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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
24
Retinal Diagnostic Center
Campbell, California, United States
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.
Time frame: 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).
Time frame: 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.
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American Institute of Research (Administrative Only)
Los Gatos, California, United States
Neurology Center Rai Kumar
San Jose, California, United States
Harmeet Sachdev, MD, FAAN
San Jose, California, United States
Santa Clara Drug
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
Clinical Specialists, LLC
Augusta, Georgia, United States
Southeast Retina Center, PC
Augusta, Georgia, United States
...and 14 more locations
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Baseline up to Day 304/ET
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.
Time frame: 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)
Time frame: 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)
Time frame: 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.
Time frame: 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)
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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).
Time frame: 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
Time frame: 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).
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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