A Voxelotor for Sickle Cell Anemia Patients at Highest Risk for Progression of Chronic Kidney Disease

Study Overview
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Brief Summary
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This study is a single center, prospective exploratory pilot study of Sickle Cell Anemia (SCA) participants. The study will enroll patients with early stages of sickle cell nephropathy (Chronic Kidney Disease (CKD) stage 1 or 2) who are at the highest risk of CKD progression (presence of both hemoglobinuria and urine albumin concentration ≥ 30 mg/g creatinin

Detailed Description
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This study is a single center, prospective exploratory pilot study of Sickle Cell Anemia (SCA) participants, age ≥18 years, with SCA. The study will enroll patients with early stages of sickle cell nephropathy (Chronic Kidney Disease (CKD) stage 1 or 2) who are at the highest risk of CKD progression (presence of both hemoglobinuria and urine albumin concentration ≥ 30 mg/g creatinin

Official Title
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A Pilot Study of Voxelotor for Sickle Cell Anemia Patients at Highest Risk for Progression of Chronic Kidney Disease

Conditions
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Sickle Cell Disease, Sickle Cell Nephropathy

Intervention / Treatment
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* Drug: Voxelotor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Documentation of SCA genotype (HbSS or HbSβ0-thalassemia) may be based on history of laboratory testing or must be confirmed by laboratory testing during screening Participants have had urine dipstick defined hemoglobinuria (positive for blood (+1 or higher) and ≤ 2 red blood cells per high power field) on 2 prior outpatient visits Participants with albuminuria (urine albumin ≥ 30 mg/g creatinine) and an eGFR ≥ 60 mL/min/1.73m2 calculated using the CKD-EPI equation on 2 prior outpatient visits Age ≥18 years Hemoglobin (Hb) ≥ 5.5 and ≤ 10.0 g/dL during screening For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable for at least 90 days prior to signing the ICF and with no anticipated need for dose adjustments or initiation during the study, in the opinion of the Investigator Endari stable dose for one month. For participants taking an angiotensin converting enzyme (ACE)-inhibitor or angiotensin receptor blocker, the dose must be stable for at least 90 days prior to signing the ICF and with no anticipated need for dose adjustments or initiation during the study, in the opinion of the Investigator Participants, who if female and of child bearing potential, are using highly effective methods of contraception from study start to 30 days after the last dose of study drug, and who if male are willing to use barrier methods of contraception, from study start to 30 days after the last dose of study drug Participant has provided documented informed consent (the informed consent form [ICF] must be reviewed and signed by each participant Exclusion Criteria Female who is breast feeding or pregnant Patients who are receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received a RBC transfusion for any reason within 30 days of signing the ICF or at any time during the screening period Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior to signing the ICF (i.e., a vaso-occlusive event cannot be within 14 days prior to ICF) Hepatic dysfunction characterized by alanine aminotransferase (ALT) >4 × ULN Participants with clinically significant bacterial, fungal, parasitic or viral infection which require therapy: Participants with acute bacterial infection requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed Participants with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the central laboratory) < 60mL/min/1.732, on chronic dialysis, or have received a kidney transplantation History of malignancy within the past 2 years prior to treatment Day 1 requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy) History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following: Unstable angina pectoris or myocardial infarction or elective coronary intervention Congestive heart failure requiring hospitalization Uncontrolled clinically significant arrhythmias Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable) Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent (or medical device) Inadequate venous access as determined by the investigator/site staff Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent Receipt of erythropoietin or other hematopoietic growth factors within 28 days of signing ICF or anticipated need for such agents during the study

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: 6 participants will take voxelotor 1500mg once a day 6 participants will be observed while receiving standard of care (SOC)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Voxelot<br>Voxelotor 1500mg once a day | Drug: Voxelotor<br>* Voxelotor 1500mg once a day<br>|
| Other: Standard of Care (SOC)<br>Observational while receiving SOC | Drug: Voxelotor<br>* Voxelotor 1500mg once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in albuminuria in voxelotor-treated SCA patients compared to the observation patients by a one-sided test | Albuminuria will be analyzed comparing the mean values from the Week 47 and 48 visits to the mean values from the baseline and screening visits | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values in albuminuria | Proportion of subjects achieving a 25% decline in albuminuria in the voxelotor-treated group compared to the observation group | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values in kidney function measure | 24 hour urine protein | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values in In kidney function measure | 24 hour urine eGFR | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values in kidney function measure | 24 hour urine albumin concentration | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values in kidney function measure | 24 hour serum creatinine | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values in Kidney function measure | 24 hour serum cystatin C | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values in Kidney function measure | 24 hour serum BUN | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values in Kidney function measure | CKD stage | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values kidney function measure | 24 hour urine retinol binding protein | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values kidney function measure | 24 hour urine β2 microglobulin | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values kidney function measure | Plasma cell-free hemoglobin | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values kidney function measure | Urine hemoglobin | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values kidney function measure | Urine dipstick-defined hemoglobinuria) | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values markers of hemolysis | Lactate dehydrogenase (LDH) | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values markers of hemolysis | Aspartate aminotransferase (AST) | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values markers of hemolysis | Indirect bilirubin | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values markers of hemolysis | Reticulocyte% | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values markers of hemolysis | Hemoglobin concentration | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values kidney injury biomarker | Urine nephrin | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values kidney injury biomarker | Urine podocalyxin | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values kidney injury biomarker | Urine KIM-1 | 48weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values kidney injury biomarker | Urine NGAL | 48 weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values oxidative injury biomarker | Serum Methylenedioxyamphetamine (MDA) | 48weeks | 
| Change from the average of the Screening and Baseline values to the Week 47 and Week 48 values oxidative injury biomarker | Serum 8-OHd | 48 weeks |