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    Clinical Trial Results:
    PARACHUTE-trial Prospective Analysis of an individualized dosing Regimen of ATG (Thymoglobulin) in Children Undergoing HCT: redUcing Toxicity and improving Efficacy – a single arm phase II study

    Summary
    EudraCT number
    2014-004849-26
    Trial protocol
    NL  
    Global end of trial date
    31 Aug 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    19 May 2022
    First version publication date
    19 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NL51460.041.14
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Dutch Competent Authority: NL51460.041.14, Medical Ethical Committee University Medical Cente: 14-672
    Sponsors
    Sponsor organisation name
    UMC Utrecht
    Sponsor organisation address
    Heidelberglaan 100, Utrecht, Netherlands,
    Public contact
    R.Admiraal, MD, UMC Utrecht, 0031 0611210706, r.admiraal@umcutrecht.nl
    Scientific contact
    R.Admiraal, MD, UMC Utrecht, 0031 0611210706, r.admiraal@umcutrecht.nl
    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
    01 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate whether an individualized dosing regimen for Thymoglobulin leads to a better immune reconstitution after HCT (definition as in primary endpoint), as compared to historically non-individualized treated patients receiving Thymoglobulin as a fixed dose per kilogram body weight. The individualized dosing regimen is based on a previously treated pediatric cohort on which a population PK-PD analysis was performed. The dosing regimen was compiled using this cohort, taking into account the influence of body weight and pre-Thymoglobulin lymphocyte count and the observed variability.
    Protection of trial subjects
    The primary endpoint in the study (early T-cell recovery), potential toxicities associated with the change in therapy (graft-versus-host-disease, graft failure), SAE’s and SUSARs were evaluated by an external data safety monitoring board. Furthermore, the trial was based on a Simon two-stage design which includes an interim efficacy analysis.
    Background therapy
    All participants received an allogeneic hematopoietic stem cell transplantation. Conditioning regimens were given according to national and international protocols. Busulfan was targeted with therapeutic drug monitoring (TDM) to reach an area under the curve (AUC) of 75–95 mg × h/day. Patients with severe aplastic anaemia and Fanconi’s anaemia received reduced intensity conditioning. Selective gut decontamination, infection prophylaxis and GvHD prophylaxis was given according to local protocols as described previously11. GvHD prophylaxis consisted of cyclosporin, with TDM to reach trough levels of 150-250 μg/L, combined with methotrexate 10 mg/m2 on day 1, 3 and 6 after infusion (bone marrow) or prednisolone 1mg/kg (cord blood). Patients were treated in high-efficiency, particle-free, air-filtered, positive-pressure isolation rooms. Conditioning regimens (except the ATG dosing), supportive care and transplant team did not change over time (enrolment trial and historical cohort).
    Evidence for comparator
    The primary endpoint was CD4+ IR, defined as a CD4+ T-cell count of at least 0·05×10⁹ cells/L at two consecutive measurements within 100±3 days after HCT. Early CD4+ IR was chosen as a primary endpoint, as it was found to be a reliable predictor (in different centres and transplant settings) for transplant outcomes such as survival, NRM, viral reactivations and GvHD.
    Actual start date of recruitment
    01 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    64
    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)
    10
    Children (2-11 years)
    34
    Adolescents (12-17 years)
    20
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Inclusion: pediatric patients receiving an allogeneic hematopoietic cell transplantation in the participating centre from 7-2015 up to 9-2018 in a third-line academic hospital.

    Pre-assignment
    Screening details
    Patients were enrolled from May 2015 until August 2018 . Patients <18 years receiving their first T-repleted unrelated HCT for any (non)-malignant indication with ATG as part of the conditioning regimen, were eligible. We excluded those not receiving the intended dose of ATG, those who received serotherapy 3 months preceding this HCT; and those not

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

    Arms
    Arm title
    Intervention arm
    Arm description
    Individualized dosing of anti-thymocyte globulin
    Arm type
    Experimental

    Investigational medicinal product name
    Thymoglobulin
    Investigational medicinal product code
    Other name
    Anti-thymocyte globulin
    Pharmaceutical forms
    Powder and solution for suspension for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Cumulative dose of 2-10 mg/kg over 1-4 days depending on body weight, lymphocyte counts before the first dose and the stem cell source. Thymoglobulin was infused as a daily 4-hour infusion.

    Number of subjects in period 1
    Intervention arm
    Started
    64
    Completed
    58
    Not completed
    6
         Protocol deviation
    2
         Adverse event, serious fatal
    2
         Adverse event, non-fatal
    2

    Baseline characteristics

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

    Reporting group values
    Overall trial Total
    Number of subjects
    64 64
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    20 20
        Children (2-11 years)
    34 34
        Adolescents (12-17 years)
    10 10
    Age continuous
    Units: years
        median (full range (min-max))
    7.4 (0.2 to 17.4) -
    Gender categorical
    Units: Subjects
        Female
    32 32
        Male
    32 32
    Subject analysis sets

    Subject analysis set title
    Efficacy-Evaluable Population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All- Treated population minus patients having events (death, relapse, graft failure) before 100 days

    Subject analysis set title
    All-Treated population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All included patients minus those with major protocol deviations, and those not receiving the full dose of Thymoglobulin

    Subject analysis sets values
    Efficacy-Evaluable Population All-Treated population
    Number of subjects
    51
    58
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
    Age continuous
    Units: years
        median (full range (min-max))
    7.4 (0.2 to 17.8)
    7.4 (0.2 to 17.8)
    Gender categorical
    Units: Subjects
        Female
    29
    29
        Male
    29
    29

    End points

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    End points reporting groups
    Reporting group title
    Intervention arm
    Reporting group description
    Individualized dosing of anti-thymocyte globulin

    Subject analysis set title
    Efficacy-Evaluable Population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All- Treated population minus patients having events (death, relapse, graft failure) before 100 days

    Subject analysis set title
    All-Treated population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All included patients minus those with major protocol deviations, and those not receiving the full dose of Thymoglobulin

    Primary: Successful CD4+ T-cell reconstitution

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    End point title
    Successful CD4+ T-cell reconstitution [1]
    End point description
    Reaching a CD4+ T-cell count >50 twice within 100 days after transplantation
    End point type
    Primary
    End point timeframe
    Within 100 days after stem cell transplantation
    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: We performed a Simon 2-stage analysis in the trial, as described in the protocol and manuscript. As the EudraCT-system would not allow us to describe the results of the single-arm statistical test, we could not upload the results of the analysis.
    End point values
    Efficacy-Evaluable Population
    Number of subjects analysed
    51
    Units: Patients
    41
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    7-2015 up to 9-2019
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.3
    Reporting groups
    Reporting group title
    All included patients
    Reporting group description
    All patients included in the study, also including major protocol violations

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non-serious adverse events registered in this study, since the treatment at hand is associated with relatively severe adverse events. Registration of non-serious events would have led to too much work.
    Serious adverse events
    All included patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 64 (23.44%)
         number of deaths (all causes)
    15
         number of deaths resulting from adverse events
    15
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Post transplant lymphoproliferative disorder
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukaemia recurrent
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Bronchiolitis obliterans syndrome
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Allergic reaction to excipient
    Additional description: To Thymoglobulin
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Allergic reaction to excipienttion
    Additional description: To liposomal amphoterocin B
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Autoimmune pancytopenia
    Additional description: Isolated thrombopenia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Capillary leak syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cytokine release syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Graft loss
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    2 / 2
    Immune system disorder
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disease progression
    Additional description: Of underlying disease (LICS: lung disease, immunodeficiency, chromosome breakage syndrome)
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Dehydration
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Feeding intolerance
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhageestinal
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Gastrooesophageal reflux diseaseme
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Venoocclusive disease
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cystitis viral
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Catheter site infection
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Epstein-Barr viraemia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Influenza
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Pneumocystis jirovecii pneumoniastis
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 2
    Sepsis
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    Skin infection
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viralitis
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    All included patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 64 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Sep 2015
    Addition of second study site (Leiden Academic Medical Center, the Netherlands)
    07 Mar 2016
    Additional data for addition of second study site (Leiden Academic Medical Center, the Netherlands)
    20 Feb 2017
    Minor protocol changes to the patient information folder, the protocol, addition of contracts with monitor
    06 Jun 2018
    Change site to Princess Maxima Center for Pediatric Oncology
    22 Oct 2018
    Addition of statistical analysis plan, prolongation of study due to incomplete recruitment
    17 Dec 2018
    Change end of study date

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/35114150
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