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

Phase 1

Completed

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

Interventions: Biological: RN6G
Biological: Placebo

Registration Number: NCT01003691

Lead Sponsor: Pfizer

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Arm 1	Placebo	-
Arm 1	RN6G	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With Toxicity or Intolerable Dose Criteria	Baseline up to Day 304/End of Treatment (ET)	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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Categorized by Severity	Baseline up to Day 304/ET	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).
Number of Participants With Ocular Treatment Emergent Adverse Events (TEAEs) Categorized by Causal Relationship to Study Drug	Baseline up to Day 304/ET	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.
Number of Participants With Systemic Treatment Emergent Adverse Events (TEAEs) Categorized by Severity	Baseline up to Day 304/ET	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).
Number of Participants With Treatment Emergent Adverse Events (TEAEs): All Causalities and TEAEs Categorized by Causal Relationship to Study Drug	Baseline up to Day 304/ET	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.
Number of Participants With Ocular Treatment Emergent Adverse Events (TEAEs) Categorized by Severity	Baseline up to Day 304/ET	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).
Number of Participants With Positive Anti-Drug-Antibodies (ADA) and Neutralizing Antibodies (Nab)	Baseline up to Day 304/ET	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.
Number of Participants With Systemic Treatment Emergent Adverse Events (TEAEs) Categorized by Causal Relationship to Study Drug	Baseline up to Day 304/ET	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.

Secondary Outcome Measures

Name	Time	Method
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
Mean Residence Time (MRT) 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	The mean total time drug resides in the body.
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) 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 hours on Day 140	Area under the concentration-time profile from time zero to time tau (τ), the dosing interval, where tau = 672 hours.
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
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 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
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
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
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
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
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
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	Baseline, 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)
Change From Baseline in Laboratory Assessments: Hematocrit at Day 28, 56, 84, 112, 140, 168, 224, 304/ET	Baseline, 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).
Change From Baseline in Laboratory Assessments: Prothrombin Time (PT), Partial Thromboplastin Time at Day 28, 56, 84, 112, 140, 168, 224, 304/ET	Baseline, Day 28, 56, 84, 112, 140, 168, 224, 304/ET	Following hematology parameters were analyzed for laboratory examination: Prothrombin Time (PT), Partial Thromboplastin Time.
Change From Baseline in Laboratory Assessments: Urine pH at Day 28, 56, 84, 112, 140, 168, 224, 304/ET	Baseline, 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.
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
Plasma Decay Half-Life (t1/2) 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 decay half-life is the time measured for the plasma concentration to decrease by one half.
Plasma Concentration (Css) at Steady State 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	Css is the concentration of the drug at the state when the amount of drug administered is equal to the amount of drug eliminated.
Systemic Clearance (CL) 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	CL is a quantitative measure of the rate at which a drug substance is removed from the body.
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	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	Amyloid (A) Beta (1-X) is a primary activator of complement in Alzheimer's disease (AD).
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	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	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.
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 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	Baseline, 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).
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: Cluster of Differentiation 4 (C4D) at Day 28, 56, 84, 112, 140	Baseline, Day 28, 56, 84, 112, 140
Volume of Distribution at Steady State (Vss) 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	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.
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 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: 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 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 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: Urine Specific Gravity at Day 28, 56, 84, 112, 140, 168, 224, 304/ET	Baseline, 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.
Change From Electrocardiogram (ECG): QTcF Interval (Fridericia's Correction) 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	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.

Trial Locations

Locations (24): Clinical Specialists, LLC
🇺🇸
Augusta, Georgia, United States
Jay Markowitz and Associates
🇺🇸
West Columbia, South Carolina, United States
American Institute of Research (Administrative Only)
🇺🇸
Los Gatos, California, United States
Heart and Vascular Institute
🇺🇸
Abilene, Texas, United States
Retinal Diagnostic Center
🇺🇸
Campbell, California, United States
Harmeet Sachdev, MD, FAAN
🇺🇸
San Jose, California, United States
Santa Clara Drug
🇺🇸
San Jose, California, United States
Neurology Center Rai Kumar
🇺🇸
San Jose, California, United States
Retina Associates of Florida, PA
🇺🇸
Tampa, Florida, United States
Hoye's Pharmacy
🇺🇸
Tampa, Florida, United States
Ranjit K. Sethi, MD, PC
🇺🇸
Augusta, Georgia, United States
Southeast Retina Center, PC
🇺🇸
Augusta, Georgia, United States
University of Rochester
🇺🇸
Rochester, New York, United States
University of Rochester Medical Center
🇺🇸
Rochester, New York, United States
Hawthorne Pharmacy
🇺🇸
West Columbia, South Carolina, United States
South Carolina Neurological
🇺🇸
West Columbia, South Carolina, United States
Palmetto Retina Center, LLC
🇺🇸
West Columbia, South Carolina, United States
Abilene Surgery Center
🇺🇸
Abilene, Texas, United States
National Central Pharmacy
🇺🇸
Abilene, Texas, United States
Brian B. Berger, MD, PA
🇺🇸
Austin, Texas, United States
Retina Research Center, PLLC
🇺🇸
Austin, Texas, United States
Sleep Medicine Consultants
🇺🇸
Austin, Texas, United States
Retina Research Institute of Texas
🇺🇸
Abilene, Texas, United States
Specialty Compounding
🇺🇸
Cedar Park, Texas, United States