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    The EU Clinical Trials Register currently displays   43866   clinical trials with a EudraCT protocol, of which   7287   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2012-001367-76
    Sponsor's Protocol Code Number:PP095
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-04-04
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBulgarian Drug Agency
    A.2EudraCT number2012-001367-76
    A.3Full title of the trial
    A double blinded, randomized, multi centre, three armed phase II trial of PledOx in two different doses in combination with FOLFOX6 compared to placebo + FOLFOX6 in patients with metastatic colorectal cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase II Trial of PledOx in combination with the cancer theraphy FOLFOX6 in patients with cancer in the large inestine
    A.3.2Name or abbreviated title of the trial where available
    PLIANT
    A.4.1Sponsor's protocol code numberPP095
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPledPharma AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPledPharma AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPCG Clinical Services AB
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressKungsängsvägen 19, 1tr
    B.5.3.2Town/ cityUppsala
    B.5.3.3Post code75323
    B.5.3.4CountrySweden
    B.5.4Telephone number0046(0)184303100
    B.5.5Fax number0046(0)184303101
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePledOx 2mM
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCalmangafodipir
    D.3.9.3Other descriptive nameCalmangafodipir
    D.3.10 Strength
    D.3.10.1Concentration unit mmol/l millimole(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product Information not present in EudraCT
    D.3.11.12Homeopathic medicinal product Information not present in EudraCT
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePledOx 10 mM
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCalmangafodipir
    D.3.9.3Other descriptive nameCalmangafodipir
    D.3.10 Strength
    D.3.10.1Concentration unit mmol/l millimole(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product Information not present in EudraCT
    D.3.11.12Homeopathic medicinal product Information not present in EudraCT
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic colorectal cancer
    E.1.1.1Medical condition in easily understood language
    Cancer in the large inestine that have spread to other parts of the body.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic colorectal cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective Dose Escalation Phase:
    To characterize the prevalence, severity, drug-relatedness and seriousness of adverse events of PledOx in two doses

    Primary Objective Randomised Treatment Phase:
    Assess the efficacy of two different doses of PledOx when added to FOLFOX6 chemotherapy as measured by protection from FOLFOX6 toxicity on neutropenia grade 3 or 4 (NCI-CTCAE v4)
    E.2.2Secondary objectives of the trial
    To assess PledOx effect on febrile neutropenia

    Assessment of anti-tumour effect of PledOx when added to FOLFOX6 chemotherapy evaluated according to RECIST criteria 1.1

    To assess PledOx effect on peripheral neuropathy

    To assess PledOx effect on oral mucositis

    To assess PledOx effects on other DLT

    To assess PledOx effect on FOLFOX6 delivered dose and dose intensity

    To assess PledOx effect on overall survival (OS)

    PledOx effect on Quality of Life (QoL)

    Characterize the pharmacokinetic (PK) profile of PledOx (and metabolites ZnDPDP, ZnPLED, ZnDPMP) as well as the metals manganese and zinc

    Safety Objectives:
    Safety profile of the combination of PledOx when added to FOLFOX6 chemotherapy
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Both the Dose Escalation Phase (Part 1) and Randomised Treatment Phase (Part 2) are described in the same protocol.
    E.3Principal inclusion criteria
    1.Advanced metastatic colorectal (stage IV) cancer verified by biopsy

    2.Patients may have received up to three previous treatment lines of chemotherapy, which may include fluoropyrimidine, irinotecan and targeted therapies. The last dose of antitumor drug must be given at least 4 weeks prior to inclusion and all toxicity (except alopecia and fatigue) resolved. Patients may also be chemotherapy-naïve, have received prior adjuvant treatment but no previous treatment with oxaliplatin

    3.CT-scan or MRI of thorax, abdomen and pelvis; within ≤4 weeks before start of chemotherapy

    4.Evaluable disease and one measurable site of disease according to RECIST 1.1 criteria (at least 10 mm for CT-scan or MRI)

    5.Neurological examination with no significant pathological findings

    6.≥18 years

    7.WHO performance status 0≤2 and Life expectancy ≥ 3 months

    8.Adequate haematological function, Hb ≥ 100 g/L, ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L

    9.Adequate renal and hepatic functions: creatinine clearance >50 cc/min, total bilirubin ≤ 1.5 times ULN, ASAT and ALAT ≤ 3 times ULN (ASAT and ALAT ≤ 5 times ULN in case of liver metastases)

    10.INR ≤1.5 times ULN, unless receiving therapeutic anticoagulation

    11.Negative pregnancy test for females of child-producing potential

    12.Written informed consent given
    E.4Principal exclusion criteria
    1.Tumours other than colorectal adenocarcinomas (within the previous 5 years) except for curatively treated non melanoma skin cancer or in situ carcinoma of the cervix
    2.Evidence of central nervous system metastases
    3.Unresolved bowel obstruction or sub-obstruction, uncontrolled Crohn’s disease or ulcerative colitis
    4.History of cardiac disease with a New York Heart Association (NYHA) Class II or greater congestive heart failure, myocardial infarction or unstable angina in the past six (6) months prior to Day 1 of treatment and serious arrhythmias requiring medication for treatment
    5.Prolonged QTC interval >450 msec
    6.Known history of stroke or cerebrovascular accident in the past six (6) months
    7.Severe diarrhoea
    8.Chronic infection or uncontrolled serious illness causing immunodeficiency
    9.Any uncontrolled serious illness or medical condition
    10.Received mangafodipir at any time
    11.Welders, mine workers or other workers in occupations (current or past) where high manganese exposure is likely
    12.Pre-existing neurodegenerative disease (Parkinson’s, Alzheimer’s, Huntington’s etc.) or neuromuscular disorder (Multiple sclerosis, Amyotrophic lateral sclerosis, Polio, hereditary neuromuscular disease)
    13.Major psychiatric disorder (major depression, psychosis)
    14.Participation in another clinical study with an investigational medicinal product within 1 month prior to inclusion.
    15. Blood manganese concentration values >18,3 µg/L at screening
    E.5 End points
    E.5.1Primary end point(s)
    Neutropenia grade 3 and 4
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of treatment phase.
    E.5.2Secondary end point(s)
    • Febrile neutropenia
    • CT or MRI of thorax, abdomen and pelvis will be used to identify and characterize target and non-target lesions, according to the RECIST 1.1. (CR, PR, SD or PD) at baseline and during treatment until progression of the disease or up to 12 months after end of investigational medicinal product (IMP) administration:
    o Response rate (RR)
    o Progression free survival (PFS)
    • Symptoms and signs of peripheral neuropathy
    o Presence of positive cold
    o Patient reported outcome: Oxaliplatin-associated sensory neuropathy scale (Leonard et al.)
    o Physician observed neuropathy: NCI-CTCAE v4 and Oxaliplatin Sanofi Specific Scale
    • Oral mucositis
    • Absolute neutrophil count and other relevant laboratory test variables
    • Neutropenia grade
    • Dose change (dose frequency and intensity)
    • Overall survival
    • QoL
    • Pharmacokinetic variables:
    o Plasma concentration half-life, t½.
    o The maximum observed plasma concentration, Cmax, and the corresponding time, tmax.
    o The area under the plasma concentration-time curve from time 0 to last observed concentration, AUCt.
    o The area under the plasma concentration-time curve from time 0 to infinity, AUC0-

    SAFETY ENDPOINTS:
    Safety parameters; Adverse drug reactions and serious adverse drug reactions, changes in haematology and chemistry values, including those associated with hepatic and renal function, and assessment of physical examinations, vital signs and cardiac function (QT prolongation).
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 months after end of treatment except for overal survival which is 20 months after end of treatment.

    Safety end points will be evaluated continouosly.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Part 1 is Open and Part 2 is double blind.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Bulgaria
    Denmark
    Georgia
    Germany
    Portugal
    Serbia
    Sweden
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of Trial is defined as last visit of the last patient (12 months after End of Treatment).

    In addition, all subjects will be followed for overall survival for 8 months after End of Trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 180
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    No
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-05-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-05-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-02-23
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