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    Clinical Trial Results:
    An Open-Label Phase 2 Proof-of-Concept Study in Patients with C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) Treated with ACH-0144471

    Summary
    EudraCT number
    2017-002674-39
    Trial protocol
    BE   NL   IT  
    Global end of trial date
    29 Mar 2021

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ACH471-205
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03459443
    WHO universal trial number (UTN)
    U1111-1203-9136
    Sponsors
    Sponsor organisation name
    Achillion Pharmaceuticals, Inc. (a subsidiary of Alexion Pharmaceuticals, Inc.)
    Sponsor organisation address
    121 Seaport Boulevard, Boston, MA, United States, 02210
    Public contact
    European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +33 147100606, clinicaltrials.eu@alexion.com
    Scientific contact
    European Clinical Trial Information, Alexion Pharmaceuticals, Inc., +33 147100606, clinicaltrials.eu@alexion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002310-PIP02-17
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of this study was to evaluate the efficacy of 12 months of oral ACH 0144471 (also known as danicopan and ALXN2040) in participants with C3G or IC-MPGN based on histologic scoring and proteinuria.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of Good Clinical Practice (GCP), according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Harmonized Tripartite Guideline, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 May 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    27 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    22
    EEA total number of subjects
    14
    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)
    5
    Adults (18-64 years)
    17
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    To enroll in the study, participants were required to have biopsy-confirmed primary C3G or IC-MPGN and clinical evidence of ongoing disease based on significant proteinuria.

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

    Arms
    Arm title
    Danicopan
    Arm description
    Danicopan was to be administered to participants with C3G or IC-MPGN at a starting dose of 100 milligrams (mg) 3 times daily (TID) for the first 2 weeks, then the dosage was to be increased to 200 mg TID for the remainder of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Danicopan
    Investigational medicinal product code
    Other name
    ACH-4471, ACH4471, 4471, ALXN2040
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Danicopan was administered for up to 40 months, which included an initial 12-month Treatment Period and up to 27-month Long-term Extension.

    Number of subjects in period 1
    Danicopan
    Started
    22
    Received at Least 1 Dose of Study Drug
    22
    Completed
    0
    Not completed
    22
         Adverse event, non-fatal
    1
         Lack of efficacy
    3
         Sponsor’s decision to close the study
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Danicopan
    Reporting group description
    Danicopan was to be administered to participants with C3G or IC-MPGN at a starting dose of 100 milligrams (mg) 3 times daily (TID) for the first 2 weeks, then the dosage was to be increased to 200 mg TID for the remainder of the study.

    Reporting group values
    Danicopan Total
    Number of subjects
    22 22
    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)
    5 5
        Adults (18-64 years)
    17 17
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    24.3 ( 9.90 ) -
    Gender categorical
    Units: Subjects
        Female
    10 10
        Male
    12 12

    End points

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    End points reporting groups
    Reporting group title
    Danicopan
    Reporting group description
    Danicopan was to be administered to participants with C3G or IC-MPGN at a starting dose of 100 milligrams (mg) 3 times daily (TID) for the first 2 weeks, then the dosage was to be increased to 200 mg TID for the remainder of the study.

    Primary: Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period

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    End point title
    Change From Baseline In Composite Biopsy Score At End Of Initial 12-Month Treatment Period [1]
    End point description
    The composite biopsy score was based on a score incorporating changes in the activity index, glomerular C3c staining, and glomerular macrophage infiltration at the end of the initial 12 months of treatment. The composite renal biopsy index scoring system ranged from 0 to 21, with higher scores indicating worse outcomes.
    End point type
    Primary
    End point timeframe
    Baseline, end of initial 12-Month Treatment Period
    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: Endpoint was summarized descriptively.
    End point values
    Danicopan
    Number of subjects analysed
    16 [2]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    10.6 ( 3.59 )
        End of 12-Month Initial Treatment Period
    8.0 ( 4.53 )
        Change from Baseline
    -0.9 ( 1.89 )
    Notes
    [2] - End of 12-Month Initial Treatment Period: n=9
    No statistical analyses for this end point

    Primary: Participants With Reduction In Proteinuria At End Of Initial 12-Month Treatment Period

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    End point title
    Participants With Reduction In Proteinuria At End Of Initial 12-Month Treatment Period [3]
    End point description
    Proteinuria reduction was defined as ≥ 30% decrease from baseline based on 24-hour urine protein (mg/day).
    End point type
    Primary
    End point timeframe
    Baseline, end of initial 12-Month Treatment Period
    Notes
    [3] - 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: Endpoint was summarized descriptively.
    End point values
    Danicopan
    Number of subjects analysed
    19
    Units: participants
        number (not applicable)
    8
    No statistical analyses for this end point

    Secondary: Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period

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    End point title
    Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
    End point description
    Proteinuria was assessed based on 24-hour urine collections at baseline and end of the initial 12-Month Treatment Period.
    End point type
    Secondary
    End point timeframe
    Baseline, end of initial 12-Month Treatment Period
    End point values
    Danicopan
    Number of subjects analysed
    22 [4]
    Units: mg/day
    arithmetic mean (standard deviation)
        Baseline
    4252.28 ( 2684.959 )
        End of Initial 12-Month Treatment Period
    3512.63 ( 3335.765 )
        Change from Baseline
    -671.11 ( 2695.592 )
    Notes
    [4] - End of the initial 12-Month Treatment Period: 19
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period

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    End point title
    Percent Change From Baseline In Proteinuria At End Of Initial 12-Month Treatment Period
    End point description
    Proteinuria was assessed based on 24-hour urine collections at baseline and end of initial 12-Month Treatment Period.
    End point type
    Secondary
    End point timeframe
    Baseline, end of initial 12-Month Treatment Period
    End point values
    Danicopan
    Number of subjects analysed
    19
    Units: percent change
        arithmetic mean (standard deviation)
    -17.1 ( 53.17 )
    No statistical analyses for this end point

    Secondary: Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To End Of Initial 12-Month Treatment Period

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    End point title
    Slope Of Estimated Glomerular Filtration Rate (eGFR) From Baseline To End Of Initial 12-Month Treatment Period
    End point description
    Slope of eGFR was estimated using a simple linear regression for each participant, including all data values from baseline until the end of the Initial 12-Month Treatment Period, with eGFR as the dependent variable and time as the independent variable.
    End point type
    Secondary
    End point timeframe
    End of initial 12-Month Treatment Period
    End point values
    Danicopan
    Number of subjects analysed
    22
    Units: mL/min/1.73 m^2 per month
        arithmetic mean (standard deviation)
    -1.24917 ( 1.811457 )
    No statistical analyses for this end point

    Secondary: Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period

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    End point title
    Change From Baseline In eGFR At End Of Initial 12-Month Treatment Period
    End point description
    Change from baseline in eGFR at end of initial 12-Month Treatment Period is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, end of initial 12-Month Treatment Period
    End point values
    Danicopan
    Number of subjects analysed
    22 [5]
    Units: mL/min/1.73 m^2
    arithmetic mean (standard deviation)
        Baseline
    90.692 ( 35.4939 )
        End of Initial 12-Month Treatment Period
    81.412 ( 38.3320 )
        Change from Baseline
    -9.795 ( 14.3806 )
    Notes
    [5] - End of the initial 12-month Treatment Period: n=20
    No statistical analyses for this end point

    Secondary: Participants With Significant Improvement In eGFR Relative To Baseline At End Of Initial 12-Month Treatment Period

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    End point title
    Participants With Significant Improvement In eGFR Relative To Baseline At End Of Initial 12-Month Treatment Period
    End point description
    Significant improvement relative to baseline was defined as a ≥ 25% increase from baseline in eGFR.
    End point type
    Secondary
    End point timeframe
    Baseline, End Of Initial 12-Month Treatment Period
    End point values
    Danicopan
    Number of subjects analysed
    20
    Units: participants
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline In eGFR Over 12 Months Of Treatment For Participants Meeting eGFR Inclusion Criteria At Study Entry

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    End point title
    Change From Baseline In eGFR Over 12 Months Of Treatment For Participants Meeting eGFR Inclusion Criteria At Study Entry
    End point description
    End point type
    Secondary
    End point timeframe
    End of initial 12-Month Treatment Period
    End point values
    Danicopan
    Number of subjects analysed
    0 [6]
    Units: mL/min/1.73 m^2
        arithmetic mean (standard deviation)
    ( )
    Notes
    [6] - No participants met the criteria.
    No statistical analyses for this end point

    Secondary: Change From Baseline In Measured GFR At The End Of The Initial 12-Month Treatment Period

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    End point title
    Change From Baseline In Measured GFR At The End Of The Initial 12-Month Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    End of initial 12-Month Treatment Period
    End point values
    Danicopan
    Number of subjects analysed
    0 [7]
    Units: mL/min/1.73 m^2
    arithmetic mean (standard deviation)
        Baseline
    ( )
        End of initial 12-Month Treatment Period
    ( )
        Change from Baseline
    ( )
    Notes
    [7] - No participants met criteria.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (after dosing) through up to 40 months. The mean study duration was 569.0 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Danicopan
    Reporting group description
    Danicopan was to be administered to participants with C3G or IC-MPGN at a starting dose of 100 mg TID for the first 2 weeks, then the dosage was to be increased to 200 mg TID for the remainder of the study.

    Serious adverse events
    Danicopan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 22 (13.64%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Rhinovirus infection
         subjects affected / exposed
    1 / 22 (4.55%)
         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
    Danicopan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 22 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Hypertensive crisis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    3
    Arteriovenous fistula
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Haematoma
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hot flush
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pallor
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Surgical and medical procedures
    Sinus operation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed [1]
    1 / 10 (10.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    11 / 22 (50.00%)
         occurrences all number
    16
    Oedema peripheral
         subjects affected / exposed
    8 / 22 (36.36%)
         occurrences all number
    15
    Fatigue
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    7
    Asthenia
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    5
    Influenza like illness
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Chills
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Facial pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Localised oedema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Oedema
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Multiple allergies
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed [2]
    2 / 10 (20.00%)
         occurrences all number
    2
    Oligomenorrhoea
         subjects affected / exposed [3]
    1 / 10 (10.00%)
         occurrences all number
    1
    Premature menopause
         subjects affected / exposed [4]
    1 / 10 (10.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    8
    Dyspnoea
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    5
    Cough
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Rhinorrhoea
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Productive cough
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Nasal congestion
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Dysphonia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Abnormal dreams
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Blood potassium decreased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Crystal urine present
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Lipids increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Transaminases increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    11
    Blood creatinine increased
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Blood potassium increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Lip injury
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Post procedural haematuria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Left ventricular failure
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    13
    Dizziness
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Migraine
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Syncope
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Restless legs syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Dizziness postural
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Migraine with aura
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Taste disorder
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5
    Leukopenia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Thrombocytosis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Anaemia macrocytic
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Leukocytosis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Neutrophilia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Vertigo
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    7
    Nausea
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Abdominal distension
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Abdominal pain lower
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Bowel movement irregularity
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hypertrophy of tongue papillae
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Paraesthesia oral
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Pruritus
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Erythema
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Acne
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dermatitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dermatitis atopic
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Ingrowing nail
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Rash erythematous
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Skin lesion
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    6
    Acute kidney injury
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Nephrotic syndrome
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Hypothyroidism
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    5
    Back pain
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Arthralgia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Bone pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Flank pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Joint effusion
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Muscle tightness
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pain in jaw
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Rhabdomyolysis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    11
    Pharyngitis
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    6
    Influenza
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    9
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    4
    Bronchitis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Tonsillitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Viral infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    2
    Bacteriuria
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Corona virus infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Ear lobe infection
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Enterobiasis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Impetigo
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    10
    Hyperphosphataemia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Metabolic acidosis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Vitamin D deficiency
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Decreased appetite
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dehydration
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Dyslipidaemia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Hypovitaminosis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Iron deficiency
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Adverse event occurs in only female participants.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Adverse event occurs in only female participants.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Adverse event occurs in only female participants.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Adverse event occurs in only female participants.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2017
    • Allowed Investigators who wished to do so to collect measured glomerular filtration rate (GFR) in addition to the existing eGFR calculations. • Modified contraception requirements, and serious adverse event (SAEs) reporting contact information was updated.
    23 Mar 2018
    • Allowed vaccinations to be administered according to local/national guidelines. • Removed intensive pharmacokinetic (PK) sampling at Day 3 in order to reduce the burden to study participants; trough PK sample on Day 3 was retained. • Simplified the complement based inclusion/exclusion criteria. • Updated contact information for reporting SAEs.
    30 Jan 2019
    • Revised the primary objective to include only improvement in proteinuria and changed improvement in eGFR to a secondary objective. • Made changes to the inclusion and exclusion criteria to better reflect the intended patient population and to facilitate enrollment. • Changed the dose escalation strategy so that all participants would escalate after 2 weeks. • Reduced sample collection and added flexibility to the collection schedule to reduce the burden on participants.
    22 Jul 2019
    • Added biopsy as a primary endpoint. • Reduced sample collection and added flexibility to the collection schedule to reduce the burden on participants. • Removed the biopsy sub study option at Week 52. • Extended the study to Week 104 (addition of a 12-month Long term Follow up Period). • Reduced the number of in clinic study visits by allowing visits by phone call.
    15 May 2020
    • Increased duration of study treatment from 24 to 40 months. • Updated stopping rules for individual participants. • Allowed home and telephone visits, local laboratory testing, and study intervention to be sent directly to participants’ homes when clinic visits were not possible due to the coronavirus disease 2019 (COVID 19) global pandemic. • Allowed optional renal biopsy to be performed when possible due to COVID 19 global pandemic. • Updated contraceptive language to align with the most recent Investigator Brochure.

    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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