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    The EU Clinical Trials Register currently displays   41472   clinical trials with a EudraCT protocol, of which   6816   are clinical trials conducted with subjects less than 18 years old.
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    Clinical Trial Results:
    A PHASE I/IIa STUDY OF THE SAFETY, TOLERABILITY AND BIOLOGICAL EFFECT OF SINGLE AND REPEAT ADMINISTRATION OF THE SELECTIVELY REPLICATION-COMPETENT HERPES SIMPLEX VIRUS HSV1716 INTO THE TUMOUR-BEARING PLEURAL CAVITY (INTRAPLEURAL) IN PATIENTS WITH INOPERABLE MALIGNANT PLEURAL MESOTHELIOMA.

    Summary
    EudraCT number
    2010-024496-37
    Trial protocol
    GB  
    Global end of trial date
    14 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jun 2018
    First version publication date
    28 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1716-12
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01721018
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Virttu Biologics Limited
    Sponsor organisation address
    BioCity Scotland, Bo'Ness Road, Newhouse, United Kingdom, ML1 5UH
    Public contact
    Clinical Trial Department, Virttu Biologics Limited, 0141 4451716,
    Scientific contact
    Clinical Trial Laboratory, Virttu Biologics Limited, 0141 4451716,
    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
    27 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to determine the safety and tolerability of HSV1716 given by single and repeat intrapleural administration in patients with inoperable malignant pleural mesothelioma. The secondary objective was to obtain evidence of HSV1716 replication and lysis of MPM cells and of patient immune responses through analysis of pleural fluid and serum samples for evidence of cell death, HSV1716 replication, changes in appropriate biomarkers and cytokine/chemokines. A subsidiary endpoint was tumour measurement as recorded by CT scans and assessed using the modified RECIST criteria for MPM.
    Protection of trial subjects
    Only patients who met the inclusion and exclusion criteria for the study were enrolled. These patients received a patient information leaflet that explained the procedures and any risks that may be involved. The patients were allowed at least 24 hours to read the information and ask any questions before consenting to the study. The safety and tolerability of HSV1716 was assessed at various time points during the study by review of pre- and post-dose clinical data including: physical examinations, full blood count, biochemical profile (urea, electrolytes, liver function tests, bilirubin, AST/ALT, serum creatinine, LDH, alkaline phosphatase, albumin, calcium) and immunological status. Reviews of this data were carried out two weeks after each patients' final dose and recruitment of another patient was based on whether or not any dose limiting toxicities were experienced. The administration procedure was designed to utilise the patients' indwelling catheters and this was done during an outpatient appointment at a time convenient to the patient.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    21 Jan 2013
    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: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    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)
    2
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment period for the study was 21st January 2013 to 14th November 2016. The study was conducted at two sites in the United Kingdom - site 01 in Sheffield and site 02 in Glasgow.

    Pre-assignment
    Screening details
    A screening assessment was carried out within one week of the planned treatment day. This involved the patient giving consent, providing medical history, undergoing a chest x-ray, CT scan and giving samples of blood and pleural fluid. Relevant data including histology details were reviewed and approved by a third party Medical Monitor.

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

    Arms
    Arm title
    HSV1716 treatment
    Arm description
    Single arm study - all patients received HSV1716.
    Arm type
    Experimental

    Investigational medicinal product name
    HSV1716
    Investigational medicinal product code
    Other name
    Herpes simplex virus lacking infected cell protein 34.5, Seprehvir
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrapleural use
    Dosage and administration details
    Patients received 1, 2 or 4 doses of 1x10^7 infectious units (iu) HSV1716 at weekly intervals, followed by a 50ml saline flush, by intrapleural administration via an Indwelling Pleural Catheter. The investigational product was provided in glass vials each containing approximately 1.2 ml of compound sodium lactate and 10% glycerol in which HSV1716 was diluted at a concentration of 2 x 10^6 iu/ml. Five vials were used for each dose and a total of 5ml drawn from the vials and administered to provide each dose of 1x10^7iu of HSV1716.

    Number of subjects in period 1
    HSV1716 treatment
    Started
    13
    Completed
    12
    Not completed
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    All patients who enrolled on to the study and received at least one administration of HSV1716.

    Reporting group values
    Overall trial Total
    Number of subjects
    13 13
    Age categorical
    The study enrolled adult patients aged 18 or over.
    Units: Subjects
        Adults (18-64 years)
    2 2
        From 65-84 years
    11 11
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    10 10
    Subject analysis sets

    Subject analysis set title
    Completed study visits
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This set of patients completed all study treatments and follow-up visits.

    Subject analysis sets values
    Completed study visits
    Number of subjects
    12
    Age categorical
    The study enrolled adult patients aged 18 or over.
    Units: Subjects
        Adults (18-64 years)
    2
        From 65-84 years
    10
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    3
        Male
    9

    End points

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    End points reporting groups
    Reporting group title
    HSV1716 treatment
    Reporting group description
    Single arm study - all patients received HSV1716.

    Subject analysis set title
    Completed study visits
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This set of patients completed all study treatments and follow-up visits.

    Primary: Safety

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    End point title
    Safety [1]
    End point description
    The primary objective of the study was to determine the safety and tolerability of HSV1716 given by single and repeat intrapleural administration in patients with inoperable malignant pleural mesothelioma. Safety results: • No ‘Dose Limiting Toxicities’ or other issues were identified and in all cases, it was concluded that recruitment could proceed to the higher dose level or in the case of Part B Group 2, recruitment could be expanded to include an additional three patients in the 4 dose cohort. • One ‘Serious Adverse Event’ reported (pleural infection) which was determined to be unlikely related to HSV1716.
    End point type
    Primary
    End point timeframe
    Patients were evaluated for safety and tolerability of the procedure from the day of the first administration of HSV1716 through to the end of the 4th week from their final administration of HSV1716.
    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: Safety data were summarised using descriptive summary statistics at each dose level of HSV1716 (1 dose, 2 doses and 4 doses) and overall (all dose levels combined). Study drug administration, compliance and tumour response were summarised by dose level only. No statistical comparison of dose levels was performed. The biological effects data were listed only.
    End point values
    Completed study visits
    Number of subjects analysed
    Units: Patients
    12
    No statistical analyses for this end point

    Secondary: Biological

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    End point title
    Biological
    End point description
    The secondary objective was to obtain evidence of HSV1716 replication and lysis of MPM cells through analysis of pleural fluid and serum samples for evidence of cell death and/or HSV1716 replication and/or changes in appropriate biomarkers. Biological results: • 11/12 patients were seropositive for HSV-1 pre-treatment, whereas 1 patient was seronegative and seroconverted • In 7/9 patients with detectable HSV DNA in pleural fluid samples, HSV-1 genomes were persistent for ≥ 14 days after the final administration, consistent with replication in tumour cells • Viral shedding was observed in 1/12 patients, no genotyping was performed to confirm whether this was HSV1716 • In 9/12 patients strong virus neutralisation by pleural fluid was observed • Pleural fluid levels of the cytokines IL-2, TNFalpha and IFNgamma increased after HSV1716 administration by 5-10-fold, and robust Th1 responses of these 3 cytokines to HSV1716 administration were observed in 8/11 patients
    End point type
    Secondary
    End point timeframe
    Patient samples were assessed for biological activity from the day of the first administration of HSV1716 through to the last study visit.
    End point values
    Completed study visits
    Number of subjects analysed
    Units: Exploratory analysis
        number (not applicable)
    12
    No statistical analyses for this end point

    Other pre-specified: Tumour measurement

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    End point title
    Tumour measurement
    End point description
    A subsidiary endpoint was tumour measurement as recorded by CT scans and assessed using the modified RECIST criteria for MPM. Response assessment results: • Tumour response was obtained by CT scanning (screening, day 29 and day 57) using the modified RECIST criteria developed for malignant mesothelioma. Six patients were reported as having stable disease and 6 were reported as having progressive disease at day 57.
    End point type
    Other pre-specified
    End point timeframe
    Tumour measurements were obtained and assessed at screening, day 29 and day 57.
    End point values
    Completed study visits
    Number of subjects analysed
    Units: Response assessment
        number (not applicable)
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the time of consent to the final study visit.
    Adverse event reporting additional description
    Listing includes all Serious Adverse Events (1 unlikely related). Listing includes only those non-serious adverse events that were possibly or probably related to the investigational product. Additional non-serious adverse events were reported but were deemed to be unlikely or not related to the investigational product.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    HSV1716 treatment arm
    Reporting group description
    All patients in study.

    Serious adverse events
    HSV1716 treatment arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Infections and infestations
    Pleural infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    HSV1716 treatment arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Chills
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 13 (7.69%)
         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
    20 Apr 2012
    To include an additional exclusion criterion as requested by the Gene Therapy Advisory Committee during their review of the study.
    14 Oct 2013
    To clarify the dose escalation scheme and confirm that a Contract Research Organisation had been contracted to provide Pharmacovigilance, Medical Monitoring and Data Management services.
    04 Mar 2014
    To include an additional site for enrolment of patients as recruitment had been slower than anticipated.

    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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