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    Clinical Trial Results:
    COBALT: Coversin Global Study: An Open-Label, Safety and Efficacy Trial in PNH Patients

    Summary
    EudraCT number
    2016-002067-33
    Trial protocol
    GB  
    Global end of trial date
    21 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jan 2019
    First version publication date
    06 Jan 2019
    Other versions
    Summary report(s)
    AK579 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    AK579
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Akari Therapeutics plc
    Sponsor organisation address
    75-75 Wimpole Street, London, United Kingdom, W1G 9RT
    Public contact
    Medical Director, Akari Therapeutics Plc, +44 0208004 0261, wwd@akaritx.com
    Scientific contact
    Medical Director, Akari Therapeutics Plc, +44 0208004 0261, wwd@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
    13 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of the study are: • To assess the safety and tolerability of Coversin for all patients for the duration of the study. • To assess efficacy of the dosage regimen to reduce haemolysis and control the signs and symptoms thereof, in PNH subjects as manifested by: i. Serum lactic dehydrogenase (LDH) change from baseline (day 1) to day 28 ii. Haemoglobin (Hb) at day 28 and day 90, absolute and change from baseline iii. Number of blood transfusions iv. Quality of Life - EORTC QLQ-C30 at day 1 (baseline), 7, 14, 21, 29, 60 and 90 days v. Quality of Life – EQ-5D-5L at baseline day 1 (baseline) up to day 60 and then at day 90. • To determine whether self-injection by subjects with PNH is well-accepted and the home care nursing supervision period sufficient using a (non validated) questionnaire at day 29 and day 90.
    Protection of trial subjects
    There were no specific measures put in place for the protection of trial subjects - normal GCP procedures were utilised
    Background therapy
    Normal standard of care excluding treatment with other complement C5 inhibitors
    Evidence for comparator
    No comparator
    Actual start date of recruitment
    25 Aug 2016
    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
    Poland: 5
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    8
    EEA total number of subjects
    8
    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)
    5
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited between 13 December 2016 and last patient last visit was 21 December 2017. The study was opened up for recruitment in both UK and Poland with the first patient being recruited in the UK and also the last patient.

    Pre-assignment
    Screening details
    Nine patients were screened with 8 being recruited. One patient was screened but withdrew consent at this point. They subsequently decided to take part in the study,

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

    Arms
    Arm title
    Intent to Treat
    Arm description
    All patients received the IMP treatment
    Arm type
    Experimental

    Investigational medicinal product name
    rVA576 (Coversin)
    Investigational medicinal product code
    rVA576
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The product is packaged as a lyophilised powder for solution for injection in a vail containing 18 mg/Vial. The product is reconstituted prior to use with 0.6mL WFI giving a concentration of 30mg/mL. Protocol version 3 used an ablating dosage scheme of 60 mg followed by three times 30 mg every 12 hours. Patients then received 15 mg every 12 hours up to Day 28 and then 30 mg once daily every 24 hours to the end of the study. Patients doses could be amended on response and patients would be dosed either every 24 hours or every 12 hours. Protocol version 4 used an refined ablating scheme of 60 mg followed by 30 mg 12 hours later and then from Days 2 -28 a dose of 22.5 mg every 12 hours. From Day 29 to the end of the study patients received 45 mg once daily. If control of CH50 was not maintained patients could have their 45 mg dose split into 22.5 mg every 12 hours.

    Number of subjects in period 1
    Intent to Treat
    Started
    8
    Completed
    7
    Not completed
    1
         Physician decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    -

    Reporting group values
    Overall Study Total
    Number of subjects
    8 8
    Age categorical
    The patients recruited were adults over the age of 18
    Units: Subjects
        Adults (18-64 years)
    5 5
        From 65-84 years
    3 3
    Gender categorical
    Patients could be male or female
    Units: Subjects
        Female
    4 4
        Male
    4 4

    End points

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    End points reporting groups
    Reporting group title
    Intent to Treat
    Reporting group description
    All patients received the IMP treatment

    Primary: Reduction in serum LDH to <=1.8 x upper limit of Normal from Day 1 to Day 29

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    End point title
    Reduction in serum LDH to <=1.8 x upper limit of Normal from Day 1 to Day 29 [1]
    End point description
    The number of patients who achieved a reduction in serum LDH to <= to 1.8 times the upper limit of normal (ULN) by Day 29. There was a drop in LDH over time with median LDH <= 1.8 x ULN reached by Day 29 and maintained throughout the remainder of the study. The number of patients who successfully achieved the primary endpoint was five out of eight.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 29
    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: Descriptive statistics were the only statistics performed on the results
    End point values
    Intent to Treat
    Number of subjects analysed
    8
    Units: Number of patients
    5
    No statistical analyses for this end point

    Secondary: Reduction in LDH at Day 29 to 50% or less of mean of all pre-dose measurements

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    End point title
    Reduction in LDH at Day 29 to 50% or less of mean of all pre-dose measurements
    End point description
    Reduction of LDH at Day 29 to 50% or less of the mean of all pre-dose measurements taken within 14 days of commencing Coversin treatment
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    Number of subjects analysed
    Units: Number
    No statistical analyses for this end point

    Secondary: Reduction in CH50 from Day 1 pre-dose to Days 7, 14, 21, 29, 60 and 90

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    End point title
    Reduction in CH50 from Day 1 pre-dose to Days 7, 14, 21, 29, 60 and 90
    End point description
    The derived average CH50 level obtained from the Day 1 pre-dose evaluation will be regarded as baseline. Changes and percentage changes from baseline to each post-baseline CH50 average assessment will be derived.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose to Day 7, 14, 21, 29, 60 and 90
    End point values
    Intent to Treat
    Number of subjects analysed
    8 [2]
    Units: Change and percentage
    7
    Notes
    [2] - One patient was withdrawn at Day 43 so no Day 60 and 90 values available
    No statistical analyses for this end point

    Secondary: Reduction in serum LDH to <= 1.8 times the ULN for the Investigators' Reference Laboratory at Day 60

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    End point title
    Reduction in serum LDH to <= 1.8 times the ULN for the Investigators' Reference Laboratory at Day 60
    End point description
    The number of patients who achieved a reduction in serum LDH to <= 1.8 times the ULN for the Investigator's reference laboratory at Day 60 and Day 90
    End point type
    Secondary
    End point timeframe
    From Day 1 pre-dose to Day 60
    End point values
    Intent to Treat
    Number of subjects analysed
    7 [3]
    Units: Number
    4
    Notes
    [3] - One patient was withdrawn at Day 43
    No statistical analyses for this end point

    Secondary: Reduction in serum LDH to < = 1.8 times the ULN for the Investigator's reference laboratory at Day 90

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    End point title
    Reduction in serum LDH to < = 1.8 times the ULN for the Investigator's reference laboratory at Day 90
    End point description
    The number of patients with a reduction in serum LDH to <=1.8 times the ULN for the Investigator's reference laboratory at Day 90
    End point type
    Secondary
    End point timeframe
    From Day 1 pre-dose to Day 90
    End point values
    Intent to Treat
    Number of subjects analysed
    7 [4]
    Units: Number
    3
    Notes
    [4] - One patient was withdrawn at Day 43
    No statistical analyses for this end point

    Secondary: Increase in haemoglobin from Day 1 to Day 29 to Day 90

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    End point title
    Increase in haemoglobin from Day 1 to Day 29 to Day 90
    End point description
    Mean Hb started at approximately 0.8x the LLN and remained at a mean of 0.8 x the LLN though out the trial
    End point type
    Secondary
    End point timeframe
    Day 1 predose to Day 90
    End point values
    Intent to Treat
    Number of subjects analysed
    7 [5]
    Units: Mean
    7
    Notes
    [5] - One patient was withdrawn at Day 43
    No statistical analyses for this end point

    Secondary: Number of blood transfusions during study period

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    End point title
    Number of blood transfusions during study period
    End point description
    The number of patients who did not require transfusions by the end of the study
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose to Day 90
    End point values
    Intent to Treat
    Number of subjects analysed
    6 [6]
    Units: Number
    3
    Notes
    [6] - Only 6 received transfusions prior to joining the study
    No statistical analyses for this end point

    Secondary: Change in EORTC QLQ-C30 Score from Day 1 (baseline) to Days 7, 14, 21, 29, 60 and 90

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    End point title
    Change in EORTC QLQ-C30 Score from Day 1 (baseline) to Days 7, 14, 21, 29, 60 and 90
    End point description
    Patients were to complete the EORTC QLQ-C30 prior to start of Coversin Administration on Day 1 and repeat on Day 7 (+/- 1), Days 14, 21, 29, 36, 60 and Days 90 (+/- 2). QLQ-C30 comprises of 30 questions on daily quality of life with each question having a response score on a scale of 1-4 or 1-7. QLQ-C30 incorporates a global health status, five functional scales, three symptom scales and six single items. THE EORTC-QLQ-C30 showed a general improvement in most aspects.
    End point type
    Secondary
    End point timeframe
    Day 1 baseline to Days 7, 14, 21, 29,, 60 and 90
    End point values
    Intent to Treat
    Number of subjects analysed
    7 [7]
    Units: Response score
    7
    Notes
    [7] - One patient was withdrawn on Day 43
    No statistical analyses for this end point

    Secondary: Change in EQ-5D-5L from Baseline Day 1 to Day 60 and Day 90

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    End point title
    Change in EQ-5D-5L from Baseline Day 1 to Day 60 and Day 90
    End point description
    Patients were to complete the EQ-5D-5L prior to start of Coversin administration on Day 1 and every day up to Day 60 then at Day 90. EQ-5D-5L comprises of 5 questions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each with five levels plus the EQ Visual Analogue scale. A general improvement in all five scales was observed in all EQ-5D-5L.
    End point type
    Secondary
    End point timeframe
    From Day 1 predose to Day 60 and Day 90
    End point values
    Intent to Treat
    Number of subjects analysed
    7 [8]
    Units: Percentage change
    7
    Notes
    [8] - One patient was withdrawn at Day 43
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study medication to end of study (approximately 90 days of treatment). All patients except one entered the separate long-term safety study
    Adverse event reporting additional description
    Reporting was a mixture of systematic and non-systematic through the use of diary cards
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    All subjects who received at least one dose of Coversin

    Serious adverse events
    Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Angina pectoris
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Staphylococcal infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 8 (75.00%)
    Investigations
    Neutrophil count decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    White blood cell count decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Lymphadenopathy
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    5 / 8 (62.50%)
         occurrences all number
    40
    Injection site pruritus
         subjects affected / exposed
    4 / 8 (50.00%)
         occurrences all number
    14
    Injection site pain
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    24
    Injection site bruising
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    8
    Injection site discharge
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    8
    Injection site haematoma
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Injection site hypersensitivity
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Injection site induration
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Injection site swelling
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    12
    Gastrointestinal disorders
    Abdominal discomfort
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hypophosphataemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2
    Hypoproteinaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jul 2016
    Protocol amendment 2 dated 27 June 2016 was updated at the request of the MHRA during their assessment of the initial CTA. The changes included the addition of a discussion on C5 polymorphisms and the need to monitor patients for complete inhibition of CH50 in accordance with the information in the IB. To include information on the fact that the phototoxicity potential of Coversin was unknown and that patients should avoid excessive exposure to sunlight or UV light. The addition of a new exclusion criteria to exclude patients with a known sensitivity to the excipients of meningococcal vaccines, ciprofloxacin or any other antibiotic being administered for the purpose of meningococcal prophylaxis.
    12 Sep 2016
    Change in ablating dose from four times 30 mg every 12 hours over to days to an initial ablating dose of 60 mg followed by three times 30 mg every 12 hours for 2 days. There was also a change in the proposed dosing scheme from 30 mg every 24 hours from Day 3 to Day 88 to the initial ablating dose would be followed by 15 mg every 12 hours from Day 3 to Day 28 and then a switch to 30 mg once daily until the end of the trial. The addition of text to state that the dose could be changed from Day 7 onwards in the case of an ineffective dose (e.g. 30 mg once daily) to either an increased dose of 45 mg once daily for example or by dividing the single dose into two doses administered 12 hours apart (e.g. 15 mg or 22.5 mg). An additional secondary endpoint was added to capture the reduction in serum LDH to <= 1.8 times the upper limit of normal (ULN) for the Investigator's reference laboratory or 500 I U/L whichever is the lower at Day 60 and at Day 90. There were other changes made throughout the protocol to reflect these updates to the dosing schedule including the frequency of blood draws and visits.
    28 Jul 2017
    The main changes to protocol amendment 4 dated 19 June 2017 was a change to the ablating dose from 60 mg followed by three times 30 mg over 12 hours for 2 days to 60 mg followed by 30 mg 12 hours later all in the first day. The initiation phase dosing was changed from 15 mg every 12 hours for 26 days to 22.5 mg every 12 hours for 27 days. The maintenance phase dosing was changed from a single dose of 30 mg every 24 hours to a single dose of 45 mg every 24 hours. Dose increases were no longer permitted but the dose could be split to 12 hourly. There was the removal of some of the homecare visits. Additional safety assessments were added.

    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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