Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, placebo-controlled trial designed to evaluate the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of COR-001 or placebo

Official Title
-----------------
A Phase 1/2 Randomized, Double-blind, Placebo Controlled, Cohort Dose-escalation Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001

Conditions
-----------------
Anemia

Intervention / Treatment
-----------------
* Drug: COR-001
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA Age greater than or equal to 18 years at the time of signing of the ICF. The patient agrees to comply with the contraception and reproduction restrictions of the study Receiving intravenous (IV) or subcutaneous (SC) erythropoietin stimulating agents (ESA) drugs continuously prescribed for a minimum of 8 weeks prior to Screening At least 2 ferritin values during Screening > 300 ng/mL At least 2 transferrin saturation (TSAT) values during Screening between 15% and 50% (inclusive) EXCLUSION CRITERIA: Use of systemic immunosuppressive drugs during the Screening Period or anticipated use of such drugs any time during the study Clinical evidence or suspicion of active or smoldering infection by clinical or serologic criteria Actively treated or active malignancy Known or suspected occult or active bleeding Received a red blood cell or whole blood transfusion within 2 months prior to Screening or anticipated to receive a blood transfusion at any time during the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: COR-001<br> | Drug: COR-001<br> <br> |
| Placebo Comparator: Placebo<br> | Other: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterization of Maximum Tolerated Dose (MTD) | The MTD assessment was based on safety data. If more than 2 of 8 active participants in a cohort experience a Dose-Limiting Toxicities (DLT), the MTD was considered to have been exceeded. The DLT threshold was defined using a threshold of greater than or equal to (>=) Grade 3 events, which includes severe: infusion-related reactions, cardiopulmonary infusion reactions, anaphylaxis, or hypersensitivity. DLTs are defined as follows: Confirmed Grade 3 neutropenia and representing a decline of > 25% from baseline Serious adverse events (SAEs) of infection in the presence of confirmed Grade 2 or higher new onset lymphopenia or new onset neutropenia. ≥ Grade 3 ALT (Alanine transaminase) or AST(Aspartate transaminase) ≥ Grade 4 hematologic toxicity ≥ Grade 3 non-hematologic toxicity | Weeks 0-24 | 
| Change in High-sensitivity C-reactive Protein (hsCRP): Week 4 | Change from the baseline in hsCRP values to week 4 are presented. | From baseline (mean of screening and day 1) to week 4 | 
| Change in Serum Amyloid A (SAA): Week 4 | Change from the baseline in serum amyloid A (SAA) values to week 4 are presented. | From baseline (mean of screening and day 1) to week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events of Special Interest | Frequency of events of interest by treatment group and dose from baseline until the end of the safety follow-up period (week 24) were reported. Adverse events of special interest included severe infusion-related reactions, hypersensitivity reaction during study drug infusion, anaphylaxis and neutropenia events of grade 2 or higher (i.e., absolute neutrophil count <1500/mm^3 and decline by at least 25% from baseline). | Weeks 0-24 | 
| Number of Treatment Emergent Adverse Events (TEAEs) | An AE (adverse event) is any undesirable event or any untoward medical occurrence that occurs to a participant during the course of a study, or the protocol-defined time after study termination, whether or not that event is considered Study Drug-related. A TEAE was defined as an AE that initiated or worsened on or after the date of first dose of study drug up to the end of study. Number of TEAEs from baseline until the end of safety follow up (week 24) were presented. | Week 0-24 | 
| Electrocardiogram (ECG) | A summary of the overall ECG interpretation and clinical significance from baseline until the end of the safety follow up period (week 24) is presented and categorized as Normal, Abnormal clinically significant (CS), Abnormal non clinically significant (NCS) and Missing. | At baseline, week 6, week 12, week 18 and week 24 | 
| Number of Participants Who Developed Anti-drug Antibodies (ADAs) | Number of participants who developed ADAs from baseline until the end of the extended follow up period (week 35) were reported. Samples with detectable ADAs were classified as positive for ADAs. Samples without detectable ADAs were classified as negative for ADAs. | Weeks 0-35 | 
| Number of Participants With ADA Titers | Number of participants with ADA titers for ADA-positive samples from baseline to week 35 is presented. | Weeks 0-35 | 
| Number of Participants With Neutralizing ADAs | Number of participants with neutralizing ADAs from baseline to week 35 are presented. | From baseline (mean of screening and week 1) to week 35 | 
| Change in Transferrin Saturation (TSAT): Week 4 | Change from baseline in TSAT to week 4 is presented. | From baseline (mean of screening and day 1) to week 4 | 
| Change in TSAT: Mean of Weeks 10-12 | Change from baseline in TSAT to the mean of weeks 10-12 is presented. | From baseline (mean of screening and day 1), week 10, week 12 | 
| Change in Reticulocyte Hemoglobin (CHr): Week 4 | Change from baseline in CHr to week 4 is presented. | From baseline (mean of screening and day 1) to week 4 | 
| Change in High Sensitivity C-reactive Protein (Hs-CRP): Mean of 10-12 Weeks | Change from baseline in hs-CRP to the mean of 10-12 weeks is presented. | From baseline (mean of screening and day 1), week 10, week 12 | 
| Change in SAA: Mean of Weeks 10-12 | Change from baseline in SAA to the mean of weeks 10-12 is presented. | From baseline (mean of screening and day 1), week 10, week 12 | 
| Change in Serum Pre-albumin: Mean of 10-12 Weeks | Change from baseline in serum pre-albumin to the mean of 10-12 weeks is presented. | From baseline (mean of screening and day 1), week 10, week 12 | 
| Change in Albumin: Week 12 | Change from baseline in albumin to week 12 is presented. | From baseline (mean of screening and day 1) to week 12 | 
| Change in Erythropoietin Resistance Index (ERI): Week 4 | Change from baseline in ERI to week 4 is presented. ERI is defined as the epoetin alfa-equivalent dose (weight-based per week in U/kg) divided by the serum hemoglobin (in g/dL). | From baseline (weekly mean of screening) to week 4 | 
| Change in ERI: Mean of Weeks 8-12 | Change from baseline in ERI to the mean of weeks 8-12 is presented. ERI is defined as the epoetin alfa-equivalent dose (weight-based per week in U/kg) divided by the serum hemoglobin (in g/dL). | From baseline (weekly mean of screening), week 8, week 12 | 
| Change in ERI: Mean of Weeks 10-12 | Change from baseline in ERI to the mean of weeks 10-12 is presented. ERI is defined as the epoetin alfa-equivalent dose (weight-based per week in U/kg) divided by the serum hemoglobin (in g/dL). | From baseline (weekly mean of screening), week 10, week 12 | 
| Change in CHr: Mean of Weeks 10-12 | Change from baseline in CHr to the mean of weeks 10-12 is presented. | From baseline (mean of screening and day 1), week 10, week 12 | 
| Change in Hemoglobin: Week 4 | Change from baseline in hemoglobin to week 4 is presented. | From baseline (mean of screening and day 1) to week 4 | 
| Change in Hemoglobin: Mean of Weeks 10-12 | Change from baseline in hemoglobin to weeks 10-12 is presented. | From baseline (mean of screening and day 1), week 10, week 12 | 
| Change in Hemoglobin: Mean of Weeks 10-12, Excluding Hemoglobin Values Following a Change in the Total Weekly ESA Dose | Change from baseline in hemoglobin to weeks 10-12, excluding hemoglobin values following a change in the total weekly ESA (erythropoiesis stimulating agent) dose is presented. A change is defined as the first time when the ESA weekly dose goes up by >25% or down by >25% relative to the previous week's dose. | From baseline (mean of screening and day 1), week 10, week 12 | 
| Change in ERI: Week 12 | Change from baseline in ERI to week 12 is presented. ERI is defined as the epoetin alfa-equivalent dose (weight-based per week in U/kg) divided by the serum hemoglobin (in g/dL). | From baseline (weekly mean of screening) to week 12 | 
| Change in ERI: Mean of Weeks 9-12 | Change from baseline in ERI to the mean of weeks 9-12 is presented. ERI is defined as the epoetin alfa-equivalent dose (weight-based per week in U/kg) divided by the serum hemoglobin (in g/dL). | From baseline (weekly mean of screening), week 9, week 12 | 
| Change in Hemoglobin: Week 12 | Change from baseline in hemoglobin to week 12 is presented. | From baseline (mean of screening and day 1) to week 12 | 
| Change in Hemoglobin: Week 24 | Change from baseline in hemoglobin to week 24 is presented. | From baseline (mean of screening and day 1) to week 24 | 
| Change in Hemoglobin From Screening to Peak Hemoglobin: Week 4 | Change in hemoglobin from screening to peak hemoglobin at week 4 is presented. | From screening to week 4 | 
| Basophils: Week 12 | The observed values of basophils at week 12 are presented. | At week 12 | 
| Basophil: Week 24 | The observed values of basophils at week 24 are presented. | At week 24 | 
| Basophils to Leukocytes Ratio: Week 12 | Basophils to leukocytes ratio at week 12 is presented. | At week 12 | 
| Basophils to Leukocytes Ratio: Week 24 | Basophils to leukocytes ratio at week 24 is presented. | At week 24 | 
| Eosinophils: Week 12 | The observed values of eosinophils at week 12 are presented. | At week 12 | 
| Eosinophils: Week 24 | The observed values of eosinophils at week 24 are presented. | At week 24 | 
| Eosinophils to Leukocytes Ratio: Week 12 | Eosinophils to leukocytes ratio at week 12 is presented. | At week 12 | 
| Eosinophils to Leukocytes Ratio: Week 24 | The eosinophils to leukocytes ratio at week 24 is presented. | At week 24 | 
| Erythrocyte Mean Corpuscular Hemoglobin: Week 12 | The observed values of erythrocyte mean corpuscular hemoglobin at week 12 are presented. | At week 12 | 
| Erythrocyte Mean Corpuscular Hemoglobin: Week 24 | The observed values of erythrocyte mean corpuscular hemoglobin at week 24 are presented. | At week 24 | 
| Erythrocyte Mean Corpuscular Hemoglobin (HGB) Concentration: Week 12 | The observed values of erythrocyte mean corpuscular HGB concentration at week 12 are presented. | At week 12 | 
| Erythrocyte Mean Corpuscular HGB Concentration: Week 24 | The observed values of erythrocyte mean corpuscular HGB concentration at week 24 are presented. | At week 24 | 
| Erythrocyte Mean Corpuscular Volume: Week 12 | The observed values of erythrocyte mean corpuscular volume at week 12 are presented. | At week 12 | 
| Erythrocyte Mean Corpuscular Volume: Week 24 | The observed values of erythrocyte mean corpuscular volume at week 24 are presented. | At week 24 | 
| Erythrocytes: Week 12 | The observed values of erythrocytes at week 12 are presented. | At week 12 | 
| Erythrocytes: Week 24 | The observed values of erythrocytes at week 24 are presented. | At week 24 | 
| Hematocrit: Week 12 | The observed values of hematocrit at week 12 are presented. | At week 12 | 
| Hematocrit: Week 24 | The observed values of hematocrit at week 24 are presented. | At week 24 | 
| Hemoglobin: Week 12 | The observed values of hemoglobin at week 12 are presented. | At week 12 | 
| Hemoglobin: Week 24 | The observed values of hemoglobin at week 24 are presented. | At week 24 | 
| Hypochromatic Red Cells Week 12 | The observed values of hypochromatic red cells at week 12 are presented. | At week 12 | 
| Hypochromatic Red Cells: Week 24 | The observed values of hypochromatic red cells at week 24 are presented. | At week 24 | 
| Leukocytes: Week 12 | The observed values of leukocytes at week 12 are presented. | At week 12 | 
| Leukocytes: Week 24 | The observed values of leukocytes at week 24 are presented. | At week 24 | 
| Lymphocytes: Week 12 | The observed values of lymphocytes at week 12 are presented. | At week 12 | 
| Lymphocytes: Week 24 | The observed values of lymphocytes at week 24 are presented. | At week 24 | 
| Lymphocytes to Leukocytes Ratio: Week 12 | Lymphocytes to leukocytes ratio at week 12 is presented. | At week 12 | 
| Lymphocytes to Leukocytes Ratio at Week 24 | Lymphocytes to leukocytes ratio at week 24 is presented. | At week 24 | 
| Monocytes: Week 12 | The observed values of monocytes at week 12 are presented. | At week 12 | 
| Monocytes: Week 24 | The observed values of monocytes at week 24 are presented. | At week 24 | 
| Monocytes to Leukocytes Ratio: Week 12 | Monocytes to leukocytes ratio at week 12 is presented. | At week 12 | 
| Monocytes to Leukocytes Ratio: Week 24 | Monocytes to leukocytes ratio at week 24 is presented. | At week 24 | 
| Neutrophils: Week 12 | The observed values of neutrophils at week 12 are presented. | At week 12 | 
| Neutrophils: Week 24 | The observed values of neutrophils at week 24 are presented. | At week 24 | 
| Neutrophils to Leukocytes Ratio: Week 12 | Neutrophils to leukocytes ratio at week 12 is presented. | At week 12 | 
| Neutrophils to Leukocytes Ratio: Week 24 | Neutrophils to leukocytes ratio at week 24 is presented. | At week 24 | 
| Platelets: Week 12 | The observed values of platelets at week 12 are presented. | At week 12 | 
| Platelets: Week 24 | The observed values of platelets at week 24 are presented. | At week 24 | 
| Reticulocytes to Erythrocytes Ratio: Week 12 | Reticulocytes to erythrocytes ratio at week 12 is presented. | At week 12 | 
| Reticulocytes to Erythrocytes Ratio: Week 24 | Reticulocytes to erythrocytes ratio at week 24 is presented. | At week 24 | 
| Alanine Aminotransferase: Week 12 | The observed values of alanine aminotransferase at week 12 are presented. | At week 12 | 
| Alanine Aminotransferase: Week 24 | The observed values of alanine aminotransferase at week 24 are presented. | At week 24 | 
| Albumin: Week 12 | The observed values of albumin at week 12 are presented. | At week 12 | 
| Albumin: Week 24 | The observed values of albumin at week 24 are presented. | At week 24 | 
| Alkaline Phosphatase: Week 12 | The observed values of alkaline phosphatase at week 12 are presented. | At week 12 | 
| Alkaline Phosphatase: Week 24 | The observed values of alkaline phosphatase at week 24 are presented. | At week 24 | 
| Aspartate Aminotransferase: Week 12 | The observed values of aspartate aminotransferase at week 12 are presented. | At week 12 | 
| Aspartate Aminotransferase: Week 24 | The observed values of aspartate aminotransferase at week 24 are presented. | At week 24 | 
| Bicarbonate: Week 12 | The observed values of bicarbonate at week 12 are presented. | At week 12 | 
| Bicarbonate: Week 24 | The observed values of bicarbonate at week 24 are presented. | At week 24 | 
| Bilirubin: Week 12 | The observed values of bilirubin at week 12 are presented. | At week 12 | 
| Bilirubin: Week 24 | The observed values of bilirubin at week 24 are presented. | At week 24 | 
| Calcium: Week 12 | The observed values of calcium at week 12 are presented. | At week 12 | 
| Calcium: Week 24 | The observed values of calcium at week 24 are presented. | At week 24 | 
| Chloride: Week 12 | The observed values of chloride at week 12 are presented. | At week 12 | 
| Chloride: Week 24 | The observed values of chloride at week 24 are presented. | At week 24 | 
| Cholesterol: Week 12 | The observed values of cholesterol at week 12 are presented. | At week 12 | 
| Cholesterol: Week 24 | The observed values of cholesterol at week 24 are presented. | At week 24 | 
| Creatinine: Week 12 | The observed values of creatinine at week 12 are presented. | At week 12 | 
| Creatinine: Week 24 | The observed values of creatinine at week 24 are presented. | At week 24 | 
| Direct Bilirubin: Week 12 | The observed values of direct bilirubin at week 12 are presented. | At week 12 | 
| Direct Bilirubin: Week 24 | The observed values of direct bilirubin at week 24 are presented. | At week 24 | 
| Glucose: Week 12 | The observed values of glucose at week 12 are presented. | At week 12 | 
| Glucose: Week 24 | The observed values of glucose at week 24 are presented. | At week 24 | 
| High-density Lipoprotein (HDL) Cholesterol: Week 12 | The observed values of HDL cholesterol at week 12 are presented. | At week 12 | 
| HDL Cholesterol: Week 24 | The observed values of HDL cholesterol at week 24 are presented. | At week 24 | 
| Hepcidin-25: Week 12 | The observed values of hepcidin-25 at week 12 are presented. | At week 12 | 
| Hepcidin-25: Week 24 | The observed values of hepcidin-25 at week 24 are presented. | At week 24 | 
| Low-density Lipoproteins (LDL) Cholesterol: Week 12 | The observed values of LDL cholesterol at week 12 are presented. | At week 12 | 
| LDL Cholesterol: Week 24 | The observed values of LDL cholesterol at week 24 are presented. | At week 24 | 
| Lipoprotein-a: Week 12 | The observed values of lipoprotein-a at week 12 are presented. | At week 12 | 
| Lipoprotein-a: Week 24 | The observed values of lipoprotein-a at week 24 are presented. | At week 24 | 
| Phosphate: Week 12 | The observed values of phosphate at week 12 are presented. | At week 12 | 
| Phosphate: Week 24 | The observed values of phosphate at week 24 are presented. | At week 24 | 
| Potassium: Week 12 | The observed values of potassium at week 12 are presented. | At week 12 | 
| Potassium: Week 24 | The observed values of potassium at week 24 are presented. | At week 24 | 
| Sodium: Week 12 | The observed values of sodium at week 12 are presented. | At week 12 | 
| Sodium: Week 24 | The observed values of sodium at week 24 are presented. | At week 24 | 
| Triglycerides: Week 12 | The observed values of triglyceride at week 12 are presented. | At week 12 | 
| Triglycerides: Week 24 | The observed values of triglycerides at week 24 are presented. | At week 24 | 
| Urea Nitrogen: Week 12 | The observed values of urea nitrogen at week 12 are presented. | At week 12 | 
| Urea Nitrogen: Week 24 | The observed values of urea nitrogen at week 24 are presented. | At week 24 | 
| Pre-dialysis Body Mass Index (BMI): Week 12 | Pre-dialysis BMI values at week 12 are presented. | At week 12 | 
| Pre-infusion BMI: Week 11 | Pre-infusion BMI values at week 11 are presented. | At week 11 | 
| Pre-dialysis Diastolic Blood Pressure: Week 12 | Pre-dialysis diastolic blood pressure values at week 12 are presented. | At week 12 | 
| Pre-dialysis Diastolic Blood Pressure: Week 24 | Pre-dialysis diastolic blood pressure values at week 24 are presented. | At week 24 | 
| Pre-infusion Diastolic Blood Pressure: Week 11 | Pre-infusion diastolic blood pressure values at week 11 are presented. | At week 11 | 
| Pre-dialysis Heart Rate: Week 12 | Pre-dialysis heart rate values at week 12 are presented. | At week 12 | 
| Pre-dialysis Heart Rate: Week 24 | Pre-dialysis heart rate values at week 24 are presented. | At week 24 | 
| Pre-infusion Heart Rate: Week 11 | Pre-infusion heart rate values at week 11 are presented. | At week 11 | 
| Pre-dialysis Respiration Rate: Week 12 | Pre-dialysis respiration rate values at week 12 are presented. | At week 12 | 
| Pre-dialysis Respiration Rate: Week 24 | Pre-dialysis respiration rate values at week 24 are presented. | At week 24 | 
| Pre-infusion Respiration Rate: Week 11 | Pre-infusion respiration rate values at week 11 are presented. | At week 11 | 
| Pre-dialysis Systolic Blood Pressure: Week 12 | Pre-dialysis values of systolic blood pressure at week 12 are presented. | At week 12 | 
| Pre-dialysis Systolic Blood Pressure: Week 24 | Pre-dialysis values of systolic blood pressure at week 24 are presented. | At week 24 | 
| Pre-infusion Systolic Blood Pressure: Week 11 | Pre-infusion systolic blood pressure values at week 11 are presented. | At week 11 | 
| Pre-dialysis Weight: Week 12 | Pre-dialysis weight values at week 12 are presented. | At week 12 | 
| Pre-infusion Weight: Week 11 | Pre-infusion weight values at week 11 are presented. | At week 11 | 
| Pre-dialysis Temperature: Week 12 | Pre-dialysis temperature values at week 12 are presented. | At week 12 | 
| Pre-dialysis Temperature: Week 24 | Pre-dialysis temperature values at week 24 are presented. | At week 24 | 
| Pre-infusion Temperature: Week 11 | Pre-infusion temperature values at week 11 are presented. | At week 11 | 
| Area Under the Serum Concentration Time Curve From Time 0 to Infinity (AUC 0-α) of COR-001 | Area under the serum concentration time curve from time 0 to infinity (AUC 0-α) of COR-001 is presented. | Week 1 (day 1, 3, and 5), Week 2 (day 8), Week 3 (day 15), Week 5 (day 29), Week 7 (day 43), Week 8 (day 50), Week 9 (day 57), Week 11 (day 71 and 75), Week 14 (day 92), Week 18 (day 120) and Week 35 (day 239). | 
| Elimination Half-life in the Initial Phase (t 1/2,α) | Elimination half-life in the initial phase (t 1/2,α) is presented from week 0 to week 35. | Week 1 (day 1, 3, and 5), Week 2 (day 8), Week 3 (day 15), Week 5 (day 29), Week 7 (day 43), Week 8 (day 50), Week 9 (day 57), Week 11 (day 71 and 75), Week 14 (day 92), Week 18 (day 120) and Week 35 (day 239). | 
| Elimination Half-life in the Terminal Phase (t 1/2, z) | Elimination half-life in the terminal phase(t 1/2, z) is presented from week 0 to week 35. | Week 1 (day 1, 3, and 5), Week 2 (day 8), Week 3 (day 15), Week 5 (day 29), Week 7 (day 43), Week 8 (day 50), Week 9 (day 57), Week 11 (day 71 and 75), Week 14 (day 92), Week 18 (day 120) and Week 35 (day 239). | 
| Maximum Serum Concentration (Cmax) | Maximum serum concentration (Cmax) of COR-001 from week 0 to week 35 is presented. | Week 1 (day 1, 3, and 5), Week 2 (day 8), Week 3 (day 15), Week 5 (day 29), Week 7 (day 43), Week 8 (day 50), Week 9 (day 57), Week 11 (day 71 and 75), Week 14 (day 92), Week 18 (day 120) and Week 35 (day 239). | 
| Impact of ADAs on Pharmacokinetics | Presence of ADA was a covariate for pharmacokinetics (PK) affecting V1 (volume of distribution for the central compartment). Impact of ADAs on V1 from baseline to week 35 is presented. In the below table, result presented is the bootstrap parameter estimate of the effect of ADA on V1 for a PK model that includes data for all arms combined. | Week 1 (day 1, 3, and 5), Week 2 (day 8), Week 3 (day 15), Week 5 (day 29), Week 7 (day 43), Week 8 (day 50), Week 9 (day 57), Week 11 (day 71 and 75), Week 14 (day 92), Week 18 (day 120) and Week 35 (day 239). |