A Phase II, Repeat Dose, Proof of Mechanism Study of Losmapimod to Reduce Proteinuria in Patients With Focal Segmental Glomerulosclerosis (FSGS)
Condition: Glomerulosclerosis, Focal Segmental
MeSH terms: Proteinuria; Glomerulosclerosis, Focal Segmental
Intervention: Losmapimod
Intervention description: 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)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: GW856553; Focal segmental glomerulosclerosis (FSGS); p38 mitogen-activated protein kinase (MAPK) inhibitor; losmapimod; nephrotic syndrome

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.
    

Eligibility criteria:

        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.