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    Summary
    EudraCT Number:2017-004707-43
    Sponsor's Protocol Code Number:PP06489
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-04-04
    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 ConcernedFrance - ANSM
    A.2EudraCT number2017-004707-43
    A.3Full title of the trial
    A Phase 3, double-blind, multicenter, placebo-controlled study of PledOx used on top of modified FOLFOX6 (5-FU/FA and Oxaliplatin) to prevent chemotherapy induced peripheral neuropathy (CIPN) in the adjuvant treatment of patients with Stage III or high-risk Stage II colorectal cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3, double-blind, multicenter, placebo-controlled study of a new drug, PledOx used on top of standard therapy to prevent damages to nerves of the peripheral nervous system, induced by chemotherapy, in the adjuvant treatment of patients with Stage III or high-risk Stage II cancer of the large intestine.
    A.4.1Sponsor's protocol code numberPP06489
    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 organisationPledPharma AB
    B.5.2Functional name of contact pointChief Medical Officer
    B.5.3 Address:
    B.5.3.1Street AddressGrev Turegatan 11c
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post codeSE 114 46
    B.5.3.4CountrySweden
    B.5.4Telephone number+46 709 641 009
    B.5.5Fax number+46 8 663 57 25
    B.5.6E-mailstefan.carlsson@pledpharma.se
    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 50mM
    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 INNnot available
    D.3.9.1CAS number 1401243-67-1
    D.3.9.2Current sponsor codeCalmangafodipir
    D.3.9.3Other descriptive nameCa4Mn(DPDP)5
    D.3.10 Strength
    D.3.10.1Concentration unit mmol/kg millimole(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.005
    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 No
    D.3.11.12Homeopathic medicinal product No
    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 placeboSolvent for solution 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
    Chemotherapy induced peripheral neuropathy
    E.1.1.1Medical condition in easily understood language
    Damages to nerves of the peripheral nervous system, induced by chemotherapy
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10079545
    E.1.2Term Chemotherapy induced peripheral neuropathy
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare PledOx (5 µmol/kg) vs placebo with respect to the proportion of patients with moderate or severe chronic CIPN
    E.2.2Secondary objectives of the trial
    To compare PledOx vs placebo:

    Efficacy
    • The proportion of patients with mild, moderate or severe chronic CIPN
    • The sensitivity to touching cold items
    • The cumulative dose of oxaliplatin during chemotherapy
    • The vibration sensitivity on the lateral malleolus
    • The worst pain in hands or feet
    • The functional impairment (in the non-dominant hand)
    • The sustained efficacy on prevention of CIPN during long-term follow-up

    Safety
    • DFS
    • Safety and tolerability

    Exploratory
    • Chronic CIPN by supporting analysis using the full FACT/GOG NTX-13
    • The cumulative dose of 5-FU during chemotherapy
    • For both oxaliplatin and 5-FU: Dose intensity, number of cycles, dose reductions, reason(s) for dose reductions, patients with dose delays, and length of dose delays
    • Quality of Life/health status
    • The functional impairment (in the non-dominant hand) during long-term follow-up
    • The worst pain in hands or feet during long-term follow-up.
    • Health economic impact
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent form before any study related assessments and willing to follow all study procedures.
    2. Male or female aged ≥18 years.
    3. Pathologically confirmed adenocarcinoma of the colon or rectum including: Stage III carcinoma (any T N1,2 M0) or Stage II carcinoma (T3,4 N0 M0).
    4. The patient has undergone curative (R0) surgical resection performed not less than 28 days and generally not more than 8-12 weeks prior to randomization.
    5. The patient has a postsurgical CEA level ≤1.5 x upper limit of normal (ULN, in current smokers, CEA level ≤2.0 x ULN is allowed).
    6. No prior anti-cancer therapy for CRC except radiotherapy or concomitant chemoradiotherapy using a fluoropyrimidine alone for locoregional rectal cancer.
    7. Patient indicated for up to 6 months of oxaliplatin-based chemotherapy and without any clinically observed neurological disorders.
    8. ECOG performance status of 0 or 1.
    9. Adequate hematological parameters: hemoglobin ≥100 g/L, absolute neutrophil count (ANC) ≥1.5 x 109 /L, platelets ≥100 x 109 /L.
    10. Adequate renal function: creatinine clearance >50 cc/min using the Cockroft and Gault formula or measured.
    11. Adequate hepatic function: total bilirubin ≤1.5 x ULN (except in the case of known
    Gilbert’s syndrome); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x ULN (AST and ALT ≤5 x ULN in case of liver metastases).
    12. Baseline blood Mn level <2.0 x ULN.
    13. For patients with a history of diabetes mellitus, HbA1c ≤7%.
    14. Negative pregnancy test for females of child-bearing potential.
    15. For men and females of childbearing potential, use of adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) while on study drug and for at least 6 months after completion of study therapy.
    E.4Principal exclusion criteria
    1. Any evidence of metastatic disease.
    2. Any unresolved toxicity by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v.4.03) >Grade 1 from previous anti-cancer therapy (including radiotherapy), except alopecia.
    3. Any grade of neuropathy from any cause.
    4. Any prior oxaliplatin-based chemotherapy <1 year before the randomization.
    5. Any evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, cardiac, unresolved bowel obstruction, hepatic or renal disease).
    6. Chronic infection or uncontrolled serious illness causing immunodeficiency.
    7. Recent (<28 days) surgery prior to entry into the study or a surgical incision that is not fully healed.
    8. Known hypersensitivity to any of the components of mFOLFOX6 and, if applicable, therapies to be used in conjunction with the chemotherapy regimen or any of the excipients of these products.
    9. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years, unless the patient has been disease free for that other malignancy for at least 2 years.
    10. Known dihydropyrimidine dehydrogenase deficiency.
    11. Pre-existing neurodegenerative disease (e.g., Parkinson’s, Alzheimer’s, Huntington’s) or neuromuscular disorder (e.g., multiple sclerosis, amyotrophic lateral sclerosis, polio, hereditary neuromuscular disease).
    12. Major psychiatric disorder (major depression, psychosis), alcohol and/or drug abuse.
    13. Patients with a history of second or third degree atrioventricular block or a family heredity.
    14. A history of a genetic or familial neuropathy.
    15. Treatment with any investigational drug within 30 days prior to randomization.
    16. Pregnancy, lactation or reluctance to using contraception.
    17. Any other condition that, in the opinion of the Investigator, places the patient at undue risk.
    18. Previous exposure to mangafodipir or calmangafodipir.
    19. Welders, mine workers or other workers in occupations (current or past) where high Mn exposure is likely.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients scoring 3 or 4, derived as the maximum score of items NTX 1 to 4, in any of the symptoms of numbness, tingling and discomfort in hands and feet in the FACT/GOG-NTX-13, 9 months after the first dose.
    E.5.1.1Timepoint(s) of evaluation of this end point
    9 months after first dose of IMP
    E.5.2Secondary end point(s)
    Secondary Endpoints

    Efficacy
    • Proportion of patients (with mild, moderate or severe chronic CIPN) scoring 2, 3, or 4, in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, 9 months after the first dose of IMP
    • Mean change from baseline in sensitivity to touching cold items on Day 2, Cycle 4 of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity questionnaire
    • Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of IMP
    • Mean change from baseline in vibration sense, on the lateral malleolus (left and right), using a graduated tuning fork, at 9 months after the first dose of IMP
    • Mean change from baseline in worst pain in hands or feet in the past week, using a numerical rating scale (NRS), at 9 months after the first dose of IMP
    • Mean change from baseline in the time to complete the grooved Pegboard with the non-dominant hand, at 9 months after the first dose of IMP
    • Proportion of patients scoring 3 or 4 in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, 12, 18, and 24 months after the first dose of IMP

    Safety
    • DFS
    • Safety and tolerability as assessed by adverse events (AEs), laboratory variables and vital signs

    Exploratory Endpoints
    • Frequency and proportion of patients with any CIPN scoring 1, 2, 3 or 4, in any of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or feet, at all other timepoints after the first dose of IMP
    • Mean score of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), at 9 months after the first dose of IMP
    • Mean score of the 13 items of the FACT/GOG-NTX-13, at 9 months after the first dose of IMP
    • Mean cumulative dose of 5-FU administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of IMP
    • For both oxaliplatin and 5-FU: Dose intensity, mean number of cycles per patient, proportion of patients with any dose reduction, reason(s) for dose reductions, proportion of patients with any dose delay, and mean duration of dose delay
    • Mean health index and mean visual analogue scale (VAS) score, using the EQ-5D-5L, at 9, 12, 18, and 24 months after the first dose of IMP
    • Mean health index, using the FACT/GOG, at 9, 12, 18, and 24 months after the first dose of IMP
    • Mean time to complete the grooved Pegboard, with the non dominant hand, at 12, 18, and 24 months after the first dose of IMP
    • Mean change from baseline in worst pain in hands or feet in the past week, using a NRS, at 12, 18, and 24 months after the first dose of IMP
    • The proportion of patients with a 2-point, 3-point and 4-point increase in worst pain in hands or feet in the past week, using a NRS, at 9, 12, 18, and 24 months after the first dose of IMP
    • Health economic impact, measured by the combined impact of medical resource utilization (hospitalizations, outpatient visits, medical procedures and medical use), patient impact (AEs, fall accidents, functional loss) and indirect societal costs (loss of ability to work), up to 24 months after the first dose of IMP
    E.5.2.1Timepoint(s) of evaluation of this end point
    - FACT/GOG-NTX-13, Grooved pegboard, Grad. Tuning fork, Pain NRS: treatment visits 1-12 (D1 of each Cyc), assessment visits M3, 6, 9, 12, 18 & 24, EoT (D14 last cycle)
    - AEs: treatment V1-12, EoT
    - DFS : assessment M3, 6, 9, 12, 18 & 24, EoS
    - Biochem & Blood Mn: Screen, treatment V1, 4, 8, 12, EoT
    - Hemato: Screen, treatment V1-12, EoT
    - Vital sign, ECOG: Screen, treatment V1-12, M3, 6, 9, 12, 18 & 24, EoT
    - Cold sensitivity: Screen, treatment V2, 4 & 8
    - QoL/health status: treatment V1, 4, 8 & 12, M6-24
    - Physical exam: Screen, assesment M3-24, EoT
    - MRI of CNS and Blood Mn incl. neuro exam: treatment visits 1-12, M3, EoT
    - ECG: Screen
    - Health eco: treament V1, EoT, M12 & M24
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    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 No
    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 trial2
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA56
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    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)
    Following the completion of the Treatment Phase, patients may continue to receive mFOLFOX6 at the discretion of the Investigator, and if so, with PledOx/placebo on top, for up to 12 months after first dose of IMP. At the end of the study (i.e. 24 months after first dose of IMP), there is no intention for further PledOx/placebo to be given.
    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 Decision2018-06-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-08-31
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