To evaluate the effect of ISIS 696844 on the rate of change of the area of GA secondary to AMD measured by fundus autofluorescence (FAF)
ID
Source
Brief title
Condition
- Congenital eye disorders (excl glaucoma)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the absolute change in the GA area at Week 49
compared to baseline, as measured by FAF in study eye.
Secondary outcome
The secondary efficacy endpoints include:
• Percent change in levels of plasma FB from Baseline
The secondary efficacy endpoints include:
• Percent change in levels of serum AH50 activity from Baseline
• Absolute change in LLVA score from Baseline at Week 49
Background summary
ISIS 696844 is in development as a potential treatment for geographic atrophy
(GA) associated with age-related macular degeneration (AMD).
AMD is a progressive disease of the macula and is the leading cause of central
vision impairment in persons over the age of 50 years in developed countries.
The disease is characterized by progressive loss of central vision, the
distortion of images and straight lines, and the presence of blurry and dark
areas in the central vision. The underlying pathophysiology drivers for AMD
are complex and the symptoms manifest in multiple related, but distinct forms.
In the early and intermediate stages of AMD, the disease is characterized by
the deposition of drusen, protein and lipid rich extracellular deposits between
the retinal pigment epithelial (RPE) cells and Bruch*s membrane. As part of
the natural course of the disease, there is a development of atrophic areas,
which enlarge continuously and correspond with an absolute scotoma/GA. This
area of GA associated with late stage AMD, corresponds with retinal regions of
impaired visual function resulting from the atrophy of photoreceptor and RPE
cells.
The complement system, an important component of innate immunity, is the most
widely accepted pathogenic pathway of the immune system implicated in AMD.
Genetic evidence from genome wide association studies (GWAS) and rare variant
analyses suggest the complement alternative pathway (AP) is overactive in AMD.
Specific polymorphisms of complement factor H (CFH), which is the negative
regulator of the AP, confer increased risk for AMD. In contrast, specific
polymorphisms of FB, the positive regulator, confer protection against AMD.
FB is synthesized primarily by the liver and at very low levels in several
extrahepatic sites. Ocular FB protein is located predominately in the
choroidal capillaries and Bruch*s membrane region and not evident in the neural
retina. Hence, choroidal FB appears to be derived from systemic sources.
Plasma concentrations of AP activation products were found to be significantly
elevated in AMD patients compared to controls. This suggests an ongoing
systemic activation of the alternative complement pathway in AMD pathogenesis
and adds to the increasing evidence that AMD is a systemic disease with local
ocular manifestation in the ageing macula.
The therapeutic objective is to delay the progression of GA associated with AMD
using systemic administration of an antisense oligonucleotide (ASO) targeting
FB messenger ribonucleic acid (mRNA) in the liver, which will subsequently
reduce the levels of plasma and ocular FB. The reduction of plasma FB, an
essential component of the AP, will diminish the hyper-activation of the AP
that is contributing to AMD pathology.
Study objective
To evaluate the effect of ISIS 696844 on the rate of change of the area of GA
secondary to AMD measured by fundus autofluorescence (FAF)
Study design
Randomized, placebo-controlled, double-masked study conducted at multiple
centers
Intervention
Initially (Stage 1), there will be approximately 60 patients, with an N = 15
per treatment group (3 different dose levels of ISIS 696844 and placebo).
Patients will be randomized equally (1:1:1) to 1 of the 3 dose cohorts and,
within each dose cohort, 3:1 to receive active or matching volume of placebo.
After review of safety, tolerability, pharmacokinetic and pharmacodynamic
changes that occur during the first 13-week Treatment Period of approximately
the first 60 patients,3 treatment groups (2 active and the placebo group) will
be expanded to include a total of 105 patients per group.
The Stage 2 patients will be randomized equally (1:1) to 1 of the 2 dose
cohorts and, within each dose cohort, 2:1 to receive active or matching volume
of placebo. The 15 or more patients of the dose group in Stage 1 that will not
be expanded will continue Treatment and Post-Treatment Periods if safety
profile is acceptable.
At the discretion of the Sponsor, additional patients may be added to 1 or more
of the treatment groups (total N not to exceed more than1.2 times the original
sample size [i.e., 126/group]), if necessary to elucidate safety or compensate
for unexpected high number of patients withdrawing from the study.
The Netherlands will not participate in Stage 1 of the study
Study burden and risks
The study contains a screening phase, treatment phase and a follow-up phase.
o 10-14 week screening period
o 45 week study treatment period
o 12 week follow-up period
Most of the visits will take about 1 to 4 hours
The subject will have to undergo several examinations, tests and/or procedures
before, during and after his/her treatment. Please refer to the procedure table
In the ICF and Appendix A of the protocol for more information.
In addition, questions are asked about the medical history, demographics and
eligibilty questions
Subjects will also be tested for HIV and hepatitis. Female patients will be
tested for pregnancy .
The anticipated total duration of the study is approximately 71 weeks (18
months)
Possible side effects that are already known are described in the
Investigator's Brochure and the patient informed consent form.
Gazelle Court 2855
Carlsbad, 92010
US
Gazelle Court 2855
Carlsbad, 92010
US
Listed location countries
Age
Inclusion criteria
A full list of the inclusion criteria can be found in section 5.1 of the
protocol. Below a list of the most important criteria:
1. Females must be non-pregnant and non-lactating, and either surgically
sterile or post-menopausal.
2. Vaccination against Neisseria meningitidis and Streptococcus pneumoniae
received at least 2 weeks prior to first dose of investigational product
3. Well-demarcated geographic atrophy (GA) due to AMD
4. Best-corrected visual acuity (BCVA) letter score of 35 letters (approx.
20/200 Snellen equivalent) or better on the ETDRS chart
5. Must have clear ocular media and adequate pupillary dilation in the study
eye to permit high-quality fundus imaging
Exclusion criteria
A full list of the exclusion criteria can be found in section 5.2 of the
protocol. Below a list of the most important criteria:
1.Clinically-significant abnormalities in medical history
2. A lack of full recovery from any infection for at least 14 days prior to the
Study Drug administration
3. Chronic treatment with steroids, including topically or intravitreally
administered
4. History or presence of diabetic retinopathy or diabetic macular edema (DME)
5. History or presence of a disease other than AMD that could affect vision or
safety assessments
6. Prior treatment with another investigational drug, biological agent, or
device
Design
Recruitment
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 | EUCTR2020-005174-94-NL |
| ClinicalTrials.gov | NCT03815825 |
| CCMO | NL77253.000.21 |