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    Clinical Trial Results:
    A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study of IMR-687 in Adult Patients with Sickle Cell Anaemia (Homozygous HbSS or Sickle-Beta^0 Thalassemia)

    Summary
    EudraCT number
    		 2017-000653-39
    Trial protocol
    		 GB  
    Global end of trial date
    28 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Sep 2021
    First version publication date
    12 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IMR-SCD-102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03401112
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imara Inc.
    Sponsor organisation address
    116 Huntington Avenue, 6th Floor, Boston, MA, United States, 02116
    Public contact
    Imara Clinical Operations , Imara Inc., 617 206-2020, info@imaratx.com
    Scientific contact
    Imara Clinical Operations , Imara Inc., 617 206-2020, info@imaratx.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
    04 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of IMR-687 in adult participants with sickle cell anaemia (SCA), defined as homozygous sickle haemoglobin or sickle-β^0 thalassemia, who are not receiving hydroxyurea (HU) and in adult SCA participants who are receiving a stable dose of HU.
    Protection of trial subjects
    This study was conducted in accordance with consensus ethical principles derived from international guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines; applicable International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines; and applicable laws and regulations, including the Medicines for Human Use (Clinical Trials) Regulations 2004 and any relevant amendments.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jan 2018
    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 States: 31
    Country: Number of subjects enrolled
    United Kingdom: 69
    Worldwide total number of subjects
    100
    EEA total number of subjects
    0
    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)
    100
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study participants were enrolled at 13 sites in 2 countries (United Kingdom and United States).

    Pre-assignment
    Screening details
    		 IMR-687 was administered in 2 populations of participants with SCA: those who were not receiving HU and those who were receiving a stable dose of HU according to standard of care. Participants on HU must have been on a stable dose for at least 60 days prior to Screening.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IMR-687 50 mg/100 mg (Without HU)
    Arm description
    		 A starting dose of IMR-687 50 milligrams (mg) with dose escalation after 4 or 12 weeks, up to 100 mg was administered to participants who were not receiving daily HU.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMR-687
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of IMR-687 once daily. Duration of administration was 24 weeks (Week 25).

    Arm title
    		 IMR-687 100 mg/200 mg (Without HU)
    Arm description
    		 A starting dose of IMR-687 100 mg with dose escalation after 4 or 12 weeks, up to 200 mg was administered to participants who were not receiving daily HU.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMR-687
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of IMR-687 once daily. Duration of administration was 24 weeks (Week 25).

    Arm title
    		 Placebo (Without HU)
    Arm description
    		 Matching placebo was administered to participants who were not receiving daily HU.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of matching placebo once daily. Duration of administration was 24 weeks (Week 25).

    Arm title
    		 IMR-687 50 mg/100 mg (With HU)
    Arm description
    		 A starting dose of IMR-687 50 mg with dose escalation after 4 or 12 weeks, up to 100 mg was administered to participants who were receiving daily HU. HU doses ranged from 500 to 2000 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMR-687
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of IMR-687 once daily. Duration of administration was 16 (Week 17) or 24 weeks (Week 25).

    Arm title
    		 Placebo (With HU)
    Arm description
    		 Matching placebo was administered to participants who were receiving daily HU. HU doses ranged from 500 to 2000 mg.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of matching placebo once daily. Duration of administration was 16 (Week 17) or 24 weeks (Week 25).

    Number of subjects in period 1
    		IMR-687 50 mg/100 mg (Without HU) IMR-687 100 mg/200 mg (Without HU) Placebo (Without HU) IMR-687 50 mg/100 mg (With HU) Placebo (With HU)
    Started
    15
    26
    22
    27
    10
    Received at Least 1 Dose of Study Drug
    12
    26
    20
    25
    10
    Completed
    10
    19
    11
    21
    10
    Not completed
    5
    7
    11
    6
    0
         Consent withdrawn by subject
    -
    3
    2
    1
    -
         Physician decision
    -
    -
    -
    2
    -
         Adverse event, non-fatal
    1
    2
    3
    2
    -
         Did not Meet Inclusion Criteria
    1
    -
    -
    -
    -
         Study was Terminated by Sponsor
    -
    -
    -
    1
    -
         Not Dosed
    -
    -
    1
    -
    -
         Missed Clinical Visit
    -
    -
    1
    -
    -
         Lost to follow-up
    1
    -
    -
    -
    -
         Day 1 Assessment not Done
    1
    -
    -
    -
    -
         Missed Doses
    -
    -
    1
    -
    -
         Noncompliance
    1
    2
    3
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IMR-687 50 mg/100 mg (Without HU)
    Reporting group description
    		 A starting dose of IMR-687 50 milligrams (mg) with dose escalation after 4 or 12 weeks, up to 100 mg was administered to participants who were not receiving daily HU.

    Reporting group title
    IMR-687 100 mg/200 mg (Without HU)
    Reporting group description
    		 A starting dose of IMR-687 100 mg with dose escalation after 4 or 12 weeks, up to 200 mg was administered to participants who were not receiving daily HU.

    Reporting group title
    Placebo (Without HU)
    Reporting group description
    		 Matching placebo was administered to participants who were not receiving daily HU.

    Reporting group title
    IMR-687 50 mg/100 mg (With HU)
    Reporting group description
    		 A starting dose of IMR-687 50 mg with dose escalation after 4 or 12 weeks, up to 100 mg was administered to participants who were receiving daily HU. HU doses ranged from 500 to 2000 mg.

    Reporting group title
    Placebo (With HU)
    Reporting group description
    		 Matching placebo was administered to participants who were receiving daily HU. HU doses ranged from 500 to 2000 mg.

    Reporting group values
    		 IMR-687 50 mg/100 mg (Without HU) IMR-687 100 mg/200 mg (Without HU) Placebo (Without HU) IMR-687 50 mg/100 mg (With HU) Placebo (With HU) Total
    Number of subjects
    		 15 26 22 27 10 100
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 15 26 22 27 10 100
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.33 ( 8.608 ) 32.04 ( 9.349 ) 35.68 ( 8.150 ) 32.33 ( 8.788 ) 28.80 ( 7.084 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 17 12 17 9 64
        Male
    		 6 9 10 10 1 36

    End points

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    End points reporting groups
    Reporting group title
    IMR-687 50 mg/100 mg (Without HU)
    Reporting group description
    		 A starting dose of IMR-687 50 milligrams (mg) with dose escalation after 4 or 12 weeks, up to 100 mg was administered to participants who were not receiving daily HU.

    Reporting group title
    IMR-687 100 mg/200 mg (Without HU)
    Reporting group description
    		 A starting dose of IMR-687 100 mg with dose escalation after 4 or 12 weeks, up to 200 mg was administered to participants who were not receiving daily HU.

    Reporting group title
    Placebo (Without HU)
    Reporting group description
    		 Matching placebo was administered to participants who were not receiving daily HU.

    Reporting group title
    IMR-687 50 mg/100 mg (With HU)
    Reporting group description
    		 A starting dose of IMR-687 50 mg with dose escalation after 4 or 12 weeks, up to 100 mg was administered to participants who were receiving daily HU. HU doses ranged from 500 to 2000 mg.

    Reporting group title
    Placebo (With HU)
    Reporting group description
    		 Matching placebo was administered to participants who were receiving daily HU. HU doses ranged from 500 to 2000 mg.

    Subject analysis set title
    All IMR-687
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received IMR-687.

    Subject analysis set title
    All Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received placebo.

    Subject analysis set title
    Pooled IMR-687 (Without HU)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants administered IMR-687 who were not receiving HU.

    Primary: Number Of Participants With Treatment-emergent Adverse Events (TEAEs) And Serious Adverse Events (SAEs)

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    End point title
    		 Number Of Participants With Treatment-emergent Adverse Events (TEAEs) And Serious Adverse Events (SAEs) [1]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An SAE was defined as any AE that resulted in 1 or more of the following outcomes: death, required or prolonged hospitalization, life-threatening, persistent or significant disability/incapacity, congenital anomaly or birth defect, or other medically important event. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
    End point type
    Primary
    End point timeframe
    Day 1 (after dosing) through up to Week 24
    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: As per protocol, descriptive summary statistics are presented.
    End point values
    		 IMR-687 50 mg/100 mg (Without HU) IMR-687 100 mg/200 mg (Without HU) Placebo (Without HU) IMR-687 50 mg/100 mg (With HU) Placebo (With HU) All IMR-687 All Placebo
    Number of subjects analysed
    12
    26
    20
    25
    10
    63
    30
    Units: participants
    number (not applicable)
        TEAEs
    12
    24
    18
    23
    10
    59
    28
        SAEs
    4
    7
    8
    5
    3
    16
    11
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) Of Participants Who Did Not Concomitantly Receive HU: Maximum Plasma Concentration (Cmax) Of IMR-687

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    End point title
    		 Pharmacokinetics (PK) Of Participants Who Did Not Concomitantly Receive HU: Maximum Plasma Concentration (Cmax) Of IMR-687 [2]
    End point description
    For PK assessments of participants who did not concomitantly receive HU, serial blood samples for IMR-687 plasma concentrations were drawn predose at 0.5, 1, 1.5, 2, 4, 6, and 8 hours after administration of study drug; and at 24 hours after administration of study drug. Day 1 (single-dose) and steady-state (Week 25) assessments are presented.
    End point type
    Secondary
    End point timeframe
    Day 1 and Week 25
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK analyses of IMR-687 was not conducted for placebo groups. The IMR-687 50 mg/100 mg (without HU) and IMR-687 100 mg/200 mg (without HU) groups are presented.
    End point values
    		 IMR-687 50 mg/100 mg (Without HU) IMR-687 100 mg/200 mg (Without HU)
    Number of subjects analysed
    12 [3]
    13 [4]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 1: Single Dose
    512 ( 30.1 )
    1130 ( 33.5 )
        Week 25: Steady State
    1290 ( 36.4 )
    2180 ( 24.1 )
    Notes
    [3] - Week 25: n= 8
    [4] - Week 25: n= 8
    No statistical analyses for this end point

    Secondary: PK Of Participants Who Did Not Concomitantly Received HU: Area Under The Concentration-time Curve (AUC) From Time 0 To 24 Hours Postdose (AUC0-24h) Of IMR-687

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    End point title
    		 PK Of Participants Who Did Not Concomitantly Received HU: Area Under The Concentration-time Curve (AUC) From Time 0 To 24 Hours Postdose (AUC0-24h) Of IMR-687 [5]
    End point description
    For PK assessments of participants who did not concomitantly receive HU, serial blood samples for IMR-687 plasma concentrations were drawn predose at 0.5, 1, 1.5, 2, 4, 6, and 8 hours after administration of study drug; and at 24 hours after administration of study drug. Day 1 (single-dose) and steady-state (Week 25) assessments are presented.
    End point type
    Secondary
    End point timeframe
    Day 1 and Week 25
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK analyses of IMR-687 was not conducted for placebo groups. The IMR-687 50 mg/100 mg (without HU) and IMR-687 100 mg/200 mg (without HU) groups are presented.
    End point values
    		 IMR-687 50 mg/100 mg (Without HU) IMR-687 100 mg/200 mg (Without HU)
    Number of subjects analysed
    11 [6]
    10 [7]
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        Day 1: Single Dose
    2850 ( 12.5 )
    6590 ( 17.7 )
        Week 25: Steady State
    8420 ( 24.1 )
    15000 ( 22.3 )
    Notes
    [6] - Week 25: n=7
    [7] - Week 25: n=6
    No statistical analyses for this end point

    Secondary: PK Of Participants Who Concomitantly Received HU: Cmax Of IMR-687

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    End point title
    		 PK Of Participants Who Concomitantly Received HU: Cmax Of IMR-687 [8]
    End point description
    For PK assessments of participants who concomitantly received HU, serial blood samples for IMR-687 PK were drawn predose at 0.5, 1, 1.5, 2, 4, 6, and 8 hours after administration of study drug; and at 24 hours after administration of study drug. Day 1 (single-dose) and steady-state (Week 17) assessments are presented.
    End point type
    Secondary
    End point timeframe
    Day 1 and Week 17
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK analyses of IMR-687 was not conducted for placebo groups. The IMR-687 50 mg/100 mg (with HU) group is presented.
    End point values
    		 IMR-687 50 mg/100 mg (With HU)
    Number of subjects analysed
    13 [9]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 1: Single Dose
    657 ( 24.7 )
        Week 17: Steady State
    1370 ( 18.6 )
    Notes
    [9] - Week 17: n=8
    No statistical analyses for this end point

    Secondary: PK Of Participants Who Concomitantly Received HU: AUC0-24h Of IMR-687

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    End point title
    		 PK Of Participants Who Concomitantly Received HU: AUC0-24h Of IMR-687 [10]
    End point description
    For PK assessments of participants who concomitantly received HU, serial blood samples for IMR-687 plasma concentrations were drawn predose at 0.5, 1, 1.5, 2, 4, 6, and 8 hours after administration of study drug; and at 24 hours after administration of study drug. Day 1 (single-dose) and steady-state (Week 17) assessments are presented.
    End point type
    Secondary
    End point timeframe
    Day 1 and Week 17
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK analyses of IMR-687 was not conducted for placebo groups. The IMR-687 50 mg/100 mg (with HU) group is presented.
    End point values
    		 IMR-687 50 mg/100 mg (With HU)
    Number of subjects analysed
    12 [11]
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        Day 1: Single Dose
    3090 ( 34.0 )
        Week 17: Steady State
    7300 ( 16.1 )
    Notes
    [11] - Week 17: n=8
    No statistical analyses for this end point

    Secondary: PK Of Participants Who Concomitantly Received HU: Cmax of HU

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    End point title
    		 PK Of Participants Who Concomitantly Received HU: Cmax of HU [12]
    End point description
    For PK assessments of participants who concomitantly received HU, serial blood samples for HU PK were drawn predose and at 0.5, 1, 1.5, 3, 6, 8, and 10 hours after self-administration of the prescribed dose of HU. HU in the presence (end of treatment [EOT]: Week 17) or absence of IMR-687 (Baselines 1 and 2) are presented. HU concentration data were not sorted with respect to HU dose.
    End point type
    Secondary
    End point timeframe
    Baseline (1 and 2) and Week 17
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The IMR-687 50 mg/100 mg (with HU) and placebo (with HU) groups are presented.
    End point values
    		 IMR-687 50 mg/100 mg (With HU) Placebo (With HU)
    Number of subjects analysed
    14 [13]
    6 [14]
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Baseline 1
    25.3 ( 36.7 )
    20.6 ( 87.8 )
        Baseline 2
    24.8 ( 38.1 )
    25.4 ( 98.6 )
        Week 17
    24.5 ( 55.2 )
    20.5 ( 127 )
    Notes
    [13] - Week 17: n=10
    [14] - Week 17: n=5
    No statistical analyses for this end point

    Secondary: PK Of Participants Who Concomitantly Received HU: AUC0-24h Of HU

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    End point title
    		 PK Of Participants Who Concomitantly Received HU: AUC0-24h Of HU [15]
    End point description
    For PK assessments of participants who concomitantly received HU, serial blood samples for HU PK were drawn predose and at 0.5, 1, 1.5, 3, 6, 8, and 10 hours after self-administration of the prescribed dose of HU. HU in the presence (EOT: Week 17) or absence of IMR-687 (Baselines 1 and 2) are presented. HU concentration data were not sorted with respect to HU dose.
    End point type
    Secondary
    End point timeframe
    Baseline (1 and 2) and Week 17
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The IMR-687 50 mg/100 mg (with HU) and placebo (with HU) groups are presented.
    End point values
    		 IMR-687 50 mg/100 mg (With HU) Placebo (With HU)
    Number of subjects analysed
    12 [16]
    5 [17]
    Units: h*μg/mL
    geometric mean (geometric coefficient of variation)
        Baseline 1
    99.2 ( 32.4 )
    113 ( 87.7 )
        Baseline 2
    103 ( 30.7 )
    129 ( 71.7 )
        Week 17
    122 ( 23.0 )
    91.4 ( 127 )
    Notes
    [16] - Baseline 1: n=11 Week 17: n=8
    [17] - Baseline 1: n=4 Week 17: n=4
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline In F-Cells

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    End point title
    		 Change From Baseline In F-Cells
    End point description
    Absolute least squares (LS) mean change from Baseline at EOT is presented. Change from Baseline in pharmacodynamic (PD) biomarkers was analyzed using mixed models for repeated measures with covariate of treatment, visit, treatment-by-visit interaction, and baseline value.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, EOT (Week 25 for participants without HU and Weeks 17 or 25 for participants with HU)
    End point values
    		 IMR-687 50 mg/100 mg (Without HU) IMR-687 100 mg/200 mg (Without HU) Placebo (Without HU) IMR-687 50 mg/100 mg (With HU) Placebo (With HU) Pooled IMR-687 (Without HU)
    Number of subjects analysed
    7
    13
    7
    5
    1
    20
    Units: Percentage
        least squares mean (standard error)
    3.97 ( 4.07 )
    5.66 ( 2.87 )
    -6.00 ( 3.77 )
    -2.49 ( 6.00 )
    7.38 ( 15.54 )
    4.81 ( 2.48 )
    No statistical analyses for this end point

    Post-hoc: Percentage Of Participants With Vaso-occlusive Crisis (VOCs)

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    End point title
    		 Percentage Of Participants With Vaso-occlusive Crisis (VOCs)
    End point description
    VOCs include the events of acute painful crisis and acute chest symptoms (includes fever, cough, sputum production, shortness of breath, tachypnea, hypoxia, and chest pain).
    End point type
    Post-hoc
    End point timeframe
    Day 1 (after dosing) through up to Week 24
    End point values
    		 IMR-687 50 mg/100 mg (Without HU) IMR-687 100 mg/200 mg (Without HU) Placebo (Without HU) IMR-687 50 mg/100 mg (With HU) Placebo (With HU) All IMR-687 All Placebo
    Number of subjects analysed
    12
    26
    20
    25
    10
    63
    30
    Units: percentage of participants
        number (not applicable)
    50
    54
    70
    40
    70
    48
    70
    No statistical analyses for this end point

    Post-hoc: Time To First VOC Event

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    End point title
    		 Time To First VOC Event
    End point description
    VOCs include the events of acute painful crisis and acute chest symptoms (includes fever, cough, sputum production, shortness of breath, tachypnea, hypoxia, and chest pain). Time to first VOC event was assessed by Kaplan Meier analysis in the pooled analysis of all IMR-687 and placebo populations.
    End point type
    Post-hoc
    End point timeframe
    Day 1 (after dosing) through up to Week 24
    End point values
    		 All IMR-687 All Placebo
    Number of subjects analysed
    63 [18]
    30
    Units: days
        median (confidence interval 95%)
    169.00 (80.00 to 9999)
    87.00 (26.00 to 167.00)
    Notes
    [18] - The upper confidence limit was non-estimable due to insufficient number of participants.
    Statistical analysis title
    		 Time To First VOC Event
    Comparison groups
    All IMR-687 v All Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0294
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (after dosing) through up to Week 24
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    IMR-687 50 mg/100 mg (Without HU)
    Reporting group description
    		 A starting dose of IMR-687 50 mg with dose escalation after 4 or 12 weeks, up to 100 mg was administered to participants who were not receiving daily HU.

    Reporting group title
    IMR-687 100 mg/200 mg (Without HU)
    Reporting group description
    		 A starting dose of IMR-687 100 mg with dose escalation after 4 or 12 weeks, up to 200 mg was administered to participants who were not receiving daily HU.

    Reporting group title
    Placebo (Without HU)
    Reporting group description
    		 Matching placebo was administered to participants who were not receiving daily HU.

    Reporting group title
    IMR-687 50 mg/100 mg (With HU)
    Reporting group description
    		 A starting dose of IMR-687 50 mg with dose escalation after 4 or 12 weeks, up to 100 mg was administered to participants who were receiving daily HU. HU doses ranged from 500 to 2000 mg.

    Reporting group title
    Placebo (With HU)
    Reporting group description
    		 Matching placebo was administered to participants who were receiving daily HU.

    Reporting group title
    All IMR-687
    Reporting group description
    		 All participants who received IMR-687.

    Reporting group title
    All Placebo
    Reporting group description
    		 All participants who received placebo.

    Serious adverse events
    		 IMR-687 50 mg/100 mg (Without HU) IMR-687 100 mg/200 mg (Without HU) Placebo (Without HU) IMR-687 50 mg/100 mg (With HU) Placebo (With HU) All IMR-687 All Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 12 (33.33%)
    7 / 26 (26.92%)
    8 / 20 (40.00%)
    5 / 25 (20.00%)
    3 / 10 (30.00%)
    16 / 63 (25.40%)
    11 / 30 (36.67%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed [1]
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    0 / 15 (0.00%)
    0 / 9 (0.00%)
    1 / 40 (2.50%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Multiple injuries
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    1 / 63 (1.59%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    1 / 63 (1.59%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    3 / 12 (25.00%)
    7 / 26 (26.92%)
    7 / 20 (35.00%)
    3 / 25 (12.00%)
    3 / 10 (30.00%)
    13 / 63 (20.63%)
    10 / 30 (33.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
    0 / 11
    0 / 3
    0 / 3
    0 / 15
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    1 / 63 (1.59%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    1 / 63 (1.59%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed [2]
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 12 (0.00%)
    1 / 15 (6.67%)
    0 / 9 (0.00%)
    1 / 40 (2.50%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic lesion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    1 / 63 (1.59%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash generalised
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    0 / 63 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The adverse event occurs in female participants only.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: The adverse event occurs in female participants only.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 IMR-687 50 mg/100 mg (Without HU) IMR-687 100 mg/200 mg (Without HU) Placebo (Without HU) IMR-687 50 mg/100 mg (With HU) Placebo (With HU) All IMR-687 All Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    22 / 26 (84.62%)
    16 / 20 (80.00%)
    23 / 25 (92.00%)
    10 / 10 (100.00%)
    57 / 63 (90.48%)
    26 / 30 (86.67%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    1 / 63 (1.59%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    1
    0
    1
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 12 (16.67%)
    8 / 26 (30.77%)
    4 / 20 (20.00%)
    12 / 25 (48.00%)
    4 / 10 (40.00%)
    22 / 63 (34.92%)
    8 / 30 (26.67%)
         occurrences all number
    2
    11
    6
    18
    6
    31
    12
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    2 / 63 (3.17%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    2
    1
    2
    2
    Lethargy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    0 / 63 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    3
    Blood and lymphatic system disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    5 / 12 (41.67%)
    9 / 26 (34.62%)
    9 / 20 (45.00%)
    10 / 25 (40.00%)
    6 / 10 (60.00%)
    24 / 63 (38.10%)
    15 / 30 (50.00%)
         occurrences all number
    15
    15
    14
    14
    23
    44
    37
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 26 (7.69%)
    2 / 20 (10.00%)
    4 / 25 (16.00%)
    2 / 10 (20.00%)
    7 / 63 (11.11%)
    4 / 30 (13.33%)
         occurrences all number
    1
    2
    2
    6
    2
    9
    4
    Influenza like illness
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 26 (7.69%)
    2 / 20 (10.00%)
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    6 / 63 (9.52%)
    2 / 30 (6.67%)
         occurrences all number
    2
    3
    2
    5
    0
    10
    2
    Pain
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    4 / 63 (6.35%)
    1 / 30 (3.33%)
         occurrences all number
    2
    2
    2
    1
    0
    5
    2
    Oedema peripheral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 63 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    1 / 63 (1.59%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    1
    1
    1
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 12 (16.67%)
    8 / 26 (30.77%)
    0 / 20 (0.00%)
    4 / 25 (16.00%)
    5 / 10 (50.00%)
    14 / 63 (22.22%)
    5 / 30 (16.67%)
         occurrences all number
    3
    14
    0
    4
    5
    21
    5
    Abdominal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 26 (11.54%)
    1 / 20 (5.00%)
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    5 / 63 (7.94%)
    1 / 30 (3.33%)
         occurrences all number
    0
    4
    1
    3
    0
    7
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    5 / 63 (7.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    2
    0
    2
    0
    5
    0
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    5 / 63 (7.94%)
    1 / 30 (3.33%)
         occurrences all number
    1
    2
    0
    2
    4
    5
    4
    Diarrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    3 / 63 (4.76%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    1
    2
    1
    3
    2
    Hepatobiliary disorders
    Ocular icterus
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 26 (7.69%)
    0 / 20 (0.00%)
    4 / 25 (16.00%)
    1 / 10 (10.00%)
    7 / 63 (11.11%)
    1 / 30 (3.33%)
         occurrences all number
    1
    2
    0
    4
    1
    7
    1
    Jaundice
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
    1 / 25 (4.00%)
    2 / 10 (20.00%)
    1 / 63 (1.59%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    3
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    3 / 63 (4.76%)
    2 / 30 (6.67%)
         occurrences all number
    1
    1
    2
    1
    0
    3
    2
    Cough
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 63 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
    0 / 25 (0.00%)
    1 / 10 (10.00%)
    0 / 63 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    0 / 63 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    6 / 26 (23.08%)
    2 / 20 (10.00%)
    1 / 25 (4.00%)
    2 / 10 (20.00%)
    7 / 63 (11.11%)
    4 / 30 (13.33%)
         occurrences all number
    0
    7
    2
    1
    2
    8
    4
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 26 (15.38%)
    1 / 20 (5.00%)
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    6 / 63 (9.52%)
    2 / 30 (6.67%)
         occurrences all number
    0
    5
    1
    2
    1
    7
    2
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 26 (7.69%)
    2 / 20 (10.00%)
    2 / 25 (8.00%)
    2 / 10 (20.00%)
    5 / 63 (7.94%)
    4 / 30 (13.33%)
         occurrences all number
    1
    2
    2
    3
    2
    6
    4
    Musculoskeletal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    3 / 63 (4.76%)
    2 / 30 (6.67%)
         occurrences all number
    1
    1
    1
    1
    1
    3
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 26 (3.85%)
    2 / 20 (10.00%)
    2 / 25 (8.00%)
    2 / 10 (20.00%)
    6 / 63 (9.52%)
    4 / 30 (13.33%)
         occurrences all number
    5
    1
    2
    3
    2
    9
    4
    Nasopharyngitis
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 26 (7.69%)
    1 / 20 (5.00%)
    1 / 25 (4.00%)
    1 / 10 (10.00%)
    5 / 63 (7.94%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    1
    1
    1
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2017
    Clarified that participants who experience VOC should receive all appropriate interventions and that the assessment and treatment of participants, as well as the decision to unblind, solely depended on the clinical judgement of the Investigator.
    09 Oct 2017
    Change in wording from compliance to compliance/adherence.
    27 Oct 2017
    Increased number of planned study sites. Updated the timing of blood draws for HU PK assessment (Population B). Removed blood draws for assessment of trough IMR-687 PK (Population A) and the 12-hour blood draw from serial sampling for IMR-687 PK (Populations A and B).
    19 Dec 2017
    Modification of the exclusion criteria to decrease the required reticulocyte count for enrollment in Population B to account for bone marrow suppression from HU use. Removal of exclusion criterion 4 because the opiate limits were too restrictive per site clinicians and key opinion leaders. Addition of 12 lead ECG assessments to Week 14, 17, and 21 visits for Population A.
    26 Mar 2018
    Several on-site visits were changed to telephonic visits (with on-site visit required only if AEs were identified) to reduce participant burden.
    10 Aug 2018
    Updated the exclusion criteria to (1) increase the upper limit of allowable hemoglobin (Hb) because participants on HU may have higher baseline Hb levels; and (2) increase the number of hospitalizations allowed within the past year for VOCs to assess a wider range of participants.
    19 Dec 2018
    Increased number of study sites. Updated the timing of blood draws for HU PK assessment. Removed all blood draws for assessment of trough IMR-687 PK and 1 additional IMR-687 PK blood draw.
    07 Jan 2019
    The treatment and study durations were clarified, and the extension phase of the study was removed. Baseline HU PK profiling in Population B1 (participants concomitantly received HU) was reduced from 2 samples to 1 sample. Also, modifications were made schedule of assessment tables.
    09 Jan 2019
    Further modifications were made to schedule of assessment tables, particularly for quality of life assessments.
    17 Jan 2019
    In Population A1, Week 4 was converted from a telephonic visit to an on-site visit, and 12-lead electrocardiogram collection was added to the Week 9 Visit. Updates were made to Appendix C to approximate the volume of blood drawn at each visit.
    28 Jun 2019
    Increased allowable enrollment from 70 to 90 participants based on the study withdrawal rates, which were similar to other studies in SCD. Provided discretion to the Principal Investigator regarding participant discontinuation based on study drug treatment compliance. Allowed for Sponsor to review unblinded interim analysis data.

    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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