A Phase II, Repeat Dose, Proof of Mechanism Study of Losmapimod to Reduce Proteinuria in Patients With Focal Segmental Glomerulosclerosis (FSGS)

Study Overview
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Brief Summary
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This is a single-arm, multicenter, open-label Phase II, proof-of-mechanism study to evaluate the efficacy, safety, tolerability and pharmacokinetics of losmapimod in approximately 21 subjects with primary (idiopathic) focal segmental glomerulosclerosis (FSGS) and substantive proteinuria as indicated by a Urinary protein/creatinine Up/c ratio >=2 gram/gram (g/g) or 24 hr urine protein >=2 g/day. Losmapimod will be orally administered twice daily over a 24-week treatment phase followed by a 12-week follow-up for safety and relapse assessments.

Official Title
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Study of Losmapimod to Reduce Proteinuria in Idiopathic Focal Segmental Glomerulosclerosis (FSGS)

Conditions
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Glomerulosclerosis, Focal Segmental

Intervention / Treatment
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* Drug: Losmapimod


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is between 18 and 70 years of age inclusive. Subject has a clinical diagnosis of primary (idiopathic) focal segmental glomerulosclerosis (FSGS) as verified by renal biopsy. This must be confirmed by independent review of the histopathology report and/or biopsy specimen(s) by the study central pathologist. Subject will have substantive proteinuria, as indicated by a spot Up/c>=2g/g or 24 hour urine total protein >=2g/day. A female subject is eligible to participate if she is of non-childbearing potential; criteria to be considered of 'non-childbearing potential' as described in the protocol. A female subject is eligible to participate if she is of child-bearing potential. Females of child-bearing potential must agree to use two of the approved contraception methods listed in the protocol from 14 days before the first dose of study drug until 30 days after the last dose of study drug. Only females of child-bearing potential with negative pregnancy test, as determined by serum human chorionic gonadotropin (hCG) test at screening and urine hCG test prior to dosing at baseline visit and during the study at the indicated times, will be administered losmapimod. Subject is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form and is willing and able to return for all study visits. Exclusion Criteria: Subject has received a live attenuated vaccine within 6 weeks of first study treatment. Subject has collapsing FSGS lesion. Subject has secondary FSGS or renal impairment from a condition that is not FSGS. Causes of secondary FSGS include but are not limited to: Drugs and toxins: Analgesics, heroin, cocaine and pamidronate; Infectious or parasitic diseases: Hepatitis B, Hepatitis C, HIV (known as HIV-Associated Nephropathy), parvovirus; Adaptive structural-functional response likely mediated by glomerular hypertrophy/hyperfiltration: Hemodynamic factors - With reduced renal mass: solitary kidney, renal allograft, renal dysplasia, renal agenesis, oligomeganephronia, segmental hypoplasia, vesicoureteric reflux; Hemodynamic causes - Without reduced renal mass: sickle cell nephropathy, congenital cyanotic heart disease, hypertension; Malignancies: Lymphomas and other malignancies; for skin or cervical cancer consult medical monitor; Diabetic Nephropathy; Other forms of glomerular nephropathy: focal proliferative glomerulonephritis (IgA nephropathy, lupus, nephritis, pauci-immune focal necrotizing and crescentic glomerulonephritis), hereditary nephritis, hypertensive arterionephrosclerosis, membranous glomerulopathy, thrombotic microangiopathies; Miscellaneous: Alport syndrome, sarcoidosis, radiation nephritis; Genetic forms of FSGS (e.g. patient is known to carry FSGS causing genetic mutation). History of congestive heart failure. History of diabetes mellitus type 1 or 2. History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. Clinically significant systemic illness or infection within the last 28 days (e.g. chronic persistent or acute infection) that is likely to result in deterioration of the subject's condition or affect the subject's safety during the study. Any condition or situation, including clinically significant abnormalities in screening laboratory assessments (not related to the disease), which in the opinion of the Investigator could confound the results of the study or put the subject at undue risk. History of sensitivity or intolerance to the study treatment (i.e. losmapimod), or a history of drug or other allergy that in the opinion of the Investigator or GSK Medical Monitor contraindicates participation. Estimated GFR <45 milliliter(mL)/minutes(min)/1.73m^2 (using 4-variable Modification of Diet in Renal Disease [MDRD] formula) at screening. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >= 2xUpper Limit of Normal (ULN); alkaline phosphatase and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Single QTc value obtained on the baseline ECG: QTc >=450 milliseconds (msec) (machine or manual overread); or QTc >=480 msec in subjects with Bundle Branch Block. If a single QTc is abnormal, then the averaged QTc values of triplicate electrocardiograms (ECGs) obtained (each separated by at least 5 min) will be utilized to determine eligibility. Hypertensive as defined as blood pressure (BP) >140/90 millimetres of mercury (mmHg) at the end of screening: If the single BP measurement is above 140 mmHg systolic or 90 mmHg diastolic, then the BP measurement can be repeated. The subject must have 2 consecutive BP readings that are less than 140 mmHg systolic and 90 mmHg diastolic, and each measurement must be separated by at least 15 minutes, to be eligible for participation in this study. A female subject is pregnant or nursing. Positive serology for chronic infection: have a historically positive Human Immunodeficiency Virus (HIV) test or test positive at screening for HIV; serologic evidence of Hepatitis B (HB) infection based on the results of testing for hepatitis B surface antigen (HBsAg), and anti- hepatitis B core antigen (HBc), positive test for Hepatitis C antibody confirmed by HCV RNA. If HCV RNA is not available, then the positive test for Hepatitis C antibody alone would be exclusionary. Subject having donated blood or blood products in excess of 500 mL within a 56 day period prior to the first dose of the current study. Participation: The subject has participated in a clinical trial where they previously received losmapimod; the subject has participated in a clinical trial and has received an investigational product 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) prior to the first dose of the current study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Losmapimod (GW856553X)<br>The subjects will be administered with 7.5 mg (1 tablet) of losmapimod following the completion of the Baseline (time zero) assessments. Subjects will continue to take one tablet in the morning and one tablet in the evening for approximately 2 weeks. After all the pre-dose assessments are completed at the Week 2 visit, subjects will be administered the first 15 mg (2 tablets) dose. Subjects will continue to take two tablets in the morning and two tablets in the evening every day for approximately 22 weeks. Doses of study treatment will be separated by at least 6 hours | Drug: Losmapimod<br>* Losmapimod (micronized GW856553X) will be supplied as a film coated white, 7 mm round, biconvex, plain faced, tablet. Oral doses of losmapimod, 7.5 mg (1 tablet) or 15 mg (2 tablets), will be taken twice daily (BID) with food and swallowed whole (not chewed or crushed)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at the Indicated Time Points | Proteinuria is defined as the presence of an excess of serum proteins in the urine. Participant was considered as a responder on achieving >=50 percent reduction in proteinuria from Baseline (measured as 24 hour total protein) and also having a stable renal function of >=70 percent of Baseline estimated glomerular filtration rate (eGFR) at end of treatment (>=16 Weeks). Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed. | Week 2, Week 4, Week 8, Week 16 and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at Any Time During the Treatment Phase (Week 2 to Week 24) | Proteinuria is defined as the presence of an excess of serum proteins in the urine. Participant was considered as responder on achieving >=50 percent reduction in proteinuria from Baseline (measured as 24 hour total protein) and also having a stable renal function of >=70 percent of Baseline eGFR at any time during the treatment phase of the study. Reduction in proteinuria assessment at any time during the treatment phase of the study was done by utilizing a responder analysis. | Any time during the treatment phase (Week 2 to Week 24) | 
| Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Reduction in proteinuria was measured by the Up/c ratio (spot and 24 hr) at Baseline, Week 2, 4, 8, 16, 24, end of study and at Follow-up (FU) visits Week 30 and 36. Spot urine sample was provided by the participants on site. The 24 hour urine collection started with the second morning void and ended with the first morning void on the following day; generally, 24 hour urine collection was initiated the day prior to the study visit. Baseline was defined as the value obtained at Week 0. Percent change from Baseline was calculated as change from Baseline value divided by Baseline value multiplied by 100. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed. | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, Week 30 and Week 36 | 
| Number of Participants With Complete Proteinuria Remissions at the Indicated Time Points | Incidence of complete remissions at any time point was defined as 24 hour total protein <0.3 gram (g) per Day and maintenance of >=70 percent of Baseline eGFR throughout the treatment period. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed. | Week 2, Week 4, Week 8, Week 16 and Week 24 | 
| Number of Participants Having Any Adverse Events (AEs), Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinaemia were categorized as SAE. Participants having any AE or SAE were included in the analysis. | From start of the study treatment (Week 0) until the Follow-up phase (Week 36) | 
| Number of Participants Withdrawn Due to Toxicities | Participants were monitored from start of the study treatment (Week 0) up to Week 36 for development of toxicity. Participants who developed toxicity during the period were to be withdrawn from the study. | From start of the study treatment (Week 0) until the Follow-up phase (Week 36) | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Blood pressure was measured in a sitting position after 5 minutes rest with comfortably seated, legs uncrossed and the back and arm supported, such that the middle of the cuff on the upper arm is at the level of the right atrium and asked to remove all clothing that covered the location of cuff placement. It was recorded at Screening, Baseline, Week 2, Week 4, Week 8, Week 16, Week 24, End of study, and until the follow-up visit (Week 30 and Week 36). Vital sign measurements were repeated if the values were < 80 mmHg or > 140 mmHg SBP and <40 mmHg or >90 mmHg for DBP. Baseline was defined as the value obtained on Week 0. Change from Baseline was calculated as visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, and until the follow-up visit (Week 30 and Week 36) | 
| Change From Baseline in Heart Rate at Indicated Time Points | Heart rate was measured at screening, Baseline and throughout the treatment phase (Week 24) and Follow-up phase (Week 36). Heart rate measurement was repeated if the values are calculated <50 beats per minute. (bpm) or >110 bpm after the start of dosing. Baseline was defined as the value obtained at Week 0. Change from Baseline was calculated as visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, and until the follow-up visit (Week 30 and Week 36) | 
| Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | Blood samples were collected at Screening (Week -4 and -2), Baseline (Week 0) and at Weeks 2, 4, 8, 16, 24 and Follow-up (Week 30 and 36) to evaluate ALT, AST, AP and GGT. Baseline was defined as the value obtained at Week 0. Change from Baseline was calculated as visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, and until the follow-up visit (Week 30 and Week 36) | 
| Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Clinical chemistry parameters: direct bilirubin and total bilirubin were assessed at Baseline (Week 0) and at Weeks 2, 4, 8, 16 24, End of studyand Follow-up (Week 30 and 36) phase. Baseline was defined as the value obtained at Week 0. Change from Baseline was calculated as visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, and until the follow-up visit (Week 30 and Week 36) | 
| Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Clinical chemistry parameters: albumin and total protein were assessed at Baseline (Week 0), at Weeks 2, 4, 8, 16, 24 and Follow up (Week 30 and 36) phase. Baseline was defined as the value obtained at Week 0. Change from Baseline was calculated as visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, and until the follow-up visit (Week 30 and Week 36) | 
| Change From Baseline in Serum Creatinine at Indicated Time Points | Serum creatinine were assessed at Baseline (Week 0), at Weeks 2, 4, 8, 16, 24 and Follow-up (Week 30 and 36) phase. Baseline was defined as the value obtained at Week 0. Change from Baseline was calculated as visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, and until the follow-up visit (Week 30 and Week 36) | 
| Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | eGFR was calculated by using the 4-variable Modification of Diet in Renal Disease (MDRD) at Baseline (Week 0), at Weeks 2, 4, 8, 16, 24 and Follow-up (Week 30 and 36) phase. Baseline was defined as the value obtained at Week 0. Change from Baseline was calculated as visit value minus value at Baseline. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, and until the follow-up visit (Week 30 and Week 36) | 
| Percent Change From Baseline in Cystatin C at Indicated Time Points | Cystatin C was assessed at Baseline (Week 0), at Weeks 2, 4, 8, 16, 24 and Follow-up (Week 30 and 36) phase. Baseline was defined as the value obtained at Week 0. Change from Baseline was calculated as visit value minus value at Baseline. | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, and until the follow-up visit (Week 30 and Week 36) | 
| Area Under Concentration-time Curve (AUC) From Time Zero to Time t (AUC[0-t]) and AUC From Time Zero to the End of Dosing Period (AUC[0-tau]) of Losmapimod 7.5 mg in Plasma | Pharmacokinetics (PK) of losmapimod 7.5 mg was evaluated in participants with focal segmental glomerulosclerosis (FSGS) using AUC over the dosing interval of losmapimod 7.5 mg. PK samples were collected at Week 0 (pre-dose and 1, 2, 4, 6 hrs post-dose). Plasma concentration-time data were collected only up to 6 hours post the first 7.5 mg dose and only up to 2 hours post the first 15 mg dose and were not adequate to conduct a noncompartmental analysis to compare with historical data. | Week 0 (Pre-dose and 1, 2, 4, 6 hrs post-dose) | 
| (AUC[0-tau]) of Losmapimod 15 mg in Plasma | PK of losmapimod 15 mg was evaluated in participants with FSGS using AUC over the dosing interval of losmapimod 15 mg. PK samples were collected at Week 2 (Pre-dose, 2 hrs post-dose) and Week 4, 8, 16, 24 (one of the following post-dose times: 0-2 hrs, 2-4 hrs, 4-6 hrs, and 6-8 hrs post-dose). Plasma concentration-time data were collected only up to 6 hours post the first 7.5 mg dose and only up to 2 hours post the first 15 mg dose and were not adequate to conduct a noncompartmental analysis to compare with historical data. | Week 2 (Pre-dose, 2 hrs post-dose) and Week 4, 8, 16, 24 (at one of the following post-dose times: 0-2 hrs, 2-4 hrs, 4-6 hrs, and 6-8 hrs post-dose) | 
| Plasma Losmapimod 7.5 mg Maximum Observed Concentration (Cmax) | PK of losmapimod 7.5 mg was evaluated in participants with FSGS using Cmax PK samples were collected at Week 0 (pre-dose and 1, 2, 4, 6 hrs post-dose). Plasma concentration-time data were collected only up to 6 hours post the first 7.5 mg dose and only up to 2 hours post the first 15 mg dose and were not adequate to conduct a noncompartmental analysis to compare with historical data. | Week 0 (Pre-dose and 1, 2, 4, 6 hrs post-dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GW856553, Focal segmental glomerulosclerosis (FSGS), p38 mitogen-activated protein kinase (MAPK) inhibitor, losmapimod, nephrotic syndrome