A Phase Ib/II Dose-finding Study to Assess the Safety and... | NCT01787552 | Trialant
NCT01787552
Sponsor
Novartis Pharmaceuticals
Status
Completed
Last Update Posted
Apr 15, 2020Actual
Enrollment
50Actual
Phase
Phase 1Phase 2
Conditions
Primary Myelofibrosis
Thrombocytosis
Essential Thrombocythemia
Polycythemia Vera
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Blood Coagulation Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Interventions
LDE225
INC424
Countries
Australia
Belgium
Canada
Denmark
France
Germany
Ireland
Italy
Netherlands
Spain
United Kingdom
Protocol Section
Identification Module
NCT ID
NCT01787552
Obsolete or Duplicate NCT IDs
Not provided
Organization Study
CLDE225X2116
Secondary IDs
ID
Type
Description
Link
2012-004023-20
EudraCT Number
Brief Title
A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF
Official Title
A Phase Ib/II, Open-label, Multi-center, Dose-finding Study to Assess the Safety and Efficacy of the Oral Combination of LDE225 and INC424 (Ruxolitinib) in Patients With Myelofibrosis
Acronym
Not provided
Organization
NovartisINDUSTRY
Status Module
Record Verification Date
Apr 2020
Overall Recruitment Status or Expanded Access Status
Completed
Last Known Status
Not provided
Delayed Posting
Not provided
Why Stopped
Not provided
Expanded Access Info
No
Start Date
May 8, 2013Actual
Primary Completion Date
Apr 10, 2018Actual
Completion Date
Apr 10, 2018Actual
First Submitted Date
Feb 6, 2013
First Submission Date that Met QC Criteria
Feb 6, 2013
First Posted Date
Feb 8, 2013Estimated
Results Waived
Not provided
Results First Submitted Date
Apr 8, 2019
Results First Submitted that Met QC Criteria
Apr 3, 2020
Results First Posted Date
Apr 15, 2020Actual
Certification/Extension (aka Delayed Results) First Submitted Date
Not provided
Certification/Extension First Submitted that Passed QC Review
Not provided
Certification/Extension First Posted Date
Not provided
Last Update Submitted Date
Apr 3, 2020
Last Update Posted Date
Apr 15, 2020Actual
Sponsor/Collaborators Module
Responsible Party, by Official Title
Sponsor
Lead Sponsor
Novartis PharmaceuticalsINDUSTRY
Collaborators
Not provided
Oversight Module
Has Data Monitoring Committee (DMC)
No
Is FDA Regulated Drug
No
Is FDA Regulated Device
No
Is Unapproved Device
Not provided
Pediatric Postmarket Surveillance of a Device Product
Not provided
Product Exported from US
Not provided
FDAAA801 Violation
Not provided
Description Module
Brief Summary
The purpose of this phase Ib/II clinical trial was to: a) evaluate the safety of the co-administration of LDE225 and INC424 in myelofibrosis patients and establish a maximum tolerated dose and/or Recommended Phase II dose of the combination and b) to assess the efficacy of the co-administration of LDE225 and INC424 on spleen volume reduction.
Detailed Description
The study is considered to have been completed because the participants completed the study as per study design at the time of trial termination. If participants were already in extension phase until discontinuation criteria were met or alternative setting was available, they were considered as completed. The study was terminated due to one of the compounds being divested.
Conditions Module
Conditions
Primary Myelofibrosis
Thrombocytosis
Essential Thrombocythemia
Polycythemia Vera
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Blood Coagulation Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Keywords
Dose escalation
Maximum Tolerated Dose
MTD
Safety Expansion
Safety
Efficacy
Myelofibrosis
Post-polycythemia vera myelofbrosis (Post PV-PMF)
Post essential thrombocythemia myelofibrosis (Post ET-MF)
Primary myelofibrosis (PMF)
Intermediate risk myelofibrosis
High risk myelofibrosis
Combination Treatment
Hedgehog Signaling Pathway
Smoothened inhibitor
JAK inhibitor
Design Module
Study Type
Interventional
Number of References to an Expanded Access Study
Not provided
Expanded Access Types
Not provided
Patient Registry
Not provided
Target Follow-Up Duration
Not provided
Phases
Phase 1Phase 2
Interventional Study Design
Allocation
Biospecimen
No data available
No data is available for this block.
Enrollment
50Actual
Arms/Interventions Module
Arm Groups
Label
Type
Description
Intervention Names
LDE225 + INC424
Experimental
LDE225 and INC424 in combination
Drug: LDE225
Drug: INC424
Interventions
Name
Type
Description
Arm Group Labels
Other Names
LDE225
Drug
LDE225 + INC424
INC424
Outcomes Module
Primary Outcomes
Measure
Description
Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)
A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
6 weeks (42 days)
Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1
Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients
Week 24 and Week 48
Secondary Outcomes
Measure
Description
Time Frame
Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)
Plasma Concentration Time Curve: AUC0-24h: Area under the concentration-time curve from time zero to 24 hours extrapolate from AUClast[mass x time x volume-1]
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Other Outcomes
Not provided
Eligibility Module
Eligibility Criteria
Inclusion Criteria:
Diagnosed with PMF per 2008 WHO criteria, post-PV MF or post-ET MF per IWG-MRT criteria.
Ineligible or unwilling to undergo stem cell transplantion.
PLT counts > or = 75X 10^9/L not reached with the aid of transfusions.
ECOG performance status ≤ 2.
Palpable splenomegaly defined as ≥ 5 cm below the left costal margin.
Intermediate risk level 1 (1 prognostic factor which is not age), Intermediate risk level 2, or high risk.
Active symptoms of MF as demonstrated by one symptom score of at least 5 (0 to10 point scale) or two symptom scores of at least 3 (0 to 10 point scale) on the MF Symptom Assessment Form (MFSAF).
Exclusion Criteria:
Previous therapy with JAK or Smoothened inhibitors.
Patient is currently on medications that interfere with coagulation (including warfarin) or platelet function with the exception of low dose aspirin (up to 100 mg) and LMWH.
Impairment of GI function or GI disease that may significantly alter the absorption of INC424 or LDE225 (e.g., uncontrolled nausea, vomiting, diarrhea; malabsorption syndrome; small bowel resection).
Splenic irradiation within 12 months prior to Screening.
Pregnant or nursing women.
WOCBP not using highly effective methods of contraception
Sexually active males who refuse condom use
Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil. Pravastatin may be used if necessary, with extra caution.
Gupta V, Wolleschak D, Hasselbalch H, Vannucchi AM, Koschmieder S, Cervantes F, Li Y, Dong T, Wroclawska M, Bharathy S, Harrison C. Safety and efficacy of the combination of sonidegib and ruxolitinib in myelofibrosis: a phase 1b/2 dose-finding study. Blood Adv. 2020 Jul 14;4(13):3063-3071. doi: 10.1182/bloodadvances.2019001212.
See Also Links
Not provided
Available IPD Information
Not provided
IPD Sharing Statement Module
Plan to Share IPD
Yes
Description
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
A total of 50 subjects were enrolled in the study, of which 23 subjects were enrolled in Phase Ib part of dose-escalation phase and 27 subjects were enrolled in Phase Ib dose-expansion phase and Phase II Stage 1.
Recruitment Details
A total of 50 subjects were enrolled in the study, of which 23 subjects were enrolled in Phase Ib part of dose-escalation phase and 27 subjects were enrolled in Phase Ib dose-expansion phase and Phase II Stage 1.
Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast
AUC0-12h: Area under the concentration-time curve from time zero to 12 hours extrapolate from AUClast[mass x time x volume-1]. AUCinf: Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase [mass x time x volume-1]. AUClast: Area under the concentration-time curve from time zero to the time of last measurable concentration [mass x time x volume-1].
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)
Cmax: Maximum observed plasma concentration after drug administration [mass x volume-
1].
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)
Tmax: Time to reach Cmax [time]
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)
CL/F: Apparent total plasma clearance of drug after oral administration [volume x time-1]
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1
The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.
Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1
Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden
Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers
Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1
Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores
The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, & bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score.
Week 24, Week 48
Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores
The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, & bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score.
Baseline, Week 25, Week 49
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48
EORTC QLQ-C30 is the European Organization for Research & Treatment of Cancer, Quality of Life (QoL) Questionnaire & is one of the most widely used & validated instruments to measure health-related QoL in subjects with cancer. The scale includes 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning & social functioning), global health status/QoL & 9 symptom scale/items (fatigue, nausea & vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, & financial difficulties). This instrument asks the subject to respond according to the past week, with the exception of the first 5 questions that represent physical functioning & capture the subject's current status. The range of scores for all of the scales is from 0 to 100. For functional & global health status/QoL scales, higher scores indicate better QoL & level of functioning; for symptom scales, higher scores indicate greater level of symptoms or difficulties.
Week 24, Week 48
Phase Ib and Phase II: LDE225: PK Parameter: Racc
Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 [fold]
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1
Phase Ib and Phase II: INC424: PK Parameter: T1/2
T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve [time]
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
Phase Ib and Phase II: INC424: PK Parameter: Vss/F
Vss/F: Apparent volume of distribution at steady state after oral administration [volume]
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
Woolloongabba
Queensland
4102
Australia
Novartis Investigative Site
Leuven
3000
Belgium
Novartis Investigative Site
Toronto
Ontario
M5G 2M9
Canada
Novartis Investigative Site
Montreal
Quebec
H3T 1E2
Canada
Novartis Investigative Site
Roskilde
4000
Denmark
Novartis Investigative Site
Marseille
13273
France
Novartis Investigative Site
Aachen
52074
Germany
Novartis Investigative Site
Magdeburg
39120
Germany
Novartis Investigative Site
Galway
Ireland
Novartis Investigative Site
Florence
FI
50134
Italy
Novartis Investigative Site
Reggio Calabria
RC
89124
Italy
Novartis Investigative Site
Amsterdam
1081 HV
Netherlands
Novartis Investigative Site
Rotterdam
3015 GD
Netherlands
Novartis Investigative Site
Barcelona
Catalonia
08036
Spain
Novartis Investigative Site
Madrid
28034
Spain
Novartis Investigative Site
Glasgow
Scotland
G12 0YN
United Kingdom
Novartis Investigative Site
London
SE1 9RT
United Kingdom
Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase
Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
BG004
Total
Total of all reporting groups
Denominators
Units
Counts
Participants
BG0008
BG00110
BG0025
BG00327
BG00450
Baseline Measures
Title
Description
Population Description
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Denominator Units Selected
Denominators
Classes
Age, Continuous
Mean
Standard Deviation
Years
Title
Denominators
Categories
Title
Measurements
BG00070.9± 5.19
BG00159.9± 11.59
BG00264.6± 13.18
BG003
Sex: Female, Male
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
Female
BG0001
BG0015
BG002
Race (NIH/OMB)
Count of Participants
Participants
Title
Denominators
Categories
Title
Measurements
American Indian or Alaska Native
BG0000
BG0010
BG002
Type
Title
Description
Population Description
Reporting Status
Anticipated Posting Date
Parameter Type
Dispersion Type
Unit of Measure
Calculate Percentage
Time Frame
Units Analyzed
Denominator Units Selected
Arm/Group Information
Denominators
Classes
Analyses
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)
A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
Safety Analysis Set (SAS) included all participants in Phase Ib & Phase II who received at least 1 dose of LDE225 and/or INC424 & had at least 1 valid post-baseline safety assessment. DLT was measured in the Phase Ib dose escalation & expansion phase, as part of the primary outcome. All participants in the safety set were considered for toxicities.
Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Units
Counts
Participants
OG0008
OG00110
OG0025
OG003
Title
Denominators
Categories
Title
Measurements
Blood creatine phosphokinase increased
OG0000
OG0012
OG0020
OG003
Primary
Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1
Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients
The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424. The data disclosed includes only participants from Phase Ib dose expansion phase and Ph II Stage 1. This data does not include dose escalation Phase Ib participants.
Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Units
Counts
Participants
OG000
Secondary
Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)
Plasma Concentration Time Curve: AUC0-24h: Area under the concentration-time curve from time zero to 24 hours extrapolate from AUClast[mass x time x volume-1]
The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng*hr/mL
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase
Secondary
Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast
AUC0-12h: Area under the concentration-time curve from time zero to 12 hours extrapolate from AUClast[mass x time x volume-1]. AUCinf: Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase [mass x time x volume-1]. AUClast: Area under the concentration-time curve from time zero to the time of last measurable concentration [mass x time x volume-1].
The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng*hr/mL
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)
Cmax: Maximum observed plasma concentration after drug administration [mass x volume-
1].
The pharmacokinetic analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.
Posted
Geometric Mean
Geometric Coefficient of Variation
ng/mL
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase
OG003
Secondary
Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)
Tmax: Time to reach Cmax [time]
The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.
Posted
Median
Full Range
hour (hr)
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)
CL/F: Apparent total plasma clearance of drug after oral administration [volume x time-1]
The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.
Posted
Median
Full Range
L/hr
0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1
The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.
The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.
Posted
Number
Percentage of Participants
Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1
Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden
The Biomarker Analysis Set (BAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable biomarker sample.
Posted
Median
Full Range
Percentage of JAK allele burden mutation
Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers
Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1
The Biomarker Analysis Set (BAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable biomarker sample.
Posted
Median
Full Range
ng/mL
Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores
The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, & bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score.
The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.
Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase
Secondary
Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores
The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, & bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score.
The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.
Participants who took a combination of LDE225 400mg and INC424 15mg in the dose escalation phase.
Secondary
Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48
EORTC QLQ-C30 is the European Organization for Research & Treatment of Cancer, Quality of Life (QoL) Questionnaire & is one of the most widely used & validated instruments to measure health-related QoL in subjects with cancer. The scale includes 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning & social functioning), global health status/QoL & 9 symptom scale/items (fatigue, nausea & vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, & financial difficulties). This instrument asks the subject to respond according to the past week, with the exception of the first 5 questions that represent physical functioning & capture the subject's current status. The range of scores for all of the scales is from 0 to 100. For functional & global health status/QoL scales, higher scores indicate better QoL & level of functioning; for symptom scales, higher scores indicate greater level of symptoms or difficulties.
The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.
Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 [fold]
The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.
T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve [time]
The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.
Phase Ib and Phase II: INC424: PK Parameter: Vss/F
Vss/F: Apparent volume of distribution at steady state after oral administration [volume]
The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.
Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 1505 days.
Description
Not provided
All-Cause Mortality Comment
Not provided
Arm/Groups
ID
Title
Description
Deaths (Affected)
Deaths (At Risk)
Serious Events (Affected)
Serious Events (At Risk)
Other Events (Affected)
Other Events (At Risk)
EG000
LDE225 400 mg + INC424 10 mg
Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase
1
8
5
8
8
8
EG001
LDE225 400 mg + INC424 15 mg
Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase
1
10
6
10
10
10
EG002
LDE225 400 mg + INC424 20 mg
Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase
1
5
2
5
5
5
EG003
LDE225 400 mg + INC424 20 mg (Dose Expansion)
Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
1
27
13
27
27
27
EG004
All Patients
All Patients
4
50
26
50
50
50
Serious Adverse Events
Term
Organ System
Source Vocabulary
Assessment Type
Notes
Statistical Information
Anaemia
Blood and lymphatic system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG0032 affected27 at risk
EG0042 affected50 at risk
Extramedullary haemopoiesis
Blood and lymphatic system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Atrial fibrillation
Cardiac disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Right ventricular failure
Cardiac disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Constipation
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Diarrhoea
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Duodenal ulcer haemorrhage
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Gastric ulcer
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Gastric ulcer haemorrhage
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Gastrointestinal haemorrhage
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0012 affected10 at risk
EG0020 affected5 at risk
EG003
Melaena
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Vomiting
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Face oedema
General disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Multiple organ dysfunction syndrome
General disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Pyrexia
General disorders
MedDRA (19.1)
Systematic Assessment
EG0002 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Diverticulitis
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Erysipelas
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Gastroenteritis
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Infection
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Fall
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Meniscus injury
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Post procedural haemorrhage
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Aspartate aminotransferase increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Blood creatine phosphokinase increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0012 affected10 at risk
EG0020 affected5 at risk
EG003
Myoglobin blood increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Hyperkalaemia
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Hyponatraemia
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Myalgia
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Myositis
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Acute myeloid leukaemia
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
B-cell lymphoma
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Cholangiocarcinoma
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Chronic myeloid leukaemia
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Squamous cell carcinoma of skin
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Cerebrovascular accident
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Presyncope
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Other Adverse Events
Term
Organ System
Source Vocabulary
Assessment Type
Notes
Statistical Information
Anaemia
Blood and lymphatic system disorders
MedDRA (19.1)
Systematic Assessment
EG0005 affected8 at risk
EG0014 affected10 at risk
EG0024 affected5 at risk
EG00316 affected27 at risk
EG00429 affected50 at risk
Extramedullary haemopoiesis
Blood and lymphatic system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Leukocytosis
Blood and lymphatic system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Neutropenia
Blood and lymphatic system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Thrombocytopenia
Blood and lymphatic system disorders
MedDRA (19.1)
Systematic Assessment
EG0003 affected8 at risk
EG0012 affected10 at risk
EG0023 affected5 at risk
EG003
Supraventricular extrasystoles
Cardiac disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Retinal detachment
Eye disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Vision blurred
Eye disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Abdominal discomfort
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Abdominal distension
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Abdominal pain
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0002 affected8 at risk
EG0013 affected10 at risk
EG0020 affected5 at risk
EG003
Abdominal pain upper
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Bile acid malabsorption
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Constipation
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0002 affected8 at risk
EG0011 affected10 at risk
EG0021 affected5 at risk
EG003
Diarrhoea
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0003 affected8 at risk
EG0013 affected10 at risk
EG0024 affected5 at risk
EG003
Diverticulum
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Diverticulum intestinal
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Dry mouth
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Duodenal ulcer
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Dyspepsia
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Flatulence
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Functional gastrointestinal disorder
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Gastric ulcer
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Gastric varices
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Gastritis
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0021 affected5 at risk
EG003
Gastrooesophageal reflux disease
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Haematochezia
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0021 affected5 at risk
EG003
Melaena
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Nausea
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0003 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Stomatitis
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Toothache
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Vomiting
Gastrointestinal disorders
MedDRA (19.1)
Systematic Assessment
EG0003 affected8 at risk
EG0012 affected10 at risk
EG0021 affected5 at risk
EG003
Asthenia
General disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0012 affected10 at risk
EG0021 affected5 at risk
EG003
Catheter site bruise
General disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Early satiety
General disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Fatigue
General disorders
MedDRA (19.1)
Systematic Assessment
EG0006 affected8 at risk
EG0013 affected10 at risk
EG0020 affected5 at risk
EG003
Gait disturbance
General disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
General physical health deterioration
General disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Influenza like illness
General disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Malaise
General disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Oedema peripheral
General disorders
MedDRA (19.1)
Systematic Assessment
EG0002 affected8 at risk
EG0012 affected10 at risk
EG0020 affected5 at risk
EG003
Pyrexia
General disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0012 affected10 at risk
EG0022 affected5 at risk
EG003
Thirst
General disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Cholelithiasis
Hepatobiliary disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Hyperbilirubinaemia
Hepatobiliary disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Bronchitis
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Cystitis
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Ear infection
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Escherichia infection
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Folliculitis
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Fungal skin infection
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Gastroenteritis viral
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Herpes zoster
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Influenza
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Nasopharyngitis
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0012 affected10 at risk
EG0022 affected5 at risk
EG003
Oesophageal candidiasis
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Oral herpes
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Pharyngitis
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Pneumonia
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Tooth infection
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Upper respiratory tract infection
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0013 affected10 at risk
EG0021 affected5 at risk
EG003
Urinary tract infection
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Urinary tract infection bacterial
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Wound infection
Infections and infestations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Animal bite
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Contusion
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0022 affected5 at risk
EG003
Fall
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0002 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Hyphaema
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Laceration
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Meniscus injury
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Procedural hypotension
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Scratch
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Spinal compression fracture
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Tooth fracture
Injury, poisoning and procedural complications
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Alanine aminotransferase increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0012 affected10 at risk
EG0021 affected5 at risk
EG003
Amylase increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Aspartate aminotransferase increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0013 affected10 at risk
EG0021 affected5 at risk
EG003
Blood alkaline phosphatase increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Blood bilirubin increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Blood creatine phosphokinase increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0012 affected10 at risk
EG0023 affected5 at risk
EG003
Blood creatinine increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Blood prolactin increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Blood uric acid increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Cytomegalovirus test
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Electrocardiogram QT prolonged
Investigations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Gamma-glutamyltransferase increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0021 affected5 at risk
EG003
International normalised ratio increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Lipase increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Low density lipoprotein increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0022 affected5 at risk
EG003
Platelet count decreased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Prothrombin level increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Prothrombin time prolonged
Investigations
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Weight decreased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0002 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Weight increased
Investigations
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Decreased appetite
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0003 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Hyperkalaemia
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Hypertriglyceridaemia
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Hyperuricaemia
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0013 affected10 at risk
EG0021 affected5 at risk
EG003
Hypocalcaemia
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Hypokalaemia
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Hypomagnesaemia
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Hyponatraemia
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Increased appetite
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Iron deficiency
Metabolism and nutrition disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Arthralgia
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0002 affected8 at risk
EG0012 affected10 at risk
EG0020 affected5 at risk
EG003
Back pain
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0012 affected10 at risk
EG0020 affected5 at risk
EG003
Bone pain
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Joint lock
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Muscle fatigue
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Muscle spasms
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0003 affected8 at risk
EG0016 affected10 at risk
EG0024 affected5 at risk
EG003
Muscle twitching
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Muscular weakness
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0014 affected10 at risk
EG0021 affected5 at risk
EG003
Musculoskeletal chest pain
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Musculoskeletal pain
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0002 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Myalgia
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0013 affected10 at risk
EG0020 affected5 at risk
EG003
Osteoarthritis
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Pain in extremity
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Polyarthritis
Musculoskeletal and connective tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Acute myeloid leukaemia
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Atypical fibroxanthoma
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Squamous cell carcinoma
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Amnesia
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Carpal tunnel syndrome
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Cerebral ischaemia
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Dizziness
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Dysaesthesia
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Dysgeusia
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0003 affected8 at risk
EG0014 affected10 at risk
EG0023 affected5 at risk
EG003
Head discomfort
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Headache
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0012 affected10 at risk
EG0020 affected5 at risk
EG003
Hypoaesthesia
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Memory impairment
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Muscle contractions involuntary
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0021 affected5 at risk
EG003
Paraesthesia
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Peripheral sensory neuropathy
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Post herpetic neuralgia
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Restless legs syndrome
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Syncope
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Transient ischaemic attack
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Tremor
Nervous system disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Depression
Psychiatric disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0012 affected10 at risk
EG0020 affected5 at risk
EG003
Insomnia
Psychiatric disorders
MedDRA (19.1)
Systematic Assessment
EG0002 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Dysuria
Renal and urinary disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Haematuria
Renal and urinary disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Urinary retention
Renal and urinary disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Erectile dysfunction
Reproductive system and breast disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Asthma
Respiratory, thoracic and mediastinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Cough
Respiratory, thoracic and mediastinal disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0013 affected10 at risk
EG0022 affected5 at risk
EG003
Dry throat
Respiratory, thoracic and mediastinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Dysphonia
Respiratory, thoracic and mediastinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Dyspnoea
Respiratory, thoracic and mediastinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0012 affected10 at risk
EG0020 affected5 at risk
EG003
Epistaxis
Respiratory, thoracic and mediastinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0022 affected5 at risk
EG003
Oropharyngeal pain
Respiratory, thoracic and mediastinal disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Acne
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Alopecia
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0003 affected8 at risk
EG0017 affected10 at risk
EG0023 affected5 at risk
EG003
Erythema
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Hair growth abnormal
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Hyperkeratosis
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Madarosis
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Night sweats
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0021 affected5 at risk
EG003
Onychoclasis
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Pruritus
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0012 affected10 at risk
EG0022 affected5 at risk
EG003
Pruritus generalised
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0022 affected5 at risk
EG003
Rash
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Skin discolouration
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Swelling face
Skin and subcutaneous tissue disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Aortic stenosis
Vascular disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0010 affected10 at risk
EG0020 affected5 at risk
EG003
Haematoma
Vascular disorders
MedDRA (19.1)
Systematic Assessment
EG0001 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Hypertension
Vascular disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0021 affected5 at risk
EG003
Intermittent claudication
Vascular disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0010 affected10 at risk
EG0021 affected5 at risk
EG003
Peripheral venous disease
Vascular disorders
MedDRA (19.1)
Systematic Assessment
EG0000 affected8 at risk
EG0011 affected10 at risk
EG0020 affected5 at risk
EG003
Please refer to detailed description regarding reason for early termination of study.
Certain Agreements
Are all PI(s) employees of the sponsor?
No
Restriction Type
OTHER
Results Disclosure Restriction on PI(s)?
Yes
Other Details
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie. data from all sites) in the clinical trial.