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    Clinical Trial Results:
    Randomized, Double-blind, Placebo-controlled, Crossover Design, Efficacy and Safety Study with PA101 in Patients with Indolent Systemic Mastocytosis

    Summary
    EudraCT number
    		 2014-004113-85
    Trial protocol
    		 NL   DE   ES   IT  
    Global end of trial date
    15 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Oct 2020
    First version publication date
    24 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PA101-SM-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02478957
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Patara Pharma, Inc.
    Sponsor organisation address
    11455 El Camino Real, Suite 460, San Diego, United States, CA 92130
    Public contact
    Project Manager, Patara Pharma, Inc., atutuncu@respivant.com
    Scientific contact
    Project Manager, Patara Pharma, Inc., atutuncu@respivant.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
    15 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy profile of PA101 delivered via a high efficiency nebulizer (eFlow®, PARI) in comparison with placebo following 6 weeks of treatment in subjects with indolent systemic mastocytosis (ISM) who were symptomatic despite using standard treatments.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and its revisions as well as with the valid national laws of the participating countries, with the International Council for Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice. The principal investigator was responsible for ensuring that the clinical study was performed in accordance with the Medicines for Human Use (Clinical Trials) Regulations 2004 and subsequent amendments.
    Background therapy
    		 Subjects continued taking the same daily doses of pre-randomization H1 and H2 antihistamines as well as the same daily doses of any other allowed medication during the Treatment Periods.
    Evidence for comparator
    		 Oral cromolyn sodium (Nalcrom®) is used in the management of subjects with mastocytosis and food intolerance, given orally at doses up to 200 milligrams (mg) four times daily (QID).
    Actual start date of recruitment
    26 May 2015
    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
    Netherlands: 6
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    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)
    38
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects with ISM were recruited to this Phase 2, 2-cohort, 6-week treatment, 2-period crossover study conducted in 8 study centers in 5 countries. The first subject entered the study on 26 May 2015 and the last subject completed on 15 June 2016.

    Pre-assignment
    Screening details
    		 Eligible subjects entered a 14-day Run-in Period to establish symptom scores to determine eligibility using an eDiary. At the Baseline Visit eligibility was confirmed and subjects were randomized in a 2:1 ratio to 1 of 2 treatment cohorts and to 1 of 2 treatment sequences in a 1:1 ratio (2 Treatment Periods with a 4-week washout period).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    For Cohort 1, study subjects, investigators, study staff and the sponsor were blinded to the randomization scheme until all subjects completed the study and the blind was formally broken for all subjects. In Cohort 2, treatment was open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: PA101 then Placebo
    Arm description
    		 Cohort 1 was randomized, double-blind, and placebo-controlled. Subjects were randomly assigned to PA101 or Placebo for Treatment Period 1, and crossed over to the alternative treatment in Treatment Period 2. There was a 4-week washout period between Treatment Periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PA101
    Investigational medicinal product code
    Other name
    Inhaled cromolyn sodium
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    For double-blind Treatment Period 1, subjects received 40 mg PA101 3 times daily (TID), oral inhalation via eFlow for 6 weeks, followed by a 4-week washout period.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    For double-blind Treatment Period 2, subjects received matching placebo TID, oral inhalation via eFlow for 6 weeks.

    Arm title
    		 Cohort 1: Placebo then PA101
    Arm description
    		 Cohort 1 was randomized, double-blind, and placebo-controlled. Subjects were randomly assigned to PA101 or Placebo for Treatment Period 1, and the alternative treatment in Treatment Period 2. There was a 4-week washout period between Treatment Periods.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    For double-blind Treatment Period 1, subjects received matching placebo TID, oral inhalation via eFlow for 6 weeks followed by a 4-week washout period.

    Investigational medicinal product name
    PA101
    Investigational medicinal product code
    Other name
    Inhaled cromolyn sodium
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    For double-blind Treatment Period 2, subjects received 40 mg PA101 TID, oral inhalation via eFlow for 6 weeks.

    Arm title
    		 Cohort 2: PA101 then Nalcrom®
    Arm description
    		 Cohort 2 was an open-label comparison of PA101 with marketed product, oral cromolyn sodium (Nalcrom®). Subjects were randomly assigned to PA101 or Nalcrom® for Treatment Period 1, and crossed over to the alternative treatment in Treatment Period 2. There was a 4-week washout period between Treatment Periods.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PA101
    Investigational medicinal product code
    Other name
    Inhaled cromolyn sodium
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    For open-label Treatment Period 1, subjects received 40 mg PA101 TID, oral inhalation via eFlow for 6 weeks, followed by a 4-week washout period.

    Investigational medicinal product name
    Nalcrom®
    Investigational medicinal product code
    Other name
    Oral cromolyn sodium
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    For open-label Treatment Period 2, subjects received 200 mg Nalcrom® QID, oral capsule for 6 weeks.

    Arm title
    		 Cohort 2: Nalcrom® then PA101
    Arm description
    		 Cohort 2 was an open-label comparison of PA101 with marketed product, oral cromolyn sodium (Nalcrom®). Subjects were randomly assigned to PA101 or Nalcrom® for Treatment Period 1, and crossed over to the alternative treatment in Treatment Period 2. There was a 4-week washout period between each treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nalcrom®
    Investigational medicinal product code
    Other name
    Oral cromolyn sodium
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    For open-label Treatment Period 1, subjects received 200 mg Nalcrom® QID, oral capsule for 6 weeks, followed by a 4-week washout period.

    Investigational medicinal product name
    PA101
    Investigational medicinal product code
    Other name
    Inhaled cromolyn sodium
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    For open-label Treatment Period 2, subjects received 40 mg PA101 TID, oral inhalation via eFlow for 6 weeks.

    Number of subjects in period 1 [1]
    		Cohort 1: PA101 then Placebo Cohort 1: Placebo then PA101 Cohort 2: PA101 then Nalcrom® Cohort 2: Nalcrom® then PA101
    Started
    13
    14
    7
    7
    Completed Treatment Period 1
    12
    13
    7
    6
    Started Treatment Period 2
    12
    13
    7
    6
    Completed
    12
    12
    6
    5
    Not completed
    1
    2
    1
    2
         Physician decision
    -
    1
    -
    -
         Adverse event, non-fatal
    1
    -
    1
    2
         Protocol violation
    -
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 42 subjects were enrolled and randomized. One subject included in Cohort 1 was randomized in error as they did not meet all inclusion criteria. This subject did not receive any study medication and was excluded from all analysis sets. Therefore, a total of 27 subjects started Cohort 1 and 14 subjects started Cohort 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: PA101 then Placebo
    Reporting group description
    		 Cohort 1 was randomized, double-blind, and placebo-controlled. Subjects were randomly assigned to PA101 or Placebo for Treatment Period 1, and crossed over to the alternative treatment in Treatment Period 2. There was a 4-week washout period between Treatment Periods.

    Reporting group title
    Cohort 1: Placebo then PA101
    Reporting group description
    		 Cohort 1 was randomized, double-blind, and placebo-controlled. Subjects were randomly assigned to PA101 or Placebo for Treatment Period 1, and the alternative treatment in Treatment Period 2. There was a 4-week washout period between Treatment Periods.

    Reporting group title
    Cohort 2: PA101 then Nalcrom®
    Reporting group description
    		 Cohort 2 was an open-label comparison of PA101 with marketed product, oral cromolyn sodium (Nalcrom®). Subjects were randomly assigned to PA101 or Nalcrom® for Treatment Period 1, and crossed over to the alternative treatment in Treatment Period 2. There was a 4-week washout period between Treatment Periods.

    Reporting group title
    Cohort 2: Nalcrom® then PA101
    Reporting group description
    		 Cohort 2 was an open-label comparison of PA101 with marketed product, oral cromolyn sodium (Nalcrom®). Subjects were randomly assigned to PA101 or Nalcrom® for Treatment Period 1, and crossed over to the alternative treatment in Treatment Period 2. There was a 4-week washout period between each treatment.

    Reporting group values
    		 Cohort 1: PA101 then Placebo Cohort 1: Placebo then PA101 Cohort 2: PA101 then Nalcrom® Cohort 2: Nalcrom® then PA101 Total
    Number of subjects
    		 13 14 7 7 41
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.4 ( 10.67 ) 47.2 ( 12.94 ) 41.1 ( 16.83 ) 53.4 ( 15.52 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 11 5 5 29
        Male
    		 5 3 2 2 12

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: PA101 then Placebo
    Reporting group description
    		 Cohort 1 was randomized, double-blind, and placebo-controlled. Subjects were randomly assigned to PA101 or Placebo for Treatment Period 1, and crossed over to the alternative treatment in Treatment Period 2. There was a 4-week washout period between Treatment Periods.

    Reporting group title
    Cohort 1: Placebo then PA101
    Reporting group description
    		 Cohort 1 was randomized, double-blind, and placebo-controlled. Subjects were randomly assigned to PA101 or Placebo for Treatment Period 1, and the alternative treatment in Treatment Period 2. There was a 4-week washout period between Treatment Periods.

    Reporting group title
    Cohort 2: PA101 then Nalcrom®
    Reporting group description
    		 Cohort 2 was an open-label comparison of PA101 with marketed product, oral cromolyn sodium (Nalcrom®). Subjects were randomly assigned to PA101 or Nalcrom® for Treatment Period 1, and crossed over to the alternative treatment in Treatment Period 2. There was a 4-week washout period between Treatment Periods.

    Reporting group title
    Cohort 2: Nalcrom® then PA101
    Reporting group description
    		 Cohort 2 was an open-label comparison of PA101 with marketed product, oral cromolyn sodium (Nalcrom®). Subjects were randomly assigned to PA101 or Nalcrom® for Treatment Period 1, and crossed over to the alternative treatment in Treatment Period 2. There was a 4-week washout period between each treatment.

    Subject analysis set title
    Cohort 1: PA101
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All Cohort 1 subjects who received PA101 in Treatment Periods 1 and 2.

    Subject analysis set title
    Cohort 1: Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All Cohort 1 subjects who received placebo in Treatment Periods 1 and 2.

    Subject analysis set title
    Cohort 2: PA101
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All Cohort 2 subjects who received PA101 in Treatment Periods 1 and 2.

    Subject analysis set title
    Cohort 2: Nalcrom®
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All Cohort 2 subjects who received Nalcrom® in Treatment Periods 1 and 2.

    Primary: Mean Change from Baseline in the Average Daily Modified Mastocytosis Activity of Symptoms (MAS) Plus Severity Score at Week 6

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    End point title
    		 Mean Change from Baseline in the Average Daily Modified Mastocytosis Activity of Symptoms (MAS) Plus Severity Score at Week 6
    End point description
    Subjects used a daily eDiary for the assessment of symptoms using the MAS Plus questionnaire throughout the study. The MAS Plus questionnaire is a 27-item, disease-specific questionnaire designed to measure impact of systemic mastocytosis on overall health, daily life and perceived well-being of subjects across 5 different organ systems/domains: skin (pruritus, whealing, and flushing); gastrointestinal (diarrhea and abdominal pain); central nervous system (headache and difficulty concentrating); musculoskeletal (bone pain) and general system (fatigue). The MAS plus Severity Score was calculated as the total of all 9 symptoms. The maximum daily MAS Plus Severity Score is 90 with higher scores indicating a higher disease activity. The average daily score was calculated using the 14 days pre-treatment for baseline and the last 14 days of treatment for each treatment period.
    End point type
    Primary
    End point timeframe
    Baseline and Week 6.
    End point values
    		 Cohort 1: PA101 Cohort 1: Placebo Cohort 2: PA101 Cohort 2: Nalcrom®
    Number of subjects analysed
    25
    26
    13
    14
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -3.8 ( 8.41 )
    -6.8 ( 9.58 )
    -6.9 ( 12.23 )
    -4.0 ( 7.16 )
    Statistical analysis title
    		 Treatment Difference: Cohort 1 (PA101 - Placebo)
    Comparison groups
    Cohort 1: PA101 v Cohort 1: Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2695
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    2.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.99
         upper limit
    		 6.74
    Statistical analysis title
    		 Treatment Difference: Cohort 2 (PA101 - Nalcrom®)
    Comparison groups
    Cohort 2: PA101 v Cohort 2: Nalcrom®
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.542
    Method
    		 Mixed models analysis
    Parameter type
    		 LS mean difference
    Point estimate
    -1.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 4.71

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were assessed from the Baseline Visit up to Week 6 of each Treatment Period, and at the Safety Follow-up visit within 7 days after the last study treatment.
    Adverse event reporting additional description
    Treatment emergent AEs are presented overall for all subjects in both Cohorts 1 and 2 who received PA101.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Overall: PA101
    Reporting group description
    		 All subjects in Cohorts 1 and 2 who received PA101 (40 mg TID, oral inhalation via eFlow for 6 weeks) during Treatment Periods 1 and 2.

    Serious adverse events
    		 Overall: PA101
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 39 (2.56%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Vascular pseudoaneurysm ruptured
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Overall: PA101
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 39 (48.72%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Abdominal pain upper
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Dyspepsia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Genital burning sensation
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Gastrointestinal infection
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Feb 2015
    - Inclusion criterion regarding written informed consent was clarified. - Exclusion criteria were clarified regarding reliable contraception and for subjects under guardianship, trusteeship, or committed to an institution by order of government or judicial authorities or who had a relationship so that they were rendered dependent to the investigator/study center staff or the sponsor. - Examples of conditions that would warrant a termination of the study by the sponsor were added. - Tests for significance testing of the efficacy analyses were updated. - Reference for the Declaration of Helsinki was corrected.
    12 Aug 2015
    - It was clarified that subjects needed to have used at least 1 of the given therapies (i.e. H1 and/or H2 antihistamines and/or other antimediator therapy) to be eligible for the study. - A timeframe of 6 weeks for the history of systemic corticosteroid use was added to the exclusion criteria.

    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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