Clinical trial NCT02000440: A Phase II, Repeat Dose, Proof of Mechanism Study of Losmapimod to Reduce Proteinuria in Patients With Focal Segmental Glomerulosclerosis (FSGS)
Official title: Study of Losmapimod to Reduce Proteinuria in Idiopathic Focal Segmental Glomerulosclerosis (FSGS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Glomerulosclerosis, Focal Segmental
Keywords: GW856553
Focal segmental glomerulosclerosis (FSGS)
p38 mitogen-activated protein kinase (MAPK) inhibitor
losmapimod
nephrotic syndrome
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-12-04
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at the Indicated Time Points
timeFrame: Week 2, Week 4, Week 8, Week 16 and Week 24
Secondary outcomes:
measure: Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at Any Time During the Treatment Phase (Week 2 to Week 24)
timeFrame: Any time during the treatment phase (Week 2 to Week 24)
measure: Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr])
timeFrame: Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, Week 30 and Week 36
measure: Number of Participants With Complete Proteinuria Remissions at the Indicated Time Points
timeFrame: Week 2, Week 4, Week 8, Week 16 and Week 24
measure: Number of Participants Having Any Adverse Events (AEs), Serious Adverse Events (SAEs)
timeFrame: From start of the study treatment (Week 0) until the Follow-up phase (Week 36)
measure: Number of Participants Withdrawn Due to Toxicities
timeFrame: From start of the study treatment (Week 0) until the Follow-up phase (Week 36)
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: 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)
measure: Change From Baseline in Heart Rate at Indicated Time Points
timeFrame: 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)
measure: Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points
timeFrame: 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)
measure: Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points
timeFrame: 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)
measure: Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points
timeFrame: 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)
measure: Change From Baseline in Serum Creatinine at Indicated Time Points
timeFrame: 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)
measure: Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points
timeFrame: 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)
measure: Percent Change From Baseline in Cystatin C at Indicated Time Points
timeFrame: 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)
measure: 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
timeFrame: Week 0 (Pre-dose and 1, 2, 4, 6 hrs post-dose)
measure: (AUC[0-tau]) of Losmapimod 15 mg in Plasma
timeFrame: 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)
measure: Plasma Losmapimod 7.5 mg Maximum Observed Concentration (Cmax)
timeFrame: Week 0 (Pre-dose and 1, 2, 4, 6 hrs post-dose)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Stanford
country: United States
facility: GSK Investigational Site
state: California
city: New Orleans
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: