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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02175004
Registration number
NCT02175004
Ethics application status
Date submitted
12/06/2014
Date registered
26/06/2014
Date last updated
9/02/2023
Titles & IDs
Public title
Extension Study Assessing Long Term Safety and Efficacy of IONIS-TTR Rx in Familial Amyloid Polyneuropathy (FAP)
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Scientific title
An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (FAP)
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Secondary ID [1]
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2013-004561-13
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Secondary ID [2]
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ISIS 420915-CS3
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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:
FAP
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Familial Amyloid Polyneuropathy
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TTR
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Transthyretin
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Amyloidosis
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Condition category
Condition code
Neurological
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Other neurological disorders
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Neurological
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Neurodegenerative diseases
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Metabolic and Endocrine
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Metabolic disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Metabolic and Endocrine
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Other metabolic disorders
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Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
Treatment: Drugs - Inotersen
Experimental: Previous Placebo-Inotersen 300 mg - Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group.
Experimental: Previous Inotersen-Inotersen 300 mg - Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group.
Treatment: Drugs: Inotersen
Inotersen SC
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Intervention code [1]
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Treatment: Drugs
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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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Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug
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Assessment method [1]
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An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported.
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Timepoint [1]
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From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
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Primary outcome [2]
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Percentage of Participants With Change From Baseline in Vital Signs
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Assessment method [2]
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Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported.
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Timepoint [2]
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From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
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Primary outcome [3]
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Percentage of Participants With Change From Baseline in Weight
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Assessment method [3]
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As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of =7% from Baseline and increase of =7% from Baseline.
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Timepoint [3]
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From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
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Primary outcome [4]
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Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values
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Assessment method [4]
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Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= <0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10^9/L to 400×10^9/L.
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Timepoint [4]
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From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
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Primary outcome [5]
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Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG)
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Assessment method [5]
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Normal QTcF at Baseline is defined as =450 milliseconds (ms) for males or =470 ms for females. Percentage of participants with QT interval outside of normal range are reported.
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Timepoint [5]
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From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
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Primary outcome [6]
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Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders
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Assessment method [6]
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A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders.
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Timepoint [6]
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From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
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Primary outcome [7]
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Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes
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Assessment method [7]
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Timepoint [7]
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From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
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Primary outcome [8]
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Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography
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Assessment method [8]
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Timepoint [8]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
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Secondary outcome [1]
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Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156
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Assessment method [1]
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The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 Composite Score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates worsening disease. A positive change from Baseline indicates worsening of polyneuropathy impairments. Mixed Effects Model with Repeated Measures (MMRM) was used for the analysis.
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Timepoint [1]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
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Secondary outcome [2]
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Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156
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Assessment method [2]
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Heart rate to deep breathing is a quantitative autonomic test using the CASE IV instrument that measures a participant's change in heart rate after deep breathing. The score of this component ranges from 0 to 3.72 points. Higher scores indicate impairment. MMRM was used for the analysis.
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Timepoint [2]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
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Secondary outcome [3]
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Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156
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Assessment method [3]
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The nerve conduction tests are quantitative tests that measure the conduction attributes of preselected nerves. The score range of this component is 0 to 18.6 points. Higher scores indicate impairment. MMRM was used for the analysis.
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Timepoint [3]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
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Secondary outcome [4]
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Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156
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Assessment method [4]
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The Heat-Pain Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pain sensory thresholds in response to heat. The maximum score of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.
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Timepoint [4]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
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Secondary outcome [5]
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Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156
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Assessment method [5]
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The Touch-Pressure Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pressure sensory thresholds in response to touch. The score range of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.
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Timepoint [5]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
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Secondary outcome [6]
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Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5
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Assessment method [6]
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The NIS score is a measure of neurologic impairment. The NIS Score has a range of 0 to 244 and a higher NIS score indicates lower function. A positive change from Baseline indicates worsening. MMRM was used for the analysis.
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Timepoint [6]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
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Secondary outcome [7]
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Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5
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Assessment method [7]
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Cranial Nerve assessment involves testing 3rd and 6th nerves and facial, palate, and tongue weakness. The score range for this component is 0 to 40 points. Higher scores indicate worsening. MMRM was used for the analysis.
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Timepoint [7]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
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Secondary outcome [8]
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Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5
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Assessment method [8]
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Muscle weakness involves testing 19 movements of muscles. The score range of this component is 0 to 152 points. Higher scores indicate worsening. MMRM was used for the analysis.
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Timepoint [8]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
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Secondary outcome [9]
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Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5
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Assessment method [9]
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The Reflexes Score involves testing 5 reflexes to stimuli. The score range of this component is 0 to 20 points. Higher scores indicate worsening. MMRM was used for the analysis.
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Timepoint [9]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
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Secondary outcome [10]
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Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5
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Assessment method [10]
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The Sensory Score is based on testing an index finger and a big toe each to 4 stimuli. The score of this component ranges from 0 to 32 points. Higher scores indicate impairment. MMRM was used for the analysis.
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Timepoint [10]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
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Secondary outcome [11]
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Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156
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Assessment method [11]
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The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 136, and a higher Norfolk QoL-DN score indicates poorer QoL. A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.
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Timepoint [11]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
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Secondary outcome [12]
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Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score
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Assessment method [12]
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The Norfolk QoL-DN physical functioning/large fiber neuropathy domain score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN physical function/large fiber neuropathy domain score has a range of -4 to 56, and a higher Norfolk QoL-DN domain score indicates poorer quality of life (QoL). A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.
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Timepoint [12]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4
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Secondary outcome [13]
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Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156
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Assessment method [13]
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BMI=weight (kg)/[height (m)^2]. The mBMI is the BMI multiplied by the serum albumin (g/L).
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Timepoint [13]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
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Secondary outcome [14]
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Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156
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Assessment method [14]
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BMI=weight (kg)/[height (m)^2].
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Timepoint [14]
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Baseline, Weeks 78 and 156
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Secondary outcome [15]
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Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score
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Assessment method [15]
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PND score is defined as I = sensory disturbances in limbs without motor impairment; II = difficulty walking without the need of a walking aid; III = one stick or one crutch required for walking; IV = two sticks or two crutches needed. V = wheelchair required or patient confined to bed. The change from Baseline values have been categorized as: improved, not changed, worsened, and unknown. Percentage of participants with changes from Baseline are presented category-wise in this outcome measure. Only categories with at least one participant with event are reported.
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Timepoint [15]
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Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year)
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Secondary outcome [16]
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Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set
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Assessment method [16]
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GLS by ECHO is a measure of cardiac systolic function.
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Timepoint [16]
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Baseline, Weeks 78 and 156
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Secondary outcome [17]
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Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup
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Assessment method [17]
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GLS by ECHO is a measure of cardiac systolic function.
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Timepoint [17]
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Weeks 78 and 156
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Secondary outcome [18]
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Change From Baseline in Transthyretin (TTR) Level
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Assessment method [18]
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Transthyretin protein concentration in serum was measured.
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Timepoint [18]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
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Secondary outcome [19]
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Change From Baseline in Retinol Binding Protein 4 (RBP4) Level
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Assessment method [19]
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RBP4 protein concentration in serum was measured.
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Timepoint [19]
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Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
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Secondary outcome [20]
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Ctrough: Trough Plasma Concentration of ISIS 420915
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Assessment method [20]
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Timepoint [20]
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Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, 1268; Days 1359 and 1450 of Year 4; Days 1632, 1723 and 1814 of Year 5
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Eligibility
Key inclusion criteria
- Satisfactory completion of dosing & efficacy assessments in ISIS 420915-CS2
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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
- Any new condition or worsening of existing condition that could make the patient
unsuitable for participation, or interfere with the patient participating in and/or
completing the study
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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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
Parallel
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Other design features
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Phase
Phase 3
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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
26/06/2014
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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
7/01/2021
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Sample size
Target
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Accrual to date
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Final
135
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Recruitment in Australia
Recruitment state(s)
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Indiana
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Country [3]
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United States of America
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State/province [3]
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Maryland
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Country [4]
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United States of America
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State/province [4]
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Massachusetts
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Country [5]
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United States of America
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State/province [5]
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Minnesota
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Country [6]
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United States of America
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State/province [6]
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New York
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Country [7]
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United States of America
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State/province [7]
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Oregon
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Country [8]
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United States of America
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State/province [8]
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Pennsylvania
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Country [9]
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Argentina
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State/province [9]
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Buenos Aires
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Country [10]
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Brazil
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State/province [10]
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Rio de Janeiro
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Country [11]
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Brazil
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State/province [11]
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Sao Paulo
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Country [12]
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France
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State/province [12]
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Creteil
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Country [13]
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France
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State/province [13]
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Le Kremlin Bicetre
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Country [14]
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Germany
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State/province [14]
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Munster
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Country [15]
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Italy
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State/province [15]
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Sicily
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Country [16]
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Italy
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State/province [16]
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Pavia
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Country [17]
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Portugal
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State/province [17]
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Lisbon
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Country [18]
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Portugal
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State/province [18]
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Porto
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Country [19]
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Spain
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State/province [19]
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Barcelona
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Country [20]
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United Kingdom
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State/province [20]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Ionis Pharmaceuticals, Inc.
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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
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in
patients with Familial Amyloid Polyneuropathy.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02175004
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Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
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Address
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Phone
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Fax
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Email
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Contact person for public queries
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Address
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02175004
Download to PDF