A pilot study towards a therapy with prednisolone encapsulated liposomes for the treatment of Graves' Orbitopathy with reduced systemic steroid exposure|
|- candidate number||27575|
|- NTR Number||NTR6579|
|- ISRCTN||ISRCTN no longer applicable|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||21-jul-2017|
|- Secondary IDs||NL61298.078.17 OZR-2016-34|
|- Public Title||A pilot study towards a therapy with prednisolone encapsulated liposomes for the treatment of Graves' Orbitopathy with reduced systemic steroid exposure|
|- Scientific Title||A pilot study towards a therapy with prednisolone encapsulated liposomes for the treatment of Graves¡¯ Orbitopathy with reduced systemic steroid exposure|
|- ACRONYM||GO Nanocort|
|- hypothesis||Nanocort is safe and effectively reduces the inflammatory signs and symptoms of active Graves' Orbitopathy (GO).|
|- Healt Condition(s) or Problem(s) studied||Graves' orbitopathy|
|- 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.)
|- 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
17. Poor peripheral venous access (as per Investigator or site personnel opinion).
18. Current substance abuse or alcohol abuse.
19. Contraindications for MRI.
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||Single arm|
|- planned startdate ||1-sep-2017|
|- planned closingdate||31-dec-2018|
|- Target number of participants||20|
|- Interventions||The first 10 subjects in this trial will be treated with 150 mg/infusion of Nanocort administered IV at week 0 and 2. Infusion will take approximately 2.5 hours. If three or more of these patients respond to treatment, another cohort of 10 subjects will be treated with 150 mg/infusion of Nanocort administered IV at week 0, 2 and (if applicable) 4.|
|- Primary outcome||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.
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.
|- Secondary outcome||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).
Pain reported on a visual analogue scale (VAS).
|- Timepoints||presentation (day -3±2)|
screening (d -1±1)
baseline (d 0)
|- Trial web site|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES|| Rene Wubbels|
|- CONTACT for SCIENTIFIC QUERIES|| Rene Wubbels|
|- Sponsor/Initiator ||Oogziekenhuis Rotterdam (OZR)|
(Source(s) of Monetary or Material Support)
|Rotterdamse Stichting Blindenbelangen, Enceladus Pharmaceuticals Naarden|
|- Brief summary||Rationale: The mainstay of treatment for patients with moderate to severe Graves’ Orbitopathy (GO) currently consists of various dose schemes of intravenous (IV) methylprednisolone or high doses oral prednisone. To avoid the frequent and potentially serious adverse effects of such treatment, new immunomodulating therapies are required. In a small study, IV administration of long-circulating liposomal prednisolone (Nanocort, LCLP) has been shown effective in rheumatoid arthritis without causing the typical glucocorticoid-related adverse events (AEs). It is hypothesized that GO can also be effectively treated with LCLP and that the number of AEs will be reduced.|
Objective: To demonstrate that Nanocort is safe and effectively reduces the inflammatory signs and symptoms of active GO.
Study design: Open label, multicentre, dose-escalating study (phase I/II).
Study population: Maximally 20 patients (18 years or older) with active GO (CAS 3 ‒ 7).
Intervention: The first 10 subjects in this trial will be treated with 150 mg/infusion of Nanocort administered IV at week 0 and 2. Infusion will take approximately 2.5 hours. If three or more of these patients respond to treatment, another cohort of 10 subjects will be treated with 150 mg/infusion of Nanocort administered IV at week 0, 2 and (if applicable) 4.
Main study parameters/endpoints: Number of patients with a predefined response to treatment.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The incidence of infusion reactions to liposomes (empty placebo as well as drug-loaded) is not unlike that for other colloidal formulations and biologics: 5-10%. AEs (possibly) associated with Nanocort appear to be manageable.
Compared to conventional therapy, the study regimen (i.e. treatment and control visits together) involves reduced burden (12 hospital visits versus 8) and reduced steroid dose (total 4500/7500 mg methylprednisolone versus 300/450 mg Nanocort). In consequence of the lower steroid dose, it has to be expected that the incidence of AEs which are associated with systemic steroid exposure will be less.
|- Main changes (audit trail)|
|- RECORD||21-jul-2017 - 22-okt-2017|
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