Phase 2 Study of Roxadustat in Participants With Anemia and Chronic Kidney Disease Not Requiring Dialysis

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the safety, tolerability, and pharmacodynamic effects of different oral doses of roxadustat administered 2 times a week (BIW) or 3 times a week (TIW) for up to 4 weeks to participants with chronic kidney disease (CKD) not requiring dialysis.

Detailed Description
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This study in participants with CKD not requiring dialysis was conducted in 2 parts (designated Part 1 and Part 2). Part 1 evaluated roxadustat doses at 1.0 and 2.0 milligrams/kilograms (mg/kg). Part 2 evaluated roxadustat doses at 0.7, 1.5, and 2.0 mg/kg. On 08 May 2007, the Food and Drug Administration (FDA) placed a clinical hold on the study until evaluation of a report of a death due to fulminant hepatic failure in a participant with CKD in a FibroGen-sponsored clinical trial of another hypoxia inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) (FG-2216) being investigated for treatment of anemia in participants with CKD and other diseases. The clinical hold resulted in early termination of Part 1 of the study. On 24 March 2008, the FDA lifted the clinical hold and Part 2 of this study started.

Official Title
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A Randomized, Single-blind, Placebo-controlled, 4-Week Treatment Study of the Safety and Biologic Activity of Escalating Multiple Oral Doses of FG-4592 in Subjects With Chronic Kidney Disease Not Requiring Dialysis

Conditions
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Chronic Kidney Disease, Anemia

Intervention / Treatment
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* Drug: Roxadustat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 80 years of age. Participants aged over 75 years but otherwise meet all other participant selection criteria will be evaluated on a case-by-case basis and can be included in this study, per discretion of Sponsor's physician representative such as medical monitor or clinical leader. Chronic Kidney Disease Stage 3 or 4 with hemoglobin <11.0 grams (g)/deciliter (dL). Normal iron studies. Normal folate and vitamin B12 levels. Liver function tests within normal limits at screening. Absence of active or chronic rectal bleeding. Absence of diagnosis of age-related macular degeneration (AMD), diabetic macular edema, or diabetic proliferative retinopathy that is likely to require treatment during the trial. Female participants must not be pregnant nor breastfeeding and agree to use acceptable method of contraception. Male participants with partners who can have children must agree to use a medically acceptable method of contraception. Exclusion Criteria: Seropositive for HIV. History of chronic liver disease. History of polycystic kidney disease (PKD). Uncontrolled hypertension (diastolic BP >110 millimeter of mercury (mmHg) or systolic BP >170 mmHg at screening). New York Heart Association Class III or IV congestive heart failure. Recent myocardial infarction or acute coronary syndrome. History of myelodysplastic syndrome. Any history of malignancy or a known genetic predisposition for developing cancer (for example, with diagnostic markers suggesting a genetic predisposition of cancer) except for curatively resected basal cell carcinoma of skin, squamous cell carcinoma of skin, cervical carcinoma in situ, or resected benign colonic polyps. Active inflammatory infection or chronic inflammatory disease. Any clinically significant and uncontrolled medical condition considered a high risk for participation in an investigational study. Blood clots within 4 weeks. History of ongoing hemolysis or diagnosis of hemolytic syndrome. Known history of bone marrow fibrosis. History of hemosiderosis or hemochromatosis. Androgen therapy within 12 weeks. Red blood cell transfusion within 12 weeks. Therapy with an erythropoiesis stimulating agent (ESA) such as human recombinant erythropoietin within the past 60 days. Intravenous iron supplementation within the past 60 days. Currently taking dapsone or acetaminophen >2.6 g/day. History of prior organ transplantation. Alcohol consumption greater than 3 or more drinks per day within the past year. Use of an investigational medication or participation in an investigational study within 4 weeks preceding Day 1. Positive urine toxicology screen for a substance that has not been prescribed for the participant.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Roxadustat 0.7 mg/kg BIW<br>Participants will receive roxadustat 0.7 mg/kg BIW orally with doses administered at least 68 hours apart for 29 days. | Drug: Roxadustat<br>* Capsule<br>* Other names: FG-4592;|
| Experimental: Roxadustat 0.7 mg/kg TIW<br>Participants will receive roxadustat 0.7 mg/kg TIW orally with doses administered at least 46 hours apart for 26 days. | Drug: Roxadustat<br>* Capsule<br>* Other names: FG-4592;|
| Experimental: Roxadustat 1.0 mg/kg BIW<br>Participants will receive roxadustat 1.0 mg/kg BIW orally with doses administered at least 72 hours apart for 29 days. | Drug: Roxadustat<br>* Capsule<br>* Other names: FG-4592;|
| Experimental: Roxadustat 1.0 mg/kg TIW<br>Participants will receive roxadustat 1.0 mg/kg TIW orally with doses administered at least 48 hours apart for 26 days. | Drug: Roxadustat<br>* Capsule<br>* Other names: FG-4592;|
| Experimental: Roxadustat 1.5 mg/kg BIW<br>Participants will receive roxadustat 1.5 mg/kg BIW orally with doses administered at least 68 hours apart for 29 days. | Drug: Roxadustat<br>* Capsule<br>* Other names: FG-4592;|
| Experimental: Roxadustat 1.5 mg/kg TIW<br>Participants will receive roxadustat 1.5 mg/kg TIW orally with doses administered at least 46 hours apart for 26 days. | Drug: Roxadustat<br>* Capsule<br>* Other names: FG-4592;|
| Experimental: Roxadustat 2.0 mg/kg BIW<br>Participants will receive roxadustat 2.0 mg/kg BIW orally with doses administered at least 68 hours apart for 29 days. | Drug: Roxadustat<br>* Capsule<br>* Other names: FG-4592;|
| Experimental: Roxadustat 2.0 mg/kg TIW<br>Participants will receive roxadustat 2.0 mg/kg TIW orally with doses administered at least 46 hours apart for 26 days. | Drug: Roxadustat<br>* Capsule<br>* Other names: FG-4592;|
| Placebo Comparator: Placebo<br>Participants will receive placebo orally, matching to the roxadustat dose, number of days per week, and duration. | Drug: Placebo<br>* Capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Safety Outcome Measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Treatment Discontinuation (Parts 1 and 2 Combined) | An adverse event (AE) was any untoward medical event in a participant who received study drug whether or not the event is considered drug related. TEAEs defined as an AE beginning after first dose of study drug until 28 days after last dose of study drug or existing AEs that worsened after first dose of study drug until the participant's last study visit. Severe AEs defined as incapacitating, inability to perform usual activities. Drug-related TEAEs defined as TEAEs with possible, probable, or definite relationship to study drug. Serious AE criteria included death, life-threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed here. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 16 (End of Study (EoS]) | 
| Co-Primary Efficacy Outcome Measure: Change From Baseline in Hb at Day 26-29 (End of Treatment) | Mean Hb change from baseline was analyzed by treatment group and study visit. Baseline was defined as the mean of last 3 available values prior to the first dose. | Baseline, End of Treatment (EoT) (Day 26 for TIW Dosing or Day 29 for BIW Dosing) | 
| Co-Primary Efficacy Outcome Measure: Change From Baseline in Hb at Week 8 (2 Weeks of Follow Up) | Mean Hb change from baseline was analyzed by treatment group and study visit. Baseline is defined as the mean of last 3 available values prior to the first dose. | Baseline, Week 8 (2 Weeks of Follow Up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Hemoglobin Response (Not Due to a RBC Transfusion or IV Iron Supplementation During Treatment) | Hb response defined as an increase in Hb from baseline by ≥1.0 g/dL (not due to red blood cell transfusion or IV iron supplementation during treatment). The baseline for Hb was defined as the mean of the last 3 available Hb values obtained prior to the first dose. | Baseline up to Day 26-29 (EoT), up to Week 8 (2 weeks of follow up), and up to Week 16 (EoS, 4 weeks of follow up) | 
| Plasma Roxadustat Concentration (Part 2) |  | Predose on Days 3 (TIW dose groups) or 4 (BIW dose groups), 8, 15, 22, and 26 (TIW dose groups) or 29 (BIW dose groups) | 
| Change From Baseline in Plasma Erythropoietin in Part 1 Participants at Day 26 or Day 29 | Baseline is defined as the last value obtained prior to the first dose. | Baseline (Day 1), 1, 2, 3, 4, 6, 8, 12, 18, 24, 48, and 72 hours on Day 26 (TIW Dosing) or Day 29 (BIW Dosing) | 
| Change From Baseline in Plasma Erythropoietin in Part 2 Participants at 4, 8, 12, and 24 Hours on Day 1 | Baseline is defined as the last value obtained prior to the first dose. | Baseline, 4, 8, 12, and 24 hours on Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney, Chronic Kidney Disease, CKD, Stage 3 or 4 Chronic Kidney Disease, Renal, Anemia, Oral anemia treatment, Hemoglobin levels, Blood count, Erythropoietin