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    Clinical Trial Results:
    Study of apoptosis related changes and endothelial responses of multiple myeloma patients treated with chemotherapy.

    Summary
    EudraCT number
    		 2012-001813-17
    Trial protocol
    		 GB  
    Global end of trial date
    07 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2019
    First version publication date
    11 Aug 2019
    Other versions
    Summary report(s)
    		 Study summary
    Chemotherapy treatment of multiple myeloma patients increases circulating levels of endothelial micovesicles

    Trial information

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    Trial identification
    Sponsor protocol code
    R1282
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC reference: 12/YH/0328
    Sponsors
    Sponsor organisation name
    Hull and East Yorkshire Hospitals NHS Trust
    Sponsor organisation address
    Anlaby Road, Hull, United Kingdom, HU3 2JZ
    Public contact
    Professor A Maraveyas , Hull and East Yorkshire Hospitals NHS Trust, 044 01482461245, anthony.maraveyas@hey.nhs.uk
    Scientific contact
    Professor A Maraveyas , Hull and East Yorkshire Hospitals NHS Trust, 044 01482461245, anthony.maraveyas@hey.nhs.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
    08 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To study the disruption of the endothelium, platelets and the clotting cascade caused by the novel chemotherapeutic combinations used for the treatment of multiple myeloma.
    Protection of trial subjects
    No risks relating to IMPs as the study was non-interventional and did not influence the treatment or management of the patient. Only risks to subjects were the further blood draws to those that were required under standard of care and confidentiality from data collection. Both of which were managed under the hospitals Standard Operating Procedures and GCP and highlighted in the Ethics submission. No SAEs were experienced due to the blood draws and no issues relating to confidentiality were identified.
    Background therapy
    		 Study was non-interventional ( there was no IMP tested either on its own or as a comparator). Study procedures did not influence the treatment or management of the patient. Patients were treated under the standard of care for their disease (myeloma). The standard of care was relevant to the line of treatment that the patient was to receive.
    Evidence for comparator
    		 There was no IMP tested either on its own or as a comparator.
    Actual start date of recruitment
    11 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    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
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a single site study (Castle Hill Hospital - UK) with recruitment commencing from 11/10/2012 to 14/12/2016. Patients were identified in MDT when discussion for their management took place. If a patient was deemed eligible the patient was then approached during their clinical appointment at the Queens Centre for Oncology and Haematology.

    Pre-assignment
    Screening details
    		 Patients were approached in clinic following discussion in MDT when need for treatment was determined, whether a initial diagnosis, a relapse of the Myeloma, or if the patient was to be a control. The criteria used to determine each group was detailed in the protocol. No specific pre-assignment period detailed for the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Newly diagnosed MM patients: CTD
    Arm description
    		 Newly diagnosed MM patients treated with Cyclophosphamide Thalidomide & Dexamethasone. Treatment allocation NOT determined by study
    Arm type
    		 Standard chemotherapy treatment given

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    PL 00032/0335
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg orally Days 1, 8 and 15

    Investigational medicinal product name
    Thalidomide
    Investigational medicinal product code
    EU/1/08/443/001
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Thalidomide 50mg hard capsules orally, initially 100mg daily for 3 weeks, increasing to 200mg daily.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    PL0065/5045R
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg daily orally on Days 1-4 and 12-15

    Arm title
    		 Newly diagnosed MM patients: other
    Arm description
    		 Newly Diagnosed MM patients who were to receive treatment other than CTD. Treatment allocation NOT determined by study
    Arm type
    		 Standard chemotherapy treatment given

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    PL 00032/0335
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg orally on Days 1 and 8 of 28 day cycle.

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    EU/1/07/391
    Other name
    Revlimid
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg orally daily on Days 1 - 21

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    PL0065/5045R
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg daily orally on Days 1 - 4 and 12.-15

    Arm title
    		 Relapsed MM patients: BTZ+DEX
    Arm description
    		 Relapsed MM Patients to undergo Velcade & Dexamethasone. Treatment allocation NOT determined by study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Relapsed MM patients: LEN+DEX
    Arm description
    		 Relapsed MM Patients to undergo Lenalidomide & Dexamethasone. Treatment allocation NOT determined by study
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Controls: Myeloproliferative disorders
    Arm description
    		 Patients with myeloproliferative disorders have a known propensity to develop thromboses (non treatment related) and will serve as the positive control group for this study. There are three major categories of myeloproliferative disorders: Chronic myelocytic leukemia, polycythemia rubra vera and myelofibrosis. These patients are followed up in a regular clinic in haematology outpatients. Based on the expected age and gender distribution of the experimental group ten of these control patients will be approached for consent in to the study. The same exclusion criteria (3.1.3) as for the experimental group will be adhered to. Treatment allocation NOT determined by study.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Newly diagnosed MM patients: CTD Newly diagnosed MM patients: other Relapsed MM patients: BTZ+DEX Relapsed MM patients: LEN+DEX Controls: Myeloproliferative disorders
    Started
    10
    3
    8
    9
    12
    Completed
    4
    2
    5
    3
    11
    Not completed
    6
    1
    3
    6
    1
         Adverse event, serious fatal
    2
    -
    -
    2
    -
         Physician decision
    -
    1
    1
    1
    -
         Consent withdrawn by subject
    -
    -
    -
    1
    -
         Death due to myeloma
    2
    -
    -
    -
    -
         Baseline sample unsuitable for analysis
    -
    -
    1
    -
    -
         Ineligible disease type
    -
    -
    -
    -
    1
         Lost to follow-up
    -
    -
    1
    1
    -
         Lack of efficacy
    2
    -
    -
    1
    -

    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
    		 42 42
    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)
    		 40 40
        From 65-84 years
    		 0 0
        85 years and over
    		 2 2
    Gender categorical
    Males and females.
    Units: Subjects
        Female
    		 19 19
        Male
    		 23 23

    End points

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    End points reporting groups
    Reporting group title
    Newly diagnosed MM patients: CTD
    Reporting group description
    		 Newly diagnosed MM patients treated with Cyclophosphamide Thalidomide & Dexamethasone. Treatment allocation NOT determined by study

    Reporting group title
    Newly diagnosed MM patients: other
    Reporting group description
    		 Newly Diagnosed MM patients who were to receive treatment other than CTD. Treatment allocation NOT determined by study

    Reporting group title
    Relapsed MM patients: BTZ+DEX
    Reporting group description
    		 Relapsed MM Patients to undergo Velcade & Dexamethasone. Treatment allocation NOT determined by study

    Reporting group title
    Relapsed MM patients: LEN+DEX
    Reporting group description
    		 Relapsed MM Patients to undergo Lenalidomide & Dexamethasone. Treatment allocation NOT determined by study

    Reporting group title
    Controls: Myeloproliferative disorders
    Reporting group description
    		 Patients with myeloproliferative disorders have a known propensity to develop thromboses (non treatment related) and will serve as the positive control group for this study. There are three major categories of myeloproliferative disorders: Chronic myelocytic leukemia, polycythemia rubra vera and myelofibrosis. These patients are followed up in a regular clinic in haematology outpatients. Based on the expected age and gender distribution of the experimental group ten of these control patients will be approached for consent in to the study. The same exclusion criteria (3.1.3) as for the experimental group will be adhered to. Treatment allocation NOT determined by study.

    Primary: To study the disruption of the endothelium, platelets and the coagulation cascade caused by the novel bio- chemotherapeutic combinations used for the treatment of multiple myeloma.

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    End point title
    		 To study the disruption of the endothelium, platelets and the coagulation cascade caused by the novel bio- chemotherapeutic combinations used for the treatment of multiple myeloma.
    End point description
    End point type
    Primary
    End point timeframe
    Baseline Day 8 of cycle 1 Day 1 of cycle 2 and 3 At end of chemotherapy course.
    End point values
    		 Newly diagnosed MM patients: CTD Newly diagnosed MM patients: other Relapsed MM patients: BTZ+DEX Relapsed MM patients: LEN+DEX Controls: Myeloproliferative disorders
    Number of subjects analysed
    10
    3
    8
    9
    11
    Units: MV per microlitre
    10
    3
    8
    9
    12
    Statistical analysis title
    		 IBM SPSS
    Comparison groups
    Newly diagnosed MM patients: other v Relapsed MM patients: BTZ+DEX v Relapsed MM patients: LEN+DEX v Controls: Myeloproliferative disorders v Newly diagnosed MM patients: CTD
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [1]
    Method
    		 IBM SPSS v20.0
    Confidence interval
    Notes
    [1] - P values <0.05 were considered to be statistically significant.

    Secondary: To correlate clinically evident thromboembolism (TE) with the type of treatment received and laboratory findings.

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    End point title
    		 To correlate clinically evident thromboembolism (TE) with the type of treatment received and laboratory findings.
    End point description
    Any thromboembolic event included arterial.
    End point type
    Secondary
    End point timeframe
    Until 6 months after the last patient entered.
    End point values
    		 Newly diagnosed MM patients: CTD Newly diagnosed MM patients: other Relapsed MM patients: BTZ+DEX Relapsed MM patients: LEN+DEX Controls: Myeloproliferative disorders
    Number of subjects analysed
    10
    3
    8
    9
    12
    Units: Events
    10
    3
    8
    9
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From time of consent to last sample last patient.
    Adverse event reporting additional description
    Bruising or superficial venous thrombosis or infection related to venesection.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Newly diagnosed MM patients: CTD
    Reporting group description
    		 Newly diagnosed MM patients treated with Cyclophosphamide Thalidomide & Dexamethasone. Treatment allocation NOT determined by study

    Serious adverse events
    		 Newly diagnosed MM patients: CTD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Newly diagnosed MM patients: CTD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    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 venesection related non-serious adverse events.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Sep 2012
    Addition of standardised wording required by sponsor to comply with UK Trial Regulations and ICH/GCP
    01 Aug 2013
    Change to “Expected SAEs exempt from expedited notification” to include patients being treated on conventional standard of care protocols. Change to “Appendix B, Study arm/timepoint”, point 5 now reads as soon as the first line chemotherapy course ends and before the second line course begins
    16 Feb 2016
    The amendment was submitted in order to discontinue the second consent. The initial proposal included the potential genomic study (DNA) from bone marrow or white cells of patients where a second consent was necessary. This part of the study has been superseded due to the inability to gain bone marrow samples.

    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.
    The study was terminated after the primary endpoint was reported as the frequency of VTE was very low to be able to produce a valid association of the study markers to frequency of VTE.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27566844
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