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    Summary
    EudraCT Number:2017-001158-33
    Sponsor's Protocol Code Number:OZR-2016-34
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-04-10
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-001158-33
    A.3Full title of the trial
    A pilot study towards a therapy with prednisolone encapsulated liposomes for the treatment of Graves’ Orbitopathy with reduced systemic steroid exposure
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A pilot study towards a therapy with prednisolone encapsulated liposomes for the treatment of Graves’ Orbitopathy with reduced systemic steroid exposure
    A.3.2Name or abbreviated title of the trial where available
    GA Nanocort
    A.4.1Sponsor's protocol code numberOZR-2016-34
    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 SponsorThe Rotterdam Eye Hospital
    B.1.3.4CountryNetherlands
    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 supportRotterdamse Stichting Blindenbelangen
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportEnceladus Pharmaceuticals
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Rotterdam Eye Hospital
    B.5.2Functional name of contact pointRotterdam Ophthalmic Institute
    B.5.3 Address:
    B.5.3.1Street AddressPO Box 70030
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3000LM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number31104023430
    B.5.6E-mailr.wubbels@oogziekenhuis.nl
    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 nameNanocort
    D.3.4Pharmaceutical form Concentrate and solvent for 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 INNprednisolone
    D.3.9.3Other descriptive namePREDNISOLONE
    D.3.9.4EV Substance CodeSUB10018MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number300 to 450
    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 typeliposomal encapsulated active substance (Prednisolone Sodium Phosphate)
    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
    Graves' Orbitopathy
    E.1.1.1Medical condition in easily understood language
    Graves' Orbitopathy
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that Nanocort is safe and effectively reduces the inflammatory signs and symptoms of active GO.
    E.2.2Secondary objectives of the trial
    To report systemic, ophthalmic and patient reported outcomes.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female ≥ 18 years old.
    2. Informed consent.
    3. Patients are able and willing to complete the study (12 months follow-up).
    4. Active GO, defined as Clinical Activity Score (CAS) ≥ 3.
    5. Moderate to severe GO (Bartalena et al. 2016):
    Patients without sight-threatening GO whose eye disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). They usually have two or more of the following: lid retraction ≥ 2 mm, moderate or severe soft-tissue involvement, or exophthalmos ≥ 3 mm above normal for race and gender, inconstant or constant diplopia.
    6. Euthyroidism for at least 3 months with antithyroid drugs or following thyroidectomy, or 6 months following radioiodine administration. (Euthyroidism is defined as normal serum free thyroxine, total or free triiodothyronine, and thyrotropin levels below 4 mU/Liter.)
    E.4Principal exclusion criteria
    1. Sight threatening GO due to optic neuropathy (decrease of (pinhole) vision, visual field loss, prolonged VEP, diminished colour vision) or severe keratopathy.
    2. Any concurrent illness, disability or clinically significant abnormality that may, as judged by the investigator, affect the interpretation of clinical efficacy or safety data or prevent the subject from safely completing the assessments required by the protocol.
    3. Current participation in another interventional clinical trial (with subjects having
    received an investigational drug within 30 days prior to the baseline visit).
    4. Treatment with oral, rectal or injectable (including intra-articular) glucocorticoids within 6 weeks prior to baseline visit. Inhaled glucocorticoids are allowed. Topical steroids are allowed, however subjects should not have received more than 100 gram of a mild to moderate topical corticosteroid cream per week, 50 gram of a potent corticosteroid cream per week or 30 gram of a very potent topical corticosteroid cream per week in the 4 weeks prior to the baseline visit.
    5. Patients who are unlikely to adequately comply with the trial’s procedures (due for instance to medical conditions likely to require an extended interruption or discontinuation, history of substance abuse or noncompliance).
    6. Women who are lactating, pregnant (positive pregnancy test at screening) or planning to become pregnant during the course of the study.
    7. Unwillingness to use reliable and acceptable contraceptive methods untill 3 months after last study medication except for female patients who are surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy) or at least 1 year postmenopausal
    8. Uncontrolled Diabetes Mellitus.
    9. History of a psychiatric disease (psychosis, depression, mania).
    10. History of or active hepatitis or Human immunodeficiency virus.
    11. Abnormal hepatic function (ALT/AST or bilirubin > 2 x upper limit of normal) at screening.
    12. Abnormal renal function (Blood Urea Nitrogen or creatinine >1.25 x upper limit of normal) at screening.
    13. Signs of active infection, requiring systemic treatment.
    14. Major surgery within the 60 Days prior to screening or planned surgery during study period.
    15. Malignant disease, unless cured.
    16. Clinically significant out-of-range values on hematology panel, at discretion of the
    Principal Investigator.
    17. Poor peripheral venous access (as per Investigator or site personnel opinion).
    18. Current substance abuse or alcohol abuse.
    19. Contraindications for MRI.
    E.5 End points
    E.5.1Primary end point(s)
    Number of patients responding to treatment (week 6 and 13), with 'response' defined as: at least two of the following outcome measures improved in one eye, without deterioration in any of these measures in either eyes:
    i) reduction in palpebral aperture by at least 3 mm;
    ii) reduction in any of the class 2 signs of NOSPECS by at least two grades;
    iii) reduction in exophthalmos by at least 2 mm;
    iv) improvement of >8 degrees in motility in any duction or improvement in diplopia (disappearance or change in degree);
    v) improvement in CAS by at least 2 points.
    If a response to treatment is observed at week 6 and at week 13, it is qualified as sustained.

    Change of maximum T2RT of EOMs and EOM area at orbital MRI at week 13 relative to baseline.

    Safety.
    At beginning and end of the study: HbA1C, fasting glucose and insulin, blood pressure, bodyweigth, BMI, WHR.
    During entire follow up: (S)AEs, vital signs (blood pressure, heart rate and respiratory rate before, during and after infusion after the patient has been supine for at least five minutes), physical examination and laboratory tests.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 13.
    E.5.2Secondary end point(s)
    Gender, age, race, height, weight (kg), BMI, blood pressure (mm Hg; systolic/diastolic).
    General medical history, history of thyroid disease (Graves’ hyperthyroidism, euthyroid Graves’ disease, Primary hypothyroidism) and comorbidities, medication use (current thyroid treatments (levothyroxine and methimazole, levothyroxine only, methimazole only or none), previous antithyroid treatments (antithyroid drugs, radioiodine, thyroidectomy), smoking history (current smoker/ex-smoker/never-smoker).
    Duration of eye symptoms (months).
    Biochemical characteristics: TSH (mU/liter), TRab (U/liter), TRab positive, TPOab positive.
    Change of maximum T2RT of EOMs and EOM area at orbital MRI at week 52 relative to baseline.
    Quality of life (disease-specific quality-of-life questionnaire, GO-QOL; Terwee et al. 1998). Exophthalmos (proptosis; mm, Hertel exophthalmometry).
    Eyelid width (mm).
    Visual acuity (Snellen), pinhole visual acuity.
    Visual field test (HFA 30/2).
    Intraocular pressure (mm Hg).
    Ishihara colour vision test.
    Soft tissue signs (minimal/moderate/marked, atlas J Dickinson)
    Subjective diplopia (Bahn and Gorman’s score: constant/inconstant/intermittent/absent).
    Orthoptic examination (ductions).
    Portrait photography.
    Pain reported on a visual analogue scale (VAS).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Frequent visits from baseline to 12 months follow up.
    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 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 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 concerned2
    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 No
    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 years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    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: 14
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 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)
    None
    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 Decision2017-04-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-12-19
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