To assess the safety, tolerability and the effects of treatment on ocular outcomes following a single intravitreal administration of ESBA1008 compared to Lucentis in patients with exudative AMD
ID
Source
Brief title
Condition
- Retina, choroid and vitreous haemorrhages and vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety endpoints, such as AEs, changes in vital signs, laboratory
abnormalities, anti-drug antibodies, changes in the eye conditions. This will
be examined at all 13 visits throughout the study for 6 months.
Secondary outcome
Retina thickness measured by spectral domain optical coherence tomography
(SD-OCT); retinal thickness is a known sign of AMD. Decrease of the thickness
indicates improvement of AMD.
Best corrected visual acuity (BCVA) by reading the ETDRS chart. visual acuity
is the accepted clinical endpoint for AMD. Improvement of vision
indicates improvement of AMD.
This will be examined at all 13 visits throughout the study for 6 months.
Background summary
Age-related macular degeneration (AMD) is a disease associated with aging that
gradually destroys sharp, central vision. Central vision is needed for seeing
objects clearly and for common daily tasks such as reading and driving. The
form of advanced AMD investigated in this clinical study is commonly referred
to as wet AMD.
Exudative (wet) AMD is characterized by the growth of choroidal vessels through
Bruch's membrane and into the neural retina; the newly formed vessels have a
tendency to leak blood and fluid, causing retinal edema that disrupts the
neural retina leading to a loss of visual function. The growth of these new
vessels is accompanied by proliferation of fibrous tissue; extension of the
fibrotic lesions into the macula results in progressive, severe and
irreversible vision loss. Without treatmen, most affected eyes will have poor
central vision within 12 months.
Vascular endothelial growth factor (VEGF) is a well-validated clinical target
for treatment of exudative AMD. Anti-VEGF treatments, such as Lucentis
(comparator) halt the growth of the neovascular lesion and resolve retinal
edema. The study product, ESBA1008, is an inhibitor of VEGF that is being
developed for the treatment of choroidal neovascularization associated with
exudative (wet) AMD. It binds to the receptor binding site of VEGF thereby
preventing the interaction of VEGF with its receptors VEGFR1 and VEGFR2 on the
surface of endothelial cells.
Nonclinical studies have demonstrated that ESBA1008 is at least as potent as
Lucentis with a similar vitreal half-life as Lucentis and a significantly lower
systemic exposure compared to Lucentis. The low systemic exposure is suggestive
of a good safety profile even at a high dose. The higher dose, similar
half-life and at least equal potency of ESB1008 suggest a longer effect
duration compared to Lucentis.
The objective of this study is to evaluate the safety, tolerability and the
effects of the investigational product ESBA1008 for the treatment of exudative
AMD.
Study objective
To assess the safety, tolerability and the effects of treatment on ocular
outcomes following a single intravitreal administration of ESBA1008 compared to
Lucentis in patients with exudative AMD
Study design
This is a prospective, active-controlled, double-masked, single-dose ascending,
multi-center, randomized study. Patients with exudative AMD will receive a
single intravitreal dose of ESBA1008 or Lucentis. The patient will normally be
in the study for approximately 6 months.
There will be 3 (0,5mg, 3mg and 4,5mg ESBA1008) sequentially enrolled cohorts
where patients will be randomized to either ESBA1008 or Lucentis in a 5:2
ratio. Patients in the first dose cohort will be randomized to receive either
the lowest dose of ESBA1008 (0,5 mg) or Lucentis. Enrollment of the first 4
patients of the cohort will be sequential. After the first patient has received
the intravitreal injection, patients 2 to 4 will receive their intravitreal
injection after at least a 24-hour interval has passed between each patient.
Once the first 4 patients of the cohort hace received the intravitreal
injection, the remaining patients may be treated in parallel. After the last
patient of this cohort has been followed for 7(+1) days, a comprehensive review
of ocular and systemic parameters will be conducted by Medical Safety and the
Medical Monitor. Initiation of the next higher dose cohort will be based on
Medical Safety and the Medical Monitor's assessment thatthe treatment has an
acceptable safety profile in all patients in the current cohort. If the
treatment has an acceptable safety profile, enrollment of the next cohort will
begin and patients will be randomized to the next dose of ESBA1008 in the same
manner as the previous cohort.
The maximum tolerated dose (MTD) of ESBA1008 will be established based on
safety evaluation. Once MTD is established, the MTD cohort will be expanded to
further assess the safety and tolerability of ESBA1008 at MTD and to estimate
the efficacy for a future confirmatory study.
Intervention
Intravitreal injection
Study burden and risks
In a period of 6 months, patients need to come to the hospital 13 times for an
opthalmic examination. Each visit will take between 1 and 2 hours,
exceptionally it will take 3 hours. None of the tests are experimental.
The patients will receive a single intravitreal dose of ESBA1008 or Lucentis.
Like with all medicines, these medications can cause side effects, although not
everyone gets them.
Since ESBA1008 is given to man for the first time, we do not know, which side
effects we may expect.
Side effects seen with any injection given into the eye:
* eye redness
* eye pain
* sensitivity to light
* change in vision
* serious eye infection (endophthalmitis)
* detached retina
* Increased pressure in the eye
Information about possible side effects was obtained from knowledge of side
effects of Lucentis and from studies in animals.
ESBA1008 was tested in dosages up to 6 mg given three times over a period of
three weeks and observed for 4 weeks in little cynomolgus monkeys. This highest
dose corresponds to a 3.6 times higher dose than the highest planned clinical
dose (4.5 mg) in this study. At these high dosages, the monkeys tolerated the
drug well and it was safe. This animal study showed comparable levels and
duration of minimal inflammation for all doses given including the placebo that
consisted of the same ingredients except the active substance. Hence, the
effect is more due to the injection procedure rather than caused by ESBA1008.
The minimal inflammation is associated with some itching of the eye, and your
doctor will see some small particles (cells) in the anterior chamber of your
eye. These particles will reside for about 48 hours in your eye and should
completely disappear after 7 days following the injection. The eyes of the
monkeys were normal at the end of the study. There were no adverse effects on
retinal function or pathology at any dose. Only a very small amount of ESBA1008
was going into the interior of the body. The concentration of ESBA1008 in blood
is 7000 times lower than the concentration in the eye. There were no signs of
toxicity of the body or any pathological abnormalities. Hence, ESBA1008
injected into the eye even at a maximum dose of 6 mg in eyes of patients,
although not planned in this study, is considered to be safe.
When the patient is assigned to receive Lucentis®, the risks will be the same
as when he/she received this therapy outside of the study. Although uncommon,
conditions associated with eye- (e.g. blood clots arterial thromboembolic
events) and non-eye-related may occur.
Serious side effects were uncommon and included inflammation inside the eye and
increased eye pressure.
The most common eye-related side effects were red eye, eye pain, small specks
in vision, the feeling that something is in your eye, and increased tears. The
most common non-eye-related side effects were nose and throat infection,
headache, and respiratory and urinary tract infections.
Rijksweg 14
B-2870 Puurs
BE
Rijksweg 14
B-2870 Puurs
BE
Listed location countries
Age
Inclusion criteria
1. Patient must give written informed consent, be able to make the required study visits and follow instructions
2. Patient must be 50 years of age or older
3. Patient*s study eye must have:
* primary subfoveal choroidal neovascularization (CNV) secondary to AMD, including predominantly classic, minimally classic or occult lesions
* a lesion area < 30 mm2 (12 disc areas) of any lesion type (predominantly classic, minimally classic or occult)
* total area of CNV (including both classic and occult components) must comprise > 50% of the total lesion area. Total lesion area is defined as the area with angiographic evidence of neovascularization, associated contiguous areas of serous elevation of the RPE, elevated blocked fluorescence, and/or late staining
* a new diagnosis of exudative AMD or evidence of recent disease progression within the last 3 months; if the CNV in the study eye is minimally classic or occult; evidence of recent disease progression is defined as having experienced a loss of at least 1 line of vision (5 ETDRS letters or 1 Snellen line), a change in lesion size of more than 2.54 mm2 (1 disc area) or the appearance of new blood in the lesion
* retinal edema as measured by a central subfield thickness (CSF) of > 340 µm using a Spectralis SD-OCT (Heidelberg Engineering) imaging system
* a best-corrected visual acuity (BCVA) ranging between 73 letters (20/40 Snellen equivalent) and 34 letters (20/200 Snellen equivalent), inclusive
* clear ocular media and adequate pupil dilation to permit good quality photographic imaging
4. Patient*s fellow eye BCVA must be 34 letters (Snellen equivalent 20/200) or better
Exclusion criteria
1. Patient has received any previously administered therapy, approved or investigational, for exudative AMD in the study eye
2. Any current or history of ocular disease in the study eye that, in the opinion of the Investigator, may confound assessment of the macula or affect central vision, other than exudative AMD (for example: vein occlusion, diabetic retinopathy, uveitis, angioid streaks, ocular histoplasmosis, pathological myopia, retinal detachment, epiretinal membrane, macular hole)
3. Any evidence in the study eye of fibrosis or scarring within the lesion
4. Any vitreous hemorrhage or a history of rhegmatogenous retinal detachment in the study eye
5. History or evidence of the following surgery in the study eye:
* penetrating keratoplasty or vitrectomy
* cataract surgery or Lasik within the last 3 months
* OR expected to have cataract removal surgery during the study
6. Any active ocular infection or inflammation in either eye (such as: blepharitis, infectious conjunctivitis, keratitis, scleritis, endophthalmitis)
7. A history or medical diagnosis of uncontrolled glaucoma (defined as intraocular pressure > 25 mmHg despite treatment with anti-glaucoma medication), advanced glaucoma resulting in a cup/disc ratio > 0.8 in the study eye or glaucoma filtration surgery in the study eye
8. Aphakia in the study eye or violation of the posterior capsule in the study eye unless it occurred as a result of a YAG laser posterior capsulotomy in association with prior, posterior intraocular lens implantation
9. Current use or history of chronic therapy with systemic or topical ocular corticosteroids (defined as multiple doses taken daily for 3 or more consecutive days at any time within 6 months prior to enrollment)
10. History of a medical condition (disease, metabolic dysfunction, physical examination finding or clinical laboratory finding) that, in the opinion of the Investigator, would preclude scheduled study visits, completion of the study or a safe administration of study medication (eg, unstable or progressive cardiovascular, pulmonary, Parkinson's disease, liver or renal disease, cancer or dementia)
11. Any screening laboratory result (hematology, serum chemistry or urinalysis) that, in the opinion of the Investigator, would make the patient unsuitable for study participation; any screening liver function test value [AST (SGOT), ALT (SPGT), alkaline phosphatase, GGT, total bilirubin, direct bilirubin, indirect bilirubin, and LDH] that is more than twice the upper limit of normal
12. History of severe or serious hypersensitivity to any component of the test article, control article or clinically relevant sensitivity to fluorescein dye, as assessed by the Investigator
13. Women of childbearing potential, ie, premenopausal or less than 2 years postmenopausal, who are lactating, or who are pregnant as determined by serum pregnancy test at Visit 1.
Women should plan not to become pregnant during the course of the study.
Women of childbearing potential must agree to use adequate birth control methods for the duration of the study defined as:
* Hormonal: oral, implantable, topical, or injectable contraceptives
* Mechanical: IUD, spermicide in conjunction with a barrier such as condom or diaphragm
* Surgical: sterilization of self or partner
* Abstinence: If subjects intend to become sexually active, they must agree to use one of the birth control methods listed above.
14. Participation in an investigational drug or device study within the 30 days prior to screening
15. CNV associated with other ocular conditions such as pathological myopia, ocular histoplasmosis, posterior uveitis or trauma
16. Medical Monitor opinion that a subject is ineligible to participate in the study for a sound medical reason prior to enrollment into the study
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 | EUCTR2011-000536-28-NL |
| ClinicalTrials.gov | NCT01304693 |
| CCMO | NL36414.018.11 |