Safety And Tolerability Study Of RN6G In Subjects With Advanced Dry, Age-Related Macular Degeneration Including Geographic Atrophy

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and tolerability of multiple doses of RN6G in subjects with advanced dry, age-related macular degeneration including geographic atrophy.

Official Title
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A PHASE 1, DOUBLE-MASKED, PLACEBO-CONTROLLED STUDY EVALUATING THE SAFETY, TOLERABILITY, IMMUNOGENICITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF MULTIPLE ESCALATING DOSAGES OF RN6G (PF-04382923) IN SUBJECTS WITH ADVANCED DRY, AGE-RELATED MACULAR DEGENERATION (AMD) INCLUDING GEOGRAPHIC ATROPHY

Conditions
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Age-Related Maculopathy, Age-Related Maculopathies, Eye Diseases, Retinal Degeneration, Macular Degeneration

Intervention / Treatment
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* Biological: RN6G
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be of non-child bearing potential Diagnosis of dry AMD including uni- or multi-focal geographic atrophy without foveal involvement BCVA of 20/50 or better in the study eye Exclusion Criteria: Evidence of ocular disease other than advanced AMD or GA in the study eye History or diagnosis of exudative (wet) AMD, with subretinal or choroidal neovascular lesions in the study eye Presence of disease or condition that might compromise the cardiovascular, hematological, renal, hepatic, pulmonary, endocrine, central nervous immune, or gastrointestinal system Requires ocular or systemic medications that are known to be toxic to the lens, retina or optic nerve

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br> | Biological: RN6G<br>* Intravenous, multiple dose, dose ranging from 5 mg/kg up to a maximum of 15 mg/kg<br>Biological: Placebo<br>* Intravenous, multiple dose with experimental dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Toxicity or Intolerable Dose Criteria | The dose was considered intolerable if a participant developed either ocular toxicity or other toxicity as per Common Terminology Criteria for Adverse Events (CTCAE) or based on the investigator's discretion. Ocular toxicity included: Grade >= 3 (retinopathy, retinal detachment, cataract formation, optic disk edema, keratitis, vitreous hemorrhage and uveitis) and acute vision loss of greater than 3 lines of vision up to and including 140 days after the first dose. Other toxicity included serious adverse event (SAE), Grade >= 3 (increased liver transaminases, encephalopathy/leukoencephalopathy, diarrhea, enteritis or nausea, prolongation of QT interval [Fridericia's correction]), Grade >=2 (central nervous system hemorrhage, decreased total leukocyte count, increased serum creatinine) and thrombocytopenia <100*10 9 /liter. | Baseline up to Day 304/End of Treatment (ET) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) Categorized by Severity | AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to Day 304/ET that were absent before treatment or that worsened relative to pretreatment state. AE was assessed according to severity; Grade 1 (mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated), Grade 2 (moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living [ADL]), Grade 3 (severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL), Grade 4 (life-threatening consequences; urgent intervention indicated) and Grade 5 (death related to AE). | Baseline up to Day 304/ET | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs): All Causalities and TEAEs Categorized by Causal Relationship to Study Drug | All causalities AE was any untoward medical occurrence in participant who received study drug without regard to causal relationship. Drug-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to Day 304/ET that were absent before treatment or that worsened relative to pretreatment state. All causalities and drug-related AEs reported wherein drug-related AEs were reported as ocular and non-ocular AEs. Ocular AEs were events which were localized in the ocular region and non-ocular AEs were systemic events which were not localized but occurred throughout the systemic circulation. | Baseline up to Day 304/ET | 
| Number of Participants With Ocular Treatment Emergent Adverse Events (TEAEs) Categorized by Severity | AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to Day 304/ET that were absent before treatment or that worsened relative to pretreatment state. Ocular AE were events which were localized in the ocular region and was assessed according to severity; Grade 1 (mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated), Grade 2 (moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL), Grade 3 (severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL), Grade 4 (life-threatening consequences; urgent intervention indicated) and Grade 5 (death related to AE). | Baseline up to Day 304/ET | 
| Number of Participants With Ocular Treatment Emergent Adverse Events (TEAEs) Categorized by Causal Relationship to Study Drug | AE was any untoward medical occurrence in participant who received study drug without regard to causal relationship and drug-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to Day 304/ET that were absent before treatment or that worsened relative to pretreatment state. Ocular AEs were events which were localized in the ocular region. Ocular AEs reported as related and non-related to study drug. | Baseline up to Day 304/ET | 
| Number of Participants With Systemic Treatment Emergent Adverse Events (TEAEs) Categorized by Severity | AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to Day 304/ET that were absent before treatment or that worsened relative to pretreatment state. Systemic AE were events which were not localized but occurred throughout the systemic circulation and was assessed according to severity; Grade 1 (mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated), Grade 2 (moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL), Grade 3 (severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL), Grade 4 (life-threatening consequences; urgent intervention indicated) and Grade 5 (death related to AE). | Baseline up to Day 304/ET | 
| Number of Participants With Systemic Treatment Emergent Adverse Events (TEAEs) Categorized by Causal Relationship to Study Drug | AE was any untoward medical occurrence in participant who received study drug without regard to causal relationship and drug-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to Day 304/ET that were absent before treatment or that worsened relative to pretreatment state. Systemic TEAEs were events which were not localized but occurred throughout the systemic circulation and reported as related and non-related to study drug. | Baseline up to Day 304/ET | 
| Number of Participants With Positive Anti-Drug-Antibodies (ADA) and Neutralizing Antibodies (Nab) | The immunogenicity of RN6G (PF-04382923) in terms of producing an antidrug antibody (ADA) and neutralizing antibody response were assessed. Neutralizing antibody response were to be assess in participants with positive ADA samples. | Baseline up to Day 304/ET | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of RN6G (PF-04382923) | Area under the concentration-time profile from time zero to time tau (τ), the dosing interval, where tau = 672 hours. | Pre-dose: 0 hour on Day 1, 28, 56, 84,112,140; Post-dose: 1, 2, 4, 24, 168, 336 hours on Day 1 and 1, 2, 4, 24, 336, 672 hours on Day 140 | 
| Maximum Observed Plasma Concentration (Cmax) of RN6G (PF-04382923) |  | Pre-dose: 0 hour on Day 1, 28, 56, 84,112,140; Post-dose: 1, 2, 4, 24, 168, 336 hours on Day 1 and 1, 2, 4, 24, 336, 672, 1992, 3936 hours on Day 140 | 
| Minimum Observed Plasma Trough Concentration (Cmin) of RN6G (PF-04382923) |  | Pre-dose: 0 hour on Day 1, 28, 56, 84,112,140; Post-dose: 1, 2, 4, 24, 336, 672, 1992, 3936 hours on Day 140 | 
| Plasma Concentration (Css) at Steady State of RN6G (PF-04382923) | Css is the concentration of the drug at the state when the amount of drug administered is equal to the amount of drug eliminated. | Pre-dose: 0 hour on Day 1, 28, 56, 84,112,140; Post-dose: 1, 2, 4, 24, 336, 672, 1992, 3936 hours on Day 140 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of RN6G (PF-04382923) |  | Pre-dose: 0 hour on Day 1, 28, 56, 84,112,140; Post-dose: 1, 2, 4, 24, 168, 336 hours on Day 1 and 1, 2, 4, 24, 336, 672, 1992, 3936 hours on Day 140 | 
| Volume of Distribution at Steady State (Vss) of RN6G (PF-04382923) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. | Pre-dose: 0 hour on Day 1, 28, 56, 84,112,140; Post-dose: 1, 2, 4, 24, 336, 672, 1992, 3936 hours on Day 140 | 
| Mean Residence Time (MRT) of RN6G (PF-04382923) | The mean total time drug resides in the body. | Pre-dose: 0 hour on Day 1, 28, 56, 84,112,140; Post-dose: 1, 2, 4, 24, 336, 672, 1992, 3936 hours on Day 140 | 
| Systemic Clearance (CL) of RN6G (PF-04382923) | CL is a quantitative measure of the rate at which a drug substance is removed from the body. | Pre-dose: 0 hour on Day 1, 28, 56, 84,112,140; Post-dose: 1, 2, 4, 24, 336, 672, 1992, 3936 hours on Day 140 | 
| Plasma Decay Half-Life (t1/2) of RN6G (PF-04382923) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Pre-dose: 0 hour on Day 1, 28, 56, 84,112,140; Post-dose: 1, 2, 4, 24, 336, 672, 1992, 3936 hours on Day 140 | 
| Change From Baseline in Plasma Total Amyloid (A) Beta (1-X) Concentration at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET | Amyloid (A) Beta (1-X) is a primary activator of complement in Alzheimer's disease (AD). | Baseline, Day 1 (1 hour, 2 hours, 4 hours post dose), 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140 (predose, 1 hour, 2 hours, 4 hours post dose), 141, 154, 168, 224, 304/ET | 
| Percent Change From Baseline in Plasma Total Amyloid (A) Beta (1-X) Concentration at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET |  | Day 1 (1 hour , 2 hours, 4 hours post dose), 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140 (predose, 1 hour, 2 hours, 4 hours post dose), 141, 154, 168, 224, 304/ET | 
| Change From Baseline in Plasma Amyloid (A) Beta (1-40) Concentration at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET |  | Baseline, Day 1 (1 hour , 2 hours, 4 hours post dose), 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140 (predose, 1 hour, 2 hours, 4 hours post dose), 141, 154, 168, 224, 304/ET | 
| Percent Change From Baseline in Plasma Amyloid (A) Beta (1-40) Concentrations at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET |  | Day 1 (1 hour, 2 hours, 4 hours post dose), 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140 (predose, 1 hour, 2 hours, 4 hours post dose), 141, 154, 168, 224, 304/ET | 
| Change From Baseline in Plasma Amyloid (A) Beta (1-42) Concentration at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET |  | Baseline, Day 1 (1 hour, 2 hours, 4 hours post dose), 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140 (predose, 1 hour, 2 hours, 4 hours post dose), 141, 154, 168, 224, 304/ET | 
| Percent Change From Baseline in Plasma Amyloid (A) Beta (1-42) Concentrations at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET |  | Day 1 (1 hour, 2 hours, 4 hours post dose), 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140 (predose, 1 hour, 2 hours, 4 hours post dose), 141, 154, 168, 224, 304/ET | 
| Change From Baseline in Vital Signs at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET: Systolic and Diastolic Blood Pressure |  | Baseline, 1 and 4 hour (H) post-dose on Day 1; 24 H post-dose on Days 2 and 141; pre-dose and 4 - 8 H post-dose on Days 28, 56, 84, 112; pre-dose and 1, 4 H post-dose on Day 140; Day 7, 14, 19, 45, 75, 103;131, 141, 154 168, 224 and 304/ET | 
| Change From Baseline in Vital Signs at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET: Pulse Rate |  | Baseline, 1 and 4 H post-dose on Day 1; 24 H post-dose on Days 2 and 141; pre-dose and 4 - 8 H post-dose on Days 28, 56, 84, 112; pre-dose and 1, 4 H post-dose on Day 140; Day 7, 14, 19, 45, 75, 103;131, 141, 154 168, 224 and 304/ET | 
| Change From Baseline in Vital Signs at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET: Temperature |  | Baseline, 1 and 4 H post-dose on Day 1; 24 H post-dose on Days 2 and 141; pre-dose and 4 - 8 H post-dose on Days 28, 56, 84, 112; pre-dose and 1, 4 H post-dose on Day 140; Day 7, 14, 19, 45, 75, 103;131, 141, 154 168, 224 and 304/ET | 
| Change From Baseline in Vital Signs at Day 1, 2, 7, 14, 19, 28, 45, 56, 75, 84, 103, 112, 131, 140, 141, 154, 168, 224, 304/ET: Weight |  | Baseline, 1 and 4 H post-dose on Day 1; 24 H post-dose on Days 2 and 141; pre-dose and 4 - 8 H post-dose on Days 28, 56, 84, 112; pre-dose and 1, 4 H post-dose on Day 140; Day 7, 14, 19, 45, 75, 103;131, 141, 154 168, 224 and 304/ET | 
| Change From Baseline Electrocardiogram (ECG) 12-lead at Day 1, 28, 56, 84, 112, 140, 168, 224, 304/ET | Criteria for changes in ECG (12-lead) were defined as: PR interval >=220 millisecond (msec) and increase of >=20 msec; QRS interval >=120 msec; QT interval corrected using the Bazett's formula (QTcB) >=500 msec; Maximum Change from Baseline in QTcF at Borderline >=30 msec to <60 msec and Prolonged >=60 msec. | Baseline, 1 and 4 H post-dose on Day 1; pre-dose on Days 28, 56, 84, 112; pre-dose and 1, 4 H post-dose on Day 140; Day 168, 224 and 304/ET | 
| Change From Baseline in Heart Rate at Day 1, 28, 56, 84, 112, 140, 168, 224, 304/ET |  | Baseline, 1 and 4 H post-dose on Day 1; pre-dose on Days 28, 56, 84, 112; pre-dose and 1, 4 H post-dose on Day 140; Day 168, 224 and 304/ET | 
| Change From Baseline in Bilirubin, Direct Bilirubin, Blood Urea Nitrogen, Creatinine, Uric Acid, Calcium, Phosphate, Glucose, Cholesterol, Triglycerides, Immunoglobulin G, Immunoglobulin A, Immunoglobulin M at Day 28, 56, 84, 112, 140, 168, 224, 304/ET | Following parameters were analyzed for laboratory examination: Bilirubin, Direct Bilirubin, Blood Urea Nitrogen(BUN), Creatinine, Uric Acid, Calcium, Phosphate, Glucose, Cholesterol (CL)(Fasting), Triglycerides (Fasting) (TG), Immunoglobulin G (Ig G), Immunoglobulin A (Ig A), Immunoglobulin M (Ig M) | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Protein, Albumin, Hemoglobin at Day 28, 56, 84, 112, 140, 168, 224, 304/ET |  | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Aspartate Aminotransferase, Creatine Kinase, Alanine Aminotransferase, Gamma Glutamyl Transferase (GGT), Lactate Dehydrogenase, Alkaline Phosphatase at Day 28, 56, 84, 112, 140, 168, 224, 304/ET | Following parameters were analyzed for laboratory examination: Aspartate Aminotransferase (AMT), Creatine Kinase (CK), Alanine Aminotransferase (ALT), Gamma Glutamyl Transferase (GGT), Lactate Dehydrogenase (LD), Alkaline Phosphatase (AP). | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Sodium, Potassium, Chloride, Bicarbonate, Magnesium at Day 28, 56, 84, 112, 140, 168, 224, 304/ET |  | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Hematocrit at Day 28, 56, 84, 112, 140, 168, 224, 304/ET | Following hematology parameters were analyzed for laboratory examination: Hemoglobin, Hematocrit, Red blood cell (RBC) count, Platelet count, WBC count, Total neutrophils (Abs),Eosinophils (Abs),Monocytes (Abs),Basophils (Abs), Lymphocytes (Abs). | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Red Blood Cells (RBCs) at Day 28, 56, 84, 112, 140, 168, 224, 304/ET |  | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Platelets, White Blood Cells (WBCs), Neutrophils (Absolute), Eosinophils (Absolute), Basophils (Absolute), Lymphocytes (Absolute), Monocytes (Absolute) at Day 28, 56, 84, 112, 140, 168, 224, 304/ET |  | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Prothrombin Time (PT), Partial Thromboplastin Time at Day 28, 56, 84, 112, 140, 168, 224, 304/ET | Following hematology parameters were analyzed for laboratory examination: Prothrombin Time (PT), Partial Thromboplastin Time. | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Urine Specific Gravity at Day 28, 56, 84, 112, 140, 168, 224, 304/ET | Urine specific gravity is a measure of the ratio of the density of urine to the density of water. | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Urine pH at Day 28, 56, 84, 112, 140, 168, 224, 304/ET | Urine pH is a method for evaluating urine acidity measured on a 10-point scale ranging from 0 (most acidic) to 9 (most alkaline). A lower pH means more acidity. | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Baseline in Laboratory Assessments: Beta Interleukin-1, Interleukin-6, Alpha Tumor Necrosis Factor, Interferon (Gamma) at Day 28, 56, 84, 112, 140 |  | Baseline, Day 28, 56, 84, 112, 140 | 
| Change From Baseline in Laboratory Assessments: Component of Complement (C3A, C5B-9) at Day 28, 56, 84, 112, 140 |  | Baseline, Day 28, 56, 84, 112, 140 | 
| Change From Baseline in Laboratory Assessments: Cluster of Differentiation 4 (C4D) at Day 28, 56, 84, 112, 140 |  | Baseline, Day 28, 56, 84, 112, 140 | 
| Change From Baseline in Prothrombin Time (PT) International Normalized Ratio (INR) at Day 28, 56, 84, 112, 140, 168, 224, 304/ET |  | Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET | 
| Change From Electrocardiogram (ECG): QTcF Interval (Fridericia's Correction) at Day 1, 28, 56, 84, 112, 140, 168, 224, 304/ET | QT interval corrected using the Fridericia formula (QTcF) >=500 msec; Maximum Change from Baseline in QTcF at Borderline >=30 msec to <60 msec and Prolonged >=60 msec. | Baseline, 1 and 4 H post-dose on Day 1; pre-dose on Days 28, 56, 84, 112; pre-dose and 1, 4 H post-dose on Day 140; Day 168, 224 and 304/ET | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1b Advanced Dry Age-Related Macular Degeneration RN6G