Primary:• To demonstrate that RTH258 6 mg is not inferior to aflibercept 2 mg with respect to the change in best-corrected visual acuity (BCVA) from Baseline to Week 48Secondary:• To demonstrate that RTH258 6 mg is not inferior to aflibercept 2 mg…
ID
Source
Brief title
Condition
- Ocular structural change, deposit and degeneration NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint:
• Change in BCVA from Baseline to Week 48
Secondary outcome
Key Secondary Efficacy Endpoints:
• Average change in BCVA from Baseline over the period Week 36 through Week 48.
For each subject, this endpoint is defined as the average of the changes from
Baseline to Weeks 36, 40, 44 and 48.
• q12 treatment status at Week 48 (for subjects randomized to RTH258 6 mg only)
• q12 treatment status at Week 48 with no q8 need during the 1st q12 cycle (at
Week 16, Week 20) (for subjects randomized to RTH258 6 mg only)
Secondary Efficacy Endpoints:
• Change in BCVA from Baseline to each postbaseline visit
• Average change in BCVA from Baseline over the period Week 84 through Week 96
• Average change in BCVA from Baseline over the period Week 4 to Week 48/96
• Average change in BCVA from Baseline over the period Week 12 to Week 48/96
• Gain in BCVA of 15/10/5 letters or more from Baseline to each postbaseline
visit
• Loss in BCVA of 15/10/5 letters or more from baseline to each postbaseline
visit
• q12 treatment status at Week 96 (for subjects randomized to RTH258 6 mg only)
• q12 treatment status at Week 96 within the subjects with no q8 need during
the 1st q12 cycle (Week 16, Week 20) (for subjects randomized to RTH258 6 mg
only)
• Change in CSFT from Baseline to each postbaseline visit
• Change in neurosensory retinal thickness from Baseline to each postbaseline
visit
• Change in CNV lesion size from Baseline to Weeks 12, 48 and 96
• Absence of subretinal fluid at each postbaseline visit
• Absence of intraretinal fluid at each postbaseline visit
• q8 treatment need at Weeks 16, 20, 28, 32, 40, 44, 52, 56, 64, 68, 76, 80, 88
and 92
• Change in patient reported outcomes (VFQ-25) total and subscale scores from
Baseline to Weeks 24, 48, 72 and 96
Safety Endpoints
• Incidence and characteristics of treatment emergent adverse events
• Treatment emergent changes in ocular and systemic parameters
• Change in ADAs from Baseline to Weeks 12, 24, 36, 48, 68 and 88
• Extent of systemic RTH258 at Weeks 12, 24, 36, 48, 68 and 88
Background summary
Age-related macular degeneration (AMD) is the leading cause of severe vision
loss in people affecting 10%-13% of individuals over the age of 65 in North
America, Europe, and Australia (Kawasaki 2010, Rein 2009, Smith 2001). Genetic,
environmental and health factors play an important role in the pathogenesis of
the disease.
AMD is classified into 2 clinical subtypes: the non-neovascular (atrophic) or
dry form and the neovascular (exudative) or wet form (Ferris 1984, Lim 2012,
Miller 2013). Neovascular AMD is characterized by the growth of abnormal new
blood vessels (neovascularization) under the retinal pigment epithelium (RPE)
or subretinal space from the subjacent choroid, termed choroidal
neovascularization (CNV) (Ferris, 1984). These newly formed vessels have an
increased likelihood to leak blood and serum, damaging the retina by
stimulating inflammation and scar tissue formation. This damage to the retina
results in progressive, severe, and irreversible vision loss (Shah 2007, Shah
2009). Without treatment, most affected
eyes will have poor central vision (20/200) within 12 months (TAP 2003).
Although the neovascular form of the disease is only present in about 10% of
all AMD cases, it accounted for approximately 90% of the severe vision loss
from AMD prior to the introduction of anti- vascular endothelial growth factor
(VEGF) treatments (Ferris 1983, Sommer 1991, Wong 2008).
VEGF has been shown to be elevated in patients with neovascular AMD, and is
thought to play a key role in the neovascularization process (Spilsbury 2000).
The use of intravitreal (IVT) pharmacotherapy targeting VEGF has significantly
improved visual outcomes in patients with neovascular AMD (Bloch 2012, Campbell
2012). Anti-VEGF treatments, such as ranibizumab (LUCENTIS) and aflibercept
(EYLEA), inhibit VEGF signaling pathways and have been shown to halt the growth
of neovascular lesions and resolve retinal edema. While VEGF inhibitors have
vastly improved patient outcomes for neovascular AMD, there still remains a
need for treatments and regimens which offer a reduced frequency of
injections. Frequent treatment and monitoring schedules remain a significant
burden to patients, caregivers and physicians. The proposed study aims to
address these.
Study objective
Primary:
• To demonstrate that RTH258 6 mg is not inferior to aflibercept 2 mg with
respect to the change in best-corrected visual acuity (BCVA) from Baseline to
Week 48
Secondary:
• To demonstrate that RTH258 6 mg is not inferior to aflibercept 2 mg with
respect to the change in BCVA from Baseline averaged over the period Week 36 to
Week 48
• To estimate the proportion of q12 (1 injection every 12 weeks) subjects up to
Week 48 in the RTH258 6 mg treatment arm
• To estimate the predictive value of the first q12 cycle for maintenance of
q12 treatment up to Week 48 in the RTH258 6 mg treatment arm
• To evaluate the efficacy of RTH258 6 mg relative to aflibercept 2 mg over the
time period up to Week 96 by assessing changes in:
o BCVA
o Anatomical parameters of disease activity including central subfield
thickness (CSFT) and CNV area
o Presence of *q8 treatment need*, including assessment of q12 status for
patients in the RTH258 6 mg treatment arm
• To assess visual function-related, subject reported, outcomes following
treatment with RTH258 6 mg relative to aflibercept 2 mg
• To assess the safety and tolerability of RTH258 6 mg relative to aflibercept
2 mg
Study design
This study has 2 arms with 1:1 randomization. Subjects in both arms will have
visits every 4 weeks through Week 96. The primary analysis will be performed at
Week 48.
In Arm 1 (RTH258 6 mg):
RTH258 6 mg will be initially injected 3 times at 4 week intervals, at Visit
1/Baseline, Visit 2/Week 4 and Visit 3/Week 8. Following these 3 loading doses,
each subject will be injected every 12 weeks (q12) up to Visit 24/Week 92
unless there is disease activity assessed according to the guidance provided at
Visit 5/Week 16, Visit 6/Week 20, Visit 8/Week 28, Visit 9/Week 32, Visit
11/Week 40, Visit 12/Week 44, Visit 14/Week 52, Visit 15/Week 56, Visit 17/Week
64, Visit 18/Week 68, Visit 20/Week 76, Visit 21/Week 80 or Visit 23/Week88. If
disease activity is identified, the subject will be reassigned to receive
injections every 8 weeks (q8) thereafter, up to study exit. The interactive
response technology (IRT) system will make the necessary changes to the dosing
per the masked Investigator*s assessment. The disease activity assessment will
also be performed at visit 24/Week 92 but will not be entered into IRT and will
have no effect on the subject*s treatment regimen.
Disease Activity Criteria at Week 16:
• Decrease in BCVA of >= 5 letters compared with Baseline
• Decrease in BCVA of >= 3 letters and CSFT increase >= 75 µm compared with Week
12
• Decrease in BCVA of >= 5 letters due to neovascular AMD disease activity
compared with Week 12
• New or worse intraretinal cysts (IRC) /intraretinal fluid (IRF) compared with
Week 12
Disease Activity Criterion at Weeks 20, 28, 32, 40 and 44:
• Decrease in BCVA of >= 5 letters due to neovascular AMD disease activity
compared with Week 12
Disease Activity Criterion at Weeks 52, 56, 64, 68, 76, 80, 88 and 92:
• Decrease in BCVA of >= 5 letters due to neovascular AMD disease activity
compared with Week 48
In Arm 2 (aflibercept 2 mg):
Aflibercept 2 mg, (EYLEA, comparator) will be injected 3 times at 4 week
intervals (Visit 1/Baseline, Visit 2/Week 4 and Visit 3/Week 8), followed by
injections q8 up to Visit 24/Week 92.
Intervention
In Arm 1 (RTH258 6 mg):
RTH258 6 mg will be initially injected 3 times at 4 week intervals. Following
these 3 loading doses, each subject will be injected every
12 weeks (q12) up to Visit 24/Week 92. If disease activity is identified, the
subject will be reassigned to receive injections every 8 weeks (q8) thereafter,
up to study exit.
In Arm 2 (aflibercept 2 mg):
Aflibercept 2 mg, (EYLEA, comparator) will be injected 3 times at 4 week
intervals, followed by injections q8 up to Visit 24/Week 92.
Study burden and risks
In a period of about 2 years (96 weeks) the patients will be asked to visit the
hospital 26 times for an ophthalmic examination and potential administration of
study medication. Every visit will take between 2 and 3 hours of their time.
After screening, and if they fulfill the in- and exclusion criteria, the
patients will be randomized to RTH258 or the comparator aflibercept.
Earlier trials have shown that the study product has a similar safety profile
compared to the standard treatment. The study product and the comparator will
be administered as an intravitreal injection. In this procedure are some risks
(see above).
None of the assessments or procedures are experimental. However some of them
can cause some inconveniences, such as:
- An intravitreal injection can cause eye redness, eye pain, sensitivity to
light, change in vision, serious eye infection (endophthalmitis), detached
retina, increased pressure in the eye, blood in the eye (vitreous or
conjunctival hemorrhage), cataract.
- Fluorescein angiography can cause temporary nausea or vomiting, a rash, hives
or wheezing
- Intravenous Injections can cause pain or bruising at the site of the
injection, occasional feeling of lightheadedness and an infection at the site
of the injection
- During eye examinations the dilating drops or anesthetic drops may sting when
they are first placed into your eyes. Dilation of your pupils may cause some
temporary glare and blurring of vision.
- Taking images and photographs of your eyes may cause temporary discomfort
from bright lights and holding your eye wide open.
- The risks of drawing blood include temporary discomfort from the needle,
bruising, bleeding, and rarely, infection.
There will be blood draws for the patient during 9 of the 26 study visits.
There will be requested to answer a questionnaire (VFQ-25) during 5 of the 26
study visits.
Medialaan 40
Vilvoorde 1800
BE
Medialaan 40
Vilvoorde 1800
BE
Listed location countries
Age
Inclusion criteria
1. Subjects must give written informed consent before any study related procedures are performed
2. Subjects must be 50 years of age or older at Screening
3. Active CNV lesions secondary to AMD that affect the central subfield (including retinal angiomatous proliferation [RAP] lesions with a CNV component) in the study eye at Screening and confirmed by the Central Reading Center (CRC)
4. Total area of CNV (including both classic and occult components) must comprise > 50% of the total lesion area in the study eye at Screening and confirmed by the CRC
5. Intra and/or subretinal fluid affecting the central subfield of the study eye at Screening and confirmed by the CRC
6. BCVA between 78 and 23 letters, inclusive, in the study eye at Baseline using Early Treatment Diabetic Retinopathy Study (ETDRS) testing
Exclusion criteria
1. Any active intraocular or periocular infection or active intraocular inflammation (eg, infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis) in either eye at Baseline
2. Central subfield of the study eye affected by fibrosis or geographic atrophy assessed by color
fundus photography at Screening and confirmed by the CRC
3. Total area of fibrosis >= 50% of the total lesion in the study eye at Screening and confirmed by the CRC
4. Subretinal blood affecting the foveal center point and/or >= 50% of the lesion of the study eye at Screening and confirmed by the CRC
5. Subject has received any approved or investigational treatment for neovascular AMD (other than vitamin supplements) in the study eye at any time
6. Any history or evidence of a concurrent intraocular condition in the study eye, including retinal diseases other than neovascular AMD, that, in the judgment of the Investigator, could require medical or surgical intervention during the course of the study to prevent or treat visual loss that might result from that condition, or that limits the potential to gain visual acuity upon treatment with the investigational product.
7. Retinal pigment epithelium (RPE) rip/tear in the study eye at Screening
8. Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 weeks prior to Baseline
9. History or evidence of the following in the study eye:
• intraocular or refractive surgery within the 90 day period prior to Baseline
• previous penetrating keratoplasty or vitrectomy
• previous panretinal photocoagulation
• previous submacular surgery, other surgical intervention or laser treatment for AMD
10. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg on medication or according to Investigator*s judgment at Screening
11. Aphakia and/or absence of the posterior capsule in the study eye at Screening
12. Intra- or periocular use of corticosteroids in the study eye during the 6 month period prior to
Baseline
13. Use of topical ocular corticosteroids in the study eye for 60 or more consecutive days within
the 90 day period prior to Baseline
14. Use of systemic corticosteroids for 30 or more consecutive days within the 90 days prior to
Baseline, with the exception of low stable doses of corticosteroids (defined as <= 10 mg prednisolone or equivalent dose used for 90 days or more prior to Baseline). Inhaled, nasal or dermal steroids are also permitted
15. Previous therapeutic radiation near the region of the study eye
16. Treatment with aflibercept (EYLEA®), bevacizumab (AVASTIN®) or pegaptanib (MACUGEN®) within the 4 week period prior to Baseline, or with Ranibizumab, 0.5 mg (LUCENTIS®) within the 2 week period prior to Baseline in the nonstudy eye
17. History of a medical condition (disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding) that, in the judgment of the Investigator, would preclude scheduled study visits, completion of the study, or a safe administration of investigational product
18. History of hypersensitivity to any component of the test article, control article, or clinically
relevant sensitivity to fluorescein dye, as assessed by the Investigator
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after
conception and until the termination of gestation, confirmed by a positive hCG pregnancy test.
20. Women of child-bearing potential, defined as all women less than 1 year postmenopausal or less than 6 weeks since sterilization at Baseline, unless they are using highly effective methods of
contraception during dosing of study treatment. Effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject). Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation
methods) and withdrawal are not acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before Baseline. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 months prior to Baseline). For female subjects in the study, the vasectomized male partner should be the sole partner for that subject
• Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
21. Participation in an investigational drug, biologic, or device study within 30 days or the duration of 5 half-lives of the investigational product (whichever is longer) prior to Baseline Note: observational clinical studies solely involving over-the-counter vitamins, supplements, or diets are not exclusionary
22. Systemic anti-vascular endothelial growth factor (VEGF) therapy within the 90 day period prior to Baseline
23. Stroke or myocardial infarction in the 6 month period prior to Baseline
24. Uncontrolled blood pressure defined as a systolic value >= 160 mmHg or diastolic value >= 100 mmHg at Screening
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 | EUCTR2014-004886-26-NL |
| ClinicalTrials.gov | NCT02434328 |
| CCMO | NL52676.018.15 |