E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced, Dry, Age-Related Macular Degeneration including Geographic Atrophy |
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E.1.1.1 | Medical condition in easily understood language |
A progressive loss of vision in your central visual field (what’s in front of you not to the sides) due to damage of the retina. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064930 |
E.1.2 | Term | Age-related macular degeneration |
E.1.2 | System Organ Class | 10015919 - Eye disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the efficacy of RN6G in subjects with geographic atrophy in the study eye. |
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E.2.2 | Secondary objectives of the trial |
• To examine retinal structural and functional deficits with ocular assessments for the study and the fellow eye.
• To examine the safety, tolerability and immunogenicity of RN6G in subjects.
• To characterize the population pharmacokinetic (PK) profile of RN6G.
• To demonstrate the effect of RN6G on plasma Aß(1-x)(total), Aß(1-40) and Aß(1-42) concentrations.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men and women between the ages of 60 and 90 years, inclusive.
2. Diagnosis of a well demarcated area of geographic atrophy (GA) secondary to dry AMD.
One eye (designated as the study eye) must have the following for AREDS AMD Levels Defined for Eyes):
• 3d: Geographic atrophy within grid but none at the center of the macula.
• 4a: Geographic atrophy in central subfield with at least questionable involvement of center of macula.
The other eye (designated as the fellow eye) can have Level 3 or 4a AMD. If both eyes have Level 3d or 4a AMD, then
the eye with the best BCVA would be considered the study eye; otherwise it should be considered the fellow eye. If
the ETDRS BCVA is the same in each eye, then the Investigator will designate the study and fellow eye.
A subject will be excluded from study if the fellow eye has Level 4b and has been or is currently being treated with anti
VEGF therapy.
The determination of AREDS AMD Levels will be made by a Central Reader.
3. GA total area between 2.0 and 17.5 mm2.
4. Best corrected visual acuity (BCVA) of ≥54 letter (20/80 (Snellen VA equivalent) or better in the study eye as
determined using an ETDRS chart.
5. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal
representative) has been informed of all pertinent aspects of the study.
6. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study
procedures. |
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E.4 | Principal exclusion criteria |
Any disease or condition that might compromise the cardiovascular, hematological, renal, hepatic, pulmonary, endocrine, central nervous, immune, or gastrointestinal systems (unless deemed not clinically significant by the Investigator and Sponsor) such as, but not limited to:
a. Diagnosis or history of Alzheimer’s disease, dementia of any cause such as untreated thyroid disease or stroke or neuro degenerative disorders (eg, Parkinson’s disease, Lewy body disease, fronto temporal dementia, vascular dementia);
b. History or systemic signs of inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus;
c. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell cancer resolved by excision);
d. Presence of uncontrolled hypertension (uncontrolled hypertension is defined as a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure greater than 90 mm Hg, even with treatment). Subjects who have hypertension and are controlled on stable dosages of anti hypertensive medications can be included;
e. Poorly controlled Type 1 and Type 2 diabetes mellitus (HbA1c >9%). HbA1c must be obtained only for subjects with a known diagnosis of diabetes.
History or diagnosis of ocular disease other than advanced dry AMD or GA in the study eye that would confound the results of the study, such as diabetic retinopathy with microhemorrhage, uveitis (CTCAE Grade ≥2), or pseudovitelliform macular degeneration.
History or diagnosis of exudative (wet) AMD, with subretinal or choroidal neovascular lesions in the study or fellow eye.
History of ocular infection, ocular inflammation or laser or cataract surgery within 3 months of Day 1.
History of ocular trauma or surgery (other than laser or cataract surgery) within 6 months of Day 1.
History of laser photocoagulation in the study eye.
Presence of ocular lens opacities preventing vision testing: cortical opacity greater than standard 3, posterior subcapsular opacity greater than standard 2, or a nuclear opacity greater than standard 3 (as measured on the AREDS clinical lens grading system).
History of optic amblyopia, glaucoma, optic nerve or other retinal disease or dysfunction (eg, disorders leading to or associated with retinal detachment, macular edema, atrophic retinal holes, retinal tears, retinal detachment, exudative retinal detachment, retinal toxicities due to medications, retinitis pigmentosa). Subjects with cobblestone or paving stone peripheral retinal degeneration are acceptable.
Subjects expected to need ocular surgery during the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The mean reduction in the rate of growth of GA area (in mm2) at 30 days post last dose administration (Day 309) and at end of study with FAF. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The mean reduction in the rate of growth of GA area (in mm2) at 30 days post last dose administration (Day337) |
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E.5.2 | Secondary end point(s) |
BCVA
• The mean BCVA letter number and line number after RN6G at 9, 12, 15 months and end of study compared to baseline and placebo.
• The mean percentage change from baseline in the correct number of letters after RN6G at 9, 12, 15 months and end of study.
• The mean percentage change from baseline in the correct number of lines after RN6G at 9, 12, 15 months and end of study.
Low Luminance (LL) BCVA
• The mean LL BCVA letter number and line number after RN6G at 9, 12, 15 months and end of study compared to baseline and placebo.
• The mean percentage change from baseline in the correct number of letters after RN6G at 9, 12, 15 months and end of study.
• The mean percentage change from baseline in the correct number of lines after RN6G at 9, 12, 15 months and end of study.
Contrast Sensitivity
• The mean change in Logmar units compared to baseline and placebo at 9, 12, 15 months and end of study.
• The percentage change from baseline in Logmar units at 9, 12, 15 months and end of study.
Reading
• The mean reading acuity and speed change from baseline at 9, 12, 15 months and end of study.
• The mean reading acuity and speed change from placebo at 9, 12, 15 months and end of study.
• The mean critical print size change from baseline and placebo at 9, 12, 15 months and end of study.
• The percentage change from baseline in reading acuity and speed at 9, 12, 15 months and end of study.
Safety
• Incidence, severity and causal relationship of treatment emergent AEs (TEAEs).
• Incidence of abnormal and clinically relevant safety laboratories including clinical chemistry, hematology and coagulation assessments.
• Abnormal and clinically relevant changes in vital signs, BP, and ECG parameters.
• Incidence of anti-drug-antibodies.
Pharmacokinetics
• Plasma RN6G concentrations at specified time points and population PK parameter estimates for AUCτ, Cmax, Cmin, CL at steady state, and accumulation ratio on AUCτ between the first and last (11th) doses.
Pharmacodynamics
• Change from baseline (absolute and %) of plasma Aβ(1-x) (total), Aβ(1-40) and Aβ(1-42) concentrations. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) The mean BCVA letter number and line number after RN6G at 9, 12, and 15 months compared to placebo.
2) The mean percentage change from baseline in the correct number of letters after RN6G at 9, 12 and 15 months.
3) The mean percentage change from baseline in the correct number of lines after RN6G at 9, 12, and 15 months |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Germany |
Italy |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |