The objective of this trial is to evaluate the safety and efficacy of the combination of Fovista® intravitreous administration with Avastin® compared to Avastin® monotherapy.
ID
Source
Brief title
Condition
- Vision disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the mean change in visual acuity (ETDRS
letters) from baseline at the Month 18 visit.
Secondary outcome
Efficacy Endpoints:
* The proportion of subjects in each treatment group gaining 20 or more ETDRS
letters from baseline at the Month 18 visit.
* The proportion of subjects in each treatment group gaining 25 or more ETDRS
letters from baseline at the Month 18 visit.
* The proportion of subjects in each treatment group losing 5 or more ETDRS
letters from baseline at the Month 18 visit.
* The mean change in visual acuity (ETDRS letters) from baseline at the Month 5
and Month 11 visit.
Safety Endpoints
* Adverse events (AEs) and serious adverse events (SAEs)
* Vital signs (pulse, systolic and diastolic blood pressure)
* Ophthalmic variables (IOP, ophthalmic examination, fluorescein angiograms and
OCT)
* ECG (12-lead)
* Laboratory variables (blood: hematology, renal function, hepatic function,
and electrolytes; urinalysis)
Background summary
Age-related macular degeneration is a disease characterized by progressive
degenerative abnormalities in the macula of the eye, a small area in the
central portion of the retina. It is characteristically a disease of
individuals >50 years of age and is the leading cause of visual loss in
developed countries.
Neovascular proliferation is the key step in wet AMD development. These
abnormal vessels consist of endothelial cells, pericytes, and inflammatory
cells. Two factors that play important roles in proliferation and maintenance
of abnormal blood vessels are VEGF and Platelet Derived Growth Factor (PDGF).
VEGF is an endothelial cell survival factor and a key mediator in the process
of neovascularization. It is also one of the most potent inducer of vascular
permeability in biologic systems.
PDGF is a growth factor responsible for pericyte survival, maturation and
regulation.
The neovascularization process is complex and anti-VEGF resistance may result
from multiple mechanisms including endothelial cell protection by pericytes.
Simultaneous and selective inhibition of both VEGF and PDGF has the potential
to have significantly more impact on abnormal vessels than inhibition of the
VEGF alone [9].
Pharmacology studies indicate that Fovista® binds to PDGF-B with high
specificity and affinity and inhibits the functions of PDGF-B both in vitro and
in vivo. In a highly powered, randomized controlled Phase 2 trial combining
Fovista® with an anti-VEGF agent in the treatment of neovascular AMD,
combination therapy proved superior in terms of mean visual gain when compared
to eyes that were treated with anti-VEGF monotherapy
Study objective
The objective of this trial is to evaluate the safety and efficacy of the
combination of Fovista® intravitreous administration with Avastin® compared to
Avastin® monotherapy.
Study design
Subjects will be treated with study treatment, i.e., active Fovista® or sham
(an empty syringe without a needle) in combination with Avastin®, every month
for the first 6 doses and bimonthly thereafter.
Depending on how the patient reacts to the treatments, additional treatments
may be given. (see schedule of assessments in chapter 3 of the protocol)
The study is 18 months in duration (17 months treatment, 1 month follow-up)
preceeded by a screening period of 14 days to see if the patient is eligible.
Intervention
Subjects will be randomized in a 1:1 ratio to the following dose groups:
* Fovista® 1.5 mg/eye + Avastin® 1.25 mg/eye
* Fovista® sham + Avastin® 1.25 mg/eye
Study burden and risks
The study drug and procedures in this study have risks, discomforts, and side
effects associated with them. Side effects are any undesirable actions or
effects of a drug.
Effects from the Intravitreous Injection
Participants receiving an injection of Fovista®or Avastin® may experience some
side effects that may be related to the pre-injection preparation procedure
(eyelid speculum, anesthetic drops or injection, dilating drops, antibiotic
drops, and povidone-iodine drops) or the injection itself. These side effects
may include eye pain, bloodshot eye (subconjunctival hemorrhage), vitreous
floaters (small dark shapes that float through your field of vision),
irregularity or swelling of the cornea, inflammation of the eye, cataract
(clouding of the lens of the eye), increased pressure within the eye, and
visual disturbances. If you have a history of glaucoma, you may be at more
risk for experiencing increased pressure within your eye after an injection of
any substance. Although not common, injections into the eye can cause side
effects such as infections, retinal detachment (retina separates from the back
of the eye), or bleeding.
General Effects of Avastin®
The following side effects have been observed in treatment with Avastin®:
Eye-related events
Avastin® has been studied in humans in previously completed research studies.
Temporary redness of the injected eye, minor bleeding at the injection site
that resolves on its own (doesn*t require treatment), dull pain in the injected
eye, sensitivity to light, mild and temporary burning and stinging, vision
disturbances including decrease in vision, bleeding inside the injected eye
that resolves on its own, infection outside the treated eye, and mild and
self-resolving inflammation on the inside of the eye.
Less frequent side effects include infection inside the eye (endophthalmitis),
severe inflammation in the inside of the eye (uveitis), blockage of the blood
flow in the main vein inside the eye (central retinal vein occlusion),
temporary increase in the pressure inside the eye (intraocular pressure),
damage to the lens inside the eye (cataract formation), a tear through the
retinal tissue in the eye (retinal tear/detachment), a rip in the pigment cell
layer that lies beneath and nourishes the retina (retinal pigment epithelial
[RPE] tear), and inadequate response of the pupil to light entering the eye.
Some of the complications listed above may result in permanent loss of vision
or loss of the eye.
Non-eye related events
Tests have shown that low levels of Avastin® can reach your blood stream after
injection into the eye. The significance of this is not well understood. The
risk of having another side effect involving a body system other than the eye
is unknown but is believed to be very small. Additional serious side effects
have been associated with Avastin® when it is given at high levels (more than
300 times the amount injected into the eye) directly into the blood stream for
cancer patients. Strokes, transient ischemic attacks (TIAs), heart attacks, and
angina (heart-related chest pain) were 2 to 3 times more common in cancer
patients receiving Avastin® than in cancer patients not receiving Avastin®. In
addition, intestinal perforations, wound healing complications, bleeding, high
blood pressure, protein in the urine, infections, and congestive heart failure
have been more common in cancer patients receiving Avastin®. Avastin® may have
side effects that are unknown.
General Effects of Fovista®
Fovista® has been tested in combination with Lucentis® (ranibizumab) in 22
research participants in a Phase 1 study. These participants received up to
three monthly intravitreal injections of Fovista® at one of four doses (0.03,
0.3, 1.5 or 3 mg/eye) in combination with Lucentis® 0.5 mg/eye. In this Phase
1 study, Fovista® combined with Lucentis® was well tolerated. No dose-limiting
toxicity or drug-related side effects were reported at any of the dose levels
investigated. Almost all participants with side effects experienced these
effects in the study eye, which are expected and which were related to the
injection procedure and not to Fovista®. No side effects in the eye or the
rest of the body were related to Fovista®. The most frequently occurring side
effects, regardless of cause, were events that occurred in the study eye,
including foreign body sensation in the eye, conjunctival hemorrhage (bleeding
in the clear tissue that surrounds the white of the eye), eye irritation, and
punctate keratitis (irritation of the cornea). Almost all side effects were
attributed to the intravitreal injection procedure, and none were attributed to
Fovista®. The majority of side effects were mild in severity.
A Phase 2 study has recently been completed of Fovista® given in combination
with Lucentis® (ranibizumab) in a total of 449 research participants.
Participants received six monthly intravitreous injections of Fovista® given in
combination with Lucentis®. They were randomized in a 1:1:1 (equal) ratio to
the following dose groups: Fovista® 0.3 mg/eye + Lucentis® 0.5 mg/eye, Fovista®
1.5 mg/eye + Lucentis® 0.5 mg/eye, or Fovista® sham + Lucentis® 0.5 mg/eye.
Combination therapy in this Phase 2 study was well tolerated. The most common
ocular side effects were, as expected in intravitreal studies, related to the
intravitreal preparation and injection procedure and were not drug-related, for
example, conjunctival hemorrhage (bleeding in the clear tissue that surrounds
the white of the eye), punctate keratitis (irritation of the cornea), and eye
pain. There were no events of endophthalmitis (infection inside the eye),
retinal detachment (retina separates from the back of the eye), retinal tear (a
tear in the retina), or traumatic cataract (clouding of the lens of the eye
directly due to the injection procedure). As expected, the mean intraocular
pressure (IOP) increased after each intravitreal injection consistent with the
increase in volume after the injection. However, the mean IOP returned to
pre-injection level at the next visit, including at the end of the study. Some
of these side effects may cause decreased vision.
Non-eye related events
The safety profile of the combination of Fovista®/Lucentis® was similar to that
of Lucentis® given alone. Fovista® may have side effects that are unknown.
Fovista® has also been tested in animals, and there were no significant ocular
or systemic (general body) safety issues noted. Full testing in animals to see
if Fovista® causes cancer in animals has not been done. The risk of cancer to
humans is not known.
Risk of Allergic Reaction
There is a chance of allergic reaction when taking any medication (dilation
drops, antibiotic drops, betadine, fluorescein dye, Fovista®, Avastin®, etc.).
Symptoms of any allergic reaction can include a rash, hives, itching, and/or
difficulty breathing, closing of the throat, swelling of the lips, tongue or
face, and rarely death. If you experience any difficulty breathing, closing of
the throat, swelling of the lips, tongue or face, or hives, you should
immediately seek emergency medical attention. You should tell your study
doctor if you are allergic to tropicamide (such as Mydriacyl®), phenylephrine
(such as Neo-Synephrine®), fluoroquinolone antibiotics (such as Cipro®),
tetracaine, lidocaine, or povidone-iodine (such as Betadine®). These
medications may be used during this study. There are trained medical personnel
and emergency equipment and medicines available at the study center to treat
you in the event of a severe allergic reaction.
In general, allergic reactions to medicines are more likely to occur in people
who have allergies to other drugs, foods, or things in the environment, such as
dust or grass. If you have allergies to other medicines, foods, or other
things in the environment, or if you have asthma, you should let your study
doctor know.
One Penn Plaza 19th Floor
New York NY 10119
US
One Penn Plaza 19th Floor
New York NY 10119
US
Listed location countries
Age
Inclusion criteria
General Inclusion Criteria
1. Subjects of either gender aged * 50 years.
2. Performance Status 2 according to Eastern Cooperative Oncology Group (ECOG) / World Health Organization (WHO) scale .
3. Women must agree to be using two forms of effective contraception, be post-menopausal for at least 12 months prior to trial entry, or surgically sterile; if of child-bearing potential, a serum pregnancy test must be performed within 14 days prior to the first injection with a negative result. The two forms of effective contraception must be implemented during the trial and for at least 60 days following the last dose of test medication.
4. Provide written informed consent.
5. Ability to comply with study and follow-up procedures and return for all trial visits.;Ophtalmic Inclusion Criteria ;1. Presence of subfoveal "active CNV". "Active CNV* is defined as the presence of fluorescein leakage consistent with choroidal neovascularization.
2. Presence of subretinal or intraretinal fluid in the anatomic fovea by OCT.
3. Best corrected visual acuity in the study eye between 20/63 and 20/200, inclusive.
4. Total area of the lesion (including blood, neovascularization, and scar/atrophy) must be * 9 disc areas (DA), of which at least 50% must be active CNV.
5. Clear ocular media and adequate pupillary dilatation to allow collection of fundus photographs and fluorescein angiograms of a sufficient quality to be analyzed.
6. Intraocular pressure (IOP) of 21 mmHg or less.
Exclusion criteria
General Exclusion Criteria
1. Any of the following underlying conditions or diseases including:
* A definitive diagnosis of diabetes mellitus or diabetic retinopathy (regardless of HbA1c level)
* HbA1c value of *6.5%* (*If the HbA1c value is * 6.5% and * 6.9%, and the patient has no signs or symptoms of diabetes mellitus, has a normal creatinine, has no diabetic retinopathy and no glycosuria, then the patient may have an oral glucose tolerance test (OGTT) at the discretion of the investigator. If the 2-hour glucose value on OGTT is <200 mg/dL (<11.1mmol/L), then the patient may be enrolled)
* History of other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk for treatment complications.
* History or evidence of severe cardiac disease (e.g., NYHA Functional Class III or IV - see Appendix 17.6), history or clinical evidence of unstable angina, acute coronary syndrome, myocardial infarction or coronary artery revascularization within 6 months, or ventricular tachyarrythmias requiring ongoing treatment.
* Stroke (within 12 months of trial entry).
* Any major surgical procedure within one month of trial entry.
2. Any treatment with an investigational agent in the 60 days prior to randomization for any condition.
3. Known serious allergies to the fluorescein dye used in angiography (mild allergy amenable to treatment is allowable), or to the components or formulation of either Fovista® or Avastin®.;Opthalmic Exclusion Criteria
1. Any prior treatment for AMD in the study eye prior to the Day 1 visit, except oral supplements of vitamins and minerals.
2. Any prior intravitreal treatment in the study eye prior to the Day 1 visit, regardless of indication (including intravitreal corticosteroids).
3. Subjects with subfoveal scar or subfoveal atrophy (by OCT and/or by Fundus Photography)
4. More than 50% of the total lesion size consisting of subretinal hemorrhage.
5. Presence of retinal angiomatous proliferation (RAP).
6. Presence of significant serous pigment epithelial detachments (PEDs), such as large PEDs that constitute greater than 50% of the total lesion or have a vertical height of * 500 *m.
7. Presence of pure PED.
8. Presence of pigment epithelial tears or rips.
9. Presence of intraocular inflammation (* trace cell or flare), significant epiretinal membrane (causing distortion of macular anatomy and/or opacification), significant vitreomacular traction (causing distortion of macular anatomy), macular hole (full or partial thickness) or vitreous hemorrhage.
10. Aphakia or absence of the posterior capsule. Absence of an intact posterior capsule is allowed if it occurred as a result of YAG laser posterior capsulotomy in association with prior posterior chamber IOL implantation.
11. History of idiopathic or autoimmune-associated uveitis in either eye.
12. Significant media opacities, including cataract, which might interfere with visual acuity, assessment of toxicity, or fundus photography in the study eye. Subjects should not be entered if there is likelihood that they will require cataract surgery in the study eye in the next 12 months.
13. Presence of other causes of choroidal neovascularization, including pathologic myopia (spherical equivalent of -8 diopters or more, or axial length of 25mm or more), the ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, and multifocal choroiditis.
14. Any intraocular surgery or thermal laser within three (3) months of trial entry. Any prior thermal laser in the macular region, regardless of indication.
15. Any photodynamic therapy within three (3) months of trial entry.
16. Any ocular or periocular infection in the past twelve (12) weeks.
17. History of any of the following conditions or procedures in the study eye: Rhegmatogenous retinal detachment, pars plana vitrectomy, filtering surgery (e.g. trabeculectomy), glaucoma drainage device, corneal transplant.
18. Previous therapeutic radiation in the region of the study eye.
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 | EUCTR2015-000518-23-NL |
| CCMO | NL53527.018.15 |