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

    Summary
    EudraCT number
    2012-004239-21
    Trial protocol
    BE   GB   CZ   HU   DE   IT  
    Global end of trial date
    22 Apr 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    PAC325
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01773187
    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
    30 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the PERSIST-1 study was to compare the efficacy of pacritinib with that of BAT in subjects with PMF, PPV-MF, or PET-MF. The primary efficacy measure for this analysis was 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
    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
    The most common concomitant medications by ATC class in the pacritinib and BAT arms, were Antipropulsives (49.1% and 48.1%, respectively), Proton Pump Inhibitors (33.6% and 50.9 %, respectively), Preparations Inhibiting Uric Acid Production (32.7% and 42.5%, respectively), Platelet Aggregation Inhibitors Excluding Heparin (32.7% and 37.7%, respectively), and Anilides (35.0% and 40.6%, respectively).
    Evidence for comparator
    The control arm of the study consisted of best available therapies (BAT) , which was the same control arm used in the COMFORT-II phase 3 study of the currently approved JAK2 inhibitor, ruxolitinib. Due to the limitations in the approved indications for ruxolitinib and its regulatory and economic availability on a world-wide basis at the time this study was conducted, ruxolitinib was not included in the BAT treatment arm. Placebo control was deemed inappropriate for these subjects, given the likelihood of efficacy shown in early phase pacritinib clinical studies, as well as the proven efficacy of the approved ruxolitinib agent, which also inhibits the JAK2 pathway. As with the completed phase 3 registrational ruxolitinib COMFORT studies, subjects were permitted to cross over from BAT to pacritinib. This was deemed essential to achieve appropriate equipoise for the participating subjects and to encourage participation given the lack of BAT agents approved for treatment of these MF patients. Crossover provided further scientific benefit as it enabled comparison of safety and efficacy with BAT treatment prior to crossover versus pacritinib treatment after crossover.
    Actual start date of recruitment
    08 Jan 2013
    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
    United Kingdom: 25
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Australia: 46
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Czech Republic: 18
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 70
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Netherlands: 21
    Country: Number of subjects enrolled
    New Zealand: 20
    Country: Number of subjects enrolled
    Russian Federation: 53
    Worldwide total number of subjects
    327
    EEA total number of subjects
    203
    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)
    137
    From 65 to 84 years
    189
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    327 patients from 12 countries ( 8 EU countries, US, Russia and Australia and New Zealand) were enrolled. Enrolment started on 08 January 2013. Last patient visit was on 22 April 2016.

    Pre-assignment
    Screening details
    Participants had a washout period (day -35 to day -7) 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
    Investigators, site personnel, subjects, clinical monitors, and a designated field CRA were unblinded to individual study treatment assignment. Except certain CTI personnel responsible for pharmacovigilance activities, regulatory submissions, supply chain, and GCP compliance, the sponsor and independent radiographic assessors were blinded throughout the entire study. The sponsor remained blinded to individual study treatment assignment until the database lock for primary analysis.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pacritinib
    Arm description
    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 type
    Experimental

    Investigational medicinal product name
    Pacritinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    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
    Best available Therapies (BAT)
    Arm description
    Best available Therapies (BAT): Subjects receiving BAT were treated on a schedule commensurate with the therapy(ies) 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. Best available therapies may have included any physician-selected treatment for PMF, PPV-MF, or PET-MF, with the exclusion of JAK inhibitors, and may have included any treatment received before study entry. Best available therapies also could have included no treatment (watch and wait) or symptom-directed treatment without MF-specific treatment. BAT therapies could not be co-administered to subjects in the pacritinib arm for treatment of MF.
    Arm type
    Active comparator

    Investigational medicinal product name
    Hydroxyurea, prednisone, interferon-alpha, thalidomide, danazole, prednisolone, busulfan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    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. The pharmaceutical forms and routes of administration depend on the specific product and its clinical indication. Examples of the most used products, their pharmaceutical form and route of administration are shown above.

    Number of subjects in period 1
    Pacritinib Best available Therapies (BAT)
    Started
    220
    107
    Completed
    167
    75
    Not completed
    53
    32
         progressive disease
    3
    9
         Other
    4
    -
         Physician decision
    7
    18
         Adverse event, serious fatal
    1
    1
         Adverse event, non-fatal
    20
    2
         Consent withdrawn by subject
    18
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pacritinib
    Reporting group description
    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.

    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(ies) 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. Best available therapies may have included any physician-selected treatment for PMF, PPV-MF, or PET-MF, with the exclusion of JAK inhibitors, and may have included any treatment received before study entry. Best available therapies also could have included no treatment (watch and wait) or symptom-directed treatment without MF-specific treatment. BAT therapies could not be co-administered to subjects in the pacritinib arm for treatment of MF.

    Reporting group values
    Pacritinib Best available Therapies (BAT) Total
    Number of subjects
    220 107 327
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    85 52 137
        From 65-84 years
    134 55 189
        85 years and over
    1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.5 ± 10.85 64.8 ± 9.12 -
    Gender categorical
    Units: Subjects
        Female
    95 47 142
        Male
    125 60 185
    Race
    Units: Subjects
        Asian
    2 1 3
        Black
    2 0 2
        White
    191 98 289
        Not reported
    23 8 31
        Other
    2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Pacritinib
    Reporting group description
    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.

    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(ies) 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. Best available therapies may have included any physician-selected treatment for PMF, PPV-MF, or PET-MF, with the exclusion of JAK inhibitors, and may have included any treatment received before study entry. Best available therapies also could have included no treatment (watch and wait) or symptom-directed treatment without MF-specific treatment. BAT therapies could not be co-administered to subjects in the pacritinib arm for treatment of MF.

    Primary: ≥35% Spleen Volume Reduction

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    End point title
    ≥35% Spleen Volume Reduction
    End point description
    The 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. For each subject, the same imaging modality was to have been used throughout the study. Splenic progression was followed for subjects who discontinued treatment but did not progress. Subjects with progressive disease documented prior to week 24 who opted to continue on study treatment did not undergo week 24 imaging if the date of progression was at week 20 or later. For subjects who crossed over after week 24, an MRI was done within 30 days prior to the start of pacritinib treatment.
    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 Best available Therapies (BAT)
    Number of subjects analysed
    220
    107
    Units: patient number (n)
        Overall (n)
    42
    5
    Statistical analysis title
    Primary endpoint statistics
    Comparison groups
    Pacritinib v Best available Therapies (BAT)
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Fisher exact
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.1
         upper limit
    24.9

    Secondary: > 50% TSS reduction on MPN-SAF TSS 2.0

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    End point title
    > 50% TSS reduction on MPN-SAF TSS 2.0
    End point description
    The secondary endpoint in the study was the proportion of subjects with a ≥50% reduction from baseline to Week 24 in the subject reported outcome instrument, MPN-SAF TSS 2.0. The original version of this instrument (MPN-SAF TSS) was administered to the first 179 subjects enrolled in the study. However, after discussion with FDA, agreement was reached on modified questions to be included in the instrument. The new version (termed MPN-SAF TSS 2.0) was administered to all subsequently enrolled subjects throughout their participation in the study. A total of 148 subjects (100 pacritinib, 48 BAT) were tested with the MPN-SAF TSS 2.0 and comprise the ITT population for this endpoint. Responses (on a scale from 0 [absent] to 10 [worst imaginable]) to questions about the symptoms of tiredness, early satiety, abdominal discomfort, night sweats, pruritus, bone pain, and pain under the ribs on the left side were used to compute the MPN-SAF TSS 2.0 results.
    End point type
    Secondary
    End point timeframe
    Daily after receiving eDiary and throughout treatment. Subject-reported symptoms on MPN-SAF TSS 2.0: daily for 7 to 10 consecutive days prior to start of study treatment + daily from day 1 through week 48 or until subject discontinuation.
    End point values
    Pacritinib Best available Therapies (BAT)
    Number of subjects analysed
    100
    48
    Units: number of patients (n)
        Overall
    19
    5
    Statistical analysis title
    Statistics - secondary endpoint
    Comparison groups
    Best available Therapies (BAT) v Pacritinib
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.2368
    Method
    Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Subjects were evaluated from the time of signing informed consent through 30 d after the last study treatment.
    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
    Pacritinib
    Reporting group description
    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.

    Reporting group title
    Best available therapies (BAT) safety population
    Reporting group description
    Subgroup of the ITT population representing subjects who received any dose of study treatment.

    Serious adverse events
    Pacritinib Best available therapies (BAT) safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    110 / 220 (50.00%)
    8 / 106 (7.55%)
         number of deaths (all causes)
    8
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    6 / 220 (2.73%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    4 / 220 (1.82%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    3 / 220 (1.36%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    3 / 220 (1.36%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    7 / 220 (3.18%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 220 (1.82%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 220 (1.36%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    5 / 220 (2.27%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 106 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 220 (7.27%)
    4 / 106 (3.77%)
         occurrences causally related to treatment / all
    9 / 16
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 220 (1.82%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 220 (1.36%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    6 / 220 (2.73%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 220 (2.73%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    3 / 220 (1.36%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 220 (1.82%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 220 (1.36%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 220 (1.36%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    4 / 220 (1.82%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    16 / 220 (7.27%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    7 / 16
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    4 / 220 (1.82%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 220 (1.36%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 106 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Pacritinib Best available therapies (BAT) safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    207 / 220 (94.09%)
    81 / 106 (76.42%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 220 (5.00%)
    0 / 106 (0.00%)
         occurrences all number
    11
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    33 / 220 (15.00%)
    9 / 106 (8.49%)
         occurrences all number
    33
    9
    Oedema peripheral
         subjects affected / exposed
    24 / 220 (10.91%)
    16 / 106 (15.09%)
         occurrences all number
    24
    16
    Pyrexia
         subjects affected / exposed
    17 / 220 (7.73%)
    11 / 106 (10.38%)
         occurrences all number
    17
    11
    Asthenia
         subjects affected / exposed
    16 / 220 (7.27%)
    7 / 106 (6.60%)
         occurrences all number
    16
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 220 (5.91%)
    0 / 106 (0.00%)
         occurrences all number
    13
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    11 / 220 (5.00%)
    0 / 106 (0.00%)
         occurrences all number
    11
    0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    12 / 220 (5.45%)
    0 / 106 (0.00%)
         occurrences all number
    12
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    58 / 220 (26.36%)
    18 / 106 (16.98%)
         occurrences all number
    58
    18
    Thrombocytopenia
         subjects affected / exposed
    48 / 220 (21.82%)
    15 / 106 (14.15%)
         occurrences all number
    48
    15
    Neutropenia
         subjects affected / exposed
    12 / 220 (5.45%)
    0 / 106 (0.00%)
         occurrences all number
    12
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    20 / 220 (9.09%)
    9 / 106 (8.49%)
         occurrences all number
    20
    9
    Epistaxis
         subjects affected / exposed
    17 / 220 (7.73%)
    10 / 106 (9.43%)
         occurrences all number
    17
    10
    Cough
         subjects affected / exposed
    18 / 220 (8.18%)
    8 / 106 (7.55%)
         occurrences all number
    18
    8
    Oropharyngeal pain
         subjects affected / exposed
    13 / 220 (5.91%)
    0 / 106 (0.00%)
         occurrences all number
    13
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 220 (5.45%)
    0 / 106 (0.00%)
         occurrences all number
    12
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    142 / 220 (64.55%)
    14 / 106 (13.21%)
         occurrences all number
    142
    14
    Nausea
         subjects affected / exposed
    70 / 220 (31.82%)
    7 / 106 (6.60%)
         occurrences all number
    70
    7
    Vomiting
         subjects affected / exposed
    46 / 220 (20.91%)
    7 / 106 (6.60%)
         occurrences all number
    46
    7
    Abdominal pain
         subjects affected / exposed
    29 / 220 (13.18%)
    11 / 106 (10.38%)
         occurrences all number
    29
    11
    Constipation
         subjects affected / exposed
    22 / 220 (10.00%)
    8 / 106 (7.55%)
         occurrences all number
    22
    8
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    14 / 220 (6.36%)
    0 / 106 (0.00%)
         occurrences all number
    14
    0
    Rash
         subjects affected / exposed
    12 / 220 (5.45%)
    0 / 106 (0.00%)
         occurrences all number
    12
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 220 (5.91%)
    0 / 106 (0.00%)
         occurrences all number
    13
    0
    Pain in extremity
         subjects affected / exposed
    11 / 220 (5.00%)
    9 / 106 (8.49%)
         occurrences all number
    11
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 220 (9.55%)
    0 / 106 (0.00%)
         occurrences all number
    21
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 220 (7.27%)
    6 / 106 (5.66%)
         occurrences all number
    16
    6
    Urinary tract infection
         subjects affected / exposed
    12 / 220 (5.45%)
    0 / 106 (0.00%)
         occurrences all number
    12
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2012
    Amendment 1 included the following changes: - addition of a new inclusion criterion - addition of dose management guidelines for QTc interval prolongation - clarification to dose reduction for pacritinib-related, nonhematologic toxicities - change of timepoints for spleen size assessments.
    16 Mar 2013
    Amendment 2 included the following changes: - revision of secondary and exploratory objectives - addition of a crossover section from BAT to pacritinib including criteria - revision of inclusion and exclusion criteria - addition of a section for withdrawal from study procedures - revision of the method of treatment assignment - addition of explanation of QTc calculation and recalculation - addition of provision of prescription for loperamide (and instructions for use) - AE section was expanded - amendment of spleen volume measurement by MRI or CT - a modified ITT population was added - the PP population definition was revised - the Data Monitoring Committee was changed to an IDMC - major changes to study assessments.
    15 Aug 2013
    Amendment 3 included the following changes: - revision of inclusion and exclusion criteria - update of statistical methods section - revision of study design - revision of period of blinding for independent radiographic assessors - replacement of MPN-SAF TSS with MPN-SAF TSS 2.0 for subjects randomized under protocol Amendment 3 - revision of the endpoint for collection of AEs and SAEs to the last day of study participation - amendments and changes to the ITT population - Major changes to the study assessments.
    30 Jan 2014
    Amendment 4 included the following changes: - revision of sample size of randomized subjects - revision of statistical methods section - clarification of PK and PD assessments - clarification and correction of inconsistencies regarding the timing of the administration of the PGIA, MPN-SAF TSS (all versions), pain medication log, and QoL assessments; clarification regarding use of the MPN-SAF TSS (all versions) - amendment of timepoints prior to start of study treatment - revision of the SAE collection time period.
    21 Feb 2014
    Amendment 4a: - revision of sample size of randomized subjects.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Feb 2016
    PERSIST-1 was placed on Partial Clinical Hold by FDA on 2016 FEB 04 and then on Full Clinical Hold 2016 FEB 08. At the time of the FDA Partial Clinical Hold, no PERSIST-1 subjects were permitted to start pacritinib as initial or crossover treatment, and subjects not deriving benefit after 30 weeks of pacritinib treatment were to stop pacritinib. When the FDA Full Clinical Hold was imposed, all PERSIST-1 subjects discontinued pacritinib study treatment and no subjects were allowed to start pacritinib as initial or crossover treatment. Subjects continued to be followed for OS.
    -

    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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