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    Clinical Trial Results:
    A Long-Term Open-Label, Safety and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Patients with Cystinosis

    Summary
    EudraCT number
    		 2012-002773-64
    Trial protocol
    		 GB   BE   NL   IT   FR  
    Global end of trial date
    10 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jan 2018
    First version publication date
    26 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RP103-07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01733316
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Horizon Pharma USA, Inc.
    Sponsor organisation address
    150 S. Saunders Road, Lake Forest, Illinois, United States, 60045
    Public contact
    Evelyn Olson, BS, Horizon Pharma USA, Inc., clinicaltrials@horizonpharma.com
    Scientific contact
    Maria Pecoraro, MD, Horizon Pharma USA, Inc., clinicaltrials@horizonpharma.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: To demonstrate superiority of RP103 versus Cystagon® in controlling white blood cell cystine (WBC) levels over 24 hours in patients with cystinosis and to assess long-term safety and tolerability of RP103
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. The study was conducted in accordance with legal and regulatory requirements including Guidance for Good Clinical Practice (International Conference on Harmonization [ICH] 1996), and the Declaration of Helsinki (World Medical Association 2008). Written informed consent was to be obtained from the subject’s legally acceptable representative and assent by the minor subject, as applicable, before screening or baseline assessments. Instructions were given to the subject's legally acceptable representative in case of emergency or other questions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 2013
    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
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Netherlands: 5
    Worldwide total number of subjects
    41
    EEA total number of subjects
    25
    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)
    2
    Adolescents (12-17 years)
    14
    Adults (18-64 years)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A Screening Visit occurred up to 7 days prior to Day 1. Subjects were to continue with Cystagon® treatment.

    Period 1
    Period 1 title
    Cystagon® Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All Subjects: Cystagon® Phase
    Arm description
    		 From Screening and during Months 1, 2, 3: subjects received their usual dose of Cystagon® Q6H.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cystagon® Q6H
    Investigational medicinal product code
    Other name
    cysteamine bitartrate
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    From Screening and during Months 1, 2, 3: subjects receive their usual dose of Cystagon® every 6 hours (Q6H).

    Number of subjects in period 1
    		All Subjects: Cystagon® Phase
    Started
    41
    Completed
    41
    Period 2
    Period 2 title
    RP103 Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All Subjects: RP103 Phase
    Arm description
    		 During Months 3.5, 4, 5, 6, 7: subjects received RP103 Q12H.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RP103 Q12H
    Investigational medicinal product code
    RP103
    Other name
    cysteamine bitartrate delayed-release capsules; PROCYSBI®
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    From Months 3.5, 4, 5, 6, 7 and the remainder of study participation: RP103 every 12 hours (Q12H) started at a total daily dose of 70% of subjects' Cystagon® dose.

    Number of subjects in period 2
    		All Subjects: RP103 Phase
    Started
    41
    Completed
    40
    Not completed
    1
         Non-compliance
    1
    Period 3
    Period 3 title
    Long Term Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All Subjects: Long Term Phase
    Arm description
    		 On or after Month 7, for the remainder of study: subjects received RP103 Q12H.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RP103 Q12H
    Investigational medicinal product code
    RP103
    Other name
    cysteamine bitartrate delayed-release capsules; PROCYSBI®
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    From Months 3.5, 4, 5, 6, 7 and the remainder of study participation: RP103 every 12 hours (Q12H) started at a total daily dose of 70% of subjects' Cystagon® dose.

    Number of subjects in period 3 [1]
    		All Subjects: Long Term Phase
    Started
    38
    Completed
    33
    Not completed
    5
         Consent withdrawn by subject
    2
         Adverse event
    1
         Sponsor decision
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Two subjects did not enter the long term follow up period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cystagon® Phase
    Reporting group description
    		 -

    Reporting group values
    		 Cystagon® Phase Total
    Number of subjects
    		 41 41
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 24.5 ± 11.56 -
    Gender categorical
    Units: Subjects
        Female
    		 21 21
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    All Subjects: Cystagon® Phase
    Reporting group description
    		 From Screening and during Months 1, 2, 3: subjects received their usual dose of Cystagon® Q6H.
    Reporting group title
    All Subjects: RP103 Phase
    Reporting group description
    		 During Months 3.5, 4, 5, 6, 7: subjects received RP103 Q12H.
    Reporting group title
    All Subjects: Long Term Phase
    Reporting group description
    		 On or after Month 7, for the remainder of study: subjects received RP103 Q12H.

    Subject analysis set title
    Pharmacokinetic Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who report halitosis (“bad breath”) as a side effect while receiving Cystagon®.

    Primary: Average Difference Between Morning and Non-Morning Log WBC Cystine Values

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    End point title
    		 Average Difference Between Morning and Non-Morning Log WBC Cystine Values
    End point description
    The primary analysis of WBC cystine was performed using the natural log transformed WBC cystine level; the log transformation is a normalizing transformation. For each subject, the difference between the morning and corresponding non-morning log WBC cystine value (non-morning minus morning) at each monthly visit during the Cystagon® phase (Months 1, 2, and 3) was computed and these differences were averaged. The average difference between morning and non-morning log WBC cystine value was similarly computed for each subject during the RP103 phase (Months 5, 6, and 7). The primary analysis compared within-subject pairs (Cystagon® phase paired with RP103 phase) of non-morning minus morning average differences of log WBC cystine level. Pharmacodynamic (PD) Analysis Set: All subjects who received at least one treatment of Cystagon® and RP103 and who had at least one WBC cystine level recorded after each of Cystagon® treatment and RP103 treatment.
    End point type
    Primary
    End point timeframe
    While taking Cystagon® (Months 1, 2, 3): within 15 minutes pre-AM and pre-non AM dose. During 3 months of RP103 (Months 5, 6, 7): 30 minutes post-AM and post-PM dose.
    End point values
    		 All Subjects: Cystagon® Phase All Subjects: RP103 Phase
    Number of subjects analysed
    40 [1]
    40 [2]
    Units: log [nmol ½ cystine/mg protein]
        arithmetic mean (standard deviation)
    -0.229 ± 0.5027
    0.080 ± 0.3939
    Notes
    [1] - Only subjects with an average difference during both the Cystagon and RP103 phases were included.
    [2] - Only subjects with an average difference during both the Cystagon and RP103 phases were included.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Note: Number of subjects in this analysis is 40, not 80. The EudraCT system's limitations double-counted these subjects erroneously.
    Comparison groups
    All Subjects: RP103 Phase v All Subjects: Cystagon® Phase
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0048 [3]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [3] - Paired t-test testing the null hypothesis that the population average difference during the Cystagon phase is equal to the population average difference during the RP103 phase.

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs
    End point description
    AE: any untoward medical occurrence that does not necessarily have a causal relationship with study drug. SAE: any untoward medical occurrence that at any dose: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; or is medically significant, and though not included in the above list, is an important medical event, according to the Investigator. Treatment-emergent adverse events (TEAEs) occurred after first dose of study drug. Observations from Day 1 Cystagon® dosing up to the first dose of RP103 were attributed to the Cystagon® Phase; those on or after the first dose of RP103 up to Month 7 or study termination visit (which ever occurred first) were attributed to the RP103 Phase. All observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to 7 days after last dose. Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 861 days (range 30 - 1350) during the long-term RP-103 phase.
    End point values
    		 All Subjects: Cystagon® Phase All Subjects: RP103 Phase All Subjects: Long Term Phase
    Number of subjects analysed
    41
    41
    38
    Units: subjects
        At least 1 TEAE
    31
    38
    32
        At least 1 TEAE-related to study drug
    4
    20
    18
        At least 1 grade ≥ 3 TEAE
    5
    4
    13
        At least 1 serious TEAE
    5
    6
    13
        At least 1 TEAE leading to discontinuation
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine

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    End point title
    		 Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine
    End point description
    Subjects who reported halitosis (“bad breath”) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of dimethylsulfide (DMS) in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state pharmacokinetic (PK) samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered. PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data.
    End point type
    Secondary
    End point timeframe
    While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose
    End point values
    		 Pharmacokinetic Analysis Set
    Number of subjects analysed
    20 [4]
    Units: mg/L
    arithmetic mean (standard deviation)
        Cystagon® dosing period; n=19
    3.5 ± 1.87
        RP103 dosing period; n=20
    2.9 ± 1.65
    Notes
    [4] - n=Halitosis substudy subjects with data at given timepoint
    No statistical analyses for this end point

    Secondary: Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine

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    End point title
    		 Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine
    End point description
    Subjects who reported halitosis (“bad breath”) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered. PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data.
    End point type
    Secondary
    End point timeframe
    While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose
    End point values
    		 Pharmacokinetic Analysis Set
    Number of subjects analysed
    20 [5]
    Units: hour
    arithmetic mean (standard deviation)
        Cystagon® dosing period; n=19
    1.2 ± 0.87
        RP103 dosing period; n=20
    3.2 ± 1.30
    Notes
    [5] - n=Halitosis substudy subjects with data at given timepoint
    No statistical analyses for this end point

    Secondary: Halitosis Substudy: Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine

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    End point title
    		 Halitosis Substudy: Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine
    End point description
    Subjects who reported halitosis (“bad breath”) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered. PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data.
    End point type
    Secondary
    End point timeframe
    While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose
    End point values
    		 Pharmacokinetic Analysis Set
    Number of subjects analysed
    20 [6]
    Units: hr*mg/L
    arithmetic mean (standard deviation)
        Cystagon® dosing period; n=19
    7.8 ± 5.18
        RP103 dosing period; n=20
    9.4 ± 4.86
    Notes
    [6] - n=Halitosis substudy subjects with data at given timepoint
    No statistical analyses for this end point

    Secondary: Halitosis Substudy: Expired Air DMS Concentrations

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    End point title
    		 Halitosis Substudy: Expired Air DMS Concentrations
    End point description
    Subjects who reported halitosis (“bad breath”) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS will be collected over a 6 hour period when Cystagon® is administered and over a 12 hour period when RP103 is administered. Data will be summarized in final analysis. PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data.
    End point type
    Secondary
    End point timeframe
    Visit 1: up to 6 hours hours post-dose; Visit 2: 12 hours post-morning dose
    End point values
    		 Pharmacokinetic Analysis Set
    Number of subjects analysed
    20 [7]
    Units: nmol/L
    arithmetic mean (standard deviation)
        Cystagon®, within 15 minutes prior to dose; n=18
    4.7 ± 5.54
        Cystagon®, 30 minutes post dose; n=18
    4.7 ± 4.75
        Cystagon®, 1 hour post morning dose; n=18
    6.9 ± 6.75
        Cystagon®, 2 hours post morning dose; n=18
    11.9 ± 11.26
        Cystagon®, 3 hours post morning dose; n=18
    11.2 ± 13.32
        Cystagon®, 4 hours post morning dose; n=18
    8.8 ± 12.05
        Cystagon®, 6 hours post morning dose; n=18
    4.4 ± 3.77
        RP103, within 15 minutes prior to dose; n=20
    4.6 ± 6.05
        RP103, 1 hour post morning dose; n=20
    5.4 ± 7.71
        RP103, 2 hours post morning dose; n=20
    5.1 ± 6.28
        RP103, 3 hours post morning dose; n=20
    7.7 ± 8.53
        RP103, 4 hours post morning dose; n=20
    8.6 ± 11.22
        RP103, 5 hours post morning dose; n=20
    11.2 ± 15.86
        RP103, 6 hours post morning dose; n=20
    8.5 ± 13.87
        RP103, 8 hours post morning dose; n=20
    5.7 ± 10.76
        RP103, 10 hours post morning dose; n=20
    5.2 ± 8.13
        RP103, 12 hours post morning dose; n=20
    4.3 ± 5.32
    Notes
    [7] - n=Halitosis substudy subjects with a value at given time point
    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 drug to 7 days after last dose. Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 861 days (range 30 - 1350) during the long term RP-103 phase.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    All Subjects: Cystagon® Phase
    Reporting group description
    		 From Screening and during Months 1, 2, 3: subjects received their usual dose of Cystagon® Q6H.

    Reporting group title
    All Subjects: RP103 Phase
    Reporting group description
    		 During Months 3.5, 4, 5, 6, 7: subjects received RP103 Q12H.

    Reporting group title
    All Subjects: Long Term Phase
    Reporting group description
    		 On or after Month 7, for the remainder of study: subjects received RP103 Q12H.

    Serious adverse events
    		 All Subjects: Cystagon® Phase All Subjects: RP103 Phase All Subjects: Long Term Phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 41 (12.20%)
    6 / 41 (14.63%)
    13 / 38 (34.21%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arteriovenous fistula operation
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ossiculoplasty
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal transplant
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula aneurysm
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Scoliosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    2 / 38 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Graft infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Onychomycosis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 41 (2.44%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    4 / 38 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All Subjects: Cystagon® Phase All Subjects: RP103 Phase All Subjects: Long Term Phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 41 (68.29%)
    33 / 41 (80.49%)
    32 / 38 (84.21%)
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    4 / 38 (10.53%)
         occurrences all number
    0
    0
    4
    Malaise
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 41 (2.44%)
    1 / 38 (2.63%)
         occurrences all number
    3
    2
    1
    Pyrexia
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 41 (4.88%)
    2 / 38 (5.26%)
         occurrences all number
    2
    3
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    2 / 38 (5.26%)
         occurrences all number
    0
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 41 (2.44%)
    3 / 38 (7.89%)
         occurrences all number
    3
    1
    3
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    2 / 38 (5.26%)
         occurrences all number
    0
    1
    3
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    2
    Weight decreased
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 41 (2.44%)
    3 / 38 (7.89%)
         occurrences all number
    1
    1
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 41 (19.51%)
    6 / 41 (14.63%)
    7 / 38 (18.42%)
         occurrences all number
    8
    9
    15
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    4 / 38 (10.53%)
         occurrences all number
    0
    1
    4
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    3 / 38 (7.89%)
         occurrences all number
    0
    2
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 41 (7.32%)
    5 / 38 (13.16%)
         occurrences all number
    1
    3
    10
    Abdominal pain upper
         subjects affected / exposed
    2 / 41 (4.88%)
    6 / 41 (14.63%)
    3 / 38 (7.89%)
         occurrences all number
    2
    6
    4
    Constipation
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 41 (4.88%)
    3 / 38 (7.89%)
         occurrences all number
    0
    2
    3
    Diarrhoea
         subjects affected / exposed
    4 / 41 (9.76%)
    9 / 41 (21.95%)
    7 / 38 (18.42%)
         occurrences all number
    4
    10
    10
    Nausea
         subjects affected / exposed
    4 / 41 (9.76%)
    15 / 41 (36.59%)
    5 / 38 (13.16%)
         occurrences all number
    5
    22
    7
    Vomiting
         subjects affected / exposed
    2 / 41 (4.88%)
    11 / 41 (26.83%)
    7 / 38 (18.42%)
         occurrences all number
    2
    15
    10
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    3
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    2 / 38 (5.26%)
         occurrences all number
    0
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    2
    Knee deformity
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    2 / 38 (5.26%)
         occurrences all number
    0
    1
    2
    Candidiasis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 41 (2.44%)
    2 / 38 (5.26%)
         occurrences all number
    0
    1
    2
    Ear infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    0
    0
    4
    Gastroenteritis
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 41 (9.76%)
    4 / 38 (10.53%)
         occurrences all number
    1
    4
    4
    Influenza
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    4 / 38 (10.53%)
         occurrences all number
    0
    0
    6
    Nasopharyngitis
         subjects affected / exposed
    8 / 41 (19.51%)
    5 / 41 (12.20%)
    6 / 38 (15.79%)
         occurrences all number
    8
    5
    8
    Respiratory tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 41 (4.88%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 41 (0.00%)
    6 / 38 (15.79%)
         occurrences all number
    4
    0
    9
    Urinary tract infection
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 41 (7.32%)
    4 / 38 (10.53%)
         occurrences all number
    2
    4
    5
    Viral infection
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 41 (4.88%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    6
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    2
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 41 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    1
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2016
    Drug product storage condition was revised as follows: - From: Should be stored at controlled room temperature (maintained at 20-25°C, mean temperature not more than 25°C, with excursions permitted from 15 to 30°C) - To: Before opening, the bottle should be stored in a refrigerator (at 2°C - 8°C / 36°F ‑ 46°F), and after opening, the bottle should not be stored above 25°C (77°F)

    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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