To assess the safety and tolerability of ascending doses of PP-001 whenadministered as a single intravitreal injection from 0,3 *g, 0,6 *g and 1,2*g with the option of an addition cohort with a dose of 2,1 *g PP-001.To assess the efficacy of…
ID
Source
Brief title
Condition
- Eye disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary
* Safety parameters (i.e., changes in clinical signs and symptoms from
ophthalmic exam, and AEs)
Secondary outcome
Secondary
* Improvement of inflammation or of any other parameter determined at the
ophthalmic examination following the injection of PP-001
* The concentration of PP-001 in plasma at Screening, 4 h ± 1 h after dosing
and on Day 2
Background summary
PP-001 is indicated for the treatment of non-infectious uveitis (NIU). Uveitis
is a chronic or relapsing intra-ocular inflammatory disease that affects the
uvea (composed of the iris, choroid and ciliary body), retina, vitreous body,
optic nerve head, retinal pigment epithelium and the anterior chamber, but may
also involve adjacent structures, including the sclera or cornea.
The integrity and transparency of the ocular media (aqueous, lens and vitreous)
and ocular tissue (iris, ciliary body, retina, pigment epithelium and choroid)
are critical for optimal visual function because they refract, transmit,
regulate and sense light. Any distortion of the visual axis by inflammatory
processes within the eye can adversely affect vision. Uveitis is a disease with
symptoms ranging from temporary effects, including discomfort, pain or blurring
of vision, to permanent defects in visual acuity and visual field due to
irreversible tissue damage and even blindness. Visual impairment may result
from direct damage to any ocular structure (e.g., cataracts, glaucoma, macular
oedema.
Uveitis can be caused by infections or by autoimmune disease. Non-infectious
uveitis covers all uveitis cases, which are considered to be of autoimmune or
autoinflammatory origin including systemic immunological disease-associated
uveitis. It also includes acute and chronic uveitis, as well as relapsing
forms, and may occur at any location in the eye.
The main treatment strategies for NIU involve the suppression of local
inflammation. Treatments range from topical therapy (commonly corticosteroid
eye drops) to systemic immunosuppression with either corticosteroids or
steroid-sparing immunomodulatory therapeutic agents. Topical medication is
generally only used to treat uveitis that affects the anterior part of the eye
(i.e. anterior chamber). Patients suffering from intermediate and/or posterior
uveitis (i.e. that which affects the vitreous body and retina/choroid) are
routinely treated with high doses of systemic corticosteroids. Dosing of
corticosteroids depends on the timeframe and severity of inflammation. Usually,
the initial treatment includes high-dose corticosteroids, which is then slowly
tapered according to disease activity. The ultimate expected therapeutic role
of PP-001 will be as a steroid-sparing agent and allow steroid doses to be
tapered quickly. Due to its underlying mode of action, PP-001 is suitable for
the treatment of NIU only.
Study objective
To assess the safety and tolerability of ascending doses of PP-001 when
administered as a single intravitreal injection from 0,3 *g, 0,6 *g and 1,2
*g with the option of an addition cohort with a dose of 2,1 *g PP-001.
To assess the efficacy of ascending doses of PP-001 when administered
as a single intravitreal injection from 0,3 *g, 0,6 *g and 1,2 *g with the
option of an addition cohort with a dose of 2,1 *g PP-001.
Study design
This prospective, multi-centre, open-label, non-randomized, consecutive study
will be conducted in accordance with the European Union (EU) Clinical Trial
Directive 2001/20/EC and 2005/28/EC, The Medicines for Human Use (Clinical
Trials) Regulations 2004 and current amendments, the Declaration of Helsinki
(revised version of Edinburgh, Scotland 2000), Good Manufacturing Practice
(GMP), Good Clinical Practice (GCP) and the current national regulations and
guidelines, approved by both the local ethics committee and regulatory
authority.
Eighteen patients at the age of 18 and older will be enrolled and receive a
single intravitreal injection of PP-001. Patients must have chronic, posterior
uveitis, intermediate uveitis or panuveitis requiring treatment and have been
receiving an adequate therapy of e.g. systemic corticosteroid treatment or
immunosuppressive therapy (e.g. azathioprine, methotrexate, cyclosporine,
mycophenolate, tacrolimus) or any combination thereof. Any systemic therapy at
study start should be continued throughout the study. Patients must have
best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity
of 10 letters or better (approximately 1/35 or 0.032) but equal or less than 70
letters (approximately 20/40 or 0.5) in the study eye.
Patients must give written consent for the study before any study assessments
are performed. Screening assessments will be performed up to 14 days before
dosing. Baseline assessments will be performed no more than 7 days before
injection. In case screening visit and baseline visit are on the same day (-7
up to dosing), examinations scheduled for both visits need only to be performed
once and may be used for both study visits. The study will involve seven study
visits (Screening, Baseline, the day of injection (Day 0) and Days 2, 7, 14,
and 28) and telephone calls on Day 1 and Day 40.
Patients will be divided into three cohorts of four patients and will receive
the following treatments administered as a single intravitreal injection:
* Cohort 1 will receive 0.3 µg of PP-001
* Cohort 2 will receive 0.6 µg of PP-001
* Cohort 3 will receive 1.2 µg of PP-001
The patients within a cohort will be dosed consecutively with a minimum time
interval of 7 days between the dosing of the previous patient and the dosing of
the next patient. The results from each dosing day will be reviewed before
progressing towards the subsequent dosing day. The next cohort will only
receive PP-001 after the previous cohort has completed all study sessions up to
Day 28 and no safety issues have been identified after reviewed by the Safety
data management board (SDMB).
After 12 patients have been treated in the three cohorts and after all patients
have finished the last follow up an interim analysis by the SDMB will be
conducted to identify potential safety issues and to determine the highest
tolerable dose. If no safety issue can be identified, then a fourth, higher
dose will be given to a cohort of four patients (Cohort 4). The dose for a
potential Cohort 4 will be 2.1 µg of PP-001.
If safety issues are identified in any of Cohorts 2, 3 or 4, two additional
patients will receive the next lower dose.
Safety will be assessed by monitoring vital signs and recording of AEs (see
Section 7). Safety procedures will be performed by the Investigator or suitably
qualified individuals designated by the Investigator.
Pharmacokinetic sampling will take place at Screening, 4 h ± 1 h after
injection and on Day 2.
Efficacy will be evaluated by ophthalmic examination.
Intervention
Patients will receive a single intraocular dose of PP-001.
The study treatment procedure must be performed only by the qualified
Investigator in an operating room, surgical suite, or in an office setting
using sterile technique. The study medication kit should be readily available
during the procedure. The final diluted PP-001 solution will be injected at the
required dose at a volume of 100 µL. For safety reasons, an emergency pars
plana vitrectomy aiming at removal of injected drug will be available in case
of a severe adverse event including, but limited to, acute loss of visual
acuity or acute inflammatory or toxic response to injection. It is therefore
mandatory for patients to remain in the hospital for at least 4 hours after the
injection procedure.
Study burden and risks
At this stage of development, toxicity of PP-001 in human eyes cannot be ruled
out but the risk is considered low based on the safety factor calculated using
preclinical data. Considering the expected low systemic exposure of PP-001,
potential systemic side effects known from other DHODH inhibitors are not
expected. In order to minimize this risk, the first patient will receive the
lowest dose, which is approximately 90 times less than the established safe
concentration in preclinical studies. The next patient will only receive an
injection after a safety gap of 7 days and review of all data by the SDMB. The
next highest dose will only be administered after the safety of the lower dose
has been established.
The procedure of an injection into an inflamed eye has been established in
other approved types of uveitis treatment such as Ozurdex and Retisert, in
Phase III studies with sirolimus and the off-label use of intraocular
triamcinolone. These studies have not shown any significant risks associated
with eye injections. Concerns have been raised over the application of small
crystals into the eye because of the potential to induce an autoinflammatory
reaction. The type and structure of the preparation used in this study should
reduce this risk.
Study PP-001-1001 will provide valuable data on the safety, tolerance and
pharmacokinetic profile of PP-001 after single dosing in patients with severe
uveitis, which will help to define the dose for future studies.
In conclusion, based on the currently available safety data, PP-001 has an
acceptable benefit/risk profile in patients at doses in the estimated
therapeutic range of 0.3*1.2 (2.1) µg/eye, and at the same time might reduce
some of the inflammatory indices in patients with severe uveitis who have no
treatment alternative.
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Age
Inclusion criteria
1. Male or female patients at the age of 18 years and older who have diagnosis
of chronic posterior uveitis, intermediate uveitis or panuveitis.
2. Good general state of health (mentally and physically). Laboratory
parameters and vital signs of patients must be within the normal ranges.
3. A signed and dated written informed consent form.
4. A signed and dated written data protection consent form.
5. Female patients of childbearing potential must perform a negative urine
pregnancy test prior to the injection on the day of the injection visit (Day 0).
6. Male and female patients must ensure that one highly effective method
combined with an acceptable method of contraception is used for the entire
duration of the study, from first dose up to the study follow-up visit, and
refrain from becoming pregnant or fathering a child in the 3 months following
the last study drug administration. Male patient must agree with their female
partners prior to screening to use the above specified methods of contraception
while receiving protocol-specified medication, and for 3 months after stopping
the medication
7. Have diagnosis of chronic posterior uveitis, intermediate uveitis or
panuveitis (as defined by the Standardization of Uveitis Nomenclature Working
Group [Jabs et al., 2005]) in at least one eye. For patients with panuveitis,
the anterior component of inflammation must be less than the posterior
component. The investigator to his best knowledge must rule out any suspected
masquerade syndrome or infection prior to study entry.
8. Have chronic, posterior uveitis, intermediate uveitis or panuveitis
requiring treatment.
9. Have media clarity, pupillary dilation and patient cooperation sufficient
for adequate visualization of the optic nerve in the study eye.
10. Have been receiving an adequate therapy of e.g. systemic corticosteroid
treatment or immunosuppressive therapy (e.g. azathioprine, methotrexate,
cyclosporine, mycophenolate, tacrolimus) or any combination thereof. Any
systemic therapy at study start should be continued throughout the study.
11. Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual
acuity of 10 letters or better (approximately 1/35 or 0.032) but equal or less
than 70 letters (approximately 20/40 or 0.5) in the study eye
12. Best-corrected ETDRS visual acuity of 34 letters or better in the fellow
eye (approximately 20/200 or 0.1)
Exclusion criteria
1. Patients in whom media opacities (cornea, anterior or posterior synechia,
cataract, vitreous haze and others) of either eye preclude investigation and
documentation of the posterior pole and intravenous fluorescein angiography, or
optical coherence tomography evaluation in the study eye.
2. Patients receiving any local biologicals.
3. Treatment with cyclophosphamide or chlorambucil.
4. Intravitreal injections (including but not limited to anti-vascular
endothelial growth factors) 60 days prior to the baseline.
5. Posterior subtenon's injection or orbital floor injection of steroids 90
days prior to Baseline.
6. Any implantable corticosteroid-eluting device (Ozurdex, Iluvien, Retisert,
triamcinolone intravitreal implant, fluocinolone intravitreal implant) in the
study eye, with the following exceptions:
* If the device had been removed more than 90 days prior to Day 0 of this
study, the eye will be eligible for PP-001-1001.
* If Ozurdex had been implanted 6 months before Day 0 of this study, the eye
will be eligible for PP-001-1001.
* If Iluvien or Retisert had been implanted 3 years before Day 0 of this study,
the eye will be eligible for PP-001-1001.
7. Intraocular surgery within 90 days prior to Day 0 in the study eye.
8. Capsulotomy within 30 days prior to Day 0 in the study eye.
9. History of vitreoretinal surgery or scleral buckling within 90 days prior to
Day 0 in the study eye.
10. Any ocular surgery (including cataract extraction or capsulotomy) of the
study eye anticipated within the first 60 days following Day 0.
11. Intraocular pressure (IOP) *25 mmHg in the study eye (glaucoma patients
maintained on no more than one topical medication with IOP <25 mmHg are allowed
to participate).
12. Ocular hypotonia (IOP less than 6 mmHg).
13. Pupillary dilation inadequate for quality fundus photography in the study
eye.
14. Aphakia or anterior chamber lens in the study eye.
15. Visible scleral thinning, scleral ectasia or keratoconus in the study eye.
16. Presence of any ocular malignancy.
17. Ocular or periocular infection in either eye or the use of systemic
antibiotics.
18. Participation in other investigational drug or device clinical trials
within 90 days prior to Day 0, or planning to participate in other
investigational drug or device clinical trials within 180 days following Day 0.
This includes both ocular and non-ocular clinical trials.
19. Female patients who are pregnant, nursing, or planning a pregnancy, or who
are of childbearing potential and not willing to use reliable means of
contraception.
20. Use of any anticoagulant or thrombocyte aggregation inhibiting agent
(marcumar, warfarin, heparin, enoxaparin, apixaban, rivaroxaban,
pentosanpolysulfate, dabigatran) less than 7 days prior to injection visit (Day
0).
21. Known allergy or hypersensitivity to the study medication, any component of
the delivery vehicle, any corticosteroids or any diagnostic agents used during
the study (e.g., fluorescein, dilation drops, antibiotic drops, povidone).
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 | EUCTR2016-000412-15-NL |
| CCMO | NL62850.078.17 |