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    Clinical Trial Results:
    A Randomized Controlled Phase 3 Study of Oral Pacritinib versus Best Available Therapy in Patients with Thrombocytopenia and Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

    Summary
    EudraCT number
    2013-004000-19
    Trial protocol
    BE   GB   DE   HU   CZ   NL   FR  
    Global end of trial date
    26 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Aug 2018
    First version publication date
    11 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PAC326
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02055781
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CTI Life Sciences Ltd.
    Sponsor organisation address
    Highlands House, Basingstoke Road, Spencers Wood, Reading, Berkshire, United Kingdom, RG7 1NT
    Public contact
    Bruce Seeley Director, CTILS, CTI Life Sciences Ltd., +1 206-272-4260, bseeley@ctibiopharma.com
    Scientific contact
    Bruce Seeley Director, CTILS, CTI Life Sciences Ltd., +1 206-272-4260, bseeley@ctibiopharma.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
    16 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the PERSIST-2 (PAC326) study was to compare the efficacy of pacritinib pooled once-daily (QD) and twice-daily (BID) dosing arms with that of BAT in subjects with thrombocytopenia and PMF, PPV-MF, or PET-MF. The efficacy co-primary endpoints for this analysis were the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and the proportion of subjects achieving a ≥50% reduction in TSS from baseline to Week 24 as measured by the MPN-SAF TSS 2.0.
    Protection of trial subjects
    This trial was conducted in compliance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, US FDA regulations 21 Code of Federal Regulations Parts 50, 56, and 312, and with the laws and regulations of the country in which the research was conducted, whichever affords the greatest protection to the study subject. No trial procedures were performed on trial participants until written consent had been obtained from them. The informed consent form (ICF), protocol, and amendments for this trial were submitted to and approved by the Ethics committee. Routine monitoring was performed to verify that rights and well being of patients were protected. Also, any medication considered necessary for the patient’s safety and well-being was given at the discretion of the Investigator.
    Background therapy
    Subjects received full supportive care, including transfusions of blood and blood products, antidiarrheal and antiemetic agents (see below), and antibiotics when appropriate. All concomitant medications and blood products administered during the subject’s participation in the study were recorded in the source documents and electronic case report forms (eCRFs). Subjects did not receive other investigational agents during the study.
    Evidence for comparator
    Given the increasing availability of ruxolitinib worldwide, and label guidance for treatment in patients with platelet counts between 50,000/µL and 100,000/µL at the time this study was initiated, ruxolitinib administered per package insert was included as a BAT treatment option. Placebo control was deemed inappropriate for these patients, given the likelihood of efficacy given results of early phase pacritinib clinical studies, as well as the proven efficacy of the approved ruxolitinib agent, which also inhibits the JAK2 pathway.
    Actual start date of recruitment
    03 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    United States: 131
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    New Zealand: 13
    Country: Number of subjects enrolled
    Russian Federation: 30
    Worldwide total number of subjects
    311
    EEA total number of subjects
    113
    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)
    105
    From 65 to 84 years
    203
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    311 patients from 12 countries (7 EU countries, Canada, USA, Russia, Australia and New Zealand) were enrolled. Enrolment started on 02 July 2014. Last patient visit was on 26 April 2016.

    Pre-assignment
    Screening details
    Participants had a study specific washout period (day -35 to day -7, depending on prior medication) and screening evaluations between day -14 to day -5 before entering treatment.

    Period 1
    Period 1 title
    overall period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    With the exception of certain CTI personnel responsible for pharmacovigilance activities, regulatory submissions, supply chain, and quality, the sponsor and independent radiographic assessors were blinded to individual study treatment assignment until the end-of-treatment database was locked. Investigators, site personnel, subjects, clinical monitors, and a designated field CRA were unblinded throughout the duration of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pacritinib QD
    Arm description
    Subjects in the pacritinib QD arm were treated with 400 mg pacritinib (4 capsules) once a day orally, at the same time of day, with or without food. Subjects were supplied with 100 mg capsules of pacritinib for self-administration.
    Arm type
    Experimental

    Investigational medicinal product name
    Pacritinib
    Investigational medicinal product code
    Pacritinib
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule contains 100 mg pacritinib. Subjects who received pacritinib were to self-administer four 100 mg capsules per day orally, once a day (400 mg daily), at the same time of day, with or without food.

    Arm title
    Pacritinib BID
    Arm description
    Subjects in the Pacritinib BID arm were treated with 200 mg pacritinib (2 capsules) twice each day orally, at the same time of day, with or without food. Subjects were supplied with 100 mg capsules of pacritinib for self-administration.
    Arm type
    Experimental

    Investigational medicinal product name
    Pacritinib
    Investigational medicinal product code
    Pacritinib
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule contains 100 mg pacritinib. Subjects who received pacritinib were to self-administer two 100 mg capsules orally, twice per day (400 mg daily), at the same time of day, with or without food.

    Arm title
    Best available Therapies (BAT)
    Arm description
    Best available Therapies (BAT): Subjects receiving BAT were treated on a schedule commensurate with the therapy or therapies chosen by the investigator. BAT agents could be administered as monotherapy or in combinations, and could be changed (eg, new dose, new schedule, new regimen) as clinically indicated without limitation. BAT therapies included any physician-selected treatment for PMF, PPV-MF, or PET-MF, including approved JAK inhibitors, and may have included any treatment received before study entry. BAT agents also could have included no treatment (watch and wait, except in Czech Republic) or symptomdirected treatment without MF-specific treatment. Best available therapies could not be coadministered to pacritinib patients for treatment of MF.
    Arm type
    Active comparator

    Investigational medicinal product name
    PMF, PPV-MF, or PET-MF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Physician’s choice of treatment for PMF, PPV-MF, or PET-MF on a schedule commensurate with the chosen treatment. Ruxolitinib was required to be administered according to package insert for patients with thrombocytopenia.

    Number of subjects in period 1
    Pacritinib QD Pacritinib BID Best available Therapies (BAT)
    Started
    104
    107
    100
    Completed
    62
    79
    63
    Not completed
    42
    28
    37
         Physician decision
    6
    1
    3
         Adverse event, serious fatal
    22
    20
    19
         Consent withdrawn by subject
    8
    2
    8
         other
    6
    5
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pacritinib QD
    Reporting group description
    Subjects in the pacritinib QD arm were treated with 400 mg pacritinib (4 capsules) once a day orally, at the same time of day, with or without food. Subjects were supplied with 100 mg capsules of pacritinib for self-administration.

    Reporting group title
    Pacritinib BID
    Reporting group description
    Subjects in the Pacritinib BID arm were treated with 200 mg pacritinib (2 capsules) twice each day orally, at the same time of day, with or without food. Subjects were supplied with 100 mg capsules of pacritinib for self-administration.

    Reporting group title
    Best available Therapies (BAT)
    Reporting group description
    Best available Therapies (BAT): Subjects receiving BAT were treated on a schedule commensurate with the therapy or therapies chosen by the investigator. BAT agents could be administered as monotherapy or in combinations, and could be changed (eg, new dose, new schedule, new regimen) as clinically indicated without limitation. BAT therapies included any physician-selected treatment for PMF, PPV-MF, or PET-MF, including approved JAK inhibitors, and may have included any treatment received before study entry. BAT agents also could have included no treatment (watch and wait, except in Czech Republic) or symptomdirected treatment without MF-specific treatment. Best available therapies could not be coadministered to pacritinib patients for treatment of MF.

    Reporting group values
    Pacritinib QD Pacritinib BID Best available Therapies (BAT) Total
    Number of subjects
    104 107 100 311
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    32 41 32 105
        From 65-84 years
    70 65 68 203
        85 years and over
    2 1 0 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.0 ± 8.55 65.9 ± 8.75 66.9 ± 9.75 -
    Gender categorical
    Units: Subjects
        Female
    51 44 45 140
        Male
    53 63 55 171
    Race
    Units: Subjects
        White
    90 92 85 267
        Not reported
    9 10 8 27
        Asian
    3 3 4 10
        Native Hawaiian / Other Pacific Islander
    1 2 1 4
        American Indian / Alaska Native
    0 0 1 1
        Black / African American
    1 0 0 1
        Other
    0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Pacritinib QD
    Reporting group description
    Subjects in the pacritinib QD arm were treated with 400 mg pacritinib (4 capsules) once a day orally, at the same time of day, with or without food. Subjects were supplied with 100 mg capsules of pacritinib for self-administration.

    Reporting group title
    Pacritinib BID
    Reporting group description
    Subjects in the Pacritinib BID arm were treated with 200 mg pacritinib (2 capsules) twice each day orally, at the same time of day, with or without food. Subjects were supplied with 100 mg capsules of pacritinib for self-administration.

    Reporting group title
    Best available Therapies (BAT)
    Reporting group description
    Best available Therapies (BAT): Subjects receiving BAT were treated on a schedule commensurate with the therapy or therapies chosen by the investigator. BAT agents could be administered as monotherapy or in combinations, and could be changed (eg, new dose, new schedule, new regimen) as clinically indicated without limitation. BAT therapies included any physician-selected treatment for PMF, PPV-MF, or PET-MF, including approved JAK inhibitors, and may have included any treatment received before study entry. BAT agents also could have included no treatment (watch and wait, except in Czech Republic) or symptomdirected treatment without MF-specific treatment. Best available therapies could not be coadministered to pacritinib patients for treatment of MF.

    Subject analysis set title
    Pacritinib QD - ITT Efficacy
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    ITT truncated on the day of the FDA clinical hold, i.e., patients randomized prior to September 7, 2015.

    Subject analysis set title
    Pacritinib BID - ITT Efficacy
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    ITT truncated on the day of the FDA clinical hold, i.e., patients randomized prior to September 7, 2015

    Subject analysis set title
    Best available Therapies (BAT) - ITT Efficacy
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    ITT truncated on the day of the FDA clinical hold, i.e., patients randomized prior to September 7, 2015

    Subject analysis set title
    Pacritinib QD + BID - ITT Efficacy
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    ITT truncated on the day of the FDA clinical hold, i.e., patients randomized prior to September 7, 2015. Pooled from the Pacritinib QD - ITT Efficacy and Pacritinib BID - ITT Efficacy population.

    Primary: ≥35% Spleen Volume Reduction

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    End point title
    ≥35% Spleen Volume Reduction
    End point description
    The first co-primary efficacy endpoint was the proportion of subjects achieving a ≥35% spleen volume reduction (SVR) from baseline to Week 24, as measured by MRI or CT scan.
    End point type
    Primary
    End point timeframe
    MRI or CT scan (without contrast agents) was performed prior to randomization (days -10 to -4). MRI or CT scan was performed at the end of week 12 ± 7 days and every 12 weeks thereafter, and at treatment termination.
    End point values
    Pacritinib QD - ITT Efficacy Pacritinib BID - ITT Efficacy Best available Therapies (BAT) - ITT Efficacy Pacritinib QD + BID - ITT Efficacy
    Number of subjects analysed
    75
    74
    72
    149
    Units: patient number (n)
        Overall (n)
    11
    16
    2
    27
    Statistical analysis title
    Primary endpoint statistics
    Comparison groups
    Best available Therapies (BAT) - ITT Efficacy v Pacritinib QD + BID - ITT Efficacy
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011 [1]
    Method
    Fisher exact
    Parameter type
    Agresti-Caffo method
    Point estimate
    15.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.8
         upper limit
    22.1
    Notes
    [1] - BAT arm compared to pooled pacritinib arms (Pacritinib QD + BID - ITT Efficacy)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were collected during the clinical trial from the time the subject signed the informed consent through the subject’s last day of study participation.
    Adverse event reporting additional description
    The data display threshold for SAEs is set to 1% or more, that of AEs is set to 5% or more.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Best available Therapy (BAT) - Safety
    Reporting group description
    The safety population was defined as all randomized subjects who received at least one dose of study treatment, including subjects on the BAT arm who were not receiving any active study treatment (watchful waiting). All safety analyses were performed using the safety population, and subjects in this population were analyzed according to the treatment actually received.

    Reporting group title
    Pacritinib (QD and BID) - Safety
    Reporting group description
    The safety population was defined as all randomized subjects who received at least one dose of study treatment, including subjects on the BAT arm who were not receiving any active study treatment (watchful waiting). All safety analyses were performed using the safety population, and subjects in this population were analyzed according to the treatment actually received.

    Serious adverse events
    Best available Therapy (BAT) - Safety Pacritinib (QD and BID) - Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 100 (71.00%)
    91 / 211 (43.13%)
         number of deaths (all causes)
    9
    12
         number of deaths resulting from adverse events
    1
    3
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 211 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myelofibrosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (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
    Disease progression
         subjects affected / exposed
    3 / 100 (3.00%)
    7 / 211 (3.32%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 3
    1 / 7
    Pyrexia
         subjects affected / exposed
    2 / 100 (2.00%)
    5 / 211 (2.37%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 100 (2.00%)
    5 / 211 (2.37%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 100 (3.00%)
    3 / 211 (1.42%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 100 (3.00%)
    13 / 211 (6.16%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 100 (2.00%)
    8 / 211 (3.79%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Febrile neutropenia
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 211 (0.95%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 100 (1.00%)
    4 / 211 (1.90%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 211 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neurological decompensation
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    2 / 100 (2.00%)
    7 / 211 (3.32%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Periarthritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 211 (0.95%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Fluid overload
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (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
    Pneumonia
         subjects affected / exposed
    4 / 100 (4.00%)
    11 / 211 (5.21%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 211 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 211 (0.95%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Sepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 211 (0.95%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Best available Therapy (BAT) - Safety Pacritinib (QD and BID) - Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    87 / 100 (87.00%)
    204 / 211 (96.68%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    8 / 100 (8.00%)
    17 / 211 (8.06%)
         occurrences all number
    8
    17
    Fall
         subjects affected / exposed
    3 / 100 (3.00%)
    11 / 211 (5.21%)
         occurrences all number
    3
    11
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 100 (3.00%)
    11 / 211 (5.21%)
         occurrences all number
    3
    11
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    12 / 100 (12.00%)
    23 / 211 (10.90%)
         occurrences all number
    12
    23
    Cough
         subjects affected / exposed
    10 / 100 (10.00%)
    19 / 211 (9.00%)
         occurrences all number
    10
    19
    Dyspnoea
         subjects affected / exposed
    8 / 100 (8.00%)
    19 / 211 (9.00%)
         occurrences all number
    8
    19
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    22 / 100 (22.00%)
    65 / 211 (30.81%)
         occurrences all number
    22
    65
    Anaemia
         subjects affected / exposed
    13 / 100 (13.00%)
    48 / 211 (22.75%)
         occurrences all number
    13
    48
    Neutropenia
         subjects affected / exposed
    5 / 100 (5.00%)
    17 / 211 (8.06%)
         occurrences all number
    5
    17
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 100 (5.00%)
    31 / 211 (14.69%)
         occurrences all number
    5
    31
    Dysgeusia
         subjects affected / exposed
    0 / 100 (0.00%)
    16 / 211 (7.58%)
         occurrences all number
    0
    16
    Headache
         subjects affected / exposed
    5 / 100 (5.00%)
    15 / 211 (7.11%)
         occurrences all number
    5
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    16 / 100 (16.00%)
    35 / 211 (16.59%)
         occurrences all number
    16
    35
    Oedema peripheral
         subjects affected / exposed
    14 / 100 (14.00%)
    35 / 211 (16.59%)
         occurrences all number
    14
    35
    Asthenia
         subjects affected / exposed
    6 / 100 (6.00%)
    8 / 211 (3.79%)
         occurrences all number
    6
    8
    Early satiety
         subjects affected / exposed
    5 / 100 (5.00%)
    4 / 211 (1.90%)
         occurrences all number
    5
    4
    Pyrexia
         subjects affected / exposed
    1 / 100 (1.00%)
    22 / 211 (10.43%)
         occurrences all number
    1
    22
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 100 (4.00%)
    22 / 211 (10.43%)
         occurrences all number
    4
    22
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    15 / 100 (15.00%)
    121 / 211 (57.35%)
         occurrences all number
    15
    121
    Nausea
         subjects affected / exposed
    11 / 100 (11.00%)
    73 / 211 (34.60%)
         occurrences all number
    11
    73
    Vomiting
         subjects affected / exposed
    5 / 100 (5.00%)
    42 / 211 (19.91%)
         occurrences all number
    5
    42
    Abdominal pain
         subjects affected / exposed
    19 / 100 (19.00%)
    29 / 211 (13.74%)
         occurrences all number
    19
    29
    Abdominal distension
         subjects affected / exposed
    6 / 100 (6.00%)
    9 / 211 (4.27%)
         occurrences all number
    6
    9
    Abdominal pain upper
         subjects affected / exposed
    6 / 100 (6.00%)
    10 / 211 (4.74%)
         occurrences all number
    6
    10
    Constipation
         subjects affected / exposed
    6 / 100 (6.00%)
    23 / 211 (10.90%)
         occurrences all number
    6
    23
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    6 / 100 (6.00%)
    21 / 211 (9.95%)
         occurrences all number
    6
    21
    Rash
         subjects affected / exposed
    4 / 100 (4.00%)
    14 / 211 (6.64%)
         occurrences all number
    4
    14
    Night sweats
         subjects affected / exposed
    6 / 100 (6.00%)
    16 / 211 (7.58%)
         occurrences all number
    6
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 100 (3.00%)
    17 / 211 (8.06%)
         occurrences all number
    3
    17
    Bone pain
         subjects affected / exposed
    7 / 100 (7.00%)
    12 / 211 (5.69%)
         occurrences all number
    7
    12
    Pain in extremity
         subjects affected / exposed
    6 / 100 (6.00%)
    17 / 211 (8.06%)
         occurrences all number
    6
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 100 (10.00%)
    25 / 211 (11.85%)
         occurrences all number
    10
    25
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 100 (6.00%)
    19 / 211 (9.00%)
         occurrences all number
    6
    19

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2014
    The changes included: - Inconsistencies between the protocol and the schedule of assessments regarding pacritinib accountability were corrected. - A clarification regarding the pharmacodynamic assessment was added. - Inconsistencies regarding the timing of the administration of the patient global impression assessment, MPN-SAF TSS, pain medication log and quality of life assessments were clarified and/or corrected. - A detailed QTc monitoring schedule was added. - The definition of a serious adverse event was updated. - The reference safety information was further specified.
    31 Jul 2014
    The changes included: - The exclusion criterion of more than 6 months of cumulative prior JAK2 inhibitor treatment was deleted.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Feb 2016
    The FDA placed the pacritinib IND on partial clinical hold on 2016 February 04, then on full clinical hold on 2016 February 08. All subjects were notified of the clinical holds and instructed to discontinue pacritinib treatment immediately. Subjects returned to the clinic for termination and 30-day post-termination visits per schedule of assessments . Data entry and verification were completed and the end of treatment database was locked.
    -

    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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