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    Clinical Trial Results:
    Evaluation of the impact of renal function on the pharmacokinetics of hydroxyurea (Siklos®) in patients with sickle cell disease with normal renal function, with hyperfiltration, or with renal failure.

    Summary
    EudraCT number
    		 2014-005033-31
    Trial protocol
    		 FR  
    Global end of trial date
    29 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Nov 2021
    First version publication date
    07 Nov 2021
    Other versions
    Summary report(s)
    		 Pressiat 2020

    Trial information

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    Trial identification
    Sponsor protocol code
    SIK-FR14-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02522104
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Addmedica SAS
    Sponsor organisation address
    37 rue de Caumartin, Paris, France, 75009
    Public contact
    Laura Thomas-bourgneuf, Project manager, Addmedica S.A.S, 0033 0172690186, laura.thomas-bourgneuf@addmedica.com
    Scientific contact
    Corinne Duguet, Medical director, Addmedica S.A.S, 0033 0149709585, corinne.duguet@addmedica.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Comparison of the different pharmacokynetics parameters of hydroxyurea in sickle-cell patients with a renal condition (glomerular hyperfiltration and moderate renal) to those presenting a normal renal function.
    Protection of trial subjects
    Informed consent of the patient
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited during the consultations by the investigator doctor at Henri Mondor hospital in France from September 2015 to November 2016.

    Pre-assignment
    Screening details
    		 A total of 40 patients were screened but PK evaluation was not performed for 10 of them. Main reasons were : Patient’s consent withdrawal, Technical issues: blood samples could not be taken, Adverse even, Suspicion of pregnancy, Blood transfusion, planned hospitalisation. 3 patients prematurely discontinued the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NR group
    Arm description
    		 Normal-renal function: 90 ≤ glomerular filtration rate (GFR) ≤ 130 mL/min/1.73m2 inwomen or 140 mL/min/1.73m2 in men.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Siklos
    Investigational medicinal product code
    Other name
    Hydroxycarbamide
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Siklos was administered by oral route, at the usual dosage (according to the SPC of Siklos® and as per routine prescription)

    Arm title
    		 MRF group
    Arm description
    		 Moderate renal failure: 30 ≤ GFR ≤ 60 mL/min/1.73m2
    Arm type
    		 Experimental

    Investigational medicinal product name
    Siklos
    Investigational medicinal product code
    Other name
    Hydroxycarbamide
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Siklos treatment was administered by oral route, at the usual dosage (according to the summary of product characteristics [SPC] of Siklos®, as per routine dosage).

    Arm title
    		 GH group
    Arm description
    		 Glomerular hyperfiltration: GFR > 130 mL/min/1.73m2 in women and GFR > 140mL/min/1.73m2 in men.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Siklos
    Investigational medicinal product code
    Other name
    Hydroxycarbamide
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Siklos treatment was administered by oral route, at the usual dosage (according to the summary of product characteristics [SPC] of Siklos® and as per routine dosage).

    Number of subjects in period 1
    		NR group MRF group GH group
    Started
    13
    12
    15
    Completed
    10
    5
    12
    Not completed
    3
    7
    3
         Consent withdrawn by subject
    1
    2
    -
         Adverse event, non-fatal
    2
    -
    -
         Pregnancy
    -
    -
    1
         technical issue
    -
    2
    -
         Protocol deviation
    -
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NR group
    Reporting group description
    		 Normal-renal function: 90 ≤ glomerular filtration rate (GFR) ≤ 130 mL/min/1.73m2 inwomen or 140 mL/min/1.73m2 in men.

    Reporting group title
    MRF group
    Reporting group description
    		 Moderate renal failure: 30 ≤ GFR ≤ 60 mL/min/1.73m2

    Reporting group title
    GH group
    Reporting group description
    		 Glomerular hyperfiltration: GFR > 130 mL/min/1.73m2 in women and GFR > 140mL/min/1.73m2 in men.

    Reporting group values
    		 NR group MRF group GH group Total
    Number of subjects
    		 13 12 15 40
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 13 12 15 40
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.2 ± 4.8 50.0 ± 7.5 27.8 ± 7.6 -
    Gender categorical
    Units: Subjects
        Female
    		 8 5 13 26
        Male
    		 5 7 2 14

    End points

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    End points reporting groups
    Reporting group title
    NR group
    Reporting group description
    		 Normal-renal function: 90 ≤ glomerular filtration rate (GFR) ≤ 130 mL/min/1.73m2 inwomen or 140 mL/min/1.73m2 in men.

    Reporting group title
    MRF group
    Reporting group description
    		 Moderate renal failure: 30 ≤ GFR ≤ 60 mL/min/1.73m2

    Reporting group title
    GH group
    Reporting group description
    		 Glomerular hyperfiltration: GFR > 130 mL/min/1.73m2 in women and GFR > 140mL/min/1.73m2 in men.

    Primary: AUC/D 0-24h

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    End point title
    		 AUC/D 0-24h
    End point description
    Dose normalized area under the drug concentration-time curve calculated between 0 and 24 h
    End point type
    Primary
    End point timeframe
    0 to 24 hours
    End point values
    		 NR group MRF group GH group
    Number of subjects analysed
    10
    5
    12
    Units: h*µM
        arithmetic mean (standard deviation)
    1.23 ± 0.24
    2.17 ± 0.78
    1.30 ± 0.24
    Statistical analysis title
    		 comparison between the 3 groups
    Statistical analysis description
    Statistical tests were carried out for each parameter between the 3 groups. The results between the 3 groups showed statistical significant differences for normalized AUC0-24h (p = 0.006)
    Comparison groups
    NR group v MRF group v GH group
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.006
    Method
    		 Kruskal-wallis
    Confidence interval

    Primary: AUC/D 0-24h

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    End point title
    		 AUC/D 0-24h
    End point description
    Dose normalized area under the drug concentration-time curve calculated between 0 and 24 h
    End point type
    Primary
    End point timeframe
    0 to 24 hours
    End point values
    		 NR group MRF group GH group
    Number of subjects analysed
    10
    5
    12
    Units: h*μM/mg
        geometric mean (standard deviation)
    1.23 ± 0.24
    2.17 ± 0.78
    1.30 ± 0.24
    Statistical analysis title
    		 Kruskal-Wallis
    Comparison groups
    MRF group v NR group v GH group
    Number of subjects included in analysis
    27
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.006
    Method
    		 Kruskal-wallis
    Parameter type
    		 Geometric LSM
    Point estimate
    0.0058
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 0
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of signature of the consent, Throughout the duration of patient follow-upin the study, Up to 7 days after the end of the participant's follow-up in the study
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    All patients included
    Reporting group description
    		 -

    Serious adverse events
    		 All patients included
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 30 (6.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Sickle cell crisis
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aplastic anemia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 All patients included
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 30 (6.67%)
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Pregnancy, puerperium and perinatal conditions
    Normal newborn
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2016
    -Extension of inclusions period until end of July 2016 -Extension of the duration of participation of each patient until 1month after the planned date. -Possibility of inclusion patients with red cell exchange within the15 days before the inclusion -Take into consideration of GFR of the last 6 months beforeinclusion -Decrease of bonus at 50 euros in case of samples impossible -Payment of bonus within the 3 to 6 months after the end ofparticipation of the patient -Add 1 blood sample to determine percentage of dense red bloodcells -Change of one EDTA tube with an Anticoagulant Citrate DextroseSolution (ACD) tube for dosage of Fetal hemoglobin -Change of one tube with a container for urine parameters -Add of an additional sample 30 minutes after administration -Change of the method of dosage of hydroxyurea in blood and inurine -Change of volume of blood samples for each pharmacokineticsample 4mL instead of 7 mL
    16 Sep 2016
    Extension of inclusions period until 31st of December 2016

    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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