A Study of CCX140-B in Subjects With FSGS

Study Overview
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Brief Summary
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Study to Evaluate the Safety and Efficacy of CCX140-B in Subjects with FSGS to be conducted in the North America, Europe and Australia

Detailed Description
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Study to Evaluate the Safety and Efficacy of CCX140-B in Subjects with Focal Segmental Glomerulosclerosis (FSGS) to be conducted in the North America, Europe and Australia. The aim of this study is to evaluate the effect of treatment with CCX140-B, a selective antagonist of C-C chemokine receptor type 2 in subjects with focal segmental glomerulosclerosis on urinary protein excretion as assessed by changes in urine protein to creatinine ratio (UPCR)

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Study to Evaluate the Safety and Efficacy of CCX140-B in Subjects With Focal Segmental Glomerulosclerosis (FSGS)

Conditions
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FSGS, Focal Segmental Glomerulosclerosis, Glomerulosclerosis

Intervention / Treatment
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* Other: Placebo
* Drug: CCX140-B
* Drug: CCX140-B
* Drug: CCX140-B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged 18-75 UPCR ≥ 1 g protein/g creatinine (or at 113 mg.mmol) at screening Diagnosis of FSGS based on renal biopsy or high risk genetic variant Diagnosis of one of primary FSGS based on characteristic histopathology, medical history and clinical course or FSGS secondary to genetic variants associated with increased risk or severity. Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73m2 Clinical stable blood pressure not to exceed 145/95 mmHg RAAS blockers must be stable for at least 4 weeks prior to screening and projected to remain stable through week 12, unless adjustments are required for management of hypertension. Immunosuppressive or immunomodulatory therapy must be stable for at least 4 weeks prior to screening and projected to remain stable through study week 12 Glucocorticoids must be stable for at least 4 weeks prior to screening and projected to remain stable through study week 12. Both genders of childbearing potential must agree to use adequate contraception during and for at least 3 months after the last dose of study drug. Subjects must be willing and able to give written Informed Consent and to comply with protocol requirements. Subjects must be judged to be otherwise fit for the study by the Investigator. - Exclusion Criteria: Pregnant or nursing History of organ transplantation On an organ transplant waiting list or anticipated organ transplant within 6 months of screening Anti-CD20 monoclonal antibodies within 20 months of screening are exclusionary. Subjects that used anti CD20 monoclonal antibodies prior to week 20 are allowed with confirmed recovery of CD20+ B cell population to within normal range Plasmapheresis within 12 weeks of screening BMI ≥40 Participation in any clinical study of an investigational product within 12 weeks or 5 half-lives of screening Currently on dialysis or likely to require dialysis during the blinded treatment phase of the study. History or presence of any form of cancer within 5 years of screening except excised basal cell or squamous cell carcinoma or carcinoma in situ such as cervical or breast carcinoma in situ that has been excised or completed resected without evidence or recurrence. Positive HBV, HCV, or HIV viral screening test. Subjects who have received highly effective therapy for HCV demonstrated to have negative viral titers for at least 6 months following discontinuation of treatment, will be considered to have a negative HCV screening test Renal disease associated with disorders other than FSGS that is active or has significant risk of progressing during the course of the study. Disorders that are associated with FSGS lesions. Evidence of tuberculosis. Evidence of hepatic disease with the exception that isolated INR elevation in the absence of other significant liver enzyme abnormalities is explained by anticoagulant therapy, (e.g. warfarin) Hematologic abnormalities as follows: Hb <8 g/dL, platelets <50,000, ANC <1000 cells/µL) at baseline. QTcF greater than 450 msec. History of alcohol or illicit drug abuse or of lithium, pamidronate and interferon. Recreational use of cannabis is not excluded where legal. History of gastrointestinal conditions that may interfere with study medication compliance. Known hypersensitivity to CCX140-B or inactive ingredients of the CCX140-B tablets (including microcrystalline cellulose, starch, crospovidone, magnesium stearate, or silicon dioxide). History or presence of systemic disorder other than FSGS that requires, or is expected to require, systemic glucocorticoids or immune modulators during the study; topical or inhaled glucocorticoids and immune modulators are not excluded. History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the subject at unacceptable risk for study participation. Subjects taking strong CYP3A4 inducers or strong CYP3A4 inhibitors within two weeks prior to screening. Subjects taking lithium or interferon; subjects taking non-steroidal anti-inflammatory agents (NSAIDS) chronically (intermittent, i.e. occasional NSAIDS for pain or fever is discouraged, but is not excluded). -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Sequential Assignment
Interventional Model Description: Randomized, placebo-controlled, Phase 2
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group A<br>Placebo (N=10) | Other: Placebo<br>* Three placebo tablets, taken twice daily (BID), per os, for 84 days (12 weeks)<br>* Other names: CCX140-B Placebo;|
| Experimental: Group B<br>CCX140-B 5 mg once daily (N=10) | Drug: CCX140-B<br>* One 5 mg CCX140-B tablet and 2 placebo tablets in the morning; 3 placebo tablets in the evening; per os, for 84 days.<br>* Other names: Group B;|
| Experimental: Group C<br>CCX140-B 10 mg twice daily (N=10) | Drug: CCX140-B<br>* Two 5 mg CCX140-B tablets and 1 placebo tablet, taken BID; per os, for 84 days.<br>* Other names: Group C;|
| Experimental: Group D<br>CCX140-B 15 mg twice daily (N=10) | Drug: CCX140-B<br>* Three 5 mg CCX140-B tablets, taken BID; per os, for 84 days.<br>* Other names: Group D;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in UPCR at Week 12 | Least squared mean ratio of UPCR (Urine protein g:creatinine g) compared to baseline at Week 12 in the ITT population. ITT- Intent to treat | Baseline to Week 12 | 
| Number of Participants of Treatment-emergent AEs (TEAE), TEAEs Leading to Study Withdrawal, and Serious Adverse Events (SAEs) | TEAEs leading to study withdrawal means study drug discontinuation in this endpoint. | Baseline to Week 12, and Week 12 to Week 24 | 
| Change From Baseline in Activated Partial Thromboplastin Time | Normal Range: 23.9 - 40.0 | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Alanine Aminotransferase | Normal Range: 6 - 41 U/L | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Alkaline Phosphatase |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Amylase | Normal range: 22-123 U/L | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Aspartate Aminotransferase | Normal range : 9-34 U/L | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Bicarbonate | Normal range: 21-33 mmol/L | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Bilirubin | Normal range: 0.1-1.10 mg/dL | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma C Reactive Protein | Normal range: 0.0-3.0 mg/L | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Calcium | Normal range: 8.5-10.5 mg/dL | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Chloride | Normal range: 95-110 mmol/L | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Cholesterol | Normal range: 100-200 mg/dL | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Creatine Kinase | Normal range: 23-210 U/L | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Creatinine | Normal range: 0.62-1.44 mg/dL | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Cystatin C | Normal range: 0.53-0.95 mg/L | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Direct Bilirubin |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Glucose |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma HDL Cholesterol | HDL -High-density lipoprotein | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Indirect Bilirubin |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma LDL Cholesterol | LDL - Low-density lipoprotein | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Lactate Dehydrogenase |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Pancreatic Lipase |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Magnesium |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Phosphate |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Potassium |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Protein |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Prothrombin Intl. Normalised Ratio |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Prothrombin Time |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Sodium |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Triglycerides |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Urate |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Plasma Urea Nitrogen |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Basophils |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Basophils/Leukocytes |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Eosinophils |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Eosinophils/Leukocytes |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Erythrocyte Mean Corpuscular HGB Concentration | HGB - Hemoglobin | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Erythrocyte Mean Corpuscular Hemoglobin |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Erythrocyte Mean Corpuscular Volume |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Erythrocytes |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Hematocrit |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Hemoglobin |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Leukocytes |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Lymphocytes |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Lymphocytes/Leukocytes |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Monocytes/Leukocytes |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Neutrophils |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Neutrophils/Leukocytes |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Platelets |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Reticulocytes/Erythrocytes |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Urine Albumin |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Urine Creatinine |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Change From Baseline in Urine Protein |  | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12 and Week 24 | Change from baseline in eGFR calculated by the CKD-EPI Cystatin C equation, CKD-EPI Creatinine equation, CKD-EPI Creatinine-Cystatin C equation and MDRD Creatinine equation at Weeks 12 and 24. CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration; MDRD: Modification of Diet in Renal Disease Open label extension covers Baseline to Week 12 and Baseline to Week 24 | Baseline to Week 12 (double-blind treatment period) and Week 12 to Week 24 (open-label extension) | 
| Proportion of Subjects Achieving Complete or Partial Renal Remission at Week 12 and Week 24 | 1. Proportion of subjects achieving complete renal remission by the following definition at Weeks 12 and 24 o Reduction in UPCR to <0.3 g/g o Serum albumin within normal range (for subjects with abnormal serum creatinine levels at baseline, return to normal levels for that age group; for subjects with normal serum creatinine levels at baseline, final value within 20% of baseline levels) 2. Proportion of subjects achieving partial remission defined as UPCR reduction of ≥50% from baseline and UPCR <3.5 g/g (definition 1), assessed at Weeks 12 and 24 3. Proportion of subjects achieving partial remission defined Decrease in UPCR to less than 1.5 g/g and at least a 40% reduction in proteinuria from baseline (definition 2), assessed at Weeks 12 and 24 | Endpoint at Week 12 for Double-Blind Treatment Period and Endpoint at Week 24 for Open-Label Extension |