A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01787552
Collaborator
(none)
50
18
1
59.1
2.8
0

Study Details

Study Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
50 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
May 8, 2013
Actual Primary Completion Date :
Apr 10, 2018
Actual Study Completion Date :
Apr 10, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: LDE225 + INC424

LDE225 and INC424 in combination

Drug: LDE225

Drug: INC424

Outcome Measures

Primary Outcome Measures

  1. Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b) [6 weeks (42 days)]

    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.

  2. Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1 [Week 24 and Week 48]

    Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients

Secondary Outcome Measures

  1. Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h) [0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1]

    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]

  2. Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast [0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1]

    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].

  3. Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax) [0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1]

    Cmax: Maximum observed plasma concentration after drug administration [mass x volume- 1].

  4. Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax) [0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1]

    Tmax: Time to reach Cmax [time]

  5. Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F) [0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1]

    CL/F: Apparent total plasma clearance of drug after oral administration [volume x time-1]

  6. 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 [Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)]

    The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.

  7. Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1 [Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)]

    Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden

  8. Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers [Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)]

    Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1

  9. Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores [Week 24, Week 48]

    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.

  10. Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores [Baseline, Week 25, Week 49]

    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.

  11. Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 [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.

  12. Phase Ib and Phase II: LDE225: PK Parameter: Racc [0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1]

    Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 [fold]

  13. Phase Ib and Phase II: INC424: PK Parameter: T1/2 [0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1]

    T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve [time]

  14. Phase Ib and Phase II: INC424: PK Parameter: Vss/F [0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1]

    Vss/F: Apparent volume of distribution at steady state after oral administration [volume]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Novartis Investigative Site Camperdown New South Wales Australia NSW
2 Novartis Investigative Site Woolloongabba Queensland Australia 4102
3 Novartis Investigative Site Leuven Belgium 3000
4 Novartis Investigative Site Toronto Ontario Canada M5G 2M9
5 Novartis Investigative Site Montreal Quebec Canada H3T 1E2
6 Novartis Investigative Site Roskilde Denmark 4000
7 Novartis Investigative Site Marseille France 13273
8 Novartis Investigative Site Aachen Germany 52074
9 Novartis Investigative Site Magdeburg Germany 39120
10 Novartis Investigative Site Galway Ireland
11 Novartis Investigative Site Firenze FI Italy 50134
12 Novartis Investigative Site Reggio Calabria RC Italy 89124
13 Novartis Investigative Site Amsterdam Netherlands 1081 HV
14 Novartis Investigative Site Rotterdam Netherlands 3015 GD
15 Novartis Investigative Site Barcelona Catalunya Spain 08036
16 Novartis Investigative Site Madrid Spain 28034
17 Novartis Investigative Site Glasgow Scotland United Kingdom G12 0YN
18 Novartis Investigative Site London United Kingdom SE1 9RT

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01787552
Other Study ID Numbers:
  • CLDE225X2116
  • 2012-004023-20
First Posted:
Feb 8, 2013
Last Update Posted:
Apr 15, 2020
Last Verified:
Apr 1, 2020

Study Results

Participant Flow

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.
Pre-assignment Detail 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.
Arm/Group Title LDE225 400mg + INC424 10 mg (Dose Escalation Phase) LDE225 400mg + INC424 15 mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase. Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Period Title: Overall Study
STARTED 8 10 5 27
COMPLETED 0 1 0 0
NOT COMPLETED 8 9 5 27

Baseline Characteristics

Arm/Group Title LDE225 400mg + INC424 10 mg (Dose Escalation Phase) LDE225 400mg + INC424 15 mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase) Total
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase. Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase Total of all reporting groups
Overall Participants 8 10 5 27 50
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]
70.9
(5.19)
59.9
(11.59)
64.6
(13.18)
67.4
(10.02)
66.2
(10.42)
Sex: Female, Male (Count of Participants)
Female
1
12.5%
5
50%
1
20%
8
29.6%
15
30%
Male
7
87.5%
5
50%
4
80%
19
70.4%
35
70%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
0
0%
0
0%
Asian
2
25%
0
0%
0
0%
1
3.7%
3
6%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
0
0%
0
0%
Black or African American
0
0%
0
0%
0
0%
0
0%
0
0%
White
6
75%
10
100%
5
100%
26
96.3%
47
94%
More than one race
0
0%
0
0%
0
0%
0
0%
0
0%
Unknown or Not Reported
0
0%
0
0%
0
0%
0
0%
0
0%

Outcome Measures

1. Primary Outcome
Title Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)
Description 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.
Time Frame 6 weeks (42 days)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
Blood creatine phosphokinase increased
0
0%
2
20%
0
0%
1
3.7%
2. Primary Outcome
Title Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1
Description Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients
Time Frame Week 24 and Week 48

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 27
Week 24
44.4
555%
Week 48
29.6
370%
3. Secondary Outcome
Title Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)
Description 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]
Time Frame 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
LDE225 (Week 1, Day 1) (n=6,10,4,24)
2680
(33.1)
1900
(100.4)
1090
(84.0)
2060
(78.7)
LDE225 (Week 9, Day 1) (n=6,6,4,14)
15500
(31.8)
13000
(66.8)
17100
(30.8)
14500
(45.4)
4. Secondary Outcome
Title Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast
Description 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].
Time Frame 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
AUC0-12h: Wk1 Day 1 (n=8,10,5,25)
473
(29.5)
805
(45.6)
1130
(23.0)
1190
(41.0)
AUC0-12h: Wk 9 Day 1 (n=8,9,4,20)
489
(42.5)
835
(46.6)
962
(23.7)
1230
(42.4)
AUCinf: Wk1 Day 1 (n=7,9,4,16)
466
(30.9)
789
(46.1)
1140
(28.0)
1130
(47.7)
AUCinf: Wk 9 Day 1 (n=8,9,3,15)
498
(43.1)
867
(48.7)
978
(29.5)
1140
(43.0)
AUClast: Wk1 Day 1 (n=8,10,5,26)
443
(26.2)
730
(39.7)
1030
(20.8)
1070
(38.6)
AUClast: Wk 9 Day 1 (n=8,9,4,20)
460
(44.3)
776
(43.9)
891
(24.3)
1130
(38.6)
5. Secondary Outcome
Title Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)
Description Cmax: Maximum observed plasma concentration after drug administration [mass x volume- 1].
Time Frame 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
LDE225 (Week 1, Day 1) (n=6,10,5,26)
311
(35.1)
221
(103.4)
161
(94.9)
251
(83.4)
LDE225 (Week 9, Day 1) (n=8,8,5,20)
879
(38.0)
720
(57.5)
959
(39.4)
951
(51.1)
INC424 (Week 1, Day 1) (n=8,10,5,27)
154
(29.0)
244
(40.4)
351
(27.7)
338
(40.1)
INC424 (Week 9, Day 1) (n=8,9,4,20)
168
(38.8)
269
(33.2)
281
(36.5)
350
(36.0)
6. Secondary Outcome
Title Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)
Description Tmax: Time to reach Cmax [time]
Time Frame 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
LDE225 (Week 1, Day 1) (n=6,10,5,26)
3.01
2.08
2.00
2.00
LDE225 (Week 9, Day 1) (n=8,8,5,20)
1.79
2.00
2.00
3.21
INC424 (Week 1, Day 1) (n=8,10,5,27)
0.500
0.575
0.500
0.580
INC424 (Week 9, Day 1) (n=8,9,4,20)
0.875
0.500
1.00
1.00
7. Secondary Outcome
Title Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)
Description CL/F: Apparent total plasma clearance of drug after oral administration [volume x time-1]
Time Frame 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
LDE225 (Week 1, Day 1) (n=5,5,1,12)
145
238
727
122
LDE225 (Week 9, Day 1) (n=6,6,4,14)
27.8
34.5
25.1
27.0
INC424 (Week 1, Day 1) (n=7,9,4,16)
23.8
18.7
16.5
16.9
8. Secondary Outcome
Title 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
Description The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.
Time Frame Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
Baseline, grade 0 (n=0,0,0,1)
3.7
46.3%
Baseline, grade 1 (n=0,1,0,4)
10.0
125%
14.8
148%
Baseline, grade 2 (n=4,6,3,8)
50.0
625%
50.0
500%
60.0
1200%
29.6
109.6%
Baseline, grade 3 (n=3,3,0,8)
37.5
468.8%
30.0
300%
29.6
592%
Baseline, missing grade (n=1,0,2,6)
12.5
156.3%
40.0
400%
22.2
444%
Week 25 Day 1, grade 1 (n=1,1,0,1)
12.5
156.3%
10.0
100%
3.7
74%
Week 25 Day 1, grade 2 (n=0,3,2,7)
30.0
375%
40.0
400%
25.9
518%
Week 25 Day 1, grade 3 (n=5,4,1,5)
62.5
781.3%
40.0
400%
20.0
400%
18.5
68.5%
Week 25 Day 1, missing grade (n=2,2,2,14)
25.0
312.5%
20.0
200%
40.0
800%
51.9
192.2%
Week 49 Day 1, grade 0 (n=0,0,0,1)
3.7
46.3%
Week 49, Day 1 grade 1 (n=0,0,0,1)
3.7
46.3%
Week 49 Day 1, grade 2 (n=0,1,1,2)
10.0
125%
20.0
200%
7.4
148%
Week 49 Day 1, grade 3 (n=2,2,2,3)
25.0
312.5%
20.0
200%
40.0
800%
11.1
41.1%
Week 49 Day 1, missing grade (n=6,7,2,20)
75.0
937.5%
70.0
700%
40.0
800%
74.1
274.4%
9. Secondary Outcome
Title Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1
Description Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden
Time Frame Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
Baseline
84.7
61.7
88.3
55.4
Week 25 Day 1 (n=7,6,5,21)
88.6
48.0
74.9
43.8
Week 49 Day 1 (n=4,3,4,13)
86.0
54.3
75.7
46.1
10. Secondary Outcome
Title Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers
Description Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1
Time Frame Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
AFP: Week 25 Day 1 (Wk 25 D1) (n=7,8,5,22)
0.75
0.79
1.10
0.49
AFP: Week 49 Day 1 (WK25 D1) (n=4,3,4,14)
0.68
0.60
0.49
0.49
APOA-1: Week 25 Day 1 (n=7,8,5,22)
1.10
1.65
1.60
2.10
APOA-1: Week 49 Day 1 (n=4,3,4,14)
1.30
1.50
1.80
2.05
B2M: Week 25 Day 1 (n=7,8,5,22)
5.00
3.15
3.70
3.15
B2M: Week 49 Day 1 (n=4,3,4,14)
5.75
4.60
3.25
3.00
BDNF: Week 25 Day 1 (n=7,8,5,22)
0.46
0.85
0.15
0.55
BDNF: Week 49 Day 1 (n=4,3,4,14)
1.16
0.19
0.41
0.52
C Reactive Protein: Week 25 Day 1 (n=7,8,5,22)
2.60
2.70
1.30
4.50
C Reactive Protein: Week 49 Day 1 (n=4,3,4,14)
4.65
2.40
1.30
0.79
Carcinoembryyonic Antigen: Wk 25 D1 (n=7,8,5,22)
1.40
1.20
1.20
1.80
Carcinoembryyonic Antigen: Wk 49 D1 (n=4,3,4,14)
1.72
1.20
1.45
1.80
Cluster of. Diff 40: Wk 25 D1 (n=7,7,5,0)
1.90
1.10
0.91
Cluster of. Diff 40: Wk 49 D1 (n=4,2,0,0)
1.65
1.3
Eotaxin1: Wk 25 D1 (n=7,8,5,22)
155.00
119.00
101.00
118.00
Eotaxin1: Wk 49 D1 (n=4,3,4,14)
136.00
145.00
157.00
175.00
ICAM1: Wk 25 D1 (n=7,8,5,22)
266.00
203.00
168.00
185.50
ICAM1: Wk 49 D1 (n=4,3,4,14)
321.00
173.00
152.50
163.00
IL10: Wk 25 D1 (n=7,8,5,22)
9.30
7.50
3.40
6.23
IL10: Wk 49 D1 (n=4,3,4,14)
8.10
4.05
11.00
8.40
IL18: Wk 25 D1 (n=7,8,5,22)
292.00
220.50
445.00
415.50
IL18: Wk 49 D1 (n=4,3,4,14)
278.00
199.00
550.50
318.50
IL1B: Wk 25 D1 (n=7,8,5,22)
3.30
3.30
3.30
4.3
IL1B: Wk 49 D1 (n=4,3,4,14)
3.30
3.30
4.3
4.3
IL1RN: Wk 25 D1 (n=7,8,5,22)
130.00
147.00
114.00
88.00
IL1RN: Wk 49 D1 (n=4,3,4,14)
98.00
281.00
88.00
85.50
IL6: Wk 25 D1 (n=7,8,5,22)
4.70
2.3
2.3
3.40
IL6: Wk 49 D1 (n=4,3,4,14)
3.48
3.40
3.40
3.40
IL8: Wk 25 D1 (n=7,8,5,22)
28.00
9.50
15.00
29.50
IL8: Wk 49 D1 (n=4,3,4,14)
18.50
11.00
58.50
32.00
Insulin: Wk 25 D1 (n=7,8,5,22)
2.70
1.35
2.30
0.6
Insulin: Wk 49 D1 (n=4,3,4,14)
2.90
2.90
1.65
1.60
LEP: Wk 25 D1 (n=7,8,5,22)
1.50
4.75
6.00
6.40
LEP: Wk 49 D1 (n=4,3,4,14)
3.45
17.00
5.95
5.60
Macro. Inflam. Prot-1 Beta: Wk 25 D1 (n=7,8,5,22)
491.00
375.50
410.00
513.00
Macro. Inflam. Prot-1 Beta: Wk 49 D1 (n=4,3,4,14)
406.50
487.00
970.50
521.00
Macro.-derived Chemokine: Wk 25 D1 (n=7,8,5,22)
253.00
274.00
516.00
254.00
Macro.-derived Chemokine: Wk 49 D1 (n=4,3,4,14)
190.50
327.00
430.50
212.00
MPO: Wk 25 D1 (n=7,8,5,22)
327.00
323.00
335.00
164.50
MPO: Wk 49 D1 (n=4,3,4,14)
175.00
180.00
237.00
116.50
Myoglobin: Wk 25 D1 (n=7,8,5,22)
31.00
31.50
54.00
39.50
Myoglobin: Wk 49 D1 (n=4,3,4,14)
35.00
18.00
45.50
45.00
Plasmin. Activ. Inhibitor 1: Wk 25 D1 (n=7,8,5,22)
34.00
45.50
17.00
51.50
Plasmin. Activ. Inhibitor 1: Wk 49 D1 (n=4,3,4,14)
31.50
25.00
49.00
52.50
RANTES: Wk 25 D1 (n=7,8,5,22)
4.80
5.85
4.20
8.80
RANTES: Wk 49 D1 (n=4,3,4,14)
8.25
3.20
10.55
6.50
Thyroxine binding globulin Wk 25 D1 (n=7,8,5,22)
38.00
41.50
45.00
54.50
Thyroxine binding globulin: Wk 49 D1 (n=4,3,4,14)
42.00
45.00
72.50
54.00
TNFA: Wk 25 D1 (n=7,8,5,22)
27.00
18.50
25.00
12.00
TNFA: Wk 49 D1 (n=4,3,4,14)
32.50
32.00
26.50
12.00
TNFRT 2: Wk 25 D1 (n=7,8,5,22)
33.00
12.00
15.00
17.50
TNFRT 2: Wk 49 D1 (n=4,3,4,14)
28.00
21.00
16.00
12.50
VCAM1: Wk 25 D1 (n=7,8,5,22)
2040.00
1130.00
1690.00
1930.00
VCAM1: Wk 49 D1 (n=4,3,4,14)
2425.00
1210.00
2225.00
1715.00
VEGF: Wk. 25 D1 (n=7,8,5,22)
145.00
202.50
108.00
168.00
VEGF: Wks. 49 D1 (n=4,3,4,14)
227.00
106.00
163.00
217.00
VWF: Wk. 25 D1 (n=7,8,5,22)
135.00
65.50
398.00
156.50
VWF: Wk. 49 D1 (n=4,3,4,14)
140.50
67.00
716.00
154.50
11. Secondary Outcome
Title Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores
Description 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.
Time Frame Week 24, Week 48

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase. Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
Week 24
50.00
625%
40.0
400%
80.0
1600%
33.3
123.3%
Week 48
25.00
312.5%
20.0
200%
80.0
1600%
18.5
68.5%
12. Secondary Outcome
Title Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores
Description 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.
Time Frame Baseline, Week 25, Week 49

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. Participants who took a combination of LDE225 400mg and INC424 15mg in the dose escalation phase. Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase. Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
Week 25 (n = 6, 7, 5, 19)
-18.8
(15.20)
-14.0
(8.58)
-19.4
(6.43)
-6.5
(9.26)
Week 49 (n = 4, 5, 4, 10)
-18.5
(12.07)
-13.6
(10.43)
-21.0
(5.66)
-8.0
(14.61)
13. Secondary Outcome
Title Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48
Description 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.
Time Frame Week 24, Week 48

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. Participants who took a combination of LDE225 400mg and INC424 15mg in the dose escalation phase. Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase. Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
Glob. Health Status/Qol: Wk 25 (n=6,7,5,19)
-2.8
(21.52)
-2.4
(21.90)
16.7
(27.64)
2.6
(22.75)
Glob. Health Status/Qol: Wk 49(n=4,4,4,10)
-2.1
(23.94)
14.6
(45.33)
-0.0
(20.41)
-3.3
(24.91)
Phys. Func: Wk 25 (n=6,7,5,19)
15.6
(25.88)
-1.0
(14.10)
17.3
(16.73)
1.0
(23.74)
Phys. Func: Wk 49 (n=4,4,4,10)
25.0
(16.67)
-10.0
(25.82)
15.0
(22.03)
6.0
(15.85)
Role Func: Wk 25 (n=6,7,5,19)
33.3
(39.44)
-7.1
(18.90)
16.7
(20.41)
7.9
(32.09)
Role Func: Wk 49 (n=4,4,4,10)
41.7
(21.52)
-33.3
(27.22)
12.5
(25.00)
10.2
(22.50)
Emo. Func: Wk 25 (n=6,7,5,19)
25.0
(16.67)
-8.3
(31.18)
5.6
(12.42)
2.5
(18.61)
Emo. Func: Wk 49 (n=4,4,4,10)
33.3
(11.79)
-12.5
(41.67)
0.0
(15.21)
-2.5
(10.43)
Cog. Func: Wk 25 (n=6,7,5,19
14.6
(18.77)
-6.3
(19.80)
-3.3
(13.94)
2.6
(18.64)
Cog. Func: Wk 49 (n=4,4,4,10)
20.8
(15.96)
-8.3
(28.87)
4.2
(8.33)
-5.0
(22.29)
Soc. Func: Wk 25 (n=6,7,4,19)
8.3
(39.09)
-7.1
(18.90)
12.5
(15.96)
-2.6
(24.38)
Soc. Func: Wk 49 (n=3,4,4,10)
16.7
(16.67)
-4.2
(8.33)
12.5
(25.00)
-3.3
(18.92)
Fatigue: Wk 25 (n=6,7,5,19)
-20.4
(25.74)
-1.6
(26.78)
-28.9
(16.85)
-8.8
(26.86)
Fatigue: Wk 49 (n=4,4,4,10)
-27.8
(6.42)
0.
(15.71)
-33.3
(18.14)
4.4
(36.74)
Naus & Vom: Wk 25 (n=6,7,5,19)
-5.6
(13.61)
-4.8
(18.54)
-3.3
(7.45)
-3.5
(11.89)
Naus & Vom: Wk 49 (n=4,4,4,10)
-4.2
(15.96)
4.2
(28.46)
0.0
(13.61)
-10.0
(11.65)
Pain: Wk 25 (n=6,7,5,18)
-11.1
(40.37)
-4.8
(38.14)
-26.7
(25.28)
-8.3
(21.58)
Pain: Wk 49 (n=4,4,4,10)
25.0
(21.52)
-8.3
(56.93)
-20.8
(25.00)
3.3
(10.54)
Dyspnoea: Wk 25 (n=6,7,5,19)
-33.3
(29.81)
-4.8
(29.99)
-6.7
(14.91)
-1.8
(26.00)
Dyspnoea: Wk 49 (n=4,4,4,10)
-33.3
(27.22)
-16.7
(43.03)
0.0
(0.00)
6.7
(26.29)
Insomnia: Wk 25 (n=6,7,5,19)
-22.2
(27.22)
0.0
(38.49)
-33.3
(23.57)
-17.5
(34.01)
Insomnia: Wk 49 (n=4,4,4,10)
-25.0
(31.91)
8.3
(16.67)
-33.3
(27.22)
-33.3
(41.57)
Appetite loss: Wk 25 (n=6,7,5,19)
-27.8
(25.09)
4.8
(12.60)
-13.3
(18.26)
-12.3
(29.84)
Appetite loss: Wk 49 (n=4,4,4,10)
-25.0
(41.94)
8.3
(16.67)
-16.7
(19.25)
0.0
(44.44)
Constipation: Wk 25 (n=6,7,5,19)
-11.1
(17.21)
0.0
(0.00)
13.3
(29.81)
7.0
(30.59)
Constipation: Wk 49 (n=4,4,4,10)
-33.3
(47.14)
0.0
(27.22)
8.3
(16.67)
3.3
(36.68)
Diarrhoea: Wk 25 (n=6,7,5,19)
5.6
(64.69)
-9.5
(16.27)
-13.3
(18.26)
-1.8
(20.71)
Diarrhoea: Wk 49 (n=4,4,4,10)
-8.3
(16.67)
-0.0
(27.22)
16.7
(57.74)
-3.3
(18.92)
Fin. diff: Wk 25 (n=6,7,5,19)
16.7
(49.95)
19.0
(32.53)
20.0
(50.55)
8.8
(24.45)
Fin. diff: Wk 49 (n=4,4,4,10)
8.3
(63.10)
25.0
(31.91)
0.0
(27.22)
3.3
(18.92)
14. Secondary Outcome
Title Phase Ib and Phase II: LDE225: PK Parameter: Racc
Description Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 [fold]
Time Frame 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10 mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
LDE225 (Week 9, Day 1) (n=4,6,3,13)
4.60
7.40
10.9
4.75
15. Secondary Outcome
Title Phase Ib and Phase II: INC424: PK Parameter: T1/2
Description T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve [time]
Time Frame 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10 mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
Median (Full Range) [hour (h)]
1.81
2.42
2.20
1.99
16. Secondary Outcome
Title Phase Ib and Phase II: INC424: PK Parameter: Vss/F
Description Vss/F: Apparent volume of distribution at steady state after oral administration [volume]
Time Frame 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title LDE225 400mg + INC424 10 mg (Dose Escalation Phase) LDE225 400mg + INC424 15mg (Dose Escalation Phase) LDE225 400mg + INC424 20mg (Dose Escalation Phase) LDED225 400mg + INC424 20mg (Dose Expansion Phase)
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase. 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
Measure Participants 8 10 5 27
Median (Full Range) [Litre (L)]
63.7
67.1
53.1
54.5

Adverse Events

Time Frame 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.
Adverse Event Reporting Description
Arm/Group Title LDE225 400 mg + INC424 10 mg LDE225 400 mg + INC424 15 mg LDE225 400 mg + INC424 20 mg LDE225 400 mg + INC424 20 mg (Dose Expansion) All Patients
Arm/Group Description Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase 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 escalation phase Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase All Patients
All Cause Mortality
LDE225 400 mg + INC424 10 mg LDE225 400 mg + INC424 15 mg LDE225 400 mg + INC424 20 mg LDE225 400 mg + INC424 20 mg (Dose Expansion) All Patients
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1/8 (12.5%) 1/10 (10%) 1/5 (20%) 1/27 (3.7%) 4/50 (8%)
Serious Adverse Events
LDE225 400 mg + INC424 10 mg LDE225 400 mg + INC424 15 mg LDE225 400 mg + INC424 20 mg LDE225 400 mg + INC424 20 mg (Dose Expansion) All Patients
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 5/8 (62.5%) 6/10 (60%) 2/5 (40%) 13/27 (48.1%) 26/50 (52%)
Blood and lymphatic system disorders
Anaemia 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
Extramedullary haemopoiesis 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Cardiac disorders
Atrial fibrillation 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Right ventricular failure 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Gastrointestinal disorders
Constipation 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Diarrhoea 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
Duodenal ulcer haemorrhage 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Gastric ulcer 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Gastric ulcer haemorrhage 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Gastrointestinal haemorrhage 0/8 (0%) 2/10 (20%) 0/5 (0%) 0/27 (0%) 2/50 (4%)
Melaena 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Vomiting 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
General disorders
Face oedema 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Multiple organ dysfunction syndrome 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Pyrexia 2/8 (25%) 0/10 (0%) 0/5 (0%) 3/27 (11.1%) 5/50 (10%)
Infections and infestations
Diverticulitis 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Erysipelas 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Gastroenteritis 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Infection 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
Injury, poisoning and procedural complications
Fall 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Meniscus injury 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Post procedural haemorrhage 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Investigations
Aspartate aminotransferase increased 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Blood creatine phosphokinase increased 0/8 (0%) 2/10 (20%) 0/5 (0%) 3/27 (11.1%) 5/50 (10%)
Myoglobin blood increased 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Metabolism and nutrition disorders
Hyperkalaemia 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Hyponatraemia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Musculoskeletal and connective tissue disorders
Myalgia 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Myositis 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia 0/8 (0%) 0/10 (0%) 1/5 (20%) 1/27 (3.7%) 2/50 (4%)
B-cell lymphoma 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Cholangiocarcinoma 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Chronic myeloid leukaemia 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Squamous cell carcinoma of skin 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Nervous system disorders
Cerebrovascular accident 0/8 (0%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 1/50 (2%)
Presyncope 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Other (Not Including Serious) Adverse Events
LDE225 400 mg + INC424 10 mg LDE225 400 mg + INC424 15 mg LDE225 400 mg + INC424 20 mg LDE225 400 mg + INC424 20 mg (Dose Expansion) All Patients
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 8/8 (100%) 10/10 (100%) 5/5 (100%) 27/27 (100%) 50/50 (100%)
Blood and lymphatic system disorders
Anaemia 5/8 (62.5%) 4/10 (40%) 4/5 (80%) 16/27 (59.3%) 29/50 (58%)
Extramedullary haemopoiesis 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Leukocytosis 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Neutropenia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Thrombocytopenia 3/8 (37.5%) 2/10 (20%) 3/5 (60%) 7/27 (25.9%) 15/50 (30%)
Cardiac disorders
Supraventricular extrasystoles 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Eye disorders
Retinal detachment 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Vision blurred 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Gastrointestinal disorders
Abdominal discomfort 1/8 (12.5%) 0/10 (0%) 1/5 (20%) 1/27 (3.7%) 3/50 (6%)
Abdominal distension 0/8 (0%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Abdominal pain 2/8 (25%) 3/10 (30%) 0/5 (0%) 4/27 (14.8%) 9/50 (18%)
Abdominal pain upper 0/8 (0%) 0/10 (0%) 1/5 (20%) 1/27 (3.7%) 2/50 (4%)
Bile acid malabsorption 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Constipation 2/8 (25%) 1/10 (10%) 1/5 (20%) 7/27 (25.9%) 11/50 (22%)
Diarrhoea 3/8 (37.5%) 3/10 (30%) 4/5 (80%) 11/27 (40.7%) 21/50 (42%)
Diverticulum 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Diverticulum intestinal 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Dry mouth 0/8 (0%) 0/10 (0%) 0/5 (0%) 3/27 (11.1%) 3/50 (6%)
Duodenal ulcer 0/8 (0%) 0/10 (0%) 1/5 (20%) 1/27 (3.7%) 2/50 (4%)
Dyspepsia 0/8 (0%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Flatulence 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Functional gastrointestinal disorder 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Gastric ulcer 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Gastric varices 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Gastritis 0/8 (0%) 1/10 (10%) 1/5 (20%) 0/27 (0%) 2/50 (4%)
Gastrooesophageal reflux disease 0/8 (0%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Haematochezia 0/8 (0%) 1/10 (10%) 1/5 (20%) 0/27 (0%) 2/50 (4%)
Melaena 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Nausea 3/8 (37.5%) 1/10 (10%) 0/5 (0%) 8/27 (29.6%) 12/50 (24%)
Stomatitis 0/8 (0%) 0/10 (0%) 1/5 (20%) 1/27 (3.7%) 2/50 (4%)
Toothache 0/8 (0%) 0/10 (0%) 1/5 (20%) 1/27 (3.7%) 2/50 (4%)
Vomiting 3/8 (37.5%) 2/10 (20%) 1/5 (20%) 5/27 (18.5%) 11/50 (22%)
General disorders
Asthenia 1/8 (12.5%) 2/10 (20%) 1/5 (20%) 3/27 (11.1%) 7/50 (14%)
Catheter site bruise 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Early satiety 0/8 (0%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Fatigue 6/8 (75%) 3/10 (30%) 0/5 (0%) 8/27 (29.6%) 17/50 (34%)
Gait disturbance 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
General physical health deterioration 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Influenza like illness 1/8 (12.5%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 3/50 (6%)
Malaise 0/8 (0%) 0/10 (0%) 0/5 (0%) 3/27 (11.1%) 3/50 (6%)
Oedema peripheral 2/8 (25%) 2/10 (20%) 0/5 (0%) 1/27 (3.7%) 5/50 (10%)
Pyrexia 0/8 (0%) 2/10 (20%) 2/5 (40%) 7/27 (25.9%) 11/50 (22%)
Thirst 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Hepatobiliary disorders
Cholelithiasis 1/8 (12.5%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 2/50 (4%)
Hyperbilirubinaemia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Infections and infestations
Bronchitis 1/8 (12.5%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 3/50 (6%)
Cystitis 0/8 (0%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Ear infection 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Escherichia infection 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Folliculitis 0/8 (0%) 0/10 (0%) 0/5 (0%) 3/27 (11.1%) 3/50 (6%)
Fungal skin infection 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Gastroenteritis viral 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Herpes zoster 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 3/50 (6%)
Influenza 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
Nasopharyngitis 0/8 (0%) 2/10 (20%) 2/5 (40%) 2/27 (7.4%) 6/50 (12%)
Oesophageal candidiasis 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Oral herpes 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Pharyngitis 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Pneumonia 1/8 (12.5%) 0/10 (0%) 1/5 (20%) 2/27 (7.4%) 4/50 (8%)
Tooth infection 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Upper respiratory tract infection 1/8 (12.5%) 3/10 (30%) 1/5 (20%) 2/27 (7.4%) 7/50 (14%)
Urinary tract infection 1/8 (12.5%) 1/10 (10%) 0/5 (0%) 2/27 (7.4%) 4/50 (8%)
Urinary tract infection bacterial 1/8 (12.5%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 2/50 (4%)
Wound infection 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Injury, poisoning and procedural complications
Animal bite 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
Contusion 1/8 (12.5%) 0/10 (0%) 2/5 (40%) 3/27 (11.1%) 6/50 (12%)
Fall 2/8 (25%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 4/50 (8%)
Hyphaema 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Laceration 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Meniscus injury 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Procedural hypotension 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Scratch 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Spinal compression fracture 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Tooth fracture 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Investigations
Alanine aminotransferase increased 1/8 (12.5%) 2/10 (20%) 1/5 (20%) 2/27 (7.4%) 6/50 (12%)
Amylase increased 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Aspartate aminotransferase increased 1/8 (12.5%) 3/10 (30%) 1/5 (20%) 2/27 (7.4%) 7/50 (14%)
Blood alkaline phosphatase increased 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Blood bilirubin increased 1/8 (12.5%) 0/10 (0%) 1/5 (20%) 2/27 (7.4%) 4/50 (8%)
Blood creatine phosphokinase increased 1/8 (12.5%) 2/10 (20%) 3/5 (60%) 12/27 (44.4%) 18/50 (36%)
Blood creatinine increased 0/8 (0%) 0/10 (0%) 0/5 (0%) 3/27 (11.1%) 3/50 (6%)
Blood prolactin increased 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Blood uric acid increased 0/8 (0%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Cytomegalovirus test 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Electrocardiogram QT prolonged 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Gamma-glutamyltransferase increased 0/8 (0%) 1/10 (10%) 1/5 (20%) 0/27 (0%) 2/50 (4%)
International normalised ratio increased 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Lipase increased 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Low density lipoprotein increased 0/8 (0%) 0/10 (0%) 2/5 (40%) 1/27 (3.7%) 3/50 (6%)
Platelet count decreased 0/8 (0%) 0/10 (0%) 0/5 (0%) 4/27 (14.8%) 4/50 (8%)
Prothrombin level increased 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Prothrombin time prolonged 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Weight decreased 2/8 (25%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 4/50 (8%)
Weight increased 1/8 (12.5%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 3/50 (6%)
Metabolism and nutrition disorders
Decreased appetite 3/8 (37.5%) 0/10 (0%) 0/5 (0%) 4/27 (14.8%) 7/50 (14%)
Hyperkalaemia 1/8 (12.5%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 2/50 (4%)
Hypertriglyceridaemia 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Hyperuricaemia 1/8 (12.5%) 3/10 (30%) 1/5 (20%) 1/27 (3.7%) 6/50 (12%)
Hypocalcaemia 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Hypokalaemia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Hypomagnesaemia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Hyponatraemia 1/8 (12.5%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 2/50 (4%)
Increased appetite 0/8 (0%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Iron deficiency 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Musculoskeletal and connective tissue disorders
Arthralgia 2/8 (25%) 2/10 (20%) 0/5 (0%) 1/27 (3.7%) 5/50 (10%)
Back pain 0/8 (0%) 2/10 (20%) 0/5 (0%) 0/27 (0%) 2/50 (4%)
Bone pain 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
Joint lock 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Muscle fatigue 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Muscle spasms 3/8 (37.5%) 6/10 (60%) 4/5 (80%) 18/27 (66.7%) 31/50 (62%)
Muscle twitching 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Muscular weakness 1/8 (12.5%) 4/10 (40%) 1/5 (20%) 2/27 (7.4%) 8/50 (16%)
Musculoskeletal chest pain 0/8 (0%) 0/10 (0%) 1/5 (20%) 3/27 (11.1%) 4/50 (8%)
Musculoskeletal pain 2/8 (25%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 2/50 (4%)
Myalgia 1/8 (12.5%) 3/10 (30%) 0/5 (0%) 9/27 (33.3%) 13/50 (26%)
Osteoarthritis 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Pain in extremity 1/8 (12.5%) 0/10 (0%) 1/5 (20%) 3/27 (11.1%) 5/50 (10%)
Polyarthritis 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Atypical fibroxanthoma 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Squamous cell carcinoma 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Nervous system disorders
Amnesia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Carpal tunnel syndrome 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Cerebral ischaemia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Dizziness 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 4/27 (14.8%) 5/50 (10%)
Dysaesthesia 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Dysgeusia 3/8 (37.5%) 4/10 (40%) 3/5 (60%) 9/27 (33.3%) 19/50 (38%)
Head discomfort 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Headache 1/8 (12.5%) 2/10 (20%) 0/5 (0%) 5/27 (18.5%) 8/50 (16%)
Hypoaesthesia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Memory impairment 0/8 (0%) 1/10 (10%) 0/5 (0%) 2/27 (7.4%) 3/50 (6%)
Muscle contractions involuntary 0/8 (0%) 1/10 (10%) 1/5 (20%) 0/27 (0%) 2/50 (4%)
Paraesthesia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Peripheral sensory neuropathy 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Post herpetic neuralgia 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Restless legs syndrome 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Syncope 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Transient ischaemic attack 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Tremor 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
Psychiatric disorders
Depression 0/8 (0%) 2/10 (20%) 0/5 (0%) 1/27 (3.7%) 3/50 (6%)
Insomnia 2/8 (25%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 4/50 (8%)
Renal and urinary disorders
Dysuria 0/8 (0%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Haematuria 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Urinary retention 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Reproductive system and breast disorders
Erectile dysfunction 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Respiratory, thoracic and mediastinal disorders
Asthma 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Cough 1/8 (12.5%) 3/10 (30%) 2/5 (40%) 5/27 (18.5%) 11/50 (22%)
Dry throat 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Dysphonia 0/8 (0%) 1/10 (10%) 0/5 (0%) 2/27 (7.4%) 3/50 (6%)
Dyspnoea 0/8 (0%) 2/10 (20%) 0/5 (0%) 3/27 (11.1%) 5/50 (10%)
Epistaxis 0/8 (0%) 0/10 (0%) 2/5 (40%) 3/27 (11.1%) 5/50 (10%)
Oropharyngeal pain 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
Skin and subcutaneous tissue disorders
Acne 0/8 (0%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 2/50 (4%)
Alopecia 3/8 (37.5%) 7/10 (70%) 3/5 (60%) 12/27 (44.4%) 25/50 (50%)
Erythema 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Hair growth abnormal 0/8 (0%) 0/10 (0%) 0/5 (0%) 2/27 (7.4%) 2/50 (4%)
Hyperkeratosis 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Madarosis 0/8 (0%) 0/10 (0%) 1/5 (20%) 1/27 (3.7%) 2/50 (4%)
Night sweats 0/8 (0%) 1/10 (10%) 1/5 (20%) 3/27 (11.1%) 5/50 (10%)
Onychoclasis 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Pruritus 0/8 (0%) 2/10 (20%) 2/5 (40%) 0/27 (0%) 4/50 (8%)
Pruritus generalised 0/8 (0%) 0/10 (0%) 2/5 (40%) 0/27 (0%) 2/50 (4%)
Rash 1/8 (12.5%) 1/10 (10%) 0/5 (0%) 2/27 (7.4%) 4/50 (8%)
Skin discolouration 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Swelling face 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Vascular disorders
Aortic stenosis 1/8 (12.5%) 0/10 (0%) 0/5 (0%) 0/27 (0%) 1/50 (2%)
Haematoma 1/8 (12.5%) 1/10 (10%) 0/5 (0%) 1/27 (3.7%) 3/50 (6%)
Hypertension 0/8 (0%) 1/10 (10%) 1/5 (20%) 5/27 (18.5%) 7/50 (14%)
Intermittent claudication 0/8 (0%) 0/10 (0%) 1/5 (20%) 0/27 (0%) 1/50 (2%)
Peripheral venous disease 0/8 (0%) 1/10 (10%) 0/5 (0%) 0/27 (0%) 1/50 (2%)

Limitations/Caveats

Please refer to detailed description regarding reason for early termination of study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.

Results Point of Contact

Name/Title Study Director
Organization Novartis Pharmaceuticals
Phone 862-778-8300
Email Novartis.email@novartis.com
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01787552
Other Study ID Numbers:
  • CLDE225X2116
  • 2012-004023-20
First Posted:
Feb 8, 2013
Last Update Posted:
Apr 15, 2020
Last Verified:
Apr 1, 2020