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    Clinical Trial Results:
    Transplantation of umbilical cord blood (UCB) from unrelated donors (URD) in patients with haematological diseases using a reduced intensity conditioning regimen.

    Summary
    EudraCT number
    2004-003845-41
    Trial protocol
    GB  
    Global end of trial date
    01 Apr 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Nov 2021
    First version publication date
    17 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL/07/131
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00959231
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    CRUK and UCL Cancer Trials Centre, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    Scientific contact
    CRUK and UCL Cancer Trials Centre, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    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
    06 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a Phase II study for patients with haematological malignancies to validate the safety and efficacy of umbilical cord blood transplantation using a reduced intensity preparative regimen in patients with disorders of the blood using the approach developed by the University of Minnesota.
    Protection of trial subjects
    Patients underwent screening evaluations to confirm eligibility for the trial, these included: medical history, full blood count, biochemistry tests (liver and renal function), bone marrow, infection screening, imaging, cardiac function assessment and assessement by a radiation oncologist. Patients were counselled about these potential side effects prior to starting treatment. They were monitored closely for toxicity and the protocol listed details on supportive medication, dose modifications etc. In case side effects did occur out of clinic hours, all trial subjects were given patient cards with contact details of the local haematology team that they could access at any time for advice. Due to the potential effect of the trial treatment on pregnancy, the trial subjects had consented to use barrier methods of contraception during treatment for a year afterwards. All patients were assessed for toxicity and monitored regularly for adverse events.
    Background therapy
    All patients will receive prophylaxis for GVHD with 2 drugs both beginning at day -3. These included: - Ciclosporin (CsA) therapy (schedule according to local policy) beginning on day -3 maintaining a trough level of 200-400 μg/L - Mycophenolate mofetil (MMF) 1g three times daily (tds) G-CSF (Lenograstim) 5 μg/kg (IV/SC)(prepared according to local policy) was also given daily from day +7 until ANC > 2.5x109/l for 2 consecutive days. The following medications and support therapies are examples of supportive care that were permitted as outlined in the protocol: - Transfusions for anaemia, thrombocytopenia - Broad spectrum antibiotics and GCSF - Parenteral nutrition - Antibiotic, antifungal and antiviral prophylaxis - Allopurinol to prevent tumour lysis syndrome The protocol contained guidance for the Investigator on the above supportive medication and dose modifications.
    Evidence for comparator
    Not applicable - no comparator used
    Actual start date of recruitment
    17 Dec 2009
    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
    United Kingdom: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    50
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 60 patients were recruited.2 patients withdrew consent & were not included in the analysis.The 1st patient was registered 17 Dec 2009 & the last patient was registered on 20 Feb 2014. Patients were registered from 16 UK centres. Using the censored deaths method, the median follow-up time was 47 months (95% CI: 37-50).

    Pre-assignment
    Screening details
    All inclusion criteria & none of the exclusions had to be met. Patients were ≤ 70 yrs,high risk, with advanced/poorly responding haematological disease with published evidence that RIC haematopoietic stem cell transplantation was likely to be effective,with no alternative therapy likely to achieve cure/significantly prolong disease-free survival.

    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
    Not applicable

    Arms
    Arm title
    Safety & Efficacy Population
    Arm description
    60 patients were enrolled into the RIC UCBT trial. 2 patients withdrew from the trial and were not included in the analysis. Patients received a reduced intensity conditioning regimen comprising of fludarabine 40mg/m2/day day -6 to -2 (total 200mg/m2), cyclophosphamide 50mg/kg day -6 and total body irradiation 200cGy day -1. The umbilical cord blood units transplanted were selected on the basis of ≥4/6 HLA A, B DRB1 matched with the recipient. The cell dose and donor-recipient HLA disparity were used to determine an acceptable single or dual unit graft.
    Arm type
    Safety & Efficacy

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day -6: Cyclophosphamide 50 mg/kg IV over 2 hours. To be prepared according to the manufacturer’s recommendations and run as an infusion over 2 hours.

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day -6 to Day -2: 40 mg/m2 IV over 1 hour. To be prepared and administered according to the manufacturer’s recommendations.

    Number of subjects in period 1 [1]
    Safety & Efficacy Population
    Started
    58
    Completed
    58
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 2 patients withdrew from the trial and were not included in the analysis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    These were the 58 evaluable patients out of the 60 patients recruited into the study as 2 patients withdrew consent from trial participation and were removed from all analyses.

    Reporting group values
    Overall trial (overall period) Total
    Number of subjects
    58 58
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    48 48
        From 65-84 years
    10 10
        85 years and over
    0 0
    Age continuous
    The median age in years of the evaluable participants.
    Units: years
        median (full range (min-max))
    52 (20 to 68) -
    Gender categorical
    The gender (male or female) of the evaluable participants.
    Units: Subjects
        Female
    23 23
        Male
    35 35
    Blood Group
    The blood group of evaluable participants
    Units: Subjects
        O Blood Group
    24 24
        A Blood Group
    25 25
        B Blood Group
    6 6
        AB Blood Group
    3 3
    Ethnicity
    The Ethnic group of evaluable participants
    Units: Subjects
        White
    40 40
        Asian or Asian British
    10 10
        Mixed Race
    4 4
        Black or Black British
    3 3
        Chinese
    1 1
    Performance Status
    The performance status of evaluable participants
    Units: Subjects
        70%
    2 2
        80%
    5 5
        90%
    27 27
        100%
    24 24
    Primary Diagnosis
    The primary cancer diagnosis of the evaluable participants.
    Units: Subjects
        Acute Myeloid Leukaemia (AML)
    27 27
        Acute Lymphoblastic Leukaemia (ALL)
    7 7
        Non-Hodgkin (Follicular lymphoma, B-cell lymphoma)
    7 7
        Myelodysplasia Syndrome (MDS)
    7 7
        Other Leukaemias (CMML, T-PLL, NK cell)
    3 3
        Hodgkin Lymphoma
    3 3
        Acute Undifferentiated Leukaemia
    1 1
        Chronic Myeloid Leukaemia (CML)
    1 1
        Multiple Myeloma
    1 1
        Primary myelofibrosis transformed to AML
    1 1
    Disease Status at Registration
    The participant's disease status at the time of Registration
    Units: Subjects
        Complete Response (CR)
    46 46
        Partial Response (PR)
    8 8
        Progression/Relapse
    2 2
        Accelerated phase
    1 1
        Unknown
    1 1
    Co-morbidity Index
    The co-morbidity index of participants at Registration
    Units: Subjects
        "0"
    28 28
        "1"
    12 12
        "2"
    8 8
        "3+"
    9 9
        Not Reported
    1 1
    Lines of Prior Treatmnet
    The number of lines participats received prior to participating in the study
    Units: Subjects
        0 lines
    1 1
        1 line
    17 17
        2 lines
    26 26
        3 + lines
    14 14

    End points

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    End points reporting groups
    Reporting group title
    Safety & Efficacy Population
    Reporting group description
    60 patients were enrolled into the RIC UCBT trial. 2 patients withdrew from the trial and were not included in the analysis. Patients received a reduced intensity conditioning regimen comprising of fludarabine 40mg/m2/day day -6 to -2 (total 200mg/m2), cyclophosphamide 50mg/kg day -6 and total body irradiation 200cGy day -1. The umbilical cord blood units transplanted were selected on the basis of ≥4/6 HLA A, B DRB1 matched with the recipient. The cell dose and donor-recipient HLA disparity were used to determine an acceptable single or dual unit graft.

    Primary: Non-relapse mortality at day 100

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    End point title
    Non-relapse mortality at day 100 [1]
    End point description
    Non-relapse mortality at 100 days post-transplant was defined as the time from infusion to death not due to relapse. Patients who relapsed were censored at the date of relapse and patients who did not relapse and did not die were censored at the date of last follow-up. Statistical analysis method: Kaplan Meier method
    End point type
    Primary
    End point timeframe
    From the day of transplant to Day 100 post transplant.
    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: Descriptive statistics - Rates calculated using Kaplan Meier method
    End point values
    Safety & Efficacy Population
    Number of subjects analysed
    58 [2]
    Units: percent
    number (confidence interval 95%)
        Non-relapse mortality at 100 day post transplant %
    4 (1 to 13)
    Notes
    [2] - 58 evaluable patients
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall survival was the time from infusion until a patient died from any cause. Patient who did not die were censored at the date of last follow-up.
    End point type
    Secondary
    End point timeframe
    From infusion until death from any cause.
    End point values
    Safety & Efficacy Population
    Number of subjects analysed
    58 [3]
    Units: percent
    number (confidence interval 95%)
        The overall survival (%) at 3 months
    97 (87 to 99)
        The overall survival (%) at 1 year
    70 (57 to 80)
        The overall survival (%) at 2 years
    59 (45 to 71)
    Notes
    [3] - 58 evaluable patients
    No statistical analyses for this end point

    Secondary: Relapse-free survival

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    End point title
    Relapse-free survival
    End point description
    Relapse-free survival was the time from infusion until a patient relapsed or died, whichever occured first. Patient who did not relapse and did not die were censored at the date of last follow-up. Rates calculated using Kaplan Meier method
    End point type
    Secondary
    End point timeframe
    From infusion until a relapse or death, whiever occurs first.
    End point values
    Safety & Efficacy Population
    Number of subjects analysed
    58
    Units: percent
    number (confidence interval 95%)
        Relapse-free survival (%) at 3 months
    90 (79 to 95)
        Relapse-free survival (%) at 1 year
    60 (46 to 71)
        Relapse-free survival (%) at 2 year
    52 (39 to 64)
    No statistical analyses for this end point

    Secondary: Time to relapse

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    End point title
    Time to relapse
    End point description
    Time to relapse was calculated as duration from unit 1 date of infusion to date of relapse. Patients who did not relapse were censored at the date of last follow-up or date of death. Descriptive statistics calculated using Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    From infusion until relapse.
    End point values
    Safety & Efficacy Population
    Number of subjects analysed
    58
    Units: Percentage
    number (confidence interval 95%)
        1 year relapse rate (%)
    31 (21 to 45)
    No statistical analyses for this end point

    Secondary: Chimerism kinetics over time

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    End point title
    Chimerism kinetics over time
    End point description
    Lineage-specific chimerism studies (PBMC, B-cells, T-cells & Granulocytes) were performed on 5-10ml EDTA peripheral blood sample on days 7, 14, 21, 28, 35, 60 and 100, at 6 months, 1 year and 2 years to determine the relative contribution of donor and recipient to overall haematopoiesis. Primary engraftment was defined as neutrophil recovery associated with detectable donor chimerism within the first month after transplantation. Sustained donor engraftment was defined as ongoing neutrophil recovery and donor haematopoiesis beyond day 42. Complete donor chimerism was defined as marrow reconstitution of at least 90% donor origin. Descriptive statistics only.
    End point type
    Secondary
    End point timeframe
    day 7, 14, 21, 28, 35, 60 and 100, at 6 months, 1 year and 2 years post transplant.
    End point values
    Safety & Efficacy Population
    Number of subjects analysed
    58
    Units: patients
        Complete single unit dominance
    39
        Sustained donor-donor mixed chimerism
    3
        Sustained donor-recipient mixed chimerism
    5
        Dominance reversion
    1
        Primary graft failure
    4
    No statistical analyses for this end point

    Secondary: Haematopoietic recovery

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    End point title
    Haematopoietic recovery
    End point description
    Haematopoietic recovery was defined as a) time to 1st of 3 consecutive days with ANC > 0.5 x 109/L after first post-transplant nadir b) time to platelets > 20 x 10^9/L (first of 3 consecutive days) with no platelet transfusions in the 7 preceding days and c) time to RBC independence (Hb > 9gms and no transfusions for 15 days). Descriptive statistics only.
    End point type
    Secondary
    End point timeframe
    See description
    End point values
    Safety & Efficacy Population
    Number of subjects analysed
    58
    Units: patients
        Neutrophil recovery by day 42
    52
        Platelet recovery by day 100
    49
        Red cell recovery by day 100
    40
        Primary graft failure
    5
        Secondary graft failure
    2
    No statistical analyses for this end point

    Secondary: Incidence of acute and chronic GVHD

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    End point title
    Incidence of acute and chronic GVHD
    End point description
    Incidence of acute GVHD (Day 100) and chronic GVHD (1 year). Patients were staged for acute GVHD daily up until engraftment and discharge and thereafter weekly until day 100 post-transplant. Patients were assigned an overall acute GVHD score based on extent of skin rash, volume of diarrhoea and maximum bilirubin level. Incidence of grades II-IV and grades III-IV GVHD by day 100 was monitored. Patients were assessed for chronic GVHD on day 180 and at 1 year post-transplant. Statistical analysis method: Kaplan Meier method
    End point type
    Secondary
    End point timeframe
    Acute GVHD- from infusion unitl day 100 post transplant. Chronic GVHD - from infusion until 1 year post transolant.
    End point values
    Safety & Efficacy Population
    Number of subjects analysed
    58
    Units: patients
        Number of patients with grade II-IV acute GVHD
    19
        Number of patients with grade III-IV acute GVHD
    14
        Number of patients with limited chronic GVHD
    12
        Number of patients with extensive chronic GVHD
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the signing of informed consent to 42 days post-transplant (or after this date if the site investigator felt the event was related to the trial treatment).
    Adverse event reporting additional description
    All adverse events that occured between informed consent and 42 days post-transplant must have been recorded in the patient notes and the trial CRFs. Those meeting the definition of a Serious Adverse Event (SAE) were also reported to UCL CTC using the trial specific SAE Report.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    ALL evaluable patients
    Reporting group description
    60 patients were recruited into the study. 2 patients withdrew consent from trial participation and were removed from all analyses. All other patients (total of 58) were evaluable. All 58 patients received the conditioning regimen and GVHD prophylaxis according to protocol. 56 patients received a double CBU graft and 2 patients a single unit.

    Serious adverse events
    ALL evaluable patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 58 (25.86%)
         number of deaths (all causes)
    26
         number of deaths resulting from adverse events
    3
    Investigations
    Creatinine increased
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Intracranial hemorrhage
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Paresthesia
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Blood urea increased
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal- other- had to stop ciclosporin
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection NOS
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    Device related infection
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection- upper respiratory tract
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ALL evaluable patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 58 (96.55%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 58 (12.07%)
         occurrences all number
    7
    Hypotension
         subjects affected / exposed
    9 / 58 (15.52%)
         occurrences all number
    9
    Immune system disorders
    Anaphylaxis
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    9 / 58 (15.52%)
         occurrences all number
    9
    Fatigue
         subjects affected / exposed
    32 / 58 (55.17%)
         occurrences all number
    32
    Fever
         subjects affected / exposed
    42 / 58 (72.41%)
         occurrences all number
    42
    Flu like symptoms
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Localized edema
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 58 (8.62%)
         occurrences all number
    5
    Pain
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    4
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    8 / 58 (13.79%)
         occurrences all number
    8
    Other investigations
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    4
    Creatinine increased
         subjects affected / exposed
    5 / 58 (8.62%)
         occurrences all number
    5
    Weight loss
         subjects affected / exposed
    11 / 58 (18.97%)
         occurrences all number
    11
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    5 / 58 (8.62%)
         occurrences all number
    5
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    37 / 58 (63.79%)
         occurrences all number
    37
    Neutrophil count decreased
         subjects affected / exposed
    43 / 58 (74.14%)
         occurrences all number
    43
    Platelet count decreased
         subjects affected / exposed
    12 / 58 (20.69%)
         occurrences all number
    12
    White blood cell decreased
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Febrile Neutropenia
         subjects affected / exposed
    5 / 58 (8.62%)
         occurrences all number
    5
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 58 (18.97%)
         occurrences all number
    11
    Dyspnea
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    4
    Epistaxis
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Sore throat
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Nervous system disorders
    Depression
         subjects affected / exposed
    5 / 58 (8.62%)
         occurrences all number
    5
    Insomnia
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    4
    Dizziness
         subjects affected / exposed
    8 / 58 (13.79%)
         occurrences all number
    8
    Headache
         subjects affected / exposed
    16 / 58 (27.59%)
         occurrences all number
    16
    Peripheral sensory neuropathy
         subjects affected / exposed
    7 / 58 (12.07%)
         occurrences all number
    7
    Eye disorders
    Blurred vision
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Dry eye
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 58 (13.79%)
         occurrences all number
    8
    Diarrhea
         subjects affected / exposed
    38 / 58 (65.52%)
         occurrences all number
    38
    Nausea
         subjects affected / exposed
    37 / 58 (63.79%)
         occurrences all number
    37
    Vomiting
         subjects affected / exposed
    15 / 58 (25.86%)
         occurrences all number
    15
    Constipation
         subjects affected / exposed
    13 / 58 (22.41%)
         occurrences all number
    13
    Dry mouth
         subjects affected / exposed
    7 / 58 (12.07%)
         occurrences all number
    7
    Dyspepsia
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    4
    Mucositis (NS)
         subjects affected / exposed
    7 / 58 (12.07%)
         occurrences all number
    7
    Mucositis oral
         subjects affected / exposed
    12 / 58 (20.69%)
         occurrences all number
    12
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    5 / 58 (8.62%)
         occurrences all number
    5
    Hematuria
         subjects affected / exposed
    5 / 58 (8.62%)
         occurrences all number
    5
    Other Renal and urinary disorders
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash (NS)
         subjects affected / exposed
    8 / 58 (13.79%)
         occurrences all number
    8
    Rash maculo-papular
         subjects affected / exposed
    17 / 58 (29.31%)
         occurrences all number
    17
    Rash
    Additional description: Cord Blood Infusion-associated complication
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Alopecia
         subjects affected / exposed
    14 / 58 (24.14%)
         occurrences all number
    14
    Dry skin
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    4
    Bone pain
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Chest wall pain
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    18 / 58 (31.03%)
         occurrences all number
    18
    Hypokalemia
         subjects affected / exposed
    6 / 58 (10.34%)
         occurrences all number
    6
    Hypomagnesemia
         subjects affected / exposed
    10 / 58 (17.24%)
         occurrences all number
    10
    Infections and infestations
    Lung Infection
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Other Infections and infestations
         subjects affected / exposed
    7 / 58 (12.07%)
         occurrences all number
    7
    Sinusitis
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Upper respiratory infection
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Bacterial Coagulase-negative staphylococcus
    Additional description: Type of Infection reported
         subjects affected / exposed
    13 / 58 (22.41%)
         occurrences all number
    13
    Bacterial Haemophilus influenzae
    Additional description: Type of infection reported
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    4
    Other bacterial infection
    Additional description: Type of infection reported
         subjects affected / exposed
    18 / 58 (31.03%)
         occurrences all number
    18
    Bacterial Other gram negative
    Additional description: Type of infection reported
         subjects affected / exposed
    13 / 58 (22.41%)
         occurrences all number
    13
    Bacterial Other gram positive
    Additional description: Type of infection reported
         subjects affected / exposed
    13 / 58 (22.41%)
         occurrences all number
    13
    Fungal Candida sp
    Additional description: Type of infection reported
         subjects affected / exposed
    8 / 58 (13.79%)
         occurrences all number
    8
    Other fungal infection
    Additional description: Type of infection reported
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Viral Adenovirus
    Additional description: Type of infection reported
         subjects affected / exposed
    14 / 58 (24.14%)
         occurrences all number
    14
    Viral CMV
    Additional description: Type of infection reported
         subjects affected / exposed
    22 / 58 (37.93%)
         occurrences all number
    22
    Viral EBV
    Additional description: Type of infection reported
         subjects affected / exposed
    9 / 58 (15.52%)
         occurrences all number
    9
    Viral Other respiratory virus
    Additional description: Type of infection reported
         subjects affected / exposed
    6 / 58 (10.34%)
         occurrences all number
    6
    Other viral infection
    Additional description: Type of infection reported
         subjects affected / exposed
    21 / 58 (36.21%)
         occurrences all number
    21
    Viral RSV
    Additional description: Type of infection reported
         subjects affected / exposed
    7 / 58 (12.07%)
         occurrences all number
    7
    Viral VZV
    Additional description: Type of infection reported
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    4
    Papulopustular rash
         subjects affected / exposed
    3 / 58 (5.17%)
         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
    05 Nov 2009
    Protocol, PIS (11-15, 16+, parents), consent form CF and dispensing labels. Main changes: Protocol: Update pre-registration investigations, Addition of informed consent section, Change of blood samples required for study, Instruction to send adult blood sample samples to the Anthony Nolan Trust and paediatric samples to NHSBT, Insertion of ANT contact details, Expansion of data collection section to clarify central monitoring processes, Inclusion of an on-site monitoring section, Updated graft failure urgent event reporting procedure, Updated acute GVHD urgent event reporting procedure, Changes and clarifications of reporting mechanism for AEs and SAEs, Inclusion of information about expected AEs for IMPs in paediatric patients, Updated table of events which do not require reporting as SAEs, Addition of ‘Death’ to list of events requiring urgent reporting, Addition of Infection reporting instruction, Insertion of criteria for assessment of chronic GVHD, Insertion of cord blood selection mechanism. PIS: PIS 11-15yr version 2.0: Inclusion of the following sentences ‘You may also need to have another bone marrow test 28 days after your transplant. Your doctor will discuss this with you.’ PIS 16y+ version 3.1: Change of ‘Lymphoma Trials Office’ to ‘Haematology Trials Group’ & ‘Cancer Trails Unit’ to ‘Cancer Trials Centre’. Inclusion of the following sentence ‘You may also need another bone marrow test at 28 days after transplantation. Your consultant will discuss this with you.’ PIS parents version 3.1:Change of ‘Lymphoma Trials Office’ to ‘Haematology Trials Group’,Inclusion of the following sentence ‘Your child may also need another bone mamarrow test 28 days after transplantation.’ CF: typographical error correction. Dispensing labels: removal of redundant/duplicated informtion,add storage info,assign space to record calculated total dose,expiry date & date of administration.
    04 Dec 2009
    Patient information sheet: 11-15yr version 2.2 – nov09 Clarification of the number and timing of biopsy samples Patient information sheet: 16y+ version 3.3 – nov09 Clarification of the number and timing of biopsy samples Patient information sheet: parents version 3.3 – nov09 Clarification of the number and timing of biopsy samples
    31 Dec 2009
    Main changes Protocol: Section 6.2.1: Deletion of the sentence ‘Double units must also be ≥4/6 matched to each other.’ Section 8.4: Addition of the following sentence ‘In patients in whom the infused dose of DMSO will not exceed 1g/kg UCB grafts should be thawed and infused immediately. However, where this is not possible, steps to maintain cell viability are permissible according to local practice.’ Section 11: Addition of the sentence ‘On-site monitoring and reporting will continue as described from recruitment until 2 years post-transplant, whereupon followup reporting should continue annually until death. If a patient fails to attend a clinic or cannot be followed up at site, efforts should be made to contact the patient’s GP to assess their condition. Any patients ‘lost to follow-up’ and who subsequently die will be ‘flagged’ using the NHS Information Centre.’ Appendix 4: deletion of the line ‘Sites must contact the central radiotherapy co-investigator before exceeding a dose rate of 30cGy/minute.’ Patient information sheet: 11-15yr version 2.2 – 27nov09: Amendment to allow unused material from samples collected for central analysis to be stored at the central laboratories for potential future analyses. Patient information sheet: 16y+ version 3.3 – 27nov09: Amendment to allow unused material from samples collected for central analysis to be stored at the central laboratories for potential future analyses. Patient information sheet: parents version 3.3 – 27nov09: Amendment to allow unused material from samples collected for central analysis to be stored at the central laboratories for potential future analyses.
    28 May 2010
    Main changes: Protocol Section 3: Deletion of the objective ‘To assess immune reconstitution at 1, 2, 3, 6, 12 and 24 months after transplant as measured by quantitative recovery of B, T and NK cells (flow cytometry), qualitative recovery of T cells (TREC and spectratyping), in vivo functional T cell responses (EBV and CMV tetramers) and quantitative immunoglobulins.’ Section 10.1: Removal of the central immune reconstitution analysis to be performed as part of the RIC UCBT trial. Insertion of the following sentence ‘Sites are strongly advised to open (and register RIC UCBT patients onto) the Anthony Nolan Trust/NHSBT Immune REconstitution Study (IRES): a nationwide study to examine immune reconstitution in cord blood transplant patients.’ Patient information sheet: 11-15yr version 3.0 – mar10: Amendment to remove the collection of samples to be sent for central analysis as there will no longer be central analysis of samples for immune reconstitution analysis as part of this trial. Patient information sheet: 16y+ version 4.0 – mar10: Amendment to remove the collection of samples to be sent for central analysis as there will no longer be central analysis of samples for immune reconstitution analysis as part of this trial. Patient information sheet: parents version 4.0 – mar10: Amendment to remove the collection of samples to be sent for central analysis as there will no longer be central analysis of samples for immune reconstitution analysis as part of this trial. A ‘pregnant partner information sheet and informed consent form’ to follow up the outcome of any pregnancies occuring in female-partners of male-participants was also added.
    10 Jan 2011
    Dispensing labels for cyclophosphamide and fludarabine: permission was requested to retract these labels as there was no requirement for their submission. IMP labels for cyclophosphamide and fludarabine: Paragraph 26 of Annex 13 of the “EU Guidelines to Good Manufacturing Practice” sets out the information that should be included on labels “... unless its absence can be justified”. We proposed not to apply IMP labelling to fludaradine or cyclophosphamide for the following reason: Both fludaradine & cyclophosphamide were taken from general hospital stocks on a per patient basis, with a very short time elapsing between dispensing and reconstitution. This procedure was carried out only in pharmacies by qualified personnel. Adding an IMP label for a very short time does not seem to add anything to protect the subjects involved in the trial that is not already satisfied by the normal pharmacy accountability and labelling procedures. However, as further processing involved reconstitution of the fludaradine and cyclophosphamide in IV bags , we required sites to affix a dispensing label to the IV bag and they were provided with minimum wording for this label. This wording ensured protection of the patient, and traceability to enable identification of the product and trial and to facilitate proper use of the IMP.
    16 Dec 2011
    Main changes: Protocol Section 1: Study synopsis updated to reflect that the maximum age limit was increased to 70 years of age and deletion of requirement for units to match each other in double cord transplants. Section 6.1: Clarification that chest radiographs & radiotherapy planning CTs were optional, as per local practice. Section 6.3.2: Inclusion criteria section updated to reflect that the upper age limit was increased to 70 years of age in those patients that had a co-morbidity index of 0 - 1. Section 6.3.3: Additional statement that patients aged 60-70 years must had a co-morbidity index of 0-1. Section 6.4: Change of exclusion criteria from ‘5-6/6 HLA-A, B, DRB1’ to ‘a suitably matched’ sibling donor. Section 6.4: Exclusion criteria updated to indicate that patient’s aged 60-70 with a co-morbidity index of >1 were excluded. Section 9.3: Chimerism analysis section updated to clarify that whole PBMC samples should be analysed in addition to the B-cell, T-cell & granulocyte fractions. Section 22: References updated to include additional references for expected adverse events added to protocol appendix 6. Appendix 6: updated to show only AEs expectedness for the trial treatment rather than expectedness for the individual IMPs. Expectedness for individual IMPs was taken directly from SPCs at UCL CTC to ensure that data was always current.
    18 Sep 2013
    Main changes: Protocol: changes to bring it in line with the Sponsor’s protocol template & to reflect changes to the trial monitoring plan following an update to the risk assessment for the trial in Dec2012. Reference Safety Information: appendix 6 which listed AEs expected for the treatment regimen was updated in response to discussions at the MHRA statutory GCP inspection of the UCL CTC in Jan2013. Previously, appendix 6 included AEs expected for combination conditioning chemotherapy (FluCy), radiotherapy (TBI) and infused cells as a whole. This gave rise to concerns regarding a potential for under-reporting of SUSARs if AEs that were expected for the cells but not the drugs were classified as expected in line with the protocol appendix. The RIC UCBT CI considered it was not possible to separate out the AEs expected for the ‘TBI-chemotherapy conditioning regimen’ into separate lists for TBI and chemotherapy. The published literature addressed toxicities associated with ‘TBI-chemo conditioning’ as a whole, and all conditioning was given within the 7 days prior to transplant, therefore making it extremely difficult to undertake seperate causal assessments for individual chemotherapy agents, or for the chemotherapy conditioning regimen separately to radiotherapy. However, the CI considered it appropriate to seperate AEs expected for transplanted cell infusions from the expected AE list. Therefore for RIC-UCBT these were listed separately in appendix 6 and in section 13 of the protocol, and the expected AEs for transplanted cells were identified as exempt from SAE reporting. Details of complications of the stem cell infusion were collected as Urgent Events, to ensure the safety of the cell source continued to be assessed and recorded in the trial. SAEs not included in tthe list of AEs as expected for ‘TBI-chemotherapy conditioning' ontinued to be assessed. using SmPCs for the individual IMPs.

    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.
    Non-serious AEs: 'occurrences all number' cannot be provided as only highest grade experienced by patients was collected on CRF; Subjects affected number is entered instead Serious AEs & non-serious AEs are listed under non-serious adverse events

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/34700343
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