20-Week Repeat Oral Dose Study of AKB-6548 in Participants With Chronic Kidney Disease and Anemia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the hemoglobin response (efficacy), safety, and tolerability of orally administered AKB-6548 in participants with Chronic Kidney Disease (pre-dialysis) with anemia with dosing for 20 weeks.

Official Title
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Phase 2b Randomized, Double-Blind, Placebo-Controlled Study to Assess the Pharmacodynamic Response, Safety, and Tolerability to 20 Weeks of Oral Dosing of AKB-6548 in Participants With Anemia Secondary to Chronic Kidney Disease (CKD), GFR Categories G3a-G5 (Stages 3, 4, AND 5) (Pre-Dialysis)

Conditions
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Anemia, Chronic Kidney Disease

Intervention / Treatment
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* Drug: AKB-6548
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 18 to 82 years of age, inclusive Chronic Kidney Disease with a GFR category of G3a-G5 and not yet on dialysis eGFR ≥ 10 and ≤ 65 mL/minute/1.73 m2 Anemia secondary to CKD with an ESA status and a Screening HGB as per protocol Iron replete with ferritin and TSAT levels as defined per protocol Key Exclusion Criteria: BMI > 44.0 kg/m2 Red blood cell transfusion within 11 weeks prior to the Screening visit Androgen therapy within the previous 21 days prior to the Screening visit Intravenous iron within the past 4 weeks prior to the Screening visit AST or ALT >1.8x ULN, alkaline phosphatase >2x ULN, or total bilirubin >1.5x ULN Screening ECG with QTc > 500 msec Uncontrolled hypertension Class III or IV congestive heart failure Myocardial infarction, acute coronary syndrome, or stroke within 6 months prior to the Screening visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 82 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AKB-6548<br> | Drug: AKB-6548<br>* Oral dose administered once daily for 20 weeks. Dose adjustment based on hemoglobin level as defined in the protocol.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Oral Placebo administered once daily for 20 weeks. Dose adjustment based on hemoglobin level as defined in the protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving a Successful Hemoglobin Response | Hemoglobin (Hgb) response was defined as participants with mean Hgb ≥11.0 grams per deciliter (g/dL) (average of Weeks 19 and 20) or increase in Hgb by ≥ 1.2 g/dL (average of Weeks 19 and 20) over pre-dose average (average of the two Hgb values obtained prior to dosing) without receiving Erythropoiesis-Stimulating Agents (ESA) or transfusion. | Weeks 19 and 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Hemoglobin Value ≥13.0 g/dL at Any Time During the Study | Participants who have experienced an excursion in Hgb to ≥13.0 g/dL at any time during the study were considered as failures. Data was presented for failures. | Up to 20 Weeks | 
| Percentage of Participants Achieving a Successful Hemoglobin Response, Determined Solely Based on the Hemoglobin Value | Hgb response was defined as participants with mean Hgb ≥11.0 g/dL (average of Weeks 19 and 20) or increase in Hgb by ≥ 1.2 g/dL (average of Weeks 19 and 20) over pre-dose average (average of the two Hgb values obtained prior to dosing). Analysis of this secondary outcome measure is a reanalysis of the primary outcome measure whereby the response was determined solely by the Hgb value and receiving rescue therapy did not make the participant a failure. | Weeks 19 and 20 | 
| Percentage of Participants Achieving a Successful Hemoglobin Response in ESA Treatment naïve Group | Hgb response was defined as participants with mean Hgb ≥11.0 g/dL (average of Weeks 19 and 20) or increase in Hgb by ≥ 1.2 g/dL (average of Weeks 19 and 20) over pre-dose average (average of the two Hgb values obtained prior to dosing) without receiving ESA or transfusion. Participants were assigned to 1 of 3 study groups based on their ESA status at the screening visit: Naïve, Previously Treated and Actively Treated. Analysis of this secondary outcome measure was performed in the ESA Treatment Naïve group, defined as participants who had never received treatment with an ESA and who had a screening Hgb level of ≤10.5 g/dL. | Weeks 19 and 20 | 
| Percentage of Participants Achieving a Successful Hemoglobin Response in ESA Previously Treated Group | Hgb response was defined as participants with mean Hgb ≥11.0 g/dL (average of Weeks 19 and 20) or increase in Hgb by ≥ 1.2 g/dL (average of Weeks 19 and 20) over pre-dose average (average of the two Hgb values obtained prior to dosing) without receiving ESA or transfusion. Participants were assigned to 1 of 3 study groups based on their ESA status at the screening visit: Naïve, Previously Treated and Actively Treated. Analysis of this secondary outcome measure was performed in the ESA Previously Treated group, defined as participants who had previously received ≥1 dose of an ESA, had been off of ESA therapy for ≥11 weeks at the time of screening, and had a screening Hgb level of ≤10.5 g/dL. | Weeks 19 and 20 | 
| Percentage of Participants Achieving a Successful Hemoglobin Response in ESA Actively Treated Group | Hgb response was defined as participants with mean Hgb ≥11.0 g/dL (average of Weeks 19 and 20) or increase in Hgb by ≥ 1.2 g/dL (average of Weeks 19 and 20) over pre-dose average (average of the two Hgb values obtained prior to dosing) without receiving ESA or transfusion. Participants were assigned to 1 of 3 study groups based on their ESA status at the screening visit: Naïve, Previously Treated and Actively Treated. Analysis of this secondary outcome measure was performed in the ESA Actively Treated group, defined as participants who had been actively treated with an ESA for a minimum of 4 months before screening, had received at least 2 doses within the last 4 months, had received their last dose within 6 weeks before screening, and had a screening Hgb level ≥9.5 g/dL and ≤12.0 g/dL. | Weeks 19 and 20 | 
| Percentage of Participants Achieving a Successful Hemoglobin Response, Analyzed in mITT Population | Hgb response was defined as participants with mean Hgb ≥11.0 g/dL (average of Weeks 19 and 20) or increase in Hgb by ≥ 1.2 g/dL (average of Weeks 19 and 20) over pre-dose average (average of the two Hgb values obtained prior to dosing) without receiving ESA or transfusion. Analysis of this secondary outcome measure was performed in the mITT population. | Weeks 19 and 20 | 
| Change From Baseline in Hemoglobin | Blood samples were collected to assess Hgb. Baseline was defined as the mean of two samples obtained prior to dosing (Screening and Baseline). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A positive change from Baseline indicated Hgb concentration increased. | Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 19 and Week 20 | 
| Absolute Values of Hemoglobin | Blood samples were collected at indicated time points for analysis of hemoglobin | Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 19 and Week 20 | 
| Change From Baseline in Hematocrit | Blood samples were collected to assess Hematocrit. Baseline was defined as the mean of two samples obtained prior to dosing (Screening and Baseline). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A positive change from Baseline indicated Hematocrit concentration increased. | Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 19 and Week 20 | 
| Absolute Values of Hematocrit | Blood samples were collected at indicated time points for analysis of Hematocrit. | Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 19 and Week 20 | 
| Change From Baseline in Red Blood Cell Count | Blood samples were collected to assess red blood cell count. Baseline was defined as the mean of two samples obtained prior to dosing (Screening and Baseline). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A positive change from Baseline indicated red blood cell count increased. | Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 19 and Week 20 | 
| Absolute Values of Red Blood Cell Count | Blood samples were collected at indicated time points for analysis of red blood cell count. | Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 19 and Week 20 | 
| Change From Baseline in Reticulocyte Count | Blood samples were collected to assess reticulocyte count. Baseline was defined as mean of two samples obtained prior to dosing (Screening and Baseline). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A positive change from Baseline indicated reticulocyte count increased. | Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 19 and Week 20 | 
| Absolute Values of Reticulocyte Count | Blood samples were collected at indicated time points for analysis of reticulocyte count. | Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 19 and Week 20 | 
| Percentage of Participants Who Received ESA Rescue | Participants were administered epoetin alfa or darbepoetin alfa as a rescue medication who met the Hgb rescue criteria in addition to having experienced a clinically significant worsening of their anemia or the symptoms of anemia. | Up to 20 Weeks | 
| Mean Number of ESA Rescue Doses Administered Per Participant | Participants were administered epoetin alfa or darbepoetin alfa as a rescue medication who have met the Hgb rescue criteria in addition to having experienced a clinically significant worsening of their anemia or the symptoms of anemia. | Up to 20 Weeks | 
| Percentage of Participants Who Received Packed Red Blood Cell Transfusion Rescue | Participants were administered packed red blood cell transfusion as a rescue medication who have met the Hgb rescue criteria in addition to having experienced a clinically significant worsening of their anemia or the symptoms of anemia | Up to 20 Weeks | 
| Number of Packed Red Blood Cell Transfusion Administered Per Participant | Participants were administered packed red blood cells as a rescue medication who have met the Hgb rescue criteria in addition to having experienced a clinically significant worsening of their anemia or the symptoms of anemia. | Up to 20 Weeks | 
| Time to First Transfusion or ESA Rescue Medication Intake | Rescue therapy was defined as red blood cell transfusion or ESA administration in participants meeting Hgb rescue criteria in addition to having experienced a clinically significant worsening of their anemia or the symptoms of anemia. | Up to 20 Weeks | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) | An Adverse Event (AE) was defined as any untoward medical occurrence, signs, symptoms, disease, or laboratory or physiological observations occurring in a participant administered with drug, regardless of a causal relationship with that treatment or usage. This also included all suspected adverse medication reactions, reactions from medication overdose, abuse, withdrawal, sensitivity, toxicity, unrelated illnesses, including worsening a pre-existing condition, injury, or accidents. Serious Adverse Events (SAEs) was defined as any life-threatening condition; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or death. | Up to 20 Weeks | 
| Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameter Values | Parameters assessed for laboratory values included hematology, serum chemistry, and urinalysis. The investigator was responsible for reviewing laboratory results for clinically significant changes. | Up to 20 Weeks | 
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Parameters assessed for vital signs included sitting (at rest for a minimum of 5 minutes) heart rate, respiratory rate, body temperature, and blood pressure. The investigator was responsible for reviewing laboratory results for clinically significant changes. | Up to 20 Weeks | 
| Number of Participants With Clinically Abnormal 12-Lead Electrocardiogram (ECG) Findings | A standard 12-lead ECG was performed following dosing in a supine position for approximately 10 minutes. ECGs were taken prior to blood draws when possible. The investigator was responsible for reviewing laboratory results for clinical significance. | Up to 20 Weeks | 
| Number of Participants With Clinically Significant Changes From Baseline in Physical Examination Findings | A Baseline physical examination was performed at screening. Otherwise, abbreviated physical examinations were conducted and were to include heart, lung, and abdomen. The investigator was responsible for reviewing laboratory results for clinically significant changes. | Up to 20 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIF, anemia, chronic kidney disease, CKD, chronic renal insufficiency, renal impairment, erythropoietin, kidney, oral anemia treatment, hemoglobin, hypoxia-inducible factor, hypoxia-inducible factor prolyl-hydroxylase inhibitor, HIF-PHI, efficacy, safety, pharmacokinetics