Glomerulosclerosis, Focal Segmental
Conditions
Keywords
GW856553, Focal segmental glomerulosclerosis (FSGS), p38 mitogen-activated protein kinase (MAPK) inhibitor, losmapimod, nephrotic syndrome
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.
Interventions
DRUGLosmapimod
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)
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at the Indicated Time Points | Week 2, Week 4, Week 8, Week 16 and Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, Week 30 and Week 36 | 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. |
| Number of Participants With Complete Proteinuria Remissions at the Indicated Time Points | Week 2, Week 4, Week 8, Week 16 and Week 24 | 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. |
| Number of Participants Having Any Adverse Events (AEs), Serious Adverse Events (SAEs) | From start of the study treatment (Week 0) until the Follow-up phase (Week 36) | 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. |
| Number of Participants Withdrawn Due to Toxicities | From start of the study treatment (Week 0) until the Follow-up phase (Week 36) | 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. |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | 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) | 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). |
| Change From Baseline in Heart Rate at Indicated Time Points | 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) | 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). |
| Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | 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) | 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). |
| Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at Any Time During the Treatment Phase (Week 2 to Week 24) | 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. |
| Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | 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) | 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). |
| Change From Baseline in Serum Creatinine at Indicated Time Points | 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) | 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). |
| Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | 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) | 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). |
| Percent Change From Baseline in Cystatin C at Indicated Time Points | 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) | 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. |
| 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 | Week 0 (Pre-dose and 1, 2, 4, 6 hrs post-dose) | 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. |
| (AUC[0-tau]) of Losmapimod 15 mg in Plasma | 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) | 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. |
| Plasma Losmapimod 7.5 mg Maximum Observed Concentration (Cmax) | Week 0 (Pre-dose and 1, 2, 4, 6 hrs post-dose) | 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. |
| Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | 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) | 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). |
Countries
Canada, United States
Participant flow
Recruitment details
This single-arm, multicenter, fixed sequence open-label study consisted of 2 screening visits, run-in phase before the first dose of study treatment, followed by treatment phase in which participants received losmapimod 7.5 milligrams (mg) twice daily (BID) for 2 weeks and 15 mg BID for an additional 22 weeks, and a follow-up visit (12 weeks).
Pre-assignment details
A total of 29 participants were screened and entered into the run-in phase, of which 17 participants received at least one dose of losmapimod.
Participants by arm
| Arm | Count |
|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID Participants received losmapimod 7.5 mg BID (morning and evening), orally after 30 minutes (min.) of their starting meal for approximately 2 weeks. After all the pre-dose assessments at the Week 2 visit, participants received losmapimod 15 mg BID (2 tablets of 7.5 mg each, morning and evening), orally after 30 min. of their starting meal for approximately 22 weeks. Study treatment doses were separated by at least 6 hours. | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Other-Protocol-defined Stopping Criteria | 1 |
Baseline characteristics
| Characteristic | Losmapimod 7.5 mg BID / 15 mg BID |
|---|---|
| Age, Continuous | 40.4 Years STANDARD_DEVIATION 13.68 |
| Race/Ethnicity, Customized African American/African Heritage | 1 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 2 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 1 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 2 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 11 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 16 / 17 |
| serious Total, serious adverse events | 0 / 17 |
Outcome results
Primary
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.
Time frame: Week 2, Week 4, Week 8, Week 16 and Week 24
Population: Completed Treatment Population: comprised of participants who had completed \>=16 weeks of losmapimod treatment or who withdrew from the treatment. Participants who withdrew prior to Week 16 were considered as non-responders.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at the Indicated Time Points | Week 4, n=15 | 1 Participants |
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at the Indicated Time Points | Week 2, n= 17 | 0 Participants |
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at the Indicated Time Points | Week 8, n=15 | 0 Participants |
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at the Indicated Time Points | Week 16, n=13 | 0 Participants |
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at the Indicated Time Points | Week 24, n=13 | 0 Participants |
Secondary
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.
Time frame: Week 0 (Pre-dose and 1, 2, 4, 6 hrs post-dose)
Population: PK Population: All participants from whom a PK sample obtained and analyzed, included in the PK population.
Secondary
(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.
Time frame: 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)
Population: PK Population.
Secondary
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).
Time frame: 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)
Population: All Subject Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | GFR, Week 2, n= 17 | -0.29 milliliter/minute/1.73 square meters | Standard Deviation 8.844 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | GFR, Week 4, n= 16 | -1.87 milliliter/minute/1.73 square meters | Standard Deviation 12.148 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | GFR, Week 8, n= 15 | -5.00 milliliter/minute/1.73 square meters | Standard Deviation 10.522 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | GFR, Week 16, n= 13 | -3.00 milliliter/minute/1.73 square meters | Standard Deviation 15.422 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | GFR, Follow-up Week 30, n=15 | 4.87 milliliter/minute/1.73 square meters | Standard Deviation 19.108 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | GFR, Week 24, n= 13 | -0.38 milliliter/minute/1.73 square meters | Standard Deviation 17.524 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | GFR, End of study, n=4 | -7.00 milliliter/minute/1.73 square meters | Standard Deviation 14.095 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Glomerular Filtration Rate (GFR) at Indicated Time Points | GFR, Follow-up Week 36, n=17 | 4.24 milliliter/minute/1.73 square meters | Standard Deviation 20.398 |
Secondary
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).
Time frame: 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)
Population: All Subject Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Heart Rate at Indicated Time Points | Heart rate, Week 2, n= 17 | 2.6 bpm | Standard Deviation 7.05 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Heart Rate at Indicated Time Points | Heart rate, Week 4, n= 16 | 4.4 bpm | Standard Deviation 8.61 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Heart Rate at Indicated Time Points | Heart rate, Week 8, n= 15 | 2.3 bpm | Standard Deviation 7.45 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Heart Rate at Indicated Time Points | Heart rate, Week 16, n= 13 | 3.8 bpm | Standard Deviation 12.08 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Heart Rate at Indicated Time Points | Heart rate, End of study, n=4 | 1.3 bpm | Standard Deviation 10.31 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Heart Rate at Indicated Time Points | Heart rate, Follow-up Week 30, n=15 | 5.3 bpm | Standard Deviation 10.66 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Heart Rate at Indicated Time Points | Heart rate, Week 24, n= 13 | 1.5 bpm | Standard Deviation 8.41 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Heart Rate at Indicated Time Points | Heart rate, Follow-up Week 36, n=17 | 3.6 bpm | Standard Deviation 11.57 |
Secondary
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).
Time frame: 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)
Population: All Subject Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Albumin, Week 2, n= 17 | 0.4 Grams per liter (g/L) | Standard Deviation 2.29 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Albumin, Week 4, n= 15 | 0.2 Grams per liter (g/L) | Standard Deviation 3.03 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Albumin, Week 8, n= 15 | 0.4 Grams per liter (g/L) | Standard Deviation 4.34 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Albumin, Week 16, n= 13 | 1.8 Grams per liter (g/L) | Standard Deviation 3.39 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Albumin, Week 24, n= 13 | 1.8 Grams per liter (g/L) | Standard Deviation 3.44 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Albumin, Follow-up Week 36, n=17 | 1.8 Grams per liter (g/L) | Standard Deviation 4.73 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Total protein, Week 2, n= 17 | 0.0 Grams per liter (g/L) | Standard Deviation 2.87 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Total protein, Week 4, n= 16 | -0.6 Grams per liter (g/L) | Standard Deviation 3.63 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Albumin, End of study, n=4 | -1.8 Grams per liter (g/L) | Standard Deviation 9.64 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Albumin, Follow-up-U Week 30, n=15 | 1.9 Grams per liter (g/L) | Standard Deviation 4.22 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Total protein, Week 8, n= 15 | 0.8 Grams per liter (g/L) | Standard Deviation 6.38 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Total protein, Week 16, n= 13 | 2.4 Grams per liter (g/L) | Standard Deviation 5.09 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Total protein, Week 24, n= 13 | 2.8 Grams per liter (g/L) | Standard Deviation 4.69 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Total protein, End of study, n=4 | -1.0 Grams per liter (g/L) | Standard Deviation 13.14 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Total protein, Follow-up Week 30, n=15 | 2.2 Grams per liter (g/L) | Standard Deviation 4.04 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Albumin and Total Protein at Indicated Time Points | Total protein, Follow-up Week 36, n=17 | 2.7 Grams per liter (g/L) | Standard Deviation 5.58 |
Secondary
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).
Time frame: 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)
Population: All Subject Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AP, Week 4, n= 16 | -0.8 International Units/liter (IU/L) | Standard Deviation 8.92 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AP, Week 8, n= 15 | 3.1 International Units/liter (IU/L) | Standard Deviation 8.15 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AST, Week 2, n= 17 | 1.2 International Units/liter (IU/L) | Standard Deviation 3.34 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AST, Week 4, n= 16 | 6.4 International Units/liter (IU/L) | Standard Deviation 16.17 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AST, Week 8, n= 15 | 5.8 International Units/liter (IU/L) | Standard Deviation 13.99 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AST, Week 16, n= 13 | 2.2 International Units/liter (IU/L) | Standard Deviation 5.65 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | GGT, Follow-up Week 36, n=17 | -0.6 International Units/liter (IU/L) | Standard Deviation 13.18 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | ALT, Week 2, n= 17 | 1.8 International Units/liter (IU/L) | Standard Deviation 4.01 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | ALT, Week 4, n= 16 | 6.7 International Units/liter (IU/L) | Standard Deviation 9.44 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | ALT, Week 8, n= 15 | 7.1 International Units/liter (IU/L) | Standard Deviation 14.54 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | ALT, Week 16, n= 13 | 2.6 International Units/liter (IU/L) | Standard Deviation 6.02 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | ALT, Week 24, n= 13 | 1.2 International Units/liter (IU/L) | Standard Deviation 5.01 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | ALT, End of study, n=4 | 1.8 International Units/liter (IU/L) | Standard Deviation 3.95 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | ALT, Follow-up Week 30, n=15 | 0.5 International Units/liter (IU/L) | Standard Deviation 5.74 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | ALT, Follow-up Week 36, n=17 | 4.3 International Units/liter (IU/L) | Standard Deviation 9.47 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AP, Week 2, n= 17 | 0.6 International Units/liter (IU/L) | Standard Deviation 10.22 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AP, Week 16, n= 13 | 0.2 International Units/liter (IU/L) | Standard Deviation 9.04 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AP, Week 24, n= 13 | -0.8 International Units/liter (IU/L) | Standard Deviation 7.31 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AP, End of study, n=4 | -8.5 International Units/liter (IU/L) | Standard Deviation 21.39 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AP, Follow-up Week 30, n=15 | 2.5 International Units/liter (IU/L) | Standard Deviation 14.38 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AP, Follow-up Week 36, n=17 | 2.9 International Units/liter (IU/L) | Standard Deviation 20.23 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AST, Week 24, n= 13 | -0.3 International Units/liter (IU/L) | Standard Deviation 3.2 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AST, End of study, n=4 | -3.8 International Units/liter (IU/L) | Standard Deviation 8.18 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AST, Follow-up Week 30, n=15 | -0.5 International Units/liter (IU/L) | Standard Deviation 5.1 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | AST, Follow-up Week 36, n=17 | 2.0 International Units/liter (IU/L) | Standard Deviation 6.89 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | GGT, Week 2, n= 17 | -1.3 International Units/liter (IU/L) | Standard Deviation 5.87 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | GGT, Week 4, n= 16 | -2.0 International Units/liter (IU/L) | Standard Deviation 9.42 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | GGT, Week 8, n= 15 | -0.7 International Units/liter (IU/L) | Standard Deviation 13.45 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | GGT, Week 16, n= 13 | -1.6 International Units/liter (IU/L) | Standard Deviation 8.65 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | GGT, Week 24, n= 13 | -2.0 International Units/liter (IU/L) | Standard Deviation 7.68 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | GGT, End of study, n=4 | -10.0 International Units/liter (IU/L) | Standard Deviation 25.1 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Transferase (GGT) at Indicated Time Points | GGT, Follow-up Week 30, n=15 | -0.5 International Units/liter (IU/L) | Standard Deviation 7.75 |
Secondary
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).
Time frame: 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)
Population: All Subject Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Direct bilirubin, Week 2, n= 17 | -0.503 Micromoles per liter (umol/L) | Standard Deviation 1.0053 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Direct bilirubin, Week 8, n= 15 | -0.684 Micromoles per liter (umol/L) | Standard Deviation 0.8671 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Direct bilirubin, End of study, n=4 | 0.000 Micromoles per liter (umol/L) | Standard Deviation 1.3962 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Direct bilirubin, Follow-up Week 30, n=15 | -0.228 Micromoles per liter (umol/L) | Standard Deviation 0.883 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Total bilirubin, End of study, n=4 | 0.855 Micromoles per liter (umol/L) | Standard Deviation 2.2076 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Total bilirubin, Follow-up Week 36, n=17 | 1.006 Micromoles per liter (umol/L) | Standard Deviation 2.1848 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Direct bilirubin, Week 4, n= 16 | -0.107 Micromoles per liter (umol/L) | Standard Deviation 0.9811 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Direct bilirubin, Week 16, n= 13 | -0.263 Micromoles per liter (umol/L) | Standard Deviation 0.9485 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Direct bilirubin, Week 24, n= 13 | 0.000 Micromoles per liter (umol/L) | Standard Deviation 0 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Direct bilirubin, Follow-up Week 36, n=17 | 0.101 Micromoles per liter (umol/L) | Standard Deviation 1.2783 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Total bilirubin, Week 2, n= 17 | 0.503 Micromoles per liter (umol/L) | Standard Deviation 2.4754 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Total bilirubin, Week 4, n= 16 | 0.855 Micromoles per liter (umol/L) | Standard Deviation 1.5295 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Total bilirubin, Week 8, n= 15 | 0.114 Micromoles per liter (umol/L) | Standard Deviation 1.5112 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Total bilirubin, Week 16, n= 13 | 0.789 Micromoles per liter (umol/L) | Standard Deviation 2.2745 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Total bilirubin, Week 24, n= 13 | 0.921 Micromoles per liter (umol/L) | Standard Deviation 2.93 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Liver Function Parameters: Direct Bilirubin and Total Bilirubin at Indicated Time Points | Total bilirubin, Follow-up Week 30, n=15 | 0.684 Micromoles per liter (umol/L) | Standard Deviation 2.124 |
Secondary
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).
Time frame: 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)
Population: All Subject Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Serum Creatinine at Indicated Time Points | Serum creatinine, Week 16, n= 13 | -0.02692 Milligram per deciliter (mg/dl) | Standard Deviation 0.167252 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Serum Creatinine at Indicated Time Points | Serum creatinine, Week 24, n= 13 | -0.04538 Milligram per deciliter (mg/dl) | Standard Deviation 0.267071 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Serum Creatinine at Indicated Time Points | Serum creatinine, Follow-up Week 36, n=17 | 0.00588 Milligram per deciliter (mg/dl) | Standard Deviation 0.503079 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Serum Creatinine at Indicated Time Points | Serum creatinine, Week 2, n= 17 | 0.01294 Milligram per deciliter (mg/dl) | Standard Deviation 0.150738 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Serum Creatinine at Indicated Time Points | Serum creatinine, Week 4, n= 16 | 0.04187 Milligram per deciliter (mg/dl) | Standard Deviation 0.189076 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Serum Creatinine at Indicated Time Points | Serum creatinine, Week 8, n= 15 | 0.11933 Milligram per deciliter (mg/dl) | Standard Deviation 0.407387 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Serum Creatinine at Indicated Time Points | Serum creatinine, End of study, n=4 | 0.51000 Milligram per deciliter (mg/dl) | Standard Deviation 0.703468 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Serum Creatinine at Indicated Time Points | Serum creatinine, Follow-up Week 30, n=15 | -0.10000 Milligram per deciliter (mg/dl) | Standard Deviation 0.271662 |
Secondary
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).
Time frame: 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)
Population: All Subject Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Week 8, n= 15 | 2.0 Millimeter of mercury (mmHg) | Standard Deviation 13.5 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Week 24, n= 13 | -1.4 Millimeter of mercury (mmHg) | Standard Deviation 16.44 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Follow-up Week 30, n=15 | 0.5 Millimeter of mercury (mmHg) | Standard Deviation 15.94 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Follow-up Week 36, n=17 | 3.8 Millimeter of mercury (mmHg) | Standard Deviation 15.64 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Week 2, n= 17 | 1.5 Millimeter of mercury (mmHg) | Standard Deviation 6.21 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Week 8, n= 15 | 1.7 Millimeter of mercury (mmHg) | Standard Deviation 7.11 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Week 16, n= 13 | -3.0 Millimeter of mercury (mmHg) | Standard Deviation 9.87 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Week 24, n= 13 | 0.2 Millimeter of mercury (mmHg) | Standard Deviation 10.14 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, End of study, n=4 | 6.0 Millimeter of mercury (mmHg) | Standard Deviation 7.16 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Follow-up Week 30, n=15 | 1.3 Millimeter of mercury (mmHg) | Standard Deviation 9.85 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Follow-up Week 36, n=17 | 3.8 Millimeter of mercury (mmHg) | Standard Deviation 11.84 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Week 2, n= 17 | 3.5 Millimeter of mercury (mmHg) | Standard Deviation 9.87 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Week 4, n= 16 | 0.9 Millimeter of mercury (mmHg) | Standard Deviation 12.15 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Week 16, n= 13 | -1.8 Millimeter of mercury (mmHg) | Standard Deviation 13.16 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, End of study, n=4 | 11.3 Millimeter of mercury (mmHg) | Standard Deviation 9 |
| Losmapimod 7.5 mg BID / 15 mg BID | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Week 4, n= 16 | -1.2 Millimeter of mercury (mmHg) | Standard Deviation 7.81 |
Secondary
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.
Time frame: From start of the study treatment (Week 0) until the Follow-up phase (Week 36)
Population: All Subject Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants Having Any Adverse Events (AEs), Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants Having Any Adverse Events (AEs), Serious Adverse Events (SAEs) | Non-serious AEs | 16 Participants |
Secondary
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.
Time frame: Any time during the treatment phase (Week 2 to Week 24)
Population: Completed Treatment Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants Meeting the Definition of Responder for Reduction in Proteinuria at Any Time During the Treatment Phase (Week 2 to Week 24) | 1 Participants |
Secondary
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.
Time frame: Week 2, Week 4, Week 8, Week 16 and Week 24
Population: Completed Treatment Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants With Complete Proteinuria Remissions at the Indicated Time Points | Week 16, n= 13 | 0 Participants |
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants With Complete Proteinuria Remissions at the Indicated Time Points | Week 24, n= 13 | 0 Participants |
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants With Complete Proteinuria Remissions at the Indicated Time Points | Week 2, n= 17 | 0 Participants |
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants With Complete Proteinuria Remissions at the Indicated Time Points | Week 4, n= 15 | 0 Participants |
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants With Complete Proteinuria Remissions at the Indicated Time Points | Week 8, n= 15 | 0 Participants |
Secondary
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.
Time frame: From start of the study treatment (Week 0) until the Follow-up phase (Week 36)
Population: All Subject Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Number of Participants Withdrawn Due to Toxicities | 0 Participants |
Secondary
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.
Time frame: 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)
Population: All Subject Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Cystatin C at Indicated Time Points | Cystatin C, Week 24, n= 13 | -3.42 Percent change | Standard Deviation 19.061 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Cystatin C at Indicated Time Points | Cystatin C, End of study, n=4 | 24.70 Percent change | Standard Deviation 47.357 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Cystatin C at Indicated Time Points | Cystatin C, Follow-up Week 36, n=17 | 0.03 Percent change | Standard Deviation 28.071 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Cystatin C at Indicated Time Points | Cystatin C, Week 2, n= 17 | -6.15 Percent change | Standard Deviation 13.548 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Cystatin C at Indicated Time Points | Cystatin C, Week 4, N= 16 | -4.44 Percent change | Standard Deviation 18.61 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Cystatin C at Indicated Time Points | Cystatin C, Week 8, n= 15 | 2.93 Percent change | Standard Deviation 17.083 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Cystatin C at Indicated Time Points | Cystatin C, Week 16, n= 13 | -1.10 Percent change | Standard Deviation 17.267 |
Secondary
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.
Time frame: Baseline (Week 0), Week 2, Week 4, Week 8, Week 16, Week 24, End of study, Week 30 and Week 36
Population: All Subject Population: all eligible participants who received at least one dose of investigational drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio 24 hr, Week 16, n= 13 | -10.57111 Percent change | Standard Deviation 37.211084 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio 24 hr, Week 24, n= 13 | -0.59030 Percent change | Standard Deviation 29.616932 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio 24 hr, Week 2, n= 17 | -0.45807 Percent change | Standard Deviation 25.69689 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio 24 hr, Week 4, n= 15 | -0.07037 Percent change | Standard Deviation 28.954312 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio 24 hr, Week 8, n= 15 | 24.32547 Percent change | Standard Deviation 39.925052 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio 24 hr, End of study, n= 4 | 10.79660 Percent change | Standard Deviation 54.170928 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio 24 hr, Follow-up Week 36, n= 16 | -6.56589 Percent change | Standard Deviation 43.863442 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio spot, Week 2, n= 17 | 8.45052 Percent change | Standard Deviation 27.531444 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio spot, Week 4, n= 16 | 11.44257 Percent change | Standard Deviation 24.783744 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio spot, Week 8, n= 15 | 41.43955 Percent change | Standard Deviation 50.144228 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio spot, Week 16, n= 13 | -0.99691 Percent change | Standard Deviation 34.890578 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio spot, Week 24, n= 12 | 4.05899 Percent change | Standard Deviation 40.301958 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio spot, End of study, n= 4 | 13.88998 Percent change | Standard Deviation 57.089949 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio spot, Follow-up Week 30, n= 15 | 3.66036 Percent change | Standard Deviation 35.011255 |
| Losmapimod 7.5 mg BID / 15 mg BID | Percent Change From Baseline in Urinary Protein/Creatinine (Up/c) Ratio (Spot and 24 Hours [hr]) | Up/c ratio spot, Follow-up Week 36, n= 17 | -2.91757 Percent change | Standard Deviation 44.251282 |
Secondary
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.
Time frame: Week 0 (Pre-dose and 1, 2, 4, 6 hrs post-dose)
Population: PK Population.