Clinical Trial Results:
A Phase Ib/III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of vismodegib in combination with ruxolitinib versus placebo and ruxolitinib in patients with intermediate- or high-risk myelofibrosis
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Summary
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EudraCT number |
2015-001620-33 |
Trial protocol |
DE |
Global end of trial date |
12 Jul 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Jul 2018
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First version publication date |
20 Jul 2018
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
WO29806
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02593760 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Scientific contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Jul 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Jul 2017
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The objective of the Phase Ib portion of the study was to assess preliminary safety and efficacy data after the first ten patients completed at least 24 and up to 48 weeks of study treatment (vismodegib plus ruxolitinib).
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
26 Jan 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 3
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Country: Number of subjects enrolled |
Canada: 4
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Country: Number of subjects enrolled |
Italy: 3
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Worldwide total number of subjects |
10
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EEA total number of subjects |
3
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
3
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From 65 to 84 years |
7
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||
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Pre-assignment
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Screening details |
This study was divided into two components. Phase Ib portion of the study consisted of ten participants receiving open-label vismodegib plus ruxolitinib. Phase III portion was planned (with 84 patients in a randomized, placebo-controlled and double-blind manner) but was not conducted. | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Vismodegib + Ruxolitinib | ||||||||||||
Arm description |
Participants will receive vismodegib (150 mg PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Vismodegib
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Investigational medicinal product code |
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Other name |
Erivedge
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Vismodegib was administered at a dose of 150 mg PO QD for up to 48 weeks.
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Investigational medicinal product name |
Ruxolitinib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Ruxolitinib was administered PO BID at a starting dose depending on the participants's baseline platelet count for up to 48 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Vismodegib + Ruxolitinib
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Reporting group description |
Participants will receive vismodegib (150 mg PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Vismodegib + Ruxolitinib
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Reporting group description |
Participants will receive vismodegib (150 mg PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks. | ||
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End point title |
Percentage of Participants who Achieve a Greater Than or Equal to (>=) 35% Reduction in Spleen Volume from Baseline at Week 24 [1] | ||||||||
End point description |
Determined by an Independent Review Committee (IRC) Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Revised Response Criteria
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End point type |
Primary
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End point timeframe |
Week 24
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses for this end point. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with Complete Remission (CR) and Partial Remission (PR) at Week 24, as Determined by an IRC Using IWG-MRT Revised Response Criteria [2] | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Week 24
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analyses for this end point. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Plasma Vismodegib Concentration at Steady State | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Predose (0 hour) on Weeks 6, 12, 24, 36, and 48
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Unbound Vismodegib Concentration at Steady State | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Predose (0 hour) on Weeks 6, 12, 24, 36, and 48
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Alpha 1-Acid Glycoprotein Concentration at Steady State | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Predose (0 hour) on Weeks 6, 12, 24, 36, and 48
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage of Participants who Achieve a >= 35% Reduction in Spleen Volume from Baseline, as Determined by an IRC Using IWG-MRT Revised Response Criteria at Week 48 | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 48
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| Notes [3] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants who Achieve a >= 35% Reduction in Spleen Volume from Baseline, as Determined by an Investigator at Weeks 24 and 48 | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 24 and 48
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| Notes [4] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with CR and PR, as Determined by an IRC Using IWG-MRT Revised Response Criteria at Week 48 | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Week 48
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| Notes [5] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with CR and PR, as Determined by an Investigator at Weeks 24 and 48 | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Weeks 24 and 48
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| Notes [6] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with Overall Response Rate (CR, PR, and Clinical Improvement) at Weeks 24 and 48, as Determined by an IRC Using IWG-MRT Revised Response Criteria | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Weeks 24 and 48
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| Notes [7] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with Overall Response Rate (CR, PR, and Clinical Improvement) at Weeks 24 and 48, as Determined by the Investigator Using IWG-MRT Revised Response Criteria | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Weeks 24 and 48
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| Notes [8] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants who Achieve Anemia Response at Week 24, as Determined by the Investigator Using IWG-MRT Revised Response Criteria | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Week 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with Symptom Response (Participants who Achieve a >= 50% Reduction from Baseline in the Myeloproliferative Neoplasm Symptom Assessment Form [MPN-SAF] Total Symptom Score [TSS]) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and Week 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Response, as Determined by the Investigator and an IRC Using IWG-MRT Revised Response Criteria or Death from Any Cause During the Study | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Baseline up to 28 days after the last dose of study drug (52 weeks)
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| Notes [9] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with Improvement from Baseline in Bone Marrow Fibrosis at Week 24, as Determined by the Investigator Using the European Consensus Grading System | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline and Week 24
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with Improvement from Baseline in Bone Marrow Fibrosis at Weeks 24 and 48, as Determined by Independent Pathology Review Using the European Consensus Grading System | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 24 and 48
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| Notes [10] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression-Free Survival | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Baseline up to the end of the study (up to 1 year after completing 48 weeks of treatment by the last participant)
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| Notes [11] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants who Achieve a >= 50% Reduction in Fatigue from Baseline to Weeks 24 and 48 as Measured by MPN-SAF TSS | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 24 and 48
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| Notes [12] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants who Achieve a >= 50% Reduction in Other Symptom and Impact Item Scores from Baseline to Weeks 24 and 48, as Measured by the MPN-SAF | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 24 and 48
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| Notes [13] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants who Achieve a Meaningful Improvement on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Scale Scores from Baseline to Weeks 24 and 48 | ||||||||
End point description |
Meaningful improvement is defined as a 10-point change. This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 24 and 48
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| Notes [14] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival | ||||||||
End point description |
This outcome measure was specific to Phase III of the study, which was not conducted.
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End point type |
Secondary
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End point timeframe |
Baseline up to the end of the study (up to 1 year after completing 48 weeks treatment by the last participant)
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| Notes [15] - This outcome measure was specific to Phase III of the study, which was not conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with Adverse Events (AEs) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline up to Month 48
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with AEs Leading to Treatment Discontinuation or Interruption | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline up to Month 48
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Participants with Grade 3, 4 or 5 AEs | ||||||||||||||
End point description |
AEs were graded according to NCI CTCAE v4.0. Grade 3 includes events that are severe or medically significant, but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 include events that have life-threatening consequences or urgent intervention indicated. Grade 5 AEs are those events which led to death..
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End point type |
Secondary
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End point timeframe |
Baseline up to 48 months.
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| No statistical analyses for this end point | |||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to 48 months from baseline until clinical cutoff of 30-Oct-2017.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Vismodegib + Ruxolitinib
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Reporting group description |
Participants will receive vismodegib (150 mg PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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13 May 2016 |
Key changes to the protocol included assessment of data at Week 24 for the Phase Ib portion of the study prior to initiation of the Phase III portion and, clarifications of the outcome measures used in Phase Ib. |
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10 May 2017 |
Key change to the protocol was to the inclusion criteria in the contraception and blood donation times from 9 or 24 months to 24 months. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
