| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Birdshot Uveitis
HLA A29 retinochoroiditis |
|
| E.1.1.1 | Medical condition in easily understood language |
| A Chronic Auto-Immune mediated inflammatory Eye Disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10072959 |
| E.1.2 | Term | Birdshot chorioretinopathy |
| E.1.2 | System Organ Class | 10015919 - Eye disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
to assess the efficacy to suppress active uveitis in Birdshot uveitis and to induce inflammatory remission during the 1 year treatment. Treatment
efficacy will be assessed, using quantitative and qualitative measurements of visual function. In this trial we will also assess the utility of quantitative outcome measures in detecting disease activity. |
|
| E.2.2 | Secondary objectives of the trial |
to test safety of Abatacept in Birdshot uveitis patients
to test efficacy of Abatacept in inducing remission in Birdshot uveitis patients
to evaluate the visual function in patients taking Abatacept in Birdshot uveitis using both qualitative and quantitative outcome measures
to evaluate the utility of new outcome measures (dual scoring of FA/ICG and ERG 30hz implicit time) in detecting disease activity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject is at least 18 years of age.
Subject is diagnosed with Birdshot uveitis, HLA A 29+
Subject must have active disease at the Baseline visit as defined by the
presence of at least 1 of the following parameters in at least one eye :
-Active, inflammatory, chorioretinal and/or inflammatory retinal
vascular lesion
-≥ 1+ vitreous haze (National Eye Institute [NEI]/SUN criteria)
Subjects who do not have previous, active or latent tuberculosis (TB).
Only one TB test is required to allow the subject in the study. Subjects
with either negative purified protein derivative (PPD) (< 5 mm of
induration) or negative QuantiFERON®-TB Gold test (or interferon-
gamma release assay (IGRA) equivalent) are eligible. Subjects with a
repeat indeterminate QuantiFERON®-TB Gold test (or IGRA equivalent)
result are not eligible. Note, that only one TB screening test is allowed
and required. A repeat QuantiFERON® TB Gold test (or IGRA equivalent)
is not permitted if the PPD skin test is positive. The TB screening tests
are diagnostic tests. In the event of a negative TB screening test, the
results are to be interpreted in the context of the patient's epidemiology,
history, exam findings, etc. and it is the responsibility of the investigator
to determine if a patient has previous, active or latent tuberculosis or
not. Under no circumstances can a patient with a positive PPD result or
positive QuantiFERON®-TB Gold test (or IGRA equivalent) enter the
study. |
|
| E.4 | Principal exclusion criteria |
Subject with prior inadequate response to high-dose oral corticosteroids
(>30 mg of prednisolone or equivalent)
Subject with confirmed or suspected infectious uveitis, including but not
limited to infectious uveitis due to TB, cytomegalovirus (CMV), Human T-
Lymphotropic Virus Type 1 (HTLV-1), Whipple's disease, Herpes Zoster
virus (HZV), Lyme disease, toxoplasmosis and herpes simplex virus
(HSV).
Subject with corneal or lens opacity that precludes visualization of the
fundus or that likely requires cataract surgery during the duration of the
trial.
Subject with intraocular pressure of ≥ 25 mmHg and on ≥ 2 glaucoma
medications or evidence of glaucomatous optic nerve injury.
Subject with Best Corrected Visual Acuity (BCVA) less than 20 letters
(Early Treatment Diabetic Retinopathy Study) in at least one eye at the
Baseline Visit.
Subject with intermediate uveitis or panuveitis that has signs of
intermediate uveitis (e.g.presence or history of snowbanking or
snowballs) and symptoms and/or magnetic resonance imaging (MRI)
findings suggestive of a demyelinating disease such as multiple
sclerosis. All subjects with intermediate uveitis or panuveitis that have
signs of intermediate uveitis (e.g., presence or history of snowbanking
or snowballs) must have had a brain MRI within 90 days prior to the
Baseline Visit.
Subject has had previous exposure to anti-tumor necrosis factor (TNF)
therapy or any biologic therapy (except intravitreal anti-vascular
endothelial growth factor [VEGF] therapy) with a potential therapeutic
impact on non-infectious uveitis
Subject with exposure to classic immunosuppressive therapy, in which
the dose has been increased within the last 28 days prior to Baseline
visit or is within the following doses at the screening visit: Methotrexate
(MTX) >25 mg per week Cyclosporine > 4 mg/kg per day Mycophenolate
mofetil >2 grams per day or an equivalent drug to mycophenolate
mofetil (e.g. mycophenolic acid) at an equivalent dose approved by the
Medical Monitor. Azathioprine > 175 mg per day Tacrolimus (oral
formulation) >8 mg per day.
Subject is still on immunosuppressive therapy ( methotrexate,
Cyclosporine, Mycophenolate Mofetil, Azathioprine, Tacrolimus,
Sirolimus) at the baseline visit.
Subject has received Iluvien® (glucocorticosteroids implant) within 3
years prior to the Baseline visit or that has had complications related to
the device. Subject has had Iluvien® (glucocorticosteroids implant)
removed within 90 days prior to the Baseline visit or has had
complications related to the removal of the device.
Subject has received intraocular or periocular corticosteroids within 30
days prior to Baseline visit.
Subject with proliferative or severe non-proliferative diabetic
retinopathy or clinically significant macular edema due to diabetic
retinopathy. Subject with neovascular/wet age-related macular
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degeneration Subject with abnormality of vitreo-retinal interface (i.e.,
vitreomacular traction, epiretinal membranes, etc.) with the potential for
macular structural damage independent of the inflammatory process.
Subject with severe vitreous haze that precludes visualization of the
fundus at the Baseline visit.
Subject has received Ozurdex® (dexamethasone implant) within 6
months prior to the Baseline visit. Subject has received intravitreal anti-
VEGF therapy within 45 days of the Baseline visit for Lucentis®
(ranibizumab) or Avastin® (bevacizumab) or within 60 days of the
Baseline visit for anti-VEGF Trap (aflibercept).
Subject has received intravitreal methotrexate within 90 days prior to
the Baseline visit
Subject on systemic carbonic anhydrase inhibitor within 1 week prior to
Screening visit.
Subject with macular edema as the only sign of uveitis.
Subject with a history of scleritis.
Subject on cyclophosphamide within 30 days prior to the Baseline visit.
Subjects with a known HIV, HepB/C infection.
Subjects with an active or recent acute infection.
Subjects with a history of chronic or recurrent bacterial, viral or systemic
fungal infections.
Subjects with malignancies.
Subjects who have received any live vaccines within 3 months of the study drug |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is time to recurrence in ≥1 eye.
Patients are assessed for recurrence, if at least 1 of the following criteria
are fulfilled in at least 1 eye
-worsening of BCVA (Best Corrected Visual Acuity measured by ETDRS
chart) by >15 letters relative to best state achieved
-30% increase of central retinal thickness on OCT (Optical Coherence
Tomography) relative to best state achieved
-2-step increase in VH (Vitreous Haze) grade relative to baseline
-new active, inflammatory choroidal (detected on ICG Angiography)
and/or inflammatory retinal vascular lesions relative to baseline
(detected on FA: fluorescein angiography). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
at each visit
week 6, week 12, month 6, month 9, month 12 |
|
| E.5.2 | Secondary end point(s) |
-Change in Vitreous Haze (VH) Grade in Each Eye From Best State
Achieved Prior to Week 6 to the Final/Early Termination Visit [ Time
Frame: From Baseline to Week 6 and Final/Early Termination Visit]
Vitreous haze is measured using dilated indirect ophthalmoscopy (DIO)
and assessed by the Investigator according to National Eye Institute
(NEI) and SUN criteria:
Grade 0: No evident vitreous haze
Grade 0.5+: Slight blurring of the optic disc margin because of the haze;
normal striations and reflex of the nerve fiber layer cannot be visualized;
Grade 1+: Permits a better definition of both the optic nerve head and
the retinal vessels (compared to higher grades);
Grade 2+: Permits better visualization of the retinal vessels (compared
to higher grades);
Grade 3+: Permits the observer to see the optic nerve head, but the
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borders are quite blurry;
Grade 4+: Optic nerve head is obscured.
-Change In Logarithm of the Minimum Angle of Resolution (LogMAR)
Best Corrected Visual Acuity (BCVA) In Each Eye From Best State
Achieved Prior to Week 6 to the Final/Early Termination Visit [ Time
Frame: From Baseline to Week 6 and Final/Early Termination Visit] Using
corrective lenses based on that visit's refraction testing, participant's
best corrected visual acuity is measured using an Early Treatment
Diabetic Retinopathy Study (ETDRS) logMAR chart.
-Time to Optical Coherence Tomography (OCT) Evidence of Macular
Edema in At Least 1 Eye On or After Week 6 [ Time Frame: From Baseline
until the Final Visit ] Optical coherence tomography is performed at
every visit using the Zeiss Cirrus OCT. Images are evaluated by a central
reader (PI). Macular edema is defined as cystoid macular edema. OCT
evidence of macular edema on or after Week 6 is to be counted as an
event. Dropouts due to reasons other than OCT evidence of macular
edema are to be considered as censored observations at the time of
dropping out.
-Percent Change in Central Retinal Thickness in Each Eye From Best
State Achieved Prior to Week 6 to the Final/Early Termination Visit [
Time Frame: Baseline to Week 6 and Final/Early Termination Visit]
-Percent Change in Choroidal Thickness in Each Eye From Best State
Achieved Prior to week 6 to the Final/Early Termination Visit [ Time
Frame: From Baseline until the Final Visit ]. Choroidal thickness will be
measured using the EDI mode of the Zeiss Cirrus OCT and will be
measured by a central reader (PI).
-Change in Visual Functioning Questionnaire 25 (VFQ-25) Composite
Score From Best State Achieved Prior to Week 6 to the Final/Early
Termination Visit [ Time Frame: Baseline to Week 6 and Final/Early
Termination Visit ] The National Eye Institute VFQ-25 is an ocular
disease-specific survey that measures the influence of visual disability
and visual symptoms on generic health domains such as emotional well-
being and social functioning, in addition to task-oriented domains
related to daily visual functioning.
-Change in scoring of Dual Fluorescein and ICG angiography from best
state achieved, as defined by the Angiography Scoring for Uveitis
Working group using the Heidelberg Scanning LASER fluorescein and ICG
angiography.
-Change in ElectroRetinoGraphy (ERG) using the ISCEV standard protocols from baseline |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
at each visit
week 6, week 12, month 6, month 9, month 12 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Proof of Concept Trial in an Orphan Disease |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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