Clinical Trial Results:
A Phase 2, Double-Blind, Randomized Safety and Efficacy Study of Glasdegib (PF-04449913) versus Placebo in Patients with Myelofibrosis Previously Treated with Ruxolitinib
Summary
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EudraCT number |
2014-001048-40 |
Trial protocol |
GB ES AT FR |
Global end of trial date |
31 Jan 2018
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Results information
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Results version number |
v2(current) |
This version publication date |
18 Jan 2019
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First version publication date |
03 Dec 2017
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Other versions |
v1 |
Version creation reason |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
B1371013
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02226172 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Pfizer Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Feb 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jan 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of the lead-in cohort was to assess the safety and tolerability of glasdegib in patients with primary or secondary myelofibrosis (MF) who had been previously treated with 1 or more Janus kinase inhibitors (JAKis).
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Protection of trial subjects |
This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects. The final protocol and any amendments were reviewed and approved by the Institutional Review Board(s) and/or Independent Ethics Committee(s) at each of the investigational centers participating in the study.
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Background therapy |
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Evidence for comparator |
- | ||
Actual start date of recruitment |
06 Oct 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Japan: 5
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Country: Number of subjects enrolled |
United States: 16
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Worldwide total number of subjects |
21
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
4
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From 65 to 84 years |
17
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85 years and over |
0
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Recruitment
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Recruitment details |
In this study, 2 cohorts were involved lead-in and randomized cohort. Lead-in cohort was followed by randomized cohort. Though the drug was considered safe and tolerable in Myelofibrosis, but a key secondary efficacy end point was not met. Therefore, continuation into the randomized cohort did not proceed. | ||||||||||||||||||
Pre-assignment
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Screening details |
Subjects were screened at 1 visit or over multiple visits across a 4 week period. Following this, subjects entered the treatment phase of the study. | ||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Arm title
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Glasdegib Lead-in | ||||||||||||||||||
Arm description |
Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Glasdegib
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Investigational medicinal product code |
PF-04449913
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Glasdegib administered orally at a daily starting dose of 100 mg with approximately 8 ounces (240 mL) of water (in the morning, at the same time each day) on a continuous regimen of 28-day cycles. Subjects requiring dose reduction(s) were administered multiples of 25 mg tablets
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Baseline characteristics reporting groups
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Reporting group title |
Glasdegib Lead-in
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Reporting group description |
Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Glasdegib Lead-in
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Reporting group description |
Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles. |
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End point title |
Percentage of Subjects Achieving Spleen Volume Reduction (SVR) ≥35% as Measured by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT) Scan at Week 24 in the Randomized Cohort [1] | ||||||
End point description |
The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
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End point type |
Primary
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End point timeframe |
Week 24
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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Notes [2] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Treatment –Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort [3] | ||||||||||
End point description |
An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug (up to Week 131) that were absent before treatment or that worsened relative to pretreatment state.AEs included both serious and non-serious adverse event.All subjects treated in the lead-in portion of the study.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 131
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Treatment Emergent Treatment –Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort [4] | ||||||||||
End point description |
Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose of study drug (up to Week 131) that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator. AEs included both serious and non-serious adverse event. All subjects treated in the lead-in portion of the study.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 131
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Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects with Treatment Emergent Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03: Lead-in Cohort [5] | ||||||||||
End point description |
AE was untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. SAE was AE resulting in any outcomes or deemed significant for any other reason: death;initial or prolonged inpatient hospitalization;life-threatening experience; persistent or significant disability.Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug (up to Week 131) that were absent before treatment or that worsened relative to pretreatment state.AE were assessed according to maximum severity grading based on NCI CTCAE Version 4.03.Grade 1=mild;Grade 2=moderate:within normal limits:Grade 3=severe or medically significant but not immediately life-threatening:Grade 4=life-threatening or disabling:urgent intervention indicated;Grade 5=death.Only categories with at least 1 subject with event were reported. All subjects treated in lead-in portion of the study.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 131
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Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects With Laboratory Abnormalities: Lead-in Cohort [6] | ||||||
End point description |
Abnormality:hematology:hemoglobin less than(<)0.8*lower limit of normal(LLN),platelets <0.5*LLN greater than(>)1.75*upper limit of normal(ULN),white blood cell count(WBC)<0.6* LLN>1.5*ULN,lymphocytes,total neutrophils<0.8* LLN>1.2* ULN,band Cells, basophils,eosinophils,monocytes>1.2*ULN,blast cells>1.0*ULN.Coagulation:activated partial thromboplastin time,prothrombin international ratio >1.1* ULN.Liver function: bilirubin >1.5*ULN, AST,ALT,lactate dehydrogenase,alkaline phosphatase>3.0*ULN,protein,albumin<0.8* LLN >1.2*ULN. Renal:blood urea nitrogen,creatinine >1.3*ULN,uric acid>1.2*ULN.Electrolytes: sodium<0.95*LLN >1.05*ULN,potassium,chloride,calcium,magnesium<0.9* LLN>1.1*ULN,phosphate<0.8*LLN >1.2*ULN.Chemistry:glucose<0.6*LLN >1.5*ULN,creatine kinase >2.0*ULN,amylase,lipase >1.5*ULN.Urinalysis:protein,blood >1.0*ULN,red blood cells,WBC>=20,epithelial cells >=6,casts,granular casts,hyaline >1,cellular casts,crystals>=1,bacteria>20.All subjects treated in lead-in portion of study.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 131
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Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects with Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and above Hematological Test Abnormalities: Lead-in Cohort [7] | ||||||||||
End point description |
Anemia(grade[g]1:<LLNto10 gram per deciliter[g/dL],g2:<10 to 8g/dL,g3:<8g/dL, g4:lifethreatening);platelet (g1:<LLN to 75*10^3/millimeter[mm]^3, g2:<75*10^3/mm^3 to 50*10^3/mm^3, g3:<50*10^3/mm^3 to 25*10^3/mm^3, g4:<25*10^3/mm^3); lymphopenia (g1:<LLN to 8*10^2/mm^3, g2:<8*10^2 to 5*10^2/mm^3, g3:<5*10^2 to 2*10^2/mm^3, g4:<2*10^2/mm^3);neutrophil (Absolute) (g1:<LLN to 15*10^2/mm^3, g2:<15*10^2 to 10*10^2/mm^3, g3:<10*10^2 to 5*10^2/mm^3, g4:<5*10^2/mm^3); white blood cell count(g1:<LLN to 3*10^3/mm^3, g2:<3*10^3 to 2*10^3/mm^3, g3:<2*10^3 to 1*10^3/mm^3, g4:<1*10^3/mm^3); hemoglobin (g1:increase in hemoglobin level >0 to 2 g/dL above ULN or above baseline if baseline is above ULN, g2:increase in hemoglobin level>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3: increase in hemoglobin level>4 g/dL above ULN or above baseline if baseline is above ULN). All subjects treated in lead-in portion of study.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 131
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Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects with Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and above Chemistry Test Abnormalities: Lead-in Cohort [8] | ||||||||||
End point description |
ALT/AST g1:>ULN 3*ULN, g2:>3-5*ULN, g3:>5 20*ULN, g4:>20*ULN);Alkaline Phosphatase(g1:>ULN 2.5*ULN,g2:>2.5-5*ULN, g3:>5 20*ULN, g4:>20*ULN); Creatinine (g1:>ULN-1.5*ULN,g2:>1.5-3*ULN, g3:>3 6*ULN, g4:>6*ULN);hyperglycemia(g1:>ULN-160,g2:>160 250, g3:>250 500, g4:>500mg/dL);bilirubin(total) (g1:>ULN-1.5*ULN, g2:>1.5-3*ULN, g3:>3 10*ULN,g4:>10*ULN);hypoglycaemia(g1:<LLN-55,g2:<55-40, g3:<40 30,g4:<30mg/dL); hyperkalemia (g1:>ULN-5.5,g2:>5.5-6, g3:>6 7,g4:>7mmol/L);hypokalemia (g1:<LLN-3,g2:<LLN-3, g3:<3 2.5, g4:<2.5mmol/L);hypermagnesemia (g1:>ULN-3,g3:>3 8, g4:>8mg/dL);hypocalcemia (g1:<LLN-8,g2:<8-7, g3:<7-6, g4:<6mg/dL); hypercalcemia (g1:>ULN-11.5,g2:>11.5-12.5, g3:>12.5-13.5, g4:>13.5mg/dL); hypomagnesemia (g1:<LLN-1.2,g2:<1.2-0.9,g3:<0.9-0.7, g4:<0.7mg/dL); hyponatremia (g1:<LLN-130,g3:<130-120, g4:<120mmol/L);hypoalbuminemia (g1:<LLN-3,g2:<3 2,g3:<2, g4:lifethreatening);hypophosphatemia(g1:<LLN-2.5,g2:<2.5-2, g3:<2-1, g4:<1mg/dL).All subjects treated in lead-in portion of study.
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End point type |
Primary
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End point timeframe |
Baseline up to Week 131
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Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects Achieving SVR ≥35% as Measured by Magnetic Resonance Imaging/Computed Tomography Scan at Week 24 in the Lead-in Cohort | ||||||
End point description |
MRI (CT scan may have been permitted if MRI was contraindicated) of the spleen and the liver was performed at baseline, then every 12 weeks while the subject was on treatment. The same method of assessment used at baseline was used for the duration of the trial to ensure consistency. Spleen volume was assessed by a central, independent blinded reader.
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End point type |
Secondary
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End point timeframe |
Week 24
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects Achieving ≥50% Reduction from Baseline in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Diary (MPN-SAD) at Week 24 in the Lead-in Cohort | ||||||||
End point description |
The MPN-SAD assessed the impact of 9 MF symptoms, at their worst, over the past 7 days and over the past 24 hours on a scale of 0 (absent) to 10 (worst imaginable). The 9 symptoms are early satiety, abdominal discomfort, inactivity, night sweats, pruritus, bone pain, pain below the ribs on the left-hand side, fatigue and shortness of breath. The TSS is the sum of the individual scores, excluding inactivity and shortness of breath. The TSS at Week 24 is the average of the daily total scores from the last 28 days of symptom scores immediately prior to Week 24. A higher score indicates worse symptoms.
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End point type |
Secondary
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End point timeframe |
Week 24
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No statistical analyses for this end point |
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End point title |
Monthly Mean Change from Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort | ||||||||||||||||
End point description |
The MPN-SAD assessed the impact of 9 MF symptoms, at their worst, over the past 7 days and over the past 24 hours on a scale of 0 (absent) to 10 (worst imaginable). The 9 symptoms are early satiety, abdominal discomfort, inactivity, night sweats, pruritus, bone pain, pain below the ribs on the left-hand side, fatigue and shortness of breath. The TSS is the sum of the individual scores, excluding inactivity and shortness of breath. The TSS at Week 24 is the average of the daily total scores from the last 28 days of symptom scores immediately prior to Week 24. A higher score indicates worse symptoms.
9999 = not applicable, no standard deviation was calculable since n=1.
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End point type |
Secondary
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End point timeframe |
Weeks 12, 24, 36 and 48
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects Achieving Anemia Response (Transfusion Dependent versus Independent) in the Lead-in Cohort | ||||||||||||
End point description |
Anemia response was defined as transfusion-independent subjects with a ≥20 gram per liter (g/L) increase in hemoglobin (Hb) level where baseline Hb level was <100 g/L, or baseline transfusion-dependent patients becoming transfusion-independent post-baseline. Transfusion dependency before the start of study treatment was defined as transfusions of ≥6 units of packed red blood cells in the 12 weeks prior to start of study treatment, for a final pre-treatment Hb of <85 g/L. In addition, the most recent transfusion episode must have occurred in the 28 days prior to study enrollment. Response in transfusion-dependent patients required absence of any packed red blood cell transfusions during any consecutive rolling 12-week interval during the treatment phase, capped by a Hb level of ≥85 g/L.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment
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No statistical analyses for this end point |
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End point title |
Maximum Observed Glasdegib Plasma Concentration (Cmax), Minimum Glasdegib Plasma Concentration Observed Prior to the Next Dose (Cmin), and Average Observed Glasdegib Plasma Concentration (Cavg) in the Lead-in Cohort | ||||||||||||||
End point description |
Cmax was the highest plasma concentration of glasdegib observed directly from the plasma concentration data. Cmin was the lowest plasma concentration of glasdegib observed directly from the plasma concentration data. Cavg was the average concentration at steady state estimated using non-compartmental pharmacokinetic (PK) analysis.
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End point type |
Secondary
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End point timeframe |
Cycle 1, Day 15
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No statistical analyses for this end point |
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End point title |
Area Under the Glasdegib Plasma Concentration versus Time Profile at the End of a Dosing Interval (AUCtau) in the Lead-in Cohort | ||||||||
End point description |
AUCtau was the area under the glasdegib plasma concentration-time profile from time zero to the end of the dosing interval (24 hours) estimated by non-compartmental PK analysis using the linear/log trapezoidal method.
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End point type |
Secondary
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End point timeframe |
Cycle 1, Day 15
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No statistical analyses for this end point |
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End point title |
Time to reach Cmax (Tmax) in the Lead-in Cohort | ||||||||
End point description |
Tmax was the time of the first occurrence of Cmax observed directly from the plasma concentration data.
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End point type |
Secondary
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End point timeframe |
Cycle 1, Day 15
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects Achieving SVR ≥50% as Measured by MRI/CT Scan at Week 24 in the Randomized Cohort | ||||||
End point description |
The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
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End point type |
Secondary
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End point timeframe |
Week 24
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Notes [9] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
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No statistical analyses for this end point |
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End point title |
Monthly Mean Change from Baseline in Overall TSS in the Randomized Cohort | ||||||
End point description |
The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
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End point type |
Secondary
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End point timeframe |
Weeks 12, 24, 36 and 48
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Notes [10] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects Achieving Anemia Response (Transfusion Dependent versus Independent) in the Randomized Cohort | ||||||
End point description |
The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment
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Notes [11] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
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No statistical analyses for this end point |
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End point title |
Subject Reported Outcomes of Health Related Quality of Life and Health Status in the Randomised Cohort | ||||||
End point description |
The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment
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Notes [12] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
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No statistical analyses for this end point |
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End point title |
Median Duration of SVR in the Randomized Cohort | ||||||||
End point description |
The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline to end of treatment
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Notes [13] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
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No statistical analyses for this end point |
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End point title |
Kaplan-Meier Estimate of Overall Survival in the Randomized Cohort | ||||||||
End point description |
The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline to end of treatment
|
||||||||
|
|||||||||
Notes [14] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Glasdegib PK Parameters in the Randomized Cohort | ||||||||
End point description |
The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 1, Day 15
|
||||||||
|
|||||||||
Notes [15] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Psychometric validation of the MPN-SAD in the Randomised Cohort | ||||||||
End point description |
The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline to end of treatment
|
||||||||
|
|||||||||
Notes [16] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
|||||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects With Treatment –Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort | ||||||
End point description |
An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. The double blind, randomized, placebo controlled phase of the study was not enrolled as the study was terminated early so, no data were collected to assess this end point.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Baseline up to Week 131
|
||||||
|
|||||||
Notes [17] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects With Treatment Emergent Treatment –Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Randomized Cohort | ||||||
End point description |
Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. Relatedness to study drug was assessed by the investigator. The double blind, randomized, placebo controlled phase of the study was not enrolled as the study was terminated early so, no data were collected to assess this end point.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Baseline up to Week 131
|
||||||
|
|||||||
Notes [18] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects with Treatment Emergent Adverse Events (AEs) According to Maximum Severity: Randomized Cohort | ||||||
End point description |
AE was untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship.SAE was AE resulting in any of following outcomes or deemed significant for any other reason:death; initial or prolonged inpatient hospitalization;life-threatening experience; persistent or significant disability/incapacity; congenital anomaly.A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment,or worsened during the treatment period relative to pretreatment state.AE were assessed according to maximum severity grading based on NCI CTCAE Version 4.03.G1=mild; G2=moderate; within normal limits.G3=severe or medically significant but not immediately life-threatening;G4=life-threatening or disabling; urgent intervention indicated; G5=death. Double blind, randomized, placebo controlled phase of study was not enrolled as study was terminated early so, no data were collected to assess this end point.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Baseline up to Week 131
|
||||||
|
|||||||
Notes [19] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects With Laboratory Abnormalities in the Randomized Cohort | ||||||
End point description |
Hematology:hemoglobin<0.8*LLN,platelets<0.5*LLN>1.75*ULN,WBC<0.6*LLN>1.5* ULN,lymphocytes,total neutrophils<0.8* LLN>1.2* ULN,band cells,basophils,eosinophils,monocytes >1.2*ULN, blast cells>1.0*ULN.Coagulation:activated partial thromboplastin time,prothrombin international ratio>1.1*ULN.Liver function:bilirubin>1.5*ULN, AST,ALT,lactate dehydrogenase,alkaline phosphatase>3.0*ULN,protein,albumin<0.8*LLN>1.2*ULN.Renal:blood urea nitrogen,creatinine >1.3* ULN,uric acid >1.2* ULN.Electrolytes:sodium<0.95*LLN>1.05*ULN, potassium,chloride,calcium, magnesium<0.9* LLN >1.1*ULN,phosphate<0.8* LLN >1.2*ULN.Chemistry: glucose<0.6*LLN >1.5*ULN,creatine kinase>2.0*ULN, amylase,lipase>1.5*ULN.Urinalysis:protein,blood>1.0*ULN,red blood cells,WBC>=20,epithelial cells>=6,casts,granular casts,hyaline >1,cellularcasts,crystals>=1,bacteria >20.The double blind,randomized,placebo controlled phase of study was not enrolled as study was terminated early so,no data were collected to assess this end point.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Baseline up to Week 131
|
||||||
|
|||||||
Notes [20] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 3 and above Hematological Test Abnormalities: Randomized Cohort | ||||||
End point description |
Anemia g1:<LLN to10 g/dL, g2:<10 to 8g/dL,g3:<8g/dL,g4:lifethreatening);platelet (g1:<LLN to 75*10^3/mm^3, g2:<75*10^3/mm^3 to 50*10^3/mm^3,g3:<50*10^3/mm^3 to 25*10^3/mm^3,g4:<25*10^3/mm^3);lymphopenia (g1:<LLN to 8*10^2/mm^3, g2:<8*10^2 to 5*10^2/mm^3, g3:<5*10^2 to 2*10^2/mm^3, g4:<2*10^2/mm^3);neutrophil (absolute) (g1:<LLN to 15*10^2/mm^3, g2:<15*10^2 to 10*10^2/mm^3, g3:<10*10^2 to 5*10^2/mm^3, g4:<5*10^2/mm^3);white blood cell count (g1:<LLN to 3*10^3/mm^3,g2:<3*10^3 to 2*10^3/mm^3,g3: <2*10^3 to 1*10^3/mm^3, g4:<1*10^3/mm^3);hemoglobin(g1:increase in hemoglobin level>0 to 2 g/dL above ULN or above baseline if baseline is above ULN, g2: increase in hemoglobin level>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3:increase in hemoglobin level>4 g/dL above ULN or above baseline if baseline is above ULN). Double blind, randomized, placebo controlled phase of study was not enrolled as study was terminated early so,no data were collected to assess this end point.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Baseline up to Week 131
|
||||||
|
|||||||
Notes [21] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 3 and above Chemistry Test Abnormalities: Randomized Cohort | ||||||
End point description |
ALT/AST g1:>ULN 3*ULN, g2:>3-5*ULN, g3:>5 20*ULN,g4:>20*ULN);Alkaline Phosphatase (g1:>ULN 2.5*ULN, g2:>2.5-5*ULN, g3:>5 20*ULN,g4:>20*ULN);Creatinine (g1:>ULN-1.5*ULN, g2:>1.5-3*ULN, g3:>3 6*ULN, g4:>6*ULN);hyperglycemia (g1:>ULN-160,g2:>160 250, g3:>250 500,g4:>500mg/dL); bilirubin(total) (g1:>ULN-1.5*ULN, g2:>1.5-3*ULN, g3:>3 10*ULN,g4:>10*ULN); hypoglycaemia (g1:<LLN-55,g2:<55-40, g3:<40 30, g4:<30mg/dL);hyperkalemia (g1:>ULN-5.5,g2:>5.5-6, g3:>6 7,g4:>7mmol/L);hypokalemia (g1:<LLN-3,g2:<LLN-3,g3:<3 2.5, g4:<2.5mmol/L);hypermagnesemia (g1:>ULN-3,g3:>3 8,g4:>8mg/dL);hypocalcemia (g1:<LLN-8,g2:<8-7, g3:<7-6, g4:<6mg/dL);hypercalcemia (g1:>ULN-11.5,g2:>11.5-12.5, g3:>12.5-13.5, g4:>13.5mg/dL);hypomagnesemia (g1:<LLN-1.2,g2:<1.2-0.9, g3:<0.9-0.7,g4:<0.7mg/dL);hyponatremia (g1:<LLN-130,g3:<130-120, g4:<120mmol/L);hypoalbuminemia (g1:<LLN-3,g2:<3-2, g3:<2, g4:lifethreatening);hypophosphatemia (g1:<LLN-2.5,g2:<2.5-2,g3:<2-1,g4:<1mg/dL). Study was terminated no data were collected.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Baseline up to Week 131
|
||||||
|
|||||||
Notes [22] - The randomized part of the study was not enrolled so no data were collected to assess this endpoint. |
|||||||
No statistical analyses for this end point |
|
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Adverse events information
|
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Timeframe for reporting adverse events |
Baseline up to Week 131
|
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Adverse event reporting additional description |
Event appear as both an AE and SAE.However,what is presented are distinct events.Event may categorized as serious in 1 subject and non-serious in another subject,or 1 subject may have experienced both a serious and non-serious event.All subjects treated in lead-in portion of study.It was analysis population for analyses on lead-in portion of study.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
|
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Reporting groups
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Reporting group title |
Glasdegib Lead-in
|
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Reporting group description |
Glasdegib administered orally at a daily starting dose of 100 mg on a continuous regimen of 28-day cycles. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
07 Oct 2014 |
The requirement for 1 form of highly effective contraception was amended to 2 forms. The inclusion criterion concerning creatinine clearance and the exclusion criterion concerning corrected QT interval were clarified. A precaution was added for phototoxicity. The schedule of assessments was corrected to indicate ongoing collection of AEs during the study treatment period. |
||
19 Feb 2015 |
The schedule of assessments was amended to clarify PK, electrocardiogram and bone marrow aspirate collection time points. The threshold for prolongation of QT interval corrected by the Fridericia formula (QTcF) was clarified in the exclusion criteria. Dosing modification guidelines for treatment related QTcF were revised. An administrative update to the AE reporting section was made. Communication of results by Pfizer was updated in line with Pfizer policy. |
||
26 May 2015 |
Background information was updated, including estimated overall survival and preliminary data from B1371013 lead-in cohort. Pharmacodynamic data were added for the 50 mg glasdegib dose and details of the clinical development program were updated. Subject enrolment in the lead in cohort was revised; the potential to evaluate lower starting doses or intermittent dosing schedules for glasdegib was added, and overall survival was removed as an objective/endpoint for the lead in cohort. An inclusion criterion requiring documentation by the investigator that the subject had exhausted available therapies was added, and the exclusion criterion for prior anticancer therapy washout was revised. The inclusion criterion for MF symptom assessment to be based upon patient reported symptoms on the MPN-SAD screening form was revised. The inclusion criterion for pregnancy and contraception was updated to align with current guidelines, lifestyle guidelines were updated and a contraception check was added. The exclusion criteria for prior malignancies were revised. Protocol defined best supportive therapy was removed from the prohibited/permitted treatments section. Drug storage requirements were updated. Text emphasizing dosing compliance was added. Recommended dose modifications for muscle spasms/myalgia were added. The magnetic resonance imaging/computed tomography scan process was clarified and the requirement for a 5 day window for repeated imaging scans was removed. MPN-SAD collection was expanded. The follow up period was adjusted. Immunophenotyping and cytogenetics were removed. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |