The primary objective of this study is to assess the safety and efficacy of voclosporin as therapy in subjects with active noninfectious uveitis involving the intermediate and/or posterior segments of the eye (i.e., anterior + intermediate-,…
ID
Source
Brief title
Condition
- Ocular infections, irritations and inflammations
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The change from baseline in graded vitreous haze in the study eye at 12 weeks
of therapy or at the time of treatment failure, if earlier.
Secondary outcome
1. Time to treatment failure or inadequate response to therapy.
2. Daily mean systemic corticosteroid dose used during Weeks 12-24 in the
subset of subjects using systemic corticosteroids at baseline.
3. Change from baseline in the composite score of the National Eye Institute
(NEI) Visual Function Questionnaire-25 (VFQ-25) at Week 24.
Background summary
Noninfectious uveitis involving the intermediate or posterior segments of the
eye is a chronic inflammatory disease which is associated with significant
visual morbidity and may lead to blindness. Blindness from uveitis usually does
not occur from a single inflammatory episode; rather, recurrent episodes of
inflammation result in cumulative damage
Uveitis is the fourth leading cause of preventable vision loss in the developed
world, accounting for 10% to 20% of cases of legal blindness. In the United
States alone, approximately 30,000 people lose sight annually to uveitis. The
economic and social burdens of this disease are greatly amplified by the high
frequency of its diagnosis at a relatively young age (median 35-39 years).
Uveitis is one of the few autoimmune conditions in which corticosteroid therapy
remains the standard of care. Moreover, despite the treatment guidelines,
higher-than-recommended doses of systemic corticosteroids are often prescribed
chronically. The use of corticosteroid-sparing immunosuppressive agents to
reduce the dose of systemic corticosteroids was low (9%-16%). This may be
attributable in part to the lack of evidence-based prescribing data regarding
their appropriate use in the treatment of uveitis.
A need exists therefore for an approved therapy that can provide effective
control of inflammation, which is critical for the preservation of vision,
while reducing exposure to corticosteroids.
Voclosporin (LX211) is Lux Biosciences* designation for voclosporin capsules.
Voclosporin is a next-generation calcineurin inhibitor. Voclosporin is
structurally similar to cyclosporine A (CsA), except for a modification of a
functional group on the amino acid 1 residue of the molecule. It however
exhibits a four times higher in vitro activity as compared to CsA. CsA
furthermore has many adverse effects of which nephrotoxicity is the most
important one.
The current study aims at a comprehensive research to the efficacy and safety
of voclosporin in subjects with noninfectious uveitis.
Study objective
The primary objective of this study is to assess the safety and efficacy of
voclosporin as therapy in subjects with active noninfectious uveitis involving
the intermediate and/or posterior segments of the eye (i.e., anterior +
intermediate-, intermediate-, posterior- or pan-uveitis).
Study design
Study Eye
At least one eye must have a grade of at least 2+ vitreous haze at the baseline
visit (Visit 1) and be free of obscured ocular media (e.g., corneal scars, lens
opacities, vitreous abnormalities, etc.) or anatomic pathology that impairs
reliable assessment of the posterior segment. If both eyes qualify for study,
the eye with the highest grade of vitreous haze at the baseline visit will be
designated as the study eye. If both eyes have the same vitreous haze grade,
the Investigator will designate the eye judged to be more inflamed as the study
eye. If both eyes are judged to be equally inflamed, the right eye is to be
designated as the study eye.
Methodology
Prospective double-masked, randomized, parallel-group, placebo-controlled
design.
Subjects who meet all eligibility criteria will be randomized in a 1:1 ratio to
either
• Voclosporin 0.4 mg/kg p.o. (orally) b.i.d., not to exceed 40 mg p.o. b.i.d.
• Matching placebo p.o. b.i.d.
Following randomization, subjects who are receiving systemic corticosteroid
therapy will remain on a stable corticosteroid dose (i.e., the Visit 1
corticosteroid dose) for 4 weeks. Subsequently a corticosteroid taper to 5
mg/day over a 12-week period will be initiated.
Subjects receiving other systemic immunosuppressive therapies (e.g.,
cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil, mycophenolic
acid) must discontinue use by the evening prior to the baseline visit (Visit 1).
Fasting blood samples will be taken from all subjects for the assessment of
population pharmacokinetics
Protocol: LX211-11 August 05, 2011
Amendment 3
Lux Biosciences, Inc. 4 Proprietary & Confidential
(PK). A baseline PK blood sample will be taken at Visit 1 prior to dosing (Hour
0) and 2 hours after the first dose. At Week 4 (Visit 2), samples will be drawn
prior to dosing (Hour 0) and at 1, 2, and 4 hours post-dose. At Weeks 8, 12,
16, and 20 (Visits 3, 4, 5, and 6, respectively), samples will be drawn prior
to dosing (Hour 0) and 2 hours post-dose. At Week 24 (Visit 7, not Early
Termination) a trough sample will be drawn as part of the final study
procedures.
At all post-baseline visits, subjects must receive appropriate care (e.g.,
healthcare provider or hypertension specialist) if any blood pressure
measurements equal or exceed the threshold values of 140 mmHg systolic or 90
mmHg diastolic (confirmed average of 2nd and 3rd of three readings). In
subjects with a systolic blood pressure value of >= 140 mmHg and/or a diastolic
blood pressure of >= 90 mmHg during the screening period or at the baseline
Visit 1 (Visit 1), allowable drug therapy as described in Appendix A:, if
required, should be initiated by a healthcare provider/hypertension specialist
with the goal of reducing the blood pressure to below the threshold values of
140 mmHg systolic and 90 mmHg diastolic. Blood pressure will be monitored every
2 weeks until it is controlled.
In subjects experiencing a confirmed blood pressure elevation of >= 140/90 mmHg
while on study drug and for whom maximal doses of first- and second-line
antihypertensive agents have not resulted in control of blood pressure (i.e.,
systolic is < 140 mmHg and diastolic is < 90 mmHg), a one-time reduction of
study drug by 10 mg b.i.d. is allowed. Subjects on 20 mg voclosporin b.i.d. or
placebo b.i.d. will receive placebo b.i.d. The IWRS will be used to allocate
the appropriate drug kit while maintaining double masking. If the subject*s
blood pressure is not controlled following dose reduction an assessment of the
clinical benefit of continuing treatment with study medication should be made
by the Investigator. No further dose reduction is permitted. Electrolytes and
renal function tests will be monitored 2 weeks after first-line
antihypertensive drugs are introduced.
At all post-baseline visits, if a confirmed serum creatinine value exceeds the
average baseline measurement by >= 0.3 mg/dL (27 µmol/L), and all other
contributing factors (i.e., the addition or modification of the use of NSAIDs,
ACE inhibitors, angiotensin II receptor blockers, a concurrent state of
dehydration, overdosing with study drug, etc.) have been ruled out, the study
drug will be reduced by 10 mg b.i.d. (subjects on 20 mg b.i.d. or placebo
b.i.d. will receive placebo b.i.d.). If serum creatinine does not return to <
0.3 mg/dL above baseline within 2 weeks following dose reduction, the subject
will be withdrawn from study drug and will continue to be monitored every 2
weeks for measurement of serum creatinine, until measurement returns to < 0.3
mg/dL above the baseline measurement.
Intervention
Voclosporin versus placebo.
Study burden and risks
Adverse events to be expected most frequently are hypertension and decreased
renal function. (For a comprehensive evaluation of safety, see IB chapter 7.3)
Duration of this study is 6 months; total study-related extra time is about 15
hours.
Harborside Financial Center, Plaza 10, 14th Floor
Jersey City, NJ 07302
US
Harborside Financial Center, Plaza 10, 14th Floor
Jersey City, NJ 07302
US
Listed location countries
Age
Inclusion criteria
I.1. Active noninfectious uveitis involving the intermediate and/or posterior segment of the eye (i.e., anterior + intermediate-, intermediate-, posterior- or pan-uveitis) in at least one eye as evidenced by a vitreous haze grade of at least 2+ at the baseline visit (Visit 1). Subjects who also have anterior segment involvement need not be excluded if otherwise qualified.
I.2. Uveitis therapy
Current uveitis therapy must conform to one of the following:
* Prednisone monotherapy at a dose of >= 10 mg/day and <= 40 mg/day (or equivalent dose of another corticosteroid) for at least 2 weeks prior to the baseline visit (Visit 1).
* Prednisone, at any dose <= 40 mg/day (or equivalent dose of another corticosteroid), in addition to one immunosuppressive agent from among cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mycophenolic acid or methotrexate for at least 2 weeks prior to the baseline visit (Visit 1).
* Receiving monotherapy with azathioprine, mycophenolate mofetil, mycophenolic acid or methotrexate for at least 2 weeks prior to randomization.
* Not receiving systemic therapy and not receiving corticosteroid therapy (systemic or local) and for whom systemic or local corticosteroid therapy is medically inappropriate or refused by the patient.
N.B: All immunosuppressive therapy (excluding systemic corticosteroids) must be discontinued by the evening prior to the baseline visit (Visit 1).
I.3. Considered by the Investigator to require systemic immunosuppressive therapy.
I.4. A minimum ability to count fingers at a distance of 30 cm (1 foot) with each eye at the baseline visit (Visit 1).
I.5. At least 18 years of age.
I.6. Subjects, whether male or female, with reproductive potential and who are sexually active must agree to use double-barrier contraception methods BEFORE beginning study drug therapy, for the duration of the study (minimum of 24 weeks), and for 6 weeks following completion of study drug.
I.7. Women of childbearing potential must have a negative urine pregnancy test within 48 hours prior to subject*s assignment to study treatment at the baseline visit (Visit 1). All
female subjects (including those with tubal ligations) will be considered to be of childbearing potential unless one or more of the following criteria are met:
* Over the age of 60 years.
* Amenorrheic for at least 2 years if age 45-60 years.
* Have had a hysterectomy and/or bilateral oophorectomy.
I.8. Subjects must be:
* Capable of understanding the purpose and risks of the study.
* Able to give written informed consent.
* Able to comply with all study requirements.
Exclusion criteria
E1. OcularDisease/Conditions
E1.1. Uveitis limited to only the anterior segment of the study eye.
E1.2. Confirmed or suspected infectious uveitis in either eye, including but not limited to infectious uveitis due to tuberculosis, cytomegalovirus, Lyme disease, toxoplasmosis, Human T-Lymphotropic Virus Type 1 (HTLV-1), Whipple*s disease, herpes zoster virus (HZV), and herpes simplex virus (HSV) or history of other ocular herpetic infection; Fuchs heterochromic iridocyclitis.
E1.3. Presence of an ocular toxoplasmosis scar or suspected active infection in either eye.
E1.4. Active infection (i.e. bacterial, viral, parasitic or fungal) in either eye.
E1.5. Serpiginous choroidopathy in either eye.
E1.6. Active inflammatory lesions or vasculitis involving the central macula within 1,000 microns of the fovea (either eye).
E1.7. History of central serous chorioretinopathy in either eye.
E1.8. Proliferative or severe non-proliferative diabetic retinopathy in either eye.
E1.9. Neovascular/exudative/wet age-related macular degeneration in either eye.
E1.10. Abnormality of vitreoretinal interface (i.e., vitreomacular traction, epiretinal membranes, etc.) thought by the Investigator to interfere with measurement of macular thickness or with the potential for macular structural damage independent of the inflammatory process in the study eye.
E1.11. Clinically suspected or confirmed ocular lymphoma (either eye).
E1.12. Obscured ocular media (e.g., corneal scars, lens opacities, vitreous abnormalities, etc.) in the study eye (refer to Section 8.1 for definition of the study eye) at the
baseline (Visit 1) such that reliable evaluations and grading of either the intermediate or posterior segment cannot be performed.
E1.13. Any other ocular disease in the study eye that can interfere with the diagnosis or assessment of disease progression.
E1.14. Monocular (no light perception or anophthalmic in fellow eye).
E1.15. Intraocular pressure of < 6 mmHg or > 21 mmHg in either eye at the baseline visit (Visit 1).
E1.16. Chronic hypotony (intraocular pressure less than 6 mmHg or clinical signs such as choroidals, choroidal, or corneal folds) or pre-phthisical state (e.g., scleral thickening on ultrasonography, decreasing globe size) in either eye.
E1.17. Contraindication to pupil dilation in either eye.
E1.18. A likely need for ocular surgery (e.g., cataract extraction, laser treatment) in the study eye during the period of study participation.
E2. Prior and Current Treatment
E2.1. Presence of any implantable corticosteroid-eluting device (e.g., Retisert* [fluocinolone acetonide], Medidur* [fluocinolone acetonide], I-vation* TA [triamcinolone acetonide], Iluvien® [fluocinolone acetonide]) in the study eye within 3 years of baseline visit (Visit 1).
E2.2. Treatment with any intravitreal drug therapy (e.g., Ozurdex®, methotrexate, triamcinolone) in the study eye within 6 months of the baseline visit (Visit 1).
E2.3. Treatment with periocular (e.g., sub-Tenon*s) corticosteroid therapy of the study eye within 3 months of the baseline visit (Visit 1).
E2.4. Treatment with an immune suppression regimen that includes an alkylating agent (e.g., cyclophosphamide or chlorambucil) within 90 days prior to the baseline visit (Visit 1).
E2.5. Treatment with a monoclonal antibody or any other biologic therapy within 30 days or alemtuzumab within 12 months prior to the baseline visit (Visit 1).
E2.6. Unable to be discontinued from drugs known to either be inducers or inhibitors (strong, moderate, or weak) of cytochrome P450 3A4 and 3A5 (CYP 3A4/5) enzymes (see Table 3). Inhibitors and inducers of CYP 3A4/5 are prohibited within 7 days prior to first dose (except grapefruit [including juice] and star fruit, prohibited within 24 hours of first dose).
E2.7. Please refer to protocol for medications and medication classes prior to dosing with the washout period which are prohibited during the treatment period.
E2.8. Prior participation in a clinical trial of voclosporin.
E2.9. Known contraindication to administration of voclosporin or any of its components (vitamin E tocopherol polyethylene glycol succinate [TPGS], medium chain triglyceride [MCT] oil, polysorbate 40, ethanol).
E2.10. Participation in another clinical trial with an investigational agent in the 30 days prior to the screening visit and/or has not recovered from any reversible effects or side effects of prior investigational agent.
E3. Extraocular Conditions, for details please refer to the protocol.
E4. Laboratory, Blood Pressure and ECG Evaluations, for details please refer to the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-022128-63-NL |
| ClinicalTrials.gov | NCT01243983 |
| CCMO | NL34550.078.10 |