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    Clinical Trial Results:
    A PHASE 2 MULTICENTER,OPEN-LABEL, UNCONTROLLED STUDY TO EVALUATE THE SAFETY, TOLERABILITY, EFFICACY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF RA101495 IN SUBJECTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

    Summary
    EudraCT number
    2016-003522-16
    Trial protocol
    FI   GB   HU   DK  
    Global end of trial date
    28 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Jul 2019
    First version publication date
    05 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RA101495-01.201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03078582
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ra Pharmaceuticals, Inc.
    Sponsor organisation address
    87 Cambridge Park Drive, Cambridge, United States, MA 02140
    Public contact
    Ra Pharmaceuticals, Inc., Ra Pharmaceuticals, Inc., +1 6174014060, trials@rapharma.com
    Scientific contact
    Ra Pharmaceuticals, Inc., Ra Pharmaceuticals, Inc., +1 6174014060, trials@rapharma.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
    14 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To assess the safety and tolerability of RA101495 in subjects with PNH • To assess preliminary efficacy of RA101495 in subjects with PNH • To assess PK and PD of RA101495 in subjects with PNH
    Protection of trial subjects
    Patients were to give freely their written informed consent before entering the study. Patients were provided with updated information and re-consented if substantial changes in the study occurred. This study was performed in accordance with Good Clinical Practice standards.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Apr 2017
    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 Kingdom: 5
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    New Zealand: 4
    Worldwide total number of subjects
    26
    EEA total number of subjects
    16
    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)
    18
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 29 subjects were screened for enrollment into the study. A total of 26 subjects were enrolled into the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort A
    Arm description
    Eculizumab Naïve - included subjects who have not received eculizumab for treatment of PNH
    Arm type
    Experimental

    Investigational medicinal product name
    RA101495
    Investigational medicinal product code
    RA101495
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    RA101495 was provided as a solution for injection containing 40mg/mL of active ingredient in a daily prefilled syringe. Doses provided for the study included 0.1mg/kg and 0.3mg/kg.

    Arm title
    Cohort B
    Arm description
    Eculizumab Switch - included subjects who have received treatment with eculizumab for at least 6 months prior to Screening
    Arm type
    Experimental

    Investigational medicinal product name
    RA101495
    Investigational medicinal product code
    RA101495
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    RA101495 was provided as a solution for injection containing 40mg/mL of active ingredient in a daily prefilled syringe. Doses provided for the study included 0.1mg/kg and 0.3mg/kg.

    Number of subjects in period 1
    Cohort A Cohort B
    Started
    10
    16
    Completed
    10
    8
    Not completed
    0
    8
         Adverse event, non-fatal
    -
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    Eculizumab Naïve - included subjects who have not received eculizumab for treatment of PNH

    Reporting group title
    Cohort B
    Reporting group description
    Eculizumab Switch - included subjects who have received treatment with eculizumab for at least 6 months prior to Screening

    Reporting group values
    Cohort A Cohort B Total
    Number of subjects
    10 16 26
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    7 11 18
        From 65-84 years
    3 5 8
    Age continuous
    Units: years
        median (full range (min-max))
    56.0 (32 to 81) 53.0 (22 to 72) -
    Gender categorical
    Units: Subjects
        Female
    6 7 13
        Male
    4 9 13
    Race
    Units: Subjects
        White
    10 14 24
        Black or African American
    0 2 2
    Weight
    Units: kg
        median (full range (min-max))
    78.10 (46.0 to 100.8) 80.15 (54.9 to 109.7) -
    Height
    Units: cm
        median (full range (min-max))
    165.00 (157.5 to 188.0) 169.00 (154.2 to 182.0) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    Eculizumab Naïve - included subjects who have not received eculizumab for treatment of PNH

    Reporting group title
    Cohort B
    Reporting group description
    Eculizumab Switch - included subjects who have received treatment with eculizumab for at least 6 months prior to Screening

    Primary: Primary Efficacy Endpoint: Change in serum LDH levels

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    End point title
    Primary Efficacy Endpoint: Change in serum LDH levels [1]
    End point description
    Primary Efficacy Endpoint: Change from baseline in serum LDH levels during the primary evaluation period, defined as the mean LDH values of Weeks 6, 8, 10, and 12 minus the baseline LDH value. Efficacy Evaluable Population analysis is presented. For Cohort A subjects' baseline LDH is the average of the study Day 1 and Screening Period values. In Cohort A a Wilcoxon signed rank test is applied to assess the change from Baseline in the Primary Evaluation Period (p=0.0020 in the Efficacy Evaluable Population).
    End point type
    Primary
    End point timeframe
    Primary Evaluation Period value is the patient’s mean value across the Week 6, 8, 10, and 12 visits.
    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: The planned statistical test on the Primary Efficacy Endpoint is a comparison between the Baseline value and the Primary Evaluation Period within Cohort A only. Since statistical tests are expected to compare different groups, this statistical test cannot be entered without evoking validation error message.
    End point values
    Cohort A Cohort B
    Number of subjects analysed
    10 [2]
    8 [3]
    Units: U/L
        arithmetic mean (standard deviation)
    -695.2 ± 589.2
    216.7 ± 209.2
    Notes
    [2] - Efficacy Evaluable Population analysis is presented here.
    [3] - Efficacy Evaluable Population analysis is presented here.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For all subjects, the AE reporting period started with the first administration of study drug on Day 1 and ended with the final study visit, after which no new AEs were to be reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    Eculizumab Naïve - included subjects who have not received eculizumab for treatment of PNH

    Reporting group title
    Cohort B
    Reporting group description
    Eculizumab Switch - included subjects who have received treatment with eculizumab for at least 6 months prior to Screening

    Serious adverse events
    Cohort A Cohort B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Febrile nonhaemolytic transfusion reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort A Cohort B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    15 / 16 (93.75%)
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 16 (18.75%)
         occurrences all number
    1
    3
    Injection site bruising
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 16 (6.25%)
         occurrences all number
    3
    1
    Asthenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Crepitations
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Feeling cold
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Vaccination site pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Vaginal discharge
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Febrile nonhaemolytic transfusion reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Investigations
    Blood glucose fluctuation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Liver function test increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Haemolysis
         subjects affected / exposed
    0 / 10 (0.00%)
    7 / 16 (43.75%)
         occurrences all number
    0
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    7 / 16 (43.75%)
         occurrences all number
    1
    7
    Dizziness
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 16 (18.75%)
         occurrences all number
    2
    3
    Dysgeusia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 16 (6.25%)
         occurrences all number
    2
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    0
    3
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Enteritis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Proctalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Paroxysmal nocturnal haemoglobinuria
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 16 (12.50%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Product issues
    Device failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 16 (18.75%)
         occurrences all number
    1
    3
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    2
    Pain in extremity
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    2
    Flank pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 16 (6.25%)
         occurrences all number
    3
    1
    Localised infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Urosepsis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0

    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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