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    Clinical Trial Results:
    Coversin in Paroxysmal Nocturnal Haemoglobulinuria (PNH) in patients with resistance to Eculizumab due to complement C5 Polymorphisms

    Summary
    EudraCT number
    		 2015-003778-34
    Trial protocol
    		 NL  
    Global end of trial date
    20 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Nov 2021
    First version publication date
    18 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AK578
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02591862
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Coversin VIP578: Coversin VIP578
    Sponsors
    Sponsor organisation name
    Akari Therapeutics plc
    Sponsor organisation address
    75-76 Wimpole Street, London, United Kingdom, W1G 9RT
    Public contact
    Chief Scientific Officer, Akari Therapeutics Plc, +44 (0)2080040261, miles.nunn@akaritx.com
    Scientific contact
    Chief Scientific Officer, Akari Therapeutics Plc, +44 (0)2080040261, miles.nunn@akaritx.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
    20 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: Safety and tolerability of Nomacopan
    Protection of trial subjects
    The study was performed in accordance with the current version of the declaration of Helsinki. The trial was conducted in agreement with the International Conference on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) E6(R1) which were current at the time of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Worldwide total number of subjects
    1
    EEA total number of subjects
    1
    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)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients were screened up to 14 days prior to study treatment to confirm eligibility for the study. A total of 1 patient was screened and enrolled onto the study.

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

    Arms
    Arm title
    		 Nomacopan (Coversin)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nomacopan
    Investigational medicinal product code
    rVA576
    Other name
    Coversin, rEV576
    Pharmaceutical forms
    Powder for solution for injection, Solution for injection in vial
    Routes of administration
    Solution for injection , Subcutaneous use
    Dosage and administration details
    Patient will be given a single ablating dose of 0.57mg/kg per subject followed by daily repeat maintenance doses. The initial repeat dose will be 25% of the ablating dose. If this is insufficient to maintain complement inhibition at ≤10% of baseline (pre-treatment) level after 5 days of treatment the daily dose will be increased by doubling until that level of inhibition is achieved. In the event of 100% inhibition being achieved the dose may be titrated downwards at the PI’s discretion until a satisfactory clinical result is obtained. If at any point in treatment complement inhibition falls to less than 50% of baseline a further ablating dose of 0.57mg/kg should be given. Nomacopan lyophilised powder in each vial was diluted with 0.6 mL water for injection prior to use.

    Number of subjects in period 1
    		Nomacopan (Coversin)
    Started
    1
    Completed
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Results from 1 enrolled patient.

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 1 1
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 1 1
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 1 1
    Race
    Units: Subjects
        white
    		 1 1
    Region of enrolment
    Units: Subjects
        Netherlands
    		 1 1
    Dependency on blood transfusion
    Units: Subjects
        Dependent on blood transfusion
    		 0 0
        Not dependent on blood transfusion
    		 1 1
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 67.8 ± 0 -
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    		 172 ± 0 -
    Serum Lactate Dehydrogenase
    Units: U/L
        arithmetic mean (standard deviation)
    		 1391 ± 0 -
    Haemoglobin concentration (Hb)
    Units: Millimole(s)/litre
        arithmetic mean (standard deviation)
    		 8.2 ± 0 -
    Haptoglobin (Hp) concentration
    Units: grams(s)/litre
        arithmetic mean (standard deviation)
    		 0.0 ± 0 -

    End points

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    End points reporting groups
    Reporting group title
    Nomacopan (Coversin)
    Reporting group description
    		 -

    Primary: Measurement of Serum lactate dehydrogenase (LDH) from Day 0 (pre-dose) to Day 28 (AUC) compared with 28 days pre-treatment

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    End point title
    		 Measurement of Serum lactate dehydrogenase (LDH) from Day 0 (pre-dose) to Day 28 (AUC) compared with 28 days pre-treatment [1]
    End point description
    LDH is an indicator of disease progression in patients with PNH and is expected to fall to within 2x upper limit of normal (ULN) within 28 days in successfully treated patients. Units are measured in ratio of LDH:ULN, where the ULN is 250 U/L.
    End point type
    Primary
    End point timeframe
    Day 0 and Day 28
    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: This was an open-label study in which just one patient was recruited. Simple descriptive statistics were therefore used.
    End point values
    		 Nomacopan (Coversin)
    Number of subjects analysed
    1
    Units: ratio of LDH:ULN (250 U/L)
    number (not applicable)
        Day 0
    5.6
        Day 28
    1.9
    No statistical analyses for this end point

    Primary: Number and Type of Adverse Events (AE)

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    End point title
    		 Number and Type of Adverse Events (AE) [2]
    End point description
    The number and type of reported AEs will be recorded as well as the opinion of the Principle Investigator (PI) as to their possible relationship to the study drug.
    End point type
    Primary
    End point timeframe
    2 years
    Notes
    [2] - 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: This was an open-label study in which just one patient was recruited. Simple descriptive statistics were therefore used.
    End point values
    		 Nomacopan (Coversin)
    Number of subjects analysed
    1
    Units: Events
        Serious Adverse Events (SAE)
    2
        Adverse Event (AE) (Total)
    20
        Treatment Emergent Adverse Event (TAEA)
    13
        AE- moderate
    1
        AE- severe
    1
        AE- mild
    18
    No statistical analyses for this end point

    Secondary: Measurement of Haemoglobin (Hb) at Days 28, 90 and 180, absolute and change from baseline

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    End point title
    		 Measurement of Haemoglobin (Hb) at Days 28, 90 and 180, absolute and change from baseline
    End point description
    Measuring change in mean Hb from Day 28, Day 90 and Day 180 (absolute and change from baseline)
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28, Day 90 and 180
    End point values
    		 Nomacopan (Coversin)
    Number of subjects analysed
    1
    Units: millimole(s)/litre
    number (not applicable)
        Baseline
    8.2
        Day 28 (absolute)
    7.8
        Day 28 (change from baseline)
    -0.7
        Day 90 (absolute)
    7.8
        Day 90 (change from baseline)
    -0.4
        Day 180 (absolute)
    8.0
        Day 180 (change from baseline)
    -0.2
    No statistical analyses for this end point

    Secondary: Measurement of Lactate Dehydrogenase (LDH) at Baseline, day 90 and 180

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    End point title
    		 Measurement of Lactate Dehydrogenase (LDH) at Baseline, day 90 and 180
    End point description
    Measuring the change in LDH at Baseline, Day 90 and Day 180. LDH is an indicator of disease progression in patients with PNH and is expected to fall to within 2x upper limit of normal (ULN) within 28 days in successfully treated patients. Units are measured in ratio of LDH:ULN, where the ULN is 250 U/L.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 90 and Day 180
    End point values
    		 Nomacopan (Coversin)
    Number of subjects analysed
    1
    Units: ratio of LDH:ULN (250 U/L)
    number (not applicable)
        Day 0
    5.6
        Day 90
    1.6
        Day 180
    1.5
    No statistical analyses for this end point

    Secondary: Measurement of Haptoglobin (Hp) at Days 28, 90 and 180, Absolute and Change From Baseline

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    End point title
    		 Measurement of Haptoglobin (Hp) at Days 28, 90 and 180, Absolute and Change From Baseline
    End point description
    Measuring change in mean Hp from Day 28, Day 90 and Day 180 (absolute and change from baseline)
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28, Day 90 and Day 180
    End point values
    		 Nomacopan (Coversin)
    Number of subjects analysed
    1
    Units: gram(s)/litre
    number (not applicable)
        Baseline
    0.0
        Day 28
    0.0
        Day 90
    0.0
    No statistical analyses for this end point

    Secondary: Dependency on blood transfusion

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    End point title
    		 Dependency on blood transfusion
    End point description
    Number of participants depending on blood transfusion prior to starting the study compared to during the study.
    End point type
    Secondary
    End point timeframe
    Day 0 through to study completion (2 years)
    End point values
    		 Nomacopan (Coversin)
    Number of subjects analysed
    1
    Units: Participants
        Transfusion dependent prior to starting trial
    0
        Transfusion dependent during trial
    0
    No statistical analyses for this end point

    Secondary: Change in Functional Assessment of Chronic Illness Therapy (FACIT) Score at Days 0, 28, 90 and 180

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    End point title
    		 Change in Functional Assessment of Chronic Illness Therapy (FACIT) Score at Days 0, 28, 90 and 180
    End point description
    Functional Assessment of Chronic Illness Therapy – fatigue (FACIT-F) is a 13 item instrument designed to assess fatigue/tiredness and it’s impact on daily activities and functioning in a chronic disease setting. The scale for each question in relation to quality of life ranges from 0-4 where 0= not at all, 1= a little bit, 2= somewhat, 3 = quite a bit and 4= very much. An increase in the scale score indicates an improvement in quality of life (less fatigue). A maximum score of 52 is interpreted as no fatigue . Baseline is assumed as 0.0 to demonstrate the change in units. The subscale score (as presented) is determined as per FACIT-f guidance, by multiplying the sum of the item scores by the number of items in the subscale, then divide by the number of items answered.
    End point type
    Secondary
    End point timeframe
    Day 28, 90 and 180
    End point values
    		 Nomacopan (Coversin)
    Number of subjects analysed
    1
    Units: FACIT-f scale (Change from Baseline)
    number (not applicable)
        Day 28
    13.0
        Day 90
    13.3
        Day 180
    11.0
    No statistical analyses for this end point

    Secondary: Change in Quality Of Life Questionnaire (QOQ) Score at Days 0, 28, 90 and 180

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    End point title
    		 Change in Quality Of Life Questionnaire (QOQ) Score at Days 0, 28, 90 and 180
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) QOQ C30 instrument measures the change in the quality of of life of patients in the trial. Quality of Life Questionnaire (QLQ)-C30 comprises 30 questions on daily quality of life and incorporates a global health status, five functional scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, nausea/vomiting, pain), and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties). Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient). Baseline is assumed as 0.0 to demonstrate the change in units.
    End point type
    Secondary
    End point timeframe
    Day 28, 90 and 180
    End point values
    		 Nomacopan (Coversin)
    Number of subjects analysed
    1
    Units: QLQ-C30 scale (Change from baseline)
    number (not applicable)
        Global Health Status/ QOL (day 28)
    16.7
        Global Health Status/ QOL (day 90)
    16.7
        Global Health Status/ QOL (day 180)
    16.7
        Physical Functioning (day 28)
    6.6
        Physical Functioning (day 90)
    0.0
        Physical Functioning (day 180)
    6.6
        Role functioning (day 28)
    33.4
        Role functioning (day 90)
    33.4
        Role functioning (day 180)
    16.7
        Emotional functioning (day 28)
    16.6
        Emotional functioning (day 90)
    8.3
        Emotional functioning (day 180)
    8.3
        Cognitive functioning (day 28)
    33.3
        Cognitive functioning (day 90)
    16.7
        Cognitive functioning (day 180)
    16.7
        Social functioning (day 28)
    0.0
        Social functioning (day 90)
    0.0
        Social functioning (day 180)
    0.0
        Fatigue symptom scale (day 28)
    -11.1
        Fatigue symptom scale (day 90)
    0.0
        Fatigue symptom scale (day 180)
    0.0
        Nausea and vomiting symptom scale (day 28)
    0.0
        Nausea and vomiting symptom scale (day 90)
    0.0
        Nausea and vomiting symptom scale (day 180)
    0.0
        Pain symptom scale (day 28)
    0.0
        Pain symptom scale (day 90)
    16.7
        Pain symptom scale (day 180)
    0.0
        Symptom: Dyspnoea (day 28)
    0.0
        Symptom: Dyspnoea (day 90)
    0.0
        Symptom: Dyspnoea (day 180)
    0.0
        Symptom: Insomnia (day 28)
    -33.3
        Symptom: Insomnia (day 90)
    0.0
        Symptom: Insomnia (day 180)
    0.0
        Symptom: Appetite loss (day 28)
    0.0
        Symptom: Appetite loss (day 90)
    0.0
        Symptom: Appetite loss (day 180)
    0.0
        Symptom: constipation (day 28)
    0.0
        Symptom: constipation (day 90)
    0.0
        Symptom: constipation (day 180)
    0.0
        Symptom: diarrhoea (day 28)
    -33.3
        Symptom: diarrhoea (day 90)
    -33.3
        Symptom: diarrhoea (day 180)
    -33.3
        Symptom: financial difficulties (day 28)
    0.0
        Symptom: financial difficulties (day 90)
    0.0
        Symptom: financial difficulties (day 180)
    0.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Duration of the study (2 years)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    nomacopan (coversin)
    Reporting group description
    		 -

    Serious adverse events
    		 nomacopan (coversin)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Breakthrough haemolysis
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 nomacopan (coversin)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    Vascular disorders
    Cold fingers and toes
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    6
    Insomnia
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Cough
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Flu like symptoms
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    5
    Injection site reaction
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    13
    Malaise
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    2
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Coughing
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Sore throat
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Haemoglobinuria
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Infections and infestations
    Papulopustular rash
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Nov 2015
    - Volution Immuno Pharmaceuticals changes to Akari Therapeutics Plc - primary efficacy endpoint - Significant Reduction in serum LDH from day 0 – Day 28 (AUC) compared with 28 days pre treatment - secondary endpoint change of timepoints, and wording clarification - clarity over patient discharge before day 7 - addition of prohibited drugs - addition to clarity over patient comparisons - change to concentration of drug product for first treatment (8.9 mg/ml to 7.2 mg/ml) - addition to have vaccination against meningococci type ACW135Y as a requirement for the study - addition of patients being required to be admitted to hospital for a minimum of 2 days at the start of treatment - If an ablating dose is repeated , PK/PD and other assessment will be performed as indicated in Appendix 1 at 1hr, day 2 and day 5 - Extra samples for PK/PD may be taken at the discretion of the investigators during illness or infection - clarification over statistical approach - clarity over storage of biological samples

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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