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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT01787552
Registration number
NCT01787552
Ethics application status
Date submitted
6/02/2013
Date registered
8/02/2013
Titles & IDs
Public title
A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF
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Scientific 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
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Secondary ID [1]
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2012-004023-20
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Secondary ID [2]
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CLDE225X2116
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Primary Myelofibrosis
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Thrombocytosis
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Essential Thrombocythemia
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Polycythemia Vera
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Myeloproliferative Disorders
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Bone Marrow Diseases
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Hematologic Diseases
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Blood Coagulation Disorders
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0
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Blood Platelet Disorders
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Hemorrhagic Disorders
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Condition category
Condition code
Blood
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Haematological diseases
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Blood
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Other blood disorders
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Cardiovascular
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Diseases of the vasculature and circulation including the lymphatic system
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Blood
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Clotting disorders
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Musculoskeletal
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Other muscular and skeletal disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Leukaemia - Acute leukaemia
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Experimental: LDE225 + INC424 - LDE225 and INC424 in combination
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)
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Assessment method [1]
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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.
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Timepoint [1]
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6 weeks (42 days)
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Primary outcome [2]
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Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1
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Assessment method [2]
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Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients
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Timepoint [2]
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Week 24 and Week 48
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Secondary outcome [1]
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Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)
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Assessment method [1]
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Plasma Concentration Time Curve: AUC0-24h: Area under the concentration-time curve from time zero to 24 hours extrapolate from AUClast\[mass x time x volume-1\]
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Timepoint [1]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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Secondary outcome [2]
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Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast
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Assessment method [2]
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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 \[mass x time x volume-1\].
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Timepoint [2]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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Secondary outcome [3]
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Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)
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Assessment method [3]
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Cmax: Maximum observed plasma concentration after drug administration \[mass x volume-
1\].
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Timepoint [3]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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Secondary outcome [4]
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Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)
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Assessment method [4]
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Tmax: Time to reach Cmax \[time\]
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Timepoint [4]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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Secondary outcome [5]
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Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)
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Assessment method [5]
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CL/F: Apparent total plasma clearance of drug after oral administration \[volume x time-1\]
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Timepoint [5]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
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Secondary outcome [6]
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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
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Assessment method [6]
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The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.
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Timepoint [6]
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Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
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Secondary outcome [7]
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Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1
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Assessment method [7]
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Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden
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Timepoint [7]
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Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
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Secondary outcome [8]
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Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers
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Assessment method [8]
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Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1
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Timepoint [8]
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Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
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Secondary outcome [9]
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Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores
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Assessment method [9]
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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.
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Timepoint [9]
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Week 24, Week 48
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Secondary outcome [10]
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Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores
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Assessment method [10]
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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.
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Timepoint [10]
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Baseline, Week 25, Week 49
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Secondary outcome [11]
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Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48
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Assessment method [11]
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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.
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Timepoint [11]
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Week 24, Week 48
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Secondary outcome [12]
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Phase Ib and Phase II: LDE225: PK Parameter: Racc
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Assessment method [12]
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Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 \[fold\]
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Timepoint [12]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1
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Secondary outcome [13]
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Phase Ib and Phase II: INC424: PK Parameter: T1/2
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Assessment method [13]
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T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve \[time\]
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Timepoint [13]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
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Secondary outcome [14]
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Phase Ib and Phase II: INC424: PK Parameter: Vss/F
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Assessment method [14]
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Vss/F: Apparent volume of distribution at steady state after oral administration \[volume\]
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Timepoint [14]
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0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
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Eligibility
Key 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).
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
NA
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
8/05/2013
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
10/04/2018
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Sample size
Target
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Accrual to date
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Final
50
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Recruitment in Australia
Recruitment state(s)
NSW,QLD
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Recruitment hospital [1]
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Novartis Investigative Site - Camperdown
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Recruitment hospital [2]
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Novartis Investigative Site - Woolloongabba
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Recruitment postcode(s) [1]
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NSW - Camperdown
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Recruitment postcode(s) [2]
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4102 - Woolloongabba
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Recruitment outside Australia
Country [1]
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Belgium
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State/province [1]
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Leuven
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Country [2]
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Canada
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State/province [2]
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Ontario
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Country [3]
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Canada
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State/province [3]
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Quebec
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Country [4]
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Denmark
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State/province [4]
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Roskilde
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Country [5]
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France
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State/province [5]
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Marseille
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Country [6]
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Germany
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State/province [6]
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Aachen
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Country [7]
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Germany
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State/province [7]
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Magdeburg
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Country [8]
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Ireland
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State/province [8]
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Galway
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Country [9]
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Italy
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State/province [9]
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FI
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Country [10]
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Italy
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State/province [10]
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RC
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Country [11]
0
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Netherlands
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State/province [11]
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Amsterdam
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Country [12]
0
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Netherlands
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State/province [12]
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Rotterdam
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Country [13]
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Spain
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State/province [13]
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Catalunya
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Country [14]
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Spain
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State/province [14]
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Madrid
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Country [15]
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United Kingdom
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State/province [15]
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Scotland
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Country [16]
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United Kingdom
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State/province [16]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/study/NCT01787552
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Trial related presentations / publications
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.
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
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.
This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.
Supporting document/s available: Study protocol, Statistical analysis plan (SAP)
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When will data be available (start and end dates)?
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Available to whom?
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Available for what types of analyses?
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How or where can data be obtained?
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What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/52/NCT01787552/SAP_000.pdf
Study protocol
https://cdn.clinicaltrials.gov/large-docs/52/NCT01787552/Prot_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT01787552