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

    Summary
    EudraCT number
    2010-018365-34
    Trial protocol
    FR   NL  
    Global end of trial date
    26 Jun 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    RP103-04
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01197378
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Horizon Pharma USA, Inc.
    Sponsor organisation address
    150 S. Saunders Road, Lake Forest, United States, 60045
    Public contact
    Evelyn Olson, 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
    26 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the safety and tolerability of long-term repeat dosing of RP103 in patients with nephropathic cystinosis.
    Protection of trial subjects
    The study was conducted in accordance with Good Clinical Practice (GCP). The protocol, Informed Consent Form (ICF) and assents were reviewed and approved by the Institutional Review Board (IRB) or Ethics Committee (EC). Written informed assent for the study was obtained from all pediatric subjects and from each pediatric subject’s parent or legal guardian before protocol-specific procedures were carried out. For adults above the age of 18 years, written informed consent for the study was obtained before protocol-specific procedures were carried out.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Aug 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    United States: 33
    Worldwide total number of subjects
    60
    EEA total number of subjects
    27
    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)
    37
    Adolescents (12-17 years)
    17
    Adults (18-64 years)
    6
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Initially, only subjects who completed the previous Phase III Study RP103-03 were enrolled in this extension study. As of 27 September 2011, enrollment was opened up to additional subjects, including subjects who were less than 6 years of age and kidney transplant subjects who qualified based on the inclusion/exclusion criteria.

    Pre-assignment
    Screening details
    Of the 60 subjects who were screened for participation in the RP103-04 study, all 60 were eligible and subsequently enrolled.

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

    Arms
    Arm title
    Cysteamine bitartrate
    Arm description
    Cysteamine bitartrate delayed-release capsules were administered twice daily.
    Arm type
    Experimental

    Investigational medicinal product name
    Cysteamine Bitartrate Delayed-Release
    Investigational medicinal product code
    RP103
    Other name
    mercaptamine bitartrate, PROCYSBI
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects who entered the trial from the RP103-03 study continued treatment with RP103 Q12H at the last dose level prescribed during their participation in the study. Subjects not entering the trial from RP103-03 study were started on twice a day administration of RP103, where the total daily RP103 dose was 70% of their pre-study total daily stable Cystagon® dose.

    Number of subjects in period 1
    Cysteamine bitartrate
    Started
    60
    Received treatment
    59
    Completed
    53
    Not completed
    7
         Other
    2
         Physician decision
    1
         Adverse event, non-fatal
    3
         Consent withdrawn by subject
    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
    60 60
    Age categorical
    Units: Subjects
        Children (2-11 years)
    37 37
        Adolescent (12-17 years)
    17 17
        18-64 years
    6 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.7 ± 6.10 -
    Gender categorical
    Units: Subjects
        Female
    23 23
        Male
    37 37
    Race
    Units: Subjects
        White
    59 59
        Other
    1 1
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    3 3
        Not Hispanic/Latino
    57 57

    End points

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    End points reporting groups
    Reporting group title
    Cysteamine bitartrate
    Reporting group description
    Cysteamine bitartrate delayed-release capsules were administered twice daily.

    Primary: Number of Participants with Treatment-emergent Adverse Events

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    End point title
    Number of Participants with Treatment-emergent Adverse Events [1]
    End point description
    Drug-related includes adverse events with investigator-assessed relation to drug of: 'possibly', 'probably' or 'definitely'. The severity of AEs was categorized according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 as follows: - MILD (Grade 1): experience is minor and does not cause significant discomfort to subject or change in activities of daily living (ADL); subject is aware of symptoms but symptoms are easily tolerated; - MODERATE (Grade 2): experience is an inconvenience or concern to the subject and causes interference with ADL, but the subject is able to continue with ADL. - SEVERE (Grade 3): experience significantly interferes with ADL and the subject is incapacitated and/or unable to continue with ADL - LIFE THREATENING (Grade 4): experience that, in the view of the Investigator, places the subject at immediate risk of death from the event as it occurred.
    End point type
    Primary
    End point timeframe
    From first dose of study drug to 7 days after the last dose; median duration of treatment was 1461 days.
    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: No statistical analyses were performed in this open-label extension study.
    End point values
    Cysteamine bitartrate
    Number of subjects analysed
    59 [2]
    Units: participants
        All adverse events
    58
        Adverse events related to study drug
    37
        Adverse events ≥ Grade 3
    24
        Serious adverse events
    32
        Adverse events leading to discontinuation
    3
    Notes
    [2] - Safety population
    No statistical analyses for this end point

    Secondary: Trough Plasma Cysteamine Concentration

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    End point title
    Trough Plasma Cysteamine Concentration
    End point description
    Plasma cysteamine concentration was determined using methods employing Hydrophilic Interaction Liquid Chromatography (HILC) high pressure liquid chromatography (HPLC) tandem mass spectrometry (HPLC-MS/MS). The Pharmacokinetic/Pharmacodynamic (PK/PD) Population includes all subjects who had at least one PK/PD measurement. Day 1 results only include subjects who did not complete Study RP103-03. Month 1 results only available for subjects who did complete Study RP103-03.
    End point type
    Secondary
    End point timeframe
    Day 1 (predose) and Month 6, Years 1, 1.5, 2, 3, 4 and 5 at 0.5 hours post-dose
    End point values
    Cysteamine bitartrate
    Number of subjects analysed
    59 [3]
    Units: mg/L
    arithmetic mean (standard deviation)
        Day 1 (N = 19)
    0.17 ± 0.093
        Month 6 (N = 56)
    0.29 ± 0.613
        Year 1 (N = 56)
    0.37 ± 0.513
        Year 1.5 (N = 55)
    0.48 ± 0.718
        Year 2 (N = 45)
    0.36 ± 0.412
        Year 3 (N = 28)
    0.34 ± 0.659
        Year 4 (N = 38)
    0.47 ± 0.708
        Year 5 (N = 26)
    0.40 ± 0.399
    Notes
    [3] - PK/PD Population
    No statistical analyses for this end point

    Secondary: White Blood Cell Cystine Concentration

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    End point title
    White Blood Cell Cystine Concentration
    End point description
    White blood cell (WBC) cystine concentration was determined using high performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The Pharmacokinetic/Pharmacodynamic (PK/PD) Population includes all subjects who had at least one PK/PD measurement. Day 1 results only include subjects who did not complete Study RP103-03. Month 1 results only available for subjects who did complete Study RP103-03.
    End point type
    Secondary
    End point timeframe
    Day 1 (predose) and Month 6, Years 1, 1.5, 2, 3, 4 and 5 at 0.5 hours post-dose
    End point values
    Cysteamine bitartrate
    Number of subjects analysed
    59 [4]
    Units: nmol 1/2 Cystine/mg protein
    arithmetic mean (standard deviation)
        Day 1 (N = 18)
    1.68 ± 1.275
        Month 6 (N = 56)
    0.93 ± 1.174
        Year 1 (N = 55)
    0.65 ± 0.569
        Year 1.5 (N = 54)
    0.75 ± 0.852
        Year 2 (N = 44)
    0.65 ± 0.851
        Year 3 (N = 28)
    0.66 ± 0.575
        Year 4 (N = 28)
    1.38 ± 1.672
        Year 5 (N = 24)
    1.17 ± 2.117
    Notes
    [4] - PK/PD Population
    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 treatment was 1461 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Cysteamine bitartrate
    Reporting group description
    Cysteamine bitartrate delayed-release capsules were administered twice daily.

    Serious adverse events
    Cysteamine bitartrate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 59 (54.24%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Nephrectomy
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative care
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Impaired self-care
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Graft dysfunction
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Biopsy kidney
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Investigation
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Arnold-chiari malformation
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cryptorchism
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudoparalysis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric fistula
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure chronic
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal tubular acidosis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Knee deformity
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Acidosis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    7 / 59 (11.86%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences causally related to treatment / all
    1 / 15
         deaths causally related to treatment / all
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial diarrhoea
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Salpingitis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urethritis
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cysteamine bitartrate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 59 (98.31%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 59 (11.86%)
         occurrences all number
    7
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 59 (16.95%)
         occurrences all number
    11
    Pyrexia
         subjects affected / exposed
    8 / 59 (13.56%)
         occurrences all number
    14
    Asthenia
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Influenza like illness
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    6
    Oedema peripheral
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Pain
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    7
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    5
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    39
    Injury, poisoning and procedural complications
    Joint sprain
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Arthropod bite
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    5
    Cardiac disorders
    Left ventricular hypertrophy
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 59 (16.95%)
         occurrences all number
    14
    Epistaxis
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    7
    Oropharyngeal pain
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 59 (37.29%)
         occurrences all number
    69
    Syncope
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    5
    Lethargy
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    14 / 59 (23.73%)
         occurrences all number
    16
    Photophobia
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    40 / 59 (67.80%)
         occurrences all number
    129
    Diarrhoea
         subjects affected / exposed
    17 / 59 (28.81%)
         occurrences all number
    32
    Nausea
         subjects affected / exposed
    16 / 59 (27.12%)
         occurrences all number
    21
    Abdominal pain
         subjects affected / exposed
    12 / 59 (20.34%)
         occurrences all number
    19
    Breath odour
         subjects affected / exposed
    8 / 59 (13.56%)
         occurrences all number
    8
    Abdominal pain upper
         subjects affected / exposed
    7 / 59 (11.86%)
         occurrences all number
    15
    Constipation
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    9
    Abdominal discomfort
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Dyspepsia
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    4
    Flatulence
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Skin odour abnormal
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    6
    Acne
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    5
    Rash
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 59 (16.95%)
         occurrences all number
    13
    Pain in extremity
         subjects affected / exposed
    9 / 59 (15.25%)
         occurrences all number
    15
    Back pain
         subjects affected / exposed
    4 / 59 (6.78%)
         occurrences all number
    8
    Muscle spasms
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    7
    Decreased appetite
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    6
    Hypokalaemia
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    4
    Infections and infestations
    Influenza
         subjects affected / exposed
    14 / 59 (23.73%)
         occurrences all number
    22
    Nasopharyngitis
         subjects affected / exposed
    13 / 59 (22.03%)
         occurrences all number
    19
    Gastroenteritis
         subjects affected / exposed
    11 / 59 (18.64%)
         occurrences all number
    25
    Ear infection
         subjects affected / exposed
    10 / 59 (16.95%)
         occurrences all number
    10
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 59 (16.95%)
         occurrences all number
    24
    Sinusitis
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    9
    Urinary tract infection
         subjects affected / exposed
    6 / 59 (10.17%)
         occurrences all number
    7
    Bronchitis
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    8
    Otitis media
         subjects affected / exposed
    5 / 59 (8.47%)
         occurrences all number
    6
    Molluscum contagiosum
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Pharyngitis
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    4
    Pharyngitis streptococcal
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Rhinitis
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    5
    Tonsillitis
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3
    Varicella
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    4
    Viral infection
         subjects affected / exposed
    3 / 59 (5.08%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2010
    The objectives for Amendment 1 were: 1. To update the Background Information based on the final results obtained from the RP103-01 pilot study. 2. To revise the protocol design of version 1.1 to incorporate the following changes:  - Monthly visits for at least six (6) months for each subject followed by synchronized quarterly visits.  - Modify and clarify inclusion and exclusion criteria.  - Eliminate the GSRS from the study. - Utilize the self-report PedsQL QoL instrument instead of the parent proxy report. - Addition of safety and PK/PD data reviews, during or prior to, each study visit to allow for greater subject oversight for dose adjustments. 3. To update the bioanalytical laboratory information. - Provide specific information concerning where samples are to be sent in the US and Europe. - To update the plasma cysteamine and WBC processing instructions. 4. To update the list of abbreviations. 5. To clarify statements and instructions concerning protocol specified procedures. 6. To update administrative information. 7. To update the reference list. 8. To correct typographical and formatting errors.
    20 May 2010
    The objectives for Amendment 2 were: 1. To update the protocol to synchronize with changes incorporated in the precursor pivotal study RP103-03 Amendment 2, which included: - Allowance for subjects that are receiving Cystagon® at the conclusion of study RP103-03 to roll over into this study without the need for a Day 1 study visit.  - Clarification that WBC cystine values <1 nmol ½ cystine/mg protein represented a meaningful reduction in WBC cystine levels.  - Changing the time for RP103 trough sampling (i.e., 1 hour changed to 0.5 hours post RP103 dose administration). 2. To update and correct the inclusion and exclusion criteria. 3. To update the list of abbreviations. 4. To correct and update the total amount of blood collected over the study duration. 5. To correct typographical and formatting errors.
    09 Aug 2010
    The objectives for Amendment 3 were: 1. To revise the protocol to restrict enrollment for subjects that did not participate in the precursor study (RP103-03) to occur only after all subjects enrolled in Study RP103-03 have completed their participation in that study and the data analyzed. 2. To add stopping criteria consistent with Study no. RP103-03. 3. To correct the list of safety endpoints. 4. To update the list of abbreviations. 5. To update the responsible party for medical monitoring. 6. To clarify inclusion criteria language. 7. To make language consistency changes between protocols RP103-03 and RP103-04. 8. To correct typographical and formatting errors.
    02 May 2011
    The objectives for Amendment 4 were: 1. To change the regular daily dose of Cystagon® to 80% (instead of 70% previously)and a dose adjustment to 100% of their regular daily dose of Cystagon® (instead of 20to 25% of the dose of RP103). 2. To clarify instructions for subjects not entering the RP103-04 trial from Study RP103-03. 3. To describe a food effect on cysteamine absorption. 4. To include total protein test method comparison and describe the correction factor. 5. To include the updated prefigured guideline for the dosage of the subjects. 6. To update one table and include two new figures. 7. To update the List of Abbreviations. 8. To clarify statements and instructions. 9. To correct formatting errors.
    27 Sep 2011
    The objectives for Amendment 5 were: 1. To include published results of recently completed clinical trials: - Bioequivalence studies RP103-02 and RP103-05, in healthy volunteers. - Pivotal Phase 3 study RP103-03, in cystinosis subjects. 2. To provide final data and guidance in the following areas, which in the previous protocol amendment were based on interim results of the recently completed clinical trials: - Starting total daily dose of RP103 changed to 70% of the stable baseline - Cystagon® dose and subsequent dose adjustment increased to 100% of that stable Cystagon® dose. - Food effect on cysteamine absorption has been detailed.  - RP103 dosing recommendations with respect to food intake and timing have been updated. 3. To expand enrollment to subjects unable or unwilling to take intact capsules, the following areas were revised:  - Total number of expected study participants has been increased. - Inclusion and Exclusion criteria were updated to permit enrollment of subjects who do not receive their cysteamine dose as intact capsules, and those who receive it via gastric tube. 4. To change the Schedule of Events for subjects not entering the trial from Study RP103-03, adding a Dose Confirmation Period which includes study visits on Day 4 and Day 5. 5. To change all references to “nephropathic cystinosis” to simply “cystinosis” 6. To clarify statements and instructions. 7. To correct formatting and typographical errors.
    26 Sep 2012
    The objectives for Amendment 6 were: 1. To insert a minimum required age for study participants; 2. To increase maximum study duration from 24 to 36 months; 3. To revise investigational product description to reflect currently manufactured lots; 4. To revise maximum blood volume to be collected from subjects, reflecting the change in maximum study duration to 36 months and to include the optional PK substudy; 5. To insert an optional PK substudy visit for all subjects 6 years old and younger; 6. To insert a newly published reference (previously reported as “submitted for publication”); 7. To update the bioanalytical laboratory contact details to reflect that all PK-PD samples were to be shipped to the US location (because the EU laboratory had closed); 8. To clarify statements and instructions, specifically pertaining to RP103 dosing; 9. To correct formatting and typographical errors.
    04 Nov 2013
    The objectives for Amendment 7 were: 1. To insert changes to Sponsor company name and contact details; 2. To insert a change in Institution and contact details for the Lead Investigator; 3. To increase the maximum study duration to 48 months; 4. To provide updated information regarding the acceptable storage temperature of the investigational product, RP103; 5. To revise maximum blood volume to be collected from subjects, reflecting the change in maximum study duration to 48 months; 6. To remove references to the specific central bioanalytical laboratory “BASi” in the event that a different laboratory would be utilized in future (in which case the site laboratory instructions would be updated); 7. To clarify statements and instructions, specifically pertaining to RP103 dosing; 8. To correct minor formatting and typographical errors.
    25 Nov 2014
    The objectives for Amendment 8 were: 1. To document a change in Sponsor Medical Officer; 2. To document a change in the Sponsor medical representative responsible for receipt of serious adverse event (SAE) reports; 3. To insert changes to Sponsor physical address; 4. To increase the maximum study duration to 60 months; 5. To insert the EudraCT number associated with the trial; 6. To revise maximum blood volume to be collected from subjects, reflecting the change in maximum study duration to 60 months; 7. To correct minor formatting and typographical errors.
    18 Nov 2015
    The purpose of RP103-04 Protocol Amendment 9 were as follows: - To update Raptor Chief Medical Officer; - To clarify study duration; - To update anticipated blood collection volumes for the entire study based on clarification to study duration; - To clarify Adverse Event reporting; - Update reference to Storage Conditions and Identity of Investigational Product (RP103); - To correct formatting and typographical errors.

    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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