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    Summary
    EudraCT Number:2016-005104-25
    Sponsor's Protocol Code Number:INV500
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-11-06
    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 ConcernedUK - MHRA
    A.2EudraCT number2016-005104-25
    A.3Full title of the trial
    Relative bioavailability and comparative pharmacokinetics of 13-CRA oral liquid and extracted capsule formulations: a randomised, open label, multi-dose, cross-over clinical trial in patients requiring treatment cycles of 13-CRA.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Relative bioavailability and comparative pharmacokinetics (blood levels of the drug) of 13-CRA oral liquid and capsule formulations: a randomised, open label, multi-dose, cross-over clinical trial in children requiring treatment cycles of 13-CRA.
    A.3.2Name or abbreviated title of the trial where available
    My-CRA, Liquid 13 Cis Retinoic Acid
    A.4.1Sponsor's protocol code numberINV500
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03291080
    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 SponsorNova BioPharma Limited
    B.1.3.4CountryUnited Kingdom
    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 support DEPARTMENT OF HEALTH
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportTHE WELLCOME TRUST LIMITED
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNova BioPharma Limited
    B.5.2Functional name of contact pointProject Manager / Head of Clinical
    B.5.3 Address:
    B.5.3.1Street AddressMartin House, Gloucester Crescent, Wigston
    B.5.3.2Town/ cityLeicester
    B.5.3.3Post codeLE18 4YL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0116 2230100
    B.5.6E-mailhussain.mulla@novalabs.co.uk
    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 name13 Cis Retinoic Acid
    D.3.4Pharmaceutical form Oral suspension
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIsotretinoin
    D.3.9.1CAS number 4759-48-2
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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) Yes
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name Roaccutane
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Products Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameRoaccutane
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIsotretinoin
    D.3.9.1CAS number 4759-48-2
    D.3.9.3Other descriptive name13 Cis Retinoic Acid
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIsotretinoin
    D.3.9.1CAS number 4759-48-2
    D.3.9.3Other descriptive name13 Cis Retinoic Acid
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Neuroblastoma
    E.1.1.1Medical condition in easily understood language
    Neuroblastoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029260
    E.1.2Term Neuroblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029260
    E.1.2Term Neuroblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10029212
    E.1.2Term Nervous system neoplasms malignant NEC
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10029211
    E.1.2Term Nervous system neoplasms malignant and unspecified NEC
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine how 13-CRA is absorbed into the body, to what extent, and how it is handled in the body, when it is administered using the new liquid formulation and the current 'extract from capsule' method.
    E.2.2Secondary objectives of the trial
    To determine the safety and tolerability of the new liquid formulation compared with extraction from capsules.
    To assess palatability (taste, smell) and acceptability of the new liquid formulation and the extraction from capsule.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible for inclusion into this trial the patients must fulfil all of the following criteria:
    1. Male or female aged from 0 years to < 21 years of age.
    2. Patient with high risk neuroblastoma, or unresectable, unfavourable histology intermediate risk neuroblastoma the latter age ≥ 18 months at diagnosis
    3. Patient who is scheduled to receive at least two treatment cycles of 13-CRA.
    4. Patient who cannot swallow 13-CRA capsules (i.e. requires extraction of 13-CRA from the capsules).
    5. Negative pregnancy test for females of child-bearing potential before initiation of treatment, and sexually active patients and partners agreeing to undertake adequate contraceptive measures (see section 4.5).
    6. Provision of a single or double lumen central venous catheter for sampling (i.e. already in place).
    7. Parent(s)/legal guardian able and willing to provide written informed consent for the patient to take part in the trial.
    8. Where applicable, the patient should assent to undergo blood sampling for pharmacokinetic purposes and to allow physiological measurements to be made.
    E.4Principal exclusion criteria
    To be eligible for inclusion in this trial the patients must not meet any of the following criteria:
    1. Any clinically significant medical condition or abnormality, which, in the opinion of the investigator, might compromise the safety of the patient or which might interfere with the trial.
    2. Diagnosis of high-risk neuroblastoma (HRNBL) which is currently being treated on the SIOPEN HRNBL trial (children who have exited this trial will be eligible).
    3. Known allergy to 13-CRA or any of the excipients.
    4. Inadequate contraception measures in females of childbearing age.
    5. Receiving concomitant treatment with tetracyclines.


    CRITERIA PRIOR TO STARTING EACH CYCLE OF 13-CRA
    1. Total bilirubin ≤ 1.5 x normal, and (SGPT) ALT ≤ 5 x normal. Veno-occlusive disease if present, should be stable or improving.
    2. Skin toxicity no greater than CTCAE Grade 1(10)
    3. Serum triglycerides <5.65mmol/L.
    4. No haematuria and / or proteinuria on urinalysis.
    5. Serum calcium ≤ 2.9mmol/L.
    6. Serum creatinine based on age / gender as follows:
    Age Maximum Serum Creatinine µmol/L
    Male Female
    1 month to < 6 months 35 35
    6 months to < 1 year 44 44
    1 to < 2 years 53 53
    2 to < 6 years 70 70
    6 to < 10 years 88 88
    10 to < 13 years 106 106
    13 to < 16 years 132 124
    ≥ 16 years 150 124

    7. Patients with a seizure disorder must be well controlled and taking anticonvulsants. CNS toxicity < grade 2 (CTCAE).
    WITHDRAWAL CRITERIA
    1. Positive pregnancy test - pregnancy testing will be undertaken before treatment commences and routinely before each course of treatment in females of child-bearing potential. If a patient is found to be pregnant during the trial, the next course of treatment will not be given until the pregnancy has been discussed with the treating clinician, and the patient will be withdrawn from the trial whether or not treatment is continued.
    2. Request of the patient, for any reason.
    3. Discretion of the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoints:
    Pharmacokinetic parameters (13-CRA, and 4-oxo-13-cis-RA)
    Primary parameters:
    • Relative bioavailability
    • Clearance (CL/F),
    • Volume of distribution (V/F)
    Secondary parameters:
    • Time to maximum concentration (Tmax),
    • Maximum plasma concentration (Cmax),
    • Area under plasma concentration time curve (AUC),
    • Half-life (t1/2)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Sparse sampling will be applied. One sample at 6 hours post dose and a further three samples at selected time points from 0.5,1,1.5,2,3,4 and 5 hours post dose. One sample at 24-48 hours.
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    Safety parameters
    • Evaluate the local (oro–pharyngeal) tolerability
    • Skin toxicity
    • Hypercalcaemia
    • Hepatotoxicity
    • Triglicerides

    Oro-pharyngeal adverse event data will be listed as adverse events and separately summarised.

    Palatability and Acceptability:
    Evaluate the taste acceptability of the new oral liquid formulation of 13-CRA.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety parameters will be assessed from time of first dosing until 14 days after the last dose is given. Palatability and acceptability will be assessed at 14 days from first dose.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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) No
    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 No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 concerned12
    E.8.5The trial involves multiple Member States No
    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
    For administrative and safety reporting purposes the end of the trial will be defined as 14 days after the last patient completes treatment in My-CRA Month 2. This provides for a single and conservative definition. Last subject last follow up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 4
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 4
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 12
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    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)
    Nova Laboratories has developed the formulation and will be manufacturing it as an IMP for the study.
    Where 13-CRA therapy is set to continue after the participant leaves the study, treatment with 13-CRA will revert back to normal local practice. However, if in the opinion of the site investigator the child would benefit from continuing on the novel oral liquid formulation, Nova Labs will make the new formulation available as an unlicensed 'special' for prescription.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-12-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-09-13
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