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

Glomerulosclerosis, Focal Segmental Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02000440
• Other study ID #: 117283
• Status: Completed
• Phase: Phase 2
• First received: November 27, 2013
• Last updated: January 16, 2017
• Start date: July 2014
• Est. completion date: May 2016

Study information

• Verified date: January 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: May 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Glomerulosclerosis, Focal Segmental
• Proteinuria

Intervention

Drug:
• Losmapimod
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)

Locations

Country	Name	City	State
Canada	GSK Investigational Site	Edmonton	Alberta
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Vancouver	British Columbia
United States	GSK Investigational Site	Ann Arbor	Michigan
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	New Orleans	Louisiana
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Reduction in proteinuria at the end of treatment (>=16 weeks)	The reduction in proteinurea will be assessed by responder analysis. A Responder is defined as >=50 percent reduction in proteinuria (24 hour total protein) from baseline with a maintenance of renal function (>=70 percent of baseline Estimated Glomerular Filtration Rate [eGFR])	From Baseline up to Week 24
Secondary	Reduction in proteinuria at any time during treatment	The reduction in proteinurea will be assessed by responder analysis. A Responder is defined as >=50 percent reduction in proteinuria (24 hour total protein) from baseline with a maintenance of renal function (>=70 percent of baseline eGFR)	From Baseline up to Week 24
Secondary	Proteinuria responses	Urine sample will be collected for evaluation of proteinuria responses including incidence of complete remissions which is defined as proteinuria 24 hour total protein <0.3 g/day and maintenance of >=70 percent of baseline eGFR throughout treatment period	From Baseline up to Week 24
Secondary	Safety and tolerability of losmapimod	Safety and tolerability assessments including: adverse events (AEs), serious adverse events (SAEs), subject withdrawals due to toxicities, changes in clinical laboratory values (liver function tests [LFTs], serum creatinine, eGFR, cystatin C) and vital signs	From Baseline up to Week 36
Secondary	Pharmacokinetics (PK) of losmapimod and metabolite (GSK198602)	Blood samples will be collected for the assessment of plasma exposure post first dose and area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC [0-t]) (7.5 milligram [mg]), area under the plasma concentration-time curve during a dosage interval (AUC[0-tau]) (7.5 mg and 15 mg), and maximum observed concentration (Cmax) (7.5 mg)	Baseline (pre-dose, 1, 2, 4, and 6 hours post-dose), Week 2 (pre-dose and 2 hours post-dose), Weeks 4, 8, 16 and 24 at one of the post-dose times (0 to 2 hours/2 to 4 hours/4 to 6 hours/6 to 8 hours post-dose)
Secondary	Reduction in proteinuria by assessment of Up/c (urine protein creatinine) ratio	Up/c change from baseline will be used to confirm the findings of the total 24-hour urine protein.	From Baseline up to Week 24