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



Status:Completed
Conditions:Endocrine, Nephrology
Therapuetic Areas:Endocrinology, Nephrology / Urology
Healthy:No
Age Range:18 - 70
Updated:12/10/2016
Start Date:July 2014
End Date:May 2016

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

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.


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.
We found this trial at
9
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Ann Arbor, Michigan 48109
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Chapel Hill, North Carolina 27599
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Cleveland, Ohio 44195
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Cleveland, OH
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Columbus, Ohio 43219
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Columbus, OH
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Edmonton, Alberta
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Edmonton,
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Los Angeles, California 90025
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Los Angeles, CA
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New Orleans, Louisiana 70112
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New Orleans, LA
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Philadelphia, Pennsylvania 19104
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Philadelphia, PA
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Stanford, California 94305
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Stanford, CA
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