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    Clinical Trial Results:
    A single arm, open label, dose-escalation study of carbamylated monomeric grass pollen drops in patients with a history of allergic rhinoconjunctivitis

    Summary
    EudraCT number
    		 2018-004472-35
    Trial protocol
    		 IT  
    Global end of trial date
    18 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Aug 2021
    First version publication date
    08 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DE_LODRO_GR19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Lofarma Spa
    Sponsor organisation address
    Viale Cassala, 40, Milano, Italy,
    Public contact
    CRO, CD Pharma Srl, 039 0289051076, info@cdpharma.it
    Scientific contact
    CRO, CD Pharma Srl, 039 0289051076, info@cdpharma.it
    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
    27 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess the safety and clinical tolerability of Lais® Graminacee sublingual drops in patients with grass pollen-induced allergic rhinoconjunctivitis.
    Protection of trial subjects
    Measures in place: Stopping rules: Treatment with the IMP had to be stopped and patients had to be withdrawn from the study at any time for safety reasons. Criteria for the cessation of treatment and withdrawal of an individual patient by the investigator. Dose adjustment: A dose adjustment of the investigational product had to be performed for safety reasons.
    Background therapy
    		 Rescue medication: rhinoconjunctivitis symptoms: Desloratadine 5mg tablets. For asthmatic patients, reliever medications were allowed including beta-2-agonists.
    Evidence for comparator
    		 None
    Actual start date of recruitment
    01 Mar 2019
    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
    Italy: 39
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    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)
    39
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were enrolled in two Italian sites. The First patient was on the 25th of March 2019. Last patient out was on 18th June 2019.

    Pre-assignment
    Screening details
    		 Planned 30 patients female or male aged 18–64 years, with grass pollen-induced allergic rhinoconjunctivitis. 39 patients were enrolled in two Italian sites. 33 patients completed the study.

    Period 1
    Period 1 title
    Escalation and Maintenance (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Lais Graminacee sublingual drops
    Arm description
    		 Dose escalation phase (day 1 to 21): The IMP doses was increased incrementally to reach the patient’s individual maximum tolerable dosage. At V2, the treatment was initiated by an ultra-rush schedule with 2 doses of the IMP (2,000 UA and 5,000 UA) at 60-minute intervals in the investigator’s office. From day 2 to 6, the single dose of 5,000 UA daily was be self-administered by the patient at home. At V3 (day 7), two doses were be administered (10,000 UA and 15,000 UA) at 60-minute intervals at the investigator’s office. From day 8 to 13, the single dose of 15,000 UA daily was self-administered by the patient at home. At V4 (day 14), one dose of 25,000 UA was administered at the investigator’s office. From day 15 to 20, the single dose of 25,000 UA day. From day 22 to day 42, a single maintenance dose of 50,000 UA daily was self-administered by the patient at home.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lais® grass sublingual drops
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oromucosal drops
    Routes of administration
    Sublingual use
    Dosage and administration details
    During the dose escalation phase outside the peak grass pollen season, the doses will be increased incrementally to reach the patient’s individual maximum tolerable dosage. A dose adjustment of the investigational product had to be performed for safety reasons in case of patient experiences a moderate local reaction. Concentration of Lais® Graminacee sublingual drops span from 2000 UA to 50000 UA.

    Number of subjects in period 1
    		Lais Graminacee sublingual drops
    Started
    39
    Completed
    33
    Not completed
    6
         Consent withdrawn by subject
    3
         Physician decision
    2
         logistics
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Escalation and Maintenance
    Reporting group description
    		 -

    Reporting group values
    		 Escalation and Maintenance Total
    Number of subjects
    		 39 39
    Age categorical
    Adults between 18-64 years
    Units: Subjects
        Adults (18-64 years)
    		 39 39
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.31 ( 11.10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 16
        Male
    		 23 23
    Subject analysis sets

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population includes all patients who received at least one dose of the study treatment.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-To-Treat (ITT) population includes all patients who receive at least one dose of study treatment and have completed at least one evaluation related to the primary outcome.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol (PP) population includes all evaluable patients in the ITT population who have reached their maximum tolerated dose of drug and concluded the treatment course excluding patients with major violations.

    Subject analysis set title
    Screening
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    all screened patients includes all patients who performed the study visit V1 (Screening).

    Subject analysis sets values
    		 Safety ITT PP Screening
    Number of subjects
    34
    34
    7
    39
    Age categorical
    Adults between 18-64 years
    Units: Subjects
        Adults (18-64 years)
    34
    34
    7
    39
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    32,47 ( 11,64 )
    32,47 ( 11,64 )
    30,28 ( 10,14 )
    32,31 ( 11,10 )
    Gender categorical
    Units: Subjects
        Female
    14
    14
    4
    16
        Male
    20
    20
    3
    23

    End points

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    End points reporting groups
    Reporting group title
    Lais Graminacee sublingual drops
    Reporting group description
    		 Dose escalation phase (day 1 to 21): The IMP doses was increased incrementally to reach the patient’s individual maximum tolerable dosage. At V2, the treatment was initiated by an ultra-rush schedule with 2 doses of the IMP (2,000 UA and 5,000 UA) at 60-minute intervals in the investigator’s office. From day 2 to 6, the single dose of 5,000 UA daily was be self-administered by the patient at home. At V3 (day 7), two doses were be administered (10,000 UA and 15,000 UA) at 60-minute intervals at the investigator’s office. From day 8 to 13, the single dose of 15,000 UA daily was self-administered by the patient at home. At V4 (day 14), one dose of 25,000 UA was administered at the investigator’s office. From day 15 to 20, the single dose of 25,000 UA day. From day 22 to day 42, a single maintenance dose of 50,000 UA daily was self-administered by the patient at home.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population includes all patients who received at least one dose of the study treatment.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention-To-Treat (ITT) population includes all patients who receive at least one dose of study treatment and have completed at least one evaluation related to the primary outcome.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per Protocol (PP) population includes all evaluable patients in the ITT population who have reached their maximum tolerated dose of drug and concluded the treatment course excluding patients with major violations.

    Subject analysis set title
    Screening
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    all screened patients includes all patients who performed the study visit V1 (Screening).

    Primary: Safety

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    End point title
    		 Safety [1]
    End point description
    The primary safety endpoint was the frequency of solicited adverse events. Twenty-eight patients (82.35%) showed no such AEs, four patients (11.76%) experienced solicited local AEs and 2 patients (5.88%) experienced systemic solicited AE. Eight unsolicited AEs were observed at home and reported by the patients, all of mild severity; one was related to the treatment (itching of oral mucosa), six possibly related (sleepiness, conjunctival hyperaemia, two sneezing, upper lip wheal, nasal obstruction), and one of unknown relationship (cough). Finally, one case of abdominal pain was classified as unknow. As in routine practice, the simple use of oral antihistamine seems sufficient to control the sporadic occurrence of local and systemic reactions during updosing and maintenance phase.dose-range up to daily 50,000 UA of Lais® Graminacee sublingual drops in a suitable dose escalation scheme was generally safe and well-tolerated, thus acceptable for further investigations.
    End point type
    Primary
    End point timeframe
    from March 25th, 2019 to June 18th, 2019
    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: All data summaries and listings were performed using The SAS System version 9.4. No inferential statistics was used. All qualitative descriptive analyses about frequency and percentage were performed by proc freq statement. All quantitative descriptive analyses report N, mean, median, standard deviation, min and max were performed by proc means statement.
    End point values
    		 Lais Graminacee sublingual drops Safety
    Number of subjects analysed
    34
    34
    Units: solicited AEs
    number (not applicable)
        Systemic AEs
    2
    2
        Local AEs
    4
    4
    Attachments
    		 Delodro Appendix
    No statistical analyses for this end point

    Secondary: Safety and clinical Tollerability

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    End point title
    		 Safety and clinical Tollerability
    End point description
    Safety and clinical tolerability were assessed along the whole subjects’ treatment period by descriptive analysis: • Frequency of unsolicited (spontaneously reported during visits or by AE/CM diary card) adverse events • Proportion of patients who reached the maximum dose • Percentage/frequency of use of rescue medication during treatment phase • Physical examinations and vital signs • Laboratory tests (blood count, renal and liver function parameters) • Pulmonary function for asthmatic patients
    End point type
    Secondary
    End point timeframe
    from March 25th, 2019 to June 18th, 2019
    End point values
    		 Lais Graminacee sublingual drops ITT PP
    Number of subjects analysed
    34
    34
    7
    Units: Number
        number (not applicable)
    34
    34
    7
    Attachments
    		 Delodro Appendix
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    March 25th, 2019 - June 18th, 2019
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Lais® Graminacee sublingual drops
    Reporting group description
    		 -

    Serious adverse events
    		 Lais® Graminacee sublingual drops
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 34 (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
    		 Lais® Graminacee sublingual drops
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 34 (38.24%)
    Nervous system disorders
    Sleepiness and tingling
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Eye disorders
    Conjunctival hyperaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Gastrointestinal disorders
    Itching of oral mucosa
    Additional description: 2 AEs were solicited, 1 was unsolicited.
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    3
    Mouth ulcer
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Sneezing burst
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Sneezing
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Nasal obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Itching of lips
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Upper lip wheal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Psychiatric disorders
    sleepiness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 34 (2.94%)
         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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