reporting group description
    		 Patients in this arm are treated with amniotic membrane extract.

    Reporting group title
    Control arm
    Reporting group description
    		 Patients in this arm are treated with autologous serum.

    Primary: Efficacy of amniotic membrane extract

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    End point title
    		 Efficacy of amniotic membrane extract
    End point description
    Effectiveness is assessed by determining the tear volume and clearance by Schirmer Test type I and FCT (Fluorescein Clearance test) according to Tseng technique (10, 20 and 30 minutes), the tear stability by TBUT (tear break up time) and the ocular surface Impression cytology analysis: HLA-DR and MUC1 expression. For each of the variables per visit, the mean/median of the results obtained in the right eye and in the left eye have also been calculated and the results are indicated as "both eyes".Comparisons are made between "right eye" and "left eye". Comparisons are also made between the control and experimental branches using the variable resulting from finding the mean between the two eyes, with the data obtained in V4 and V5. No statistically significant differences were found when comparing the two treatment groups for any of the study variables.
    End point type
    Primary
    End point timeframe
    Efficacy is assessed at all trial visits.
    End point values
    		 Treatment Arm Control arm
    Number of subjects analysed
    5
    4
    Units: NA
    arithmetic mean (standard deviation)
        tear volume and clearance V4
    4 ( 4.73 )
    1.25 ( 0.65 )
        tear stability by TBUT V4
    1.3 ( 1.04 )
    3 ( 1.41 )
        HLA-DR expression V4
    1 ( 0.4 )
    3.43 ( 2.82 )
        Expresión de MUC1 V4
    6.65 ( 5.50 )
    11.1 ( 9.32 )
        tear volume and clearance V5
    2.1 ( 1.30 )
    3.63 ( 4.18 )
        tear stability by TBUT V5
    2.6 ( 1.30 )
    3.37 ( 0.48 )
    Statistical analysis title
    		 Sum of ranks Wilcoxon (U de Mann-Whitney).
    Comparison groups
    Treatment Arm v Control arm
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [1] - The results obtained in the control arm (autologous serum) versus the experimental arm (amniotic membrane extract) are compared at V4 and V5 where data were obtained for each variable explored.

    Secondary: Clinical improvement

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    End point title
    		 Clinical improvement
    End point description
    At V4, four of the five patients who received amniotic membrane serum (80%) perceived subjective clinical improvement. With autologous serum, two patients out of 4 patients (50%) improved up to V4. The direction of these changes supports the hypothesis of a possible effect of amniotic membrane serum, as the difference in ratios at V4 indicates that the experimental treatment produces a 30% greater improvement.
    End point type
    Secondary
    End point timeframe
    Subjective clinical improvement of trial patients is assessed at visits 2, 3 and 4.
    End point values
    		 Treatment Arm Control arm
    Number of subjects analysed
    5
    4
    Units: incidence of improvement
        Clinical improvement
    4
    2
        No clinical improvement
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Patient safety is assessed throughout their participation in the study. A final follow-up visit is made four weeks after the end of treatment.
    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
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    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
    3 / 12 (25.00%)
    General disorders and administration site conditions
    vocal cord oedema
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Social circumstances
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Facial rosacea
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    proctalgia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Intense pruritus on abdomen, arms and legs
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    foreign body in left hand
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    left shoulder pain
         subjects affected / exposed
    1 / 12 (8.33%)
         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.
    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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