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    Summary
    EudraCT Number:2018-002422-23
    Sponsor's Protocol Code Number:twostepala
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-07-17
    Trial 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 ConcernedNorway - NOMA
    A.2EudraCT number2018-002422-23
    A.3Full title of the trial
    Extracorporeal photopheresis of patients with Crohns disease using 5- aminolevulinic acid.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Destruction of cells separated from blood outside of the body using the drug 5-aminolevulinic and blue light for up to 10 patients with Crohns disease.
    A.3.2Name or abbreviated title of the trial where available
    twostepala
    A.4.1Sponsor's protocol code numbertwostepala
    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 SponsorAkershus University Hospital
    B.1.3.4CountryNorway
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOslo University Hospital, Radiumhospitalet
    B.4.2CountryNorway
    B.4.1Name of organisation providing supportAkershus University Hospital
    B.4.2CountryNorway
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAkershus University Hospital
    B.5.2Functional name of contact pointProject Leader
    B.5.3 Address:
    B.5.3.1Street AddressSykehusveien 25
    B.5.3.2Town/ cityLørenskog
    B.5.3.3Post code1478
    B.5.3.4CountryNorway
    B.5.6E-mailkre5@ahus.no
    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 Yes
    D.2.1.1.1Trade name Gliolan
    D.2.1.1.2Name of the Marketing Authorisation holderMedac
    D.2.1.2Country which granted the Marketing AuthorisationNorway
    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.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPExtracorporeal use
    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 Yes
    D.3.11.13.1Other medicinal product typeExtracorporeal photopheresis
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Crohns disease
    E.1.1.1Medical condition in easily understood language
    The inflammatory bowel disease Crohns disease
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10011401
    E.1.2Term Crohn's disease
    E.1.2System Organ Class 10017947 - Gastrointestinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - to assess efficacy, safety and tolerability after single and multiple treatment doses of 0.050% w/v (3 mM) 5-ALA (Gliolan®) in combination with BLUE-PIT Photopheresis System in patients with active Crohn’s disease in combination with leukapheresis (Spectra Optia with Continuous Mononuclear Cell Collection protocol) and BLUE-PIT system used for standard two-step ECP in patients with Crohns disease.
    E.2.2Secondary objectives of the trial
    - To assess efficacy parameters and mechanism of action, and to identify biomarkers for responsiveness after single and multiple treatment doses of 0.050% w/v (3 mM) 5-ALA (Gliolan®) in combination with BLUE-PIT Photopheresis System in patients with active Crohn’s disease. We will also address endoscopic improvement and improvement on cross sectional imaging when appropriate as secondary endpoints.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of informed consent
    2. Age above 18
    3. Male or female patient with active Crohn's disease (5)
    4. Inadequate response (a) or intolerance to biological therapy
    a. Inadequate response on ongoing treatment is defined as:
    i. Progressive disease: increasing HBI/Calprotectin/SES-CD and/or worsening of radiologic images after 6 months.
    ii. Stable disease: no-response after 6 months
    5. Active inflammation in the gut documented by
    a. HBI>7
    b. Endoscopy with SES-CD > 6
    c. and/or inflammatory markers; fecal calprotectin and/or C-reactive
    protein (CRP).
    E.4Principal exclusion criteria
    1. Photosensitive comorbidities, porphyria or known hypersensitivity to 5-aminolevulinic acid or porphyrins
    2. Patients with aphakia
    3. Pregnant or breast feeding women. A negative urine pregnancy test must be demonstrated in female patients of child-bearing potential at the Screening Visit and before every treatment.
    4. Ongoing cardiac and pulmonary diseases or ASAT, ALAT, Bilirubin or INR value ≥ 3x upper limit of normal or clinically significant ECG findings
    5. Subjects with polyneuropathy
    6. Uncontrolled infection or fever
    7. History of heparin-induced thrombocytopenia, absolute neutrophil
    count <1x109 L-1, platelet count <20x109 L-1
    8. Body weight below 40 kg
    9. Investigator considers subject unlikely to comply with study
    procedures, restrictions and requirements.
    10. History of any clinically significant disease or disorder which in the opinion of the investigator, may either put the patient at risk because of participation in the study, or influence the result or the patient's ability to participate in the study.
    E.5 End points
    E.5.1Primary end point(s)
    Effectiveness of treatment after 13 weeks with clinical remission Harvey Bradshaw index (HBI) < 5.

    Frequency, seriousness and intensity of adverse events, ECG, recording, vital signs and safety laboratory parameters. ALA and its derived porphyrins (mainly PpIX) are usually eliminated from the body within 24-48 hours after systemic administration and transiently increased activities of some transferases (ALP, ASAT, gGT) and bilirubin in the blood generally return to normal values within 72 hours. Blood parameters will be taken before every treatment and compared to baseline. Patients will be evaluated/asked regarding general health condition including know AEs of ALA (nausea, vomiting, photosensitization). Patients with x 3 upper reference blood parameters are excluded. If values rise 50%, new sample within 3 days and ALA-ECP postponed. If persistent beyond 6 days - ALA-ECP postponed till normalization. Treatment stoped if identified SAE occur.
    E.5.1.1Timepoint(s) of evaluation of this end point
    For safety/tolerability; continuous evalution before and after every treatment. Main evaluations at 13, 26, 38, 50, 64 weeks and three months after last treatment for the first 5 patients. If not eligible for study extension at week 13, final visit at week 28. The latter 5 patients will be assessed at week 13 and 28.
    Efficacy; after 13, 26, 38, 50, 64 weeks and three months after last treatment for the first 5 patients. The latter 5 patients will be assessed at week 13 and 28.
    E.5.2Secondary end point(s)
    Response/effectiveness of treatment after 13, 26, 38, 50, 64 weeks and three months after last treatment will be evaluated with baseline visit (prior treatment) as reference for the first 5 patients. The latter 5 will be assessed at 13 and 28 weeks. The efficacy parameters include SES-CD, Calprotectin and IBDQ in addition to clinical effect with HBI reduction > 3 from baseline but not remission.

    Mechanism of action and identification of biomarkers.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Endoscopy and SES-CD will be done at week 13 and (if eligible for study extension with treatment every 4 weeks from week 14-62) at week 64 for the first 5 patients. The latter 5 patients will have an endoscopy at week 13.

    Remaining values will be collected at week 13, 26, 38, 50, 62 and 3 months after last treatment (IBDQ, calprotectin, HBI) if eligible for extension for the first 5 patients and in week 28 for patients not eligible for study extension. For the latter 5 patients - the values will be collected at week 13 and 28.

    Mechanism of action and identification of biomarkers will be done on blood, biopsies and buffy samples throughout the trial. That is ALA-induced PpIX and PDT effects on various sub populations of leukocytes in all samples.
    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 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 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 No
    E.8.1.1Randomised No
    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 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 No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned 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: 8
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    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)
    Patients will return to standard of care for Crohns disease. At the week 13 visit - the patients (of first 5 subjects) not eligible for study extension and all the latter 5 patients will be referred to standard of care. They will additionally be offered a clinical assessment visit at week 28 in the study.
    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 Decision2018-10-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-08
    P. End of Trial
    P.End of Trial StatusCompleted
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