Safety and Tolerability Study of Oral NS-018 in Patients With Primary Myelofibrosis (MF), Post-polycythemia Vera MF or Post-essential Thrombocythemia MF
Study Details
Study Description
Brief Summary
The purpose of this study is to determine the safety and tolerability of orally administered NS-018 in patients with Primary Myelofibrosis (PMF), Post-polycythemia Vera Myelofibrosis (post-PV MF), or Post-essential Thrombocythemia Myelofibrosis (post-ET MF)
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 1/Phase 2 |
Detailed Description
This is a Phase 1/2 study that is currently enrolling Janus kinase 2 (JAK2) failures into the Phase 2 portion of the study.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Intervention: Drug: NS-018 In Phase 1 part, subjects were treated with oral NS-018 at a dose of 75 - 400 mg once daily or 100 - 400 mg twice daily. In Phase 2 part, subjects were treated with oral NS-018 at a dose of 300 mg once daily. |
Drug: NS-018
Treatment will be administered continuously as oral daily therapy in cycles of 4 weeks in duration (28 day treatment cycles).
|
Outcome Measures
Primary Outcome Measures
- Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event [From screening to until study discontinuation (approximate 8 years 10 months)]
AEs (non-serious, serious) as variables of safety and tolerability of NS-018 were assesed. The number of patients were presented as Overall summary of AEs including treatment-emergent AEs (TEAEs); Treatment-emergent SAEs; Drug-related TEAEs; Treatment-emergent AEs leading to permanent discontinuation of study drug; Hospitalization or prolongation of existing hospitalization; Death.
- Part 2: Number of Patient With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) [Cycle 7 Day 1 (duration of cycle was 4 weeks)]
Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-symptomatic burden were annotated as clinical improvement, anemia response, spleen response, orsymptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The objective response was defined as the number of patients with confirmed complete remission (CR) + partial response (PR) + clinical improvement (CI) during the treatment period.
- Part 2: Change From Baseline in Spleen Size [From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)]
Change from baseline in spleen size was assessed by magnetic resonance imaging (MRI) (computed tomography [CT] scan for patients not able to tolerate MRI).
- Part 2: Change From Baseline in Bone Marrow Assessment [From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)]
Bone marrow was assessed by aspiration and biopsy for grade changes in osteomyelofibrosis. Fibrosis was graded according to European Consensus Myelofibrosis Grading Criteria, ranging from grade 0, which corresponds to normal bone marrow, to grade 3, in which coarse bundles of collagen fibrosis are identifiable with significant osteosclerosis.
Secondary Outcome Measures
- Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) [Cycle 7 Day 1 (duration of cycle was 4 weeks)]
Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-symptomatic burden were annotated as clinical improvement, anemia response, spleen response, orsymptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The objective response was defined as the number of patients with confirmed "complete remission (CR) + partial response (PR) + clinical improvement (CI)" during the treatment period.
- Part 1: Change From Baseline in Spleen Size [From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)]
Change from baseline in spleen size was assessed by palpation.
- Part 1: Change From Baseline in Bone Marrow Assessment [From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)]
Bone marrow was assessed by aspiration and biopsy for grade changes in osteomyelofibrosis. Fibrosis was graded according to European Consensus Myelofibrosis Grading Criteria, ranging from grade 0, which corresponds to normal bone marrow, to grade 3, in which coarse bundles of collagen fibrosis are identifiable with significant osteosclerosis.
- Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) [From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)]
MF SAF is a 20-item instrument comprised of 4 subscales: 1) the Brief Fatigue Inventory [= average of 9 fatigue scores], 2) Splenomegaly associated symptoms [= average of 4 splenomegaly and associated scores], 3) Catabolic/proliferative Symptoms [= average of 3 catabolic/proliferative associated scores] and 4) Overall Quality of Life. The items were on a scale from 1 to 10 where 1= most favorable, and 10= least favorable.
- Part 2: Change From Baseline in Quality of Life Assessments Using Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF (MPN 10) [From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)]
Symptoms are evaluated by the MPN-SAF Total Symptom Score (TSS). The MPN-SAF TSS is assessed by the patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms response requires >50% reduction in the MPN-SAF TSS.
- Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels [Part 1 and Part 2: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks)]
The JAK2 V617F allele burden mean changes from baseline (%) are presented as pharmacodynamics parameters.
- Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) [From Baseline to Pre-dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks)]
The Phospho-STAT3 mean changes from baseline (%) are presented as pharmacodynamics parameters. For phospho-STAT3 values (Phase 2 only), study samples were incubated (± IL-6) and labeled with CD markers. Surface markers included CD3+ (CD4+ [helper T cells] and CD8+ [cytotoxic T cells]) and CD14+ (monocytes) to which intracellular phospho STAT3 was targeted. The levels of phospho-STAT3 in CD14+, CD3+CD4+ and CD3+CD8+ cell subtypes were quantified. Phosphorylated-STAT3 levels were evaluated in the cell types before and after IL-6 incubation (stimulation) and reported both as mean fluorescence intensity (MFI) and the percentage of positive cells. For each sample time point, the MFI was normalized to a fold change. The fold change was calculated by MFI after IL-6 treatment/MFI before IL-6 treatment. The percent positive cells were normalized by subtracting the percent positive cells before IL-6 treatment from the percent positive cells after IL-6 treatment.
- Part1 and Part 2: Observed Maximum Concentration (Cmax) [Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks)]
To determine the Cmax as pharmacokinetic parameters of NS-018.
- Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) [Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks)]
To determine the Tmax as pharmacokinetic parameters of NS-018.
- Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) [Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1 (duration of cycle was 4 weeks)]
To determine the AUC0-24 as pharmacokinetic parameters of NS-018.
- Part 1 and Part 2: Terminal Elimination Half-life (t½) [Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks)]
To determine the t½ as pharmacokinetic parameters of NS-018.
- Part1 and Part 2: Accumulation Ratio (AR) [Part 1 and Part 2: Cycle 2 Day 1 (duration of cycle was 4 weeks)]
To determine the AR as pharmacokinetic parameters of NS-018. AR was calculated as AR = (AUC0-24) Cycle 2 Day 1/ (AUC0-24) Cycle 1 Day 1.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Primary myelofibrosis, post-PV MF, or post-ET MF that requires therapy
-
MF patients must have received prior JAK2 inhibitor therapy, and been found to be intolerant, or refractory/relapsed from prior JAK2 inhibitor therapy, based on investigator assessment
-
≥18 years old
-
ECOG Performance Status of ≤ 3
-
Estimated life expectancy of ≥12 weeks
-
Male or non-pregnant, non-lactating female patients
-
Serum creatinine of ≤1.5 × the upper limit of normal (ULN)OR estimated creatinine clearance (CrCl) ≥ 40 ml/min/1.73 m2
-
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × the upper limit of normal (ULN) and total bilirubin ≤1.5 × ULN. If the total bilirubin is elevated between 1.5 x and 3 x ULN, patients with a direct bilirubin ≤ 1.5 X ULN are eligible during the Phase II portion.
-
Absolute neutrophil count (ANC) >1000/μL and Platelet count > 25,000/μL
-
QTcB ≤ 480 msec
-
No MF-directed treatment for at least 2 weeks prior to initiation of NS-018, including any use of corticosteroids for Myelofibrosis symptom or blood count management. Low dose corticosteroids ≤ 10 mg/day prednisone or equivalent is allowed for non-myelofibrosis purposes.
Exclusion Criteria:
-
Active, uncontrolled systemic infection
-
Patients with any unresolved toxicity greater than Grade 1 from previous anticancer therapy
-
Potentially curative therapy is available
-
Currently taking medication that is substantially metabolized by cytochrome P450 (CYP) 1A2 or CYP3A4 or taking medication known to be strong inhibitors or inducers of CYP3A4
-
Patients with a serious cardiac condition within the past 6 months
-
Pregnant or lactating
-
Radiation therapy for splenomegaly within 6 months prior to study entry
-
Splenectomy (Phase 2 portion of the study only)
-
Known HIV positive status
-
Known active hepatitis, a history of viral hepatitis B or hepatitis C
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Mayo Clinic Scottsdale Recruiting | Scottsdale | Arizona | United States | 85259-5499 |
2 | UC San Diego Moores Cancer Center | San Diego | California | United States | 92093-0698 |
3 | Mayo Clinic, Jacksonville | Jacksonville | Florida | United States | 32224 |
4 | Northwestern University | Chicago | Illinois | United States | 60611 |
5 | University of Chicago | Chicago | Illinois | United States | 60637 |
6 | Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02115 |
7 | University of Michigan | Ann Arbor | Michigan | United States | 48109 |
8 | Weill Cornell Medical College | New York | New York | United States | 10021 |
9 | MD Anderson Cancer Center, Department of Leukemia | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- NS Pharma, Inc.
Investigators
- Principal Investigator: Srdan Verstovsek, M.D., Ph.D., MD Anderson Cancer Center, Houston, TX, 77030
Study Documents (Full-Text)
More Information
Publications
None provided.- NS-018-101
Study Results
Participant Flow
Recruitment Details | Subjects who met all the inclusion and none of the exclusion criteria were enrolled at 09 sites in the USA. The conduct of this study started on 02 June 2011 (the first patient screened) and the last patient last visit was on 22 April 2020. A total of 48 and 29 patients were enrolled during Phase 1 and Phase 2 of the study respectively. Participants could be reduced or escalated to the noted dose at physician discretion. |
---|---|
Pre-assignment Detail | The screening period was from Day -14 to Day 0 for Phase I and Phase II. Informed consent form (ICF) was signed prior to screening procedures. All the study assessments were performed as per the schedule of assessment. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD |
---|---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Period Title: Whole Study | |||||||||||
STARTED | 3 | 3 | 3 | 6 | 3 | 3 | 3 | 8 | 8 | 8 | 29 |
COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
NOT COMPLETED | 3 | 3 | 3 | 6 | 3 | 3 | 3 | 8 | 8 | 8 | 29 |
Period Title: Whole Study | |||||||||||
STARTED | 0 | 1 | 4 | 4 | 0 | 0 | 2 | 0 | 1 | 0 | 0 |
COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
NOT COMPLETED | 0 | 1 | 4 | 4 | 0 | 0 | 2 | 0 | 1 | 0 | 0 |
Period Title: Whole Study | |||||||||||
STARTED | 0 | 0 | 3 | 5 | 1 | 2 | 8 | 0 | 3 | 0 | 0 |
COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
NOT COMPLETED | 0 | 0 | 3 | 5 | 1 | 2 | 8 | 0 | 3 | 0 | 0 |
Baseline Characteristics
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD | Total |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Total of all reporting groups |
Overall Participants | 3 | 3 | 3 | 6 | 3 | 3 | 3 | 8 | 8 | 8 | 29 | 77 |
Age (Years) [Mean (Standard Deviation) ] | ||||||||||||
Part 1 |
72.7
(1.5)
|
70.3
(14.8)
|
63.7
(12.9)
|
67.3
(9.4)
|
67.3
(3.8)
|
65.0
(8.9)
|
69.0
(3.6)
|
63.0
(11.8)
|
62.4
(11.9)
|
69.3
(7.7)
|
66.4
(9.6)
|
|
Part 2 |
67.2
(9.3)
|
67.2
(9.3)
|
||||||||||
Sex: Female, Male (Count of Participants) | ||||||||||||
Female |
0
0%
|
1
33.3%
|
0
0%
|
3
50%
|
2
66.7%
|
1
33.3%
|
0
0%
|
3
37.5%
|
6
75%
|
3
37.5%
|
14
48.3%
|
33
42.9%
|
Male |
3
100%
|
2
66.7%
|
3
100%
|
3
50%
|
1
33.3%
|
2
66.7%
|
3
100%
|
5
62.5%
|
2
25%
|
5
62.5%
|
15
51.7%
|
44
57.1%
|
Race/Ethnicity, Customized (Count of Participants) | ||||||||||||
White/Caucasian |
3
100%
|
3
100%
|
2
66.7%
|
6
100%
|
2
66.7%
|
3
100%
|
2
66.7%
|
8
100%
|
8
100%
|
8
100%
|
26
89.7%
|
71
92.2%
|
Black/African Heritage |
0
0%
|
0
0%
|
1
33.3%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
0
0%
|
0
0%
|
0
0%
|
1
3.4%
|
3
3.9%
|
Asian/Oriental |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
3.4%
|
2
2.6%
|
Other |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
3.4%
|
1
1.3%
|
Outcome Measures
Title | Part 1 and Part 2: Number of Subjects With Adverse Events and Serious Adverse Event |
---|---|
Description | AEs (non-serious, serious) as variables of safety and tolerability of NS-018 were assesed. The number of patients were presented as Overall summary of AEs including treatment-emergent AEs (TEAEs); Treatment-emergent SAEs; Drug-related TEAEs; Treatment-emergent AEs leading to permanent discontinuation of study drug; Hospitalization or prolongation of existing hospitalization; Death. |
Time Frame | From screening to until study discontinuation (approximate 8 years 10 months) |
Outcome Measure Data
Analysis Population Description |
---|
The safety population included all patients who received at least 1 dose of study drug. NS-018-101 study was dose-finding study, Principal investigator (PI) could increase or decrease dose-level per protocol. Totals are based on number of patients and not on dose-level cohort. Patients can appear in more than one dose-level cohort. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD |
---|---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 3 | 4 | 10 | 15 | 4 | 5 | 13 | 8 | 12 | 8 | 29 |
Not TEAE |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
2
66.7%
|
1
33.3%
|
3
37.5%
|
4
50%
|
2
25%
|
6
20.7%
|
Any AE |
3
100%
|
4
133.3%
|
9
300%
|
14
233.3%
|
4
133.3%
|
4
133.3%
|
11
366.7%
|
8
100%
|
12
150%
|
8
100%
|
29
100%
|
Any Treatment Emergent AE |
3
100%
|
4
133.3%
|
9
300%
|
14
233.3%
|
4
133.3%
|
4
133.3%
|
11
366.7%
|
8
100%
|
12
150%
|
8
100%
|
29
100%
|
Drug Related TEAE |
1
33.3%
|
1
33.3%
|
8
266.7%
|
11
183.3%
|
4
133.3%
|
2
66.7%
|
4
133.3%
|
5
62.5%
|
10
125%
|
7
87.5%
|
24
82.8%
|
Any Serious TEAE |
2
66.7%
|
2
66.7%
|
2
66.7%
|
6
100%
|
1
33.3%
|
1
33.3%
|
4
133.3%
|
3
37.5%
|
4
50%
|
3
37.5%
|
13
44.8%
|
TEAE Leading to Discontinuation of study drug |
1
33.3%
|
0
0%
|
0
0%
|
4
66.7%
|
0
0%
|
0
0%
|
0
0%
|
3
37.5%
|
4
50%
|
2
25%
|
5
17.2%
|
Hospitalization or Prolongation of Existing Hospitalization |
1
33.3%
|
2
66.7%
|
2
66.7%
|
6
100%
|
1
33.3%
|
1
33.3%
|
3
100%
|
2
25%
|
3
37.5%
|
1
12.5%
|
11
37.9%
|
Death |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
3.4%
|
Title | Part 2: Number of Patient With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Leukemia Net (ELN) |
---|---|
Description | Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-symptomatic burden were annotated as clinical improvement, anemia response, spleen response, orsymptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The objective response was defined as the number of patients with confirmed complete remission (CR) + partial response (PR) + clinical improvement (CI) during the treatment period. |
Time Frame | Cycle 7 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day. |
Arm/Group Title | Part 2: 300 mg QD |
---|---|
Arm/Group Description | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 12 |
Count of Participants [Participants] |
1
33.3%
|
Title | Part 2: Change From Baseline in Spleen Size |
---|---|
Description | Change from baseline in spleen size was assessed by magnetic resonance imaging (MRI) (computed tomography [CT] scan for patients not able to tolerate MRI). |
Time Frame | From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day. |
Arm/Group Title | Part 2: 300 mg QD |
---|---|
Arm/Group Description | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 16 |
Mean (Standard Deviation) [cubic millimeter (mm3)] |
-335918.1
(558459.9)
|
Title | Part 2: Change From Baseline in Bone Marrow Assessment |
---|---|
Description | Bone marrow was assessed by aspiration and biopsy for grade changes in osteomyelofibrosis. Fibrosis was graded according to European Consensus Myelofibrosis Grading Criteria, ranging from grade 0, which corresponds to normal bone marrow, to grade 3, in which coarse bundles of collagen fibrosis are identifiable with significant osteosclerosis. |
Time Frame | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day. |
Arm/Group Title | Part 2: 300 mg QD |
---|---|
Arm/Group Description | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 3 |
Increased by at least 1 grade level |
1
33.3%
|
Increased by at least 2 grade level |
0
0%
|
Decreased by at least 1 grade level |
2
66.7%
|
Decreased by at least 2 grade level |
0
0%
|
Title | Part 1: Number of Patients With Objective Response Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) |
---|---|
Description | Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-symptomatic burden were annotated as clinical improvement, anemia response, spleen response, orsymptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The objective response was defined as the number of patients with confirmed "complete remission (CR) + partial response (PR) + clinical improvement (CI)" during the treatment period. |
Time Frame | Cycle 7 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. NS-018-101 study was dose finding study, PI could increase or decrease dose-level per protocol. Patients can appear in more than one dose-level cohort. For 300 mg QD, data from 7 patients were available. 4 patients were enrolled originally and 2 patients were dose-reduced from 400 mg QD and 1 patient was dose-reduced from 250 mg BID. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID |
---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 0 | 3 | 2 | 7 | 0 | 3 | 3 | 1 | 3 | 0 |
Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
2
33.3%
|
0
0%
|
0
0%
|
1
33.3%
|
0
0%
|
1
12.5%
|
0
0%
|
Title | Part 1: Change From Baseline in Spleen Size |
---|---|
Description | Change from baseline in spleen size was assessed by palpation. |
Time Frame | From Baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. NS-018-101 study was dose finding study, PI could increase or decrease dose-level per protocol. Patients can appear in more than one dose-level cohort. At 200 mg BID cohort, 3 patients were enrolled originally, 2 patients were dose-escalated from 100 mg BID cohort and 8 patients were dose-reduced from 300 mg BID or 400 mg BID cohort. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID |
---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 0 | 3 | 2 | 6 | 0 | 3 | 13 | 1 | 3 | 0 |
Mean (Standard Deviation) [cm] |
-0.67
(2.89)
|
-8.25
(3.18)
|
-3.17
(3.97)
|
-3.00
(3.00)
|
-4.33
(6.66)
|
-7.00
(NA)
|
-2.00
(3.00)
|
Title | Part 1: Change From Baseline in Bone Marrow Assessment |
---|---|
Description | Bone marrow was assessed by aspiration and biopsy for grade changes in osteomyelofibrosis. Fibrosis was graded according to European Consensus Myelofibrosis Grading Criteria, ranging from grade 0, which corresponds to normal bone marrow, to grade 3, in which coarse bundles of collagen fibrosis are identifiable with significant osteosclerosis. |
Time Frame | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID |
---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 0 | 1 | 0 | 4 | 0 | 1 | 0 | 0 | 2 | 0 |
Increased by at least 1 grade level |
0
0%
|
1
33.3%
|
1
33.3%
|
2
33.3%
|
||||||
Increased by at least 2 grade level |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
||||||
Decreased by at least 1 grade level |
1
33.3%
|
3
100%
|
0
0%
|
0
0%
|
||||||
Decreased by at least 2 grade level |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Title | Part 1: Change From Baseline in Quality of Life Assessments Using Myelofibrosis Symptom Assessment Form (MF-SAF) |
---|---|
Description | MF SAF is a 20-item instrument comprised of 4 subscales: 1) the Brief Fatigue Inventory [= average of 9 fatigue scores], 2) Splenomegaly associated symptoms [= average of 4 splenomegaly and associated scores], 3) Catabolic/proliferative Symptoms [= average of 3 catabolic/proliferative associated scores] and 4) Overall Quality of Life. The items were on a scale from 1 to 10 where 1= most favorable, and 10= least favorable. |
Time Frame | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. NS-018-101 study was dose finding study, PI could increase or decrease dose-level per protocol. Patients can appear in more than one dose-level cohort. For 300 mg QD, data from 7 patients were available. 4 patients were enrolled originally and 2 patients were dose-reduced from 400 mg QD and 1 patient was dose-reduced from 250 mg BID. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID |
---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 0 | 3 | 2 | 7 | 0 | 3 | 2 | 1 | 3 | 0 |
Brief Fatigue Inventory Score |
0.1
(0.4)
|
-1.3
(2.0)
|
0.8
(1.3)
|
-1.9
(0.1)
|
0.4
(0.2)
|
0.7
(NA)
|
-0.8
(1.1)
|
|||
Splenomegaly-associated Symptom Score |
1.3
(1.3)
|
-0.5
(1.1)
|
0.5
(0.8)
|
-0.3
(1.8)
|
-1.1
(1.2)
|
-4.0
(NA)
|
-1.8
(1.5)
|
|||
Catabolic/Proliferative Symptoms Score |
1.2
(0.2)
|
-0.7
(0.5)
|
-0.4
(2.4)
|
-0.4
(1.0)
|
1.5
(1.6)
|
-8.0
(NA)
|
-0.6
(1.0)
|
|||
Overall Quality of Life Score |
0.3
(0.6)
|
-1.0
(1.4)
|
0.0
(3.6)
|
-1.7
(2.1)
|
-1.5
(2.1)
|
0.0
(NA)
|
-1.7
(1.5)
|
Title | Part 2: Change From Baseline in Quality of Life Assessments Using Myeloproliferative Neoplasm Symptom Assessment Form (MPN SAF (MPN 10) |
---|---|
Description | Symptoms are evaluated by the MPN-SAF Total Symptom Score (TSS). The MPN-SAF TSS is assessed by the patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms response requires >50% reduction in the MPN-SAF TSS. |
Time Frame | From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The efficacy population included all patients who received at least one dose of study drug and had one baseline and at least one post-baseline efficacy assessment. Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day. |
Arm/Group Title | Part 2: 300 mg QD |
---|---|
Arm/Group Description | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 10 |
Mean (Standard Deviation) [score on a scale] |
-0.7
(3.4)
|
Title | Part 1 and Part 2: Change in Baseline in Janus Kinase 2 (JAK2) V617F Allele Burden Levels |
---|---|
Description | The JAK2 V617F allele burden mean changes from baseline (%) are presented as pharmacodynamics parameters. |
Time Frame | Part 1 and Part 2: From baseline to Cycle 7 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The PD population included all patients who received at least one dose of study drug and had a baseline and at least one post-baseline PD assessment (for at least one PD parameter). Here, the overall number of subjects analyzed signifies only the subjects with available data that were analyzed evaluated on that specific cycle day. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD |
---|---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 0 | 1 | 1 | 2 | 0 | 2 | 2 | 2 | 2 | 4 | 11 |
Mean (Standard Deviation) [Percentage of JAK2 V617F Level] |
4.360
(NA)
|
-0.210
(NA)
|
7.410
(2.758)
|
-6.720
(10.479)
|
8.255
(4.320)
|
-4.900
(9.065)
|
-9.033
(5.352)
|
-4.368
(14.602)
|
1.782
(8.978)
|
Title | Part 2: Change From Baseline in Phosphorylated Signal Transducer and Activator of Transcription 3 (Phospho-STAT3) |
---|---|
Description | The Phospho-STAT3 mean changes from baseline (%) are presented as pharmacodynamics parameters. For phospho-STAT3 values (Phase 2 only), study samples were incubated (± IL-6) and labeled with CD markers. Surface markers included CD3+ (CD4+ [helper T cells] and CD8+ [cytotoxic T cells]) and CD14+ (monocytes) to which intracellular phospho STAT3 was targeted. The levels of phospho-STAT3 in CD14+, CD3+CD4+ and CD3+CD8+ cell subtypes were quantified. Phosphorylated-STAT3 levels were evaluated in the cell types before and after IL-6 incubation (stimulation) and reported both as mean fluorescence intensity (MFI) and the percentage of positive cells. For each sample time point, the MFI was normalized to a fold change. The fold change was calculated by MFI after IL-6 treatment/MFI before IL-6 treatment. The percent positive cells were normalized by subtracting the percent positive cells before IL-6 treatment from the percent positive cells after IL-6 treatment. |
Time Frame | From Baseline to Pre-dose at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The PD population included all patients who received at least one dose of study drug and had a baseline and at least one post-baseline PD assessment (for at least one PD parameter). Here, number analyzed reflects number of patients evaluated on that specific cycle day. Data from 17 out of 24 participants were available and contributed to the analysis. Samples from 7 patients were analyzed, but data were not available due to quantities not sufficient. |
Arm/Group Title | Part 2: 300 mg QD |
---|---|
Arm/Group Description | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 24 |
Cycle 1 Day 1: Change percentage of Phospho-STAT3 Levels in CD14+ Positive cells |
-9.406
(19.357)
|
Cycle 1 Day 15: Change percentage of Phospho-STAT3 Levels in CD14+ Positive cells |
-2.738
(16.191)
|
Cycle 2 Day 1: Change percentage of Phospho-STAT3 Levels in CD14+ Positive cells |
-0.422
(20.092)
|
Cycle 1 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD4+ Positive cells |
-10.614
(11.178)
|
Cycle 1 Day 15: Change percentage of Phospho-STAT3 Levels in CD3+ CD4+ Positive cells |
6.217
(20.717)
|
Cycle 2 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD4+ Positive cells |
-5.878
(16.304)
|
Cycle 1 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD8+ Positive cells |
-3.707
(11.222)
|
Cycle 1 Day 15: Change percentage of Phospho-STAT3 Levels in CD3+ CD8+ Positive cells |
5.533
(14.513)
|
Cycle 2 Day 1: Change percentage of Phospho-STAT3 Levels in CD3+ CD8+ Positive cells |
-1.644
(6.615)
|
Title | Part1 and Part 2: Observed Maximum Concentration (Cmax) |
---|---|
Description | To determine the Cmax as pharmacokinetic parameters of NS-018. |
Time Frame | Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The PK population include all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile, Here, number analyzed reflects number of patients evaluated on that specific cycle day. Part 2: 1 patient was completely excluded from PK Population due to critical samples missing, 1 patient was excluded from the analysis due to sample missing at timepoint, So the overall number of participants was 27. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD |
---|---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 3 | 3 | 3 | 6 | 3 | 3 | 3 | 6 | 8 | 8 | 27 |
Cycle 1 Day 1 |
66.5600
(79.0171)
|
404.5333
(26.4258)
|
377.8000
(184.2086)
|
726.0667
(232.0338)
|
1643.0333
(789.0036)
|
242.0333
(174.3374)
|
351.0000
(257.1729)
|
853.5833
(271.7900)
|
1077.4750
(366.9158)
|
1261.7000
(658.9141)
|
957.9852
(306.7937)
|
Cycle 1 Day 8 (Part 1 only) |
30.6700
(13.3077)
|
324.8667
(57.3280)
|
539.6667
(160.0954)
|
805.4333
(236.8877)
|
1554.6667
(351.6765)
|
412.8000
(232.9342)
|
606.8333
(233.7812)
|
806.8333
(464.3206)
|
969.0167
(342.3090)
|
1352.2200
(307.1358)
|
|
Cycle 1 Day 15 (Part 2 only) |
732.5000
(313.5822)
|
||||||||||
Cycle 2 Day 1 |
67.6467
(55.6250)
|
450.6667
(187.4735)
|
556.9000
(52.8463)
|
1066.0000
(271.1854)
|
1556.0000
(676.3941)
|
408.6000
(127.0765)
|
596.1333
(362.6751)
|
830.7333
(166.0701)
|
1272.5600
(420.7722)
|
1040.6500
(321.5215)
|
1035.3087
(445.9895)
|
Title | Part 1 and Part 2: Time to Maximum Plasma Concentration (Tmax) |
---|---|
Description | To determine the Tmax as pharmacokinetic parameters of NS-018. |
Time Frame | Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The PK population include all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile, Here, number analyzed reflects number of patients evaluated on that specific cycle day. Part 2: 1 patient was completely excluded from PK Population due to critical samples missing, 1 patient was excluded from the analysis due to sample missing at timepoint, So the overall number of participants was 27. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD |
---|---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 3 | 3 | 3 | 6 | 3 | 3 | 3 | 6 | 8 | 8 | 27 |
Cycle 1 Day 1 |
1.00
|
1.08
|
2.00
|
1.04
|
1.00
|
1.00
|
1.00
|
1.46
|
1.02
|
2.00
|
2.00
|
Cycle 1 Day 8 (Part 1 only) |
0.78
|
1.00
|
1.00
|
1.54
|
2.00
|
1.00
|
1.00
|
1.98
|
1.52
|
2.03
|
|
Cycle 2 Day 1 |
1.00
|
1.00
|
1.00
|
1.05
|
1.00
|
1.00
|
1.00
|
2.07
|
2.08
|
2.00
|
1.08
|
Title | Part1 and Part 2: Area Under the Plasma Concentration-time Curve (AUC0-24) |
---|---|
Description | To determine the AUC0-24 as pharmacokinetic parameters of NS-018. |
Time Frame | Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The PK Population includes all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile, regardless of whether derived from parent drug or metabolites. Part 2: One patient was completely excluded from the PK Population due to critical samples missing; Two patients were excluded from the analysis due to sample missing at time point. so the overall number of participants analyzed was 26. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD |
---|---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 3 | 3 | 3 | 5 | 3 | 3 | 3 | 4 | 8 | 7 | 26 |
Cycle 1 Day 1 |
246.3454
(325.7347)
|
1510.0507
(123.2939)
|
1326.3929
(815.0175)
|
2299.2216
(877.2554)
|
5162.4119
(2485.9489)
|
1022.0977
(521.6626)
|
1241.5005
(461.6010)
|
2117.1396
(449.2456)
|
5666.7063
(5182.5571)
|
7592.4070
(3031.4332)
|
3672.2041
(1551.7435)
|
Cycle 2 Day 1 (Part 1 only) |
253.6953
(306.7728)
|
1905.2058
(938.2984)
|
1816.8251
(559.9071)
|
3175.6938
(794.6091)
|
5443.2874
(986.8497)
|
1561.1245
(621.5414)
|
3470.6269
(2587.3663)
|
5876.1106
(5133.4208)
|
6132.2596
(3393.0644)
|
3828.0995
(NA)
|
Title | Part 1 and Part 2: Terminal Elimination Half-life (t½) |
---|---|
Description | To determine the t½ as pharmacokinetic parameters of NS-018. |
Time Frame | Pre-dose, 0.5 to 24 hours post-dose for Part 1: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and for Part 2: Cycle 1 Day 1, Cycle 2 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The PK population include all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile, Here, number analyzed reflects number of patients evaluated on that specific cycle day. Part 2: 1 patient was completely excluded from PK Population due to critical samples missing, 1 patient was excluded from the analysis due to sample missing at timepoint, So the overall number of participants was 27. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD |
---|---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 3 | 3 | 3 | 6 | 3 | 3 | 3 | 6 | 7 | 7 | 27 |
Cycle 1 Day 1 |
2.4878
(2.1008)
|
5.1659
(0.5209)
|
3.6685
(2.2953)
|
4.4899
(1.5478)
|
6.0302
(2.4730)
|
9.7153
(5.2865)
|
10.0780
(1.3932)
|
5.9468
(3.8500)
|
30.0521
(42.0129)
|
13.4566
(7.3992)
|
5.4384
(1.7469)
|
Cycle 1 Day 8 (Part 1 only) |
1.9170
(0.5066)
|
2.4735
(0.3469)
|
2.0217
(0.2653)
|
2.6237
(0.5050)
|
2.8480
(1.3889)
|
2.3007
(0.0899)
|
3.5204
(1.6584)
|
2.6280
(0.8577)
|
3.2062
(0.8054)
|
2.8287
(1.2416)
|
|
Cycle 2 Day 1 |
3.7488
(2.9554)
|
5.6743
(1.3845)
|
5.4356
(0.7253)
|
5.9316
(0.8500)
|
8.5232
(5.0118)
|
16.5535
(6.8417)
|
8.7138
(6.8781)
|
10.8357
(1.0282)
|
13.7574
(8.1372)
|
7.7683
(5.3755)
|
2.8030
(1.2594)
|
Title | Part1 and Part 2: Accumulation Ratio (AR) |
---|---|
Description | To determine the AR as pharmacokinetic parameters of NS-018. AR was calculated as AR = (AUC0-24) Cycle 2 Day 1/ (AUC0-24) Cycle 1 Day 1. |
Time Frame | Part 1 and Part 2: Cycle 2 Day 1 (duration of cycle was 4 weeks) |
Outcome Measure Data
Analysis Population Description |
---|
The PK Population includes all patients who received at least one dose of study drug and have at least 50% of the planned samples above the limit of quantitation to provide evaluable PK profile (i.e. at least Cmax and AUC evaluable), regardless of whether derived from parent drug or metabolites. |
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 300 mg BID | Part 1: 250 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD |
---|---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. |
Measure Participants | 1 | 3 | 2 | 4 | 3 | 2 | 2 | 3 | 3 | 1 | 22 |
Mean (Standard Deviation) [Ratio] |
0.9778
(NA)
|
1.2517
(0.5579)
|
1.1728
(0.0372)
|
1.3581
(0.3108)
|
1.2026
(0.4755)
|
1.9941
(0.6140)
|
3.3229
(0.3197)
|
3.0501
(2.6306)
|
1.5452
(0.4025)
|
1.2514
(NA)
|
1.0543
(0.2572)
|
Adverse Events
Time Frame | Part 1 and Part 2: From screening to until study discontinuation (approximate 8 years 10 months) | |||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Adverse Event Reporting Description | Safety population: NS-018-101 study was dose finding study, PI could increase or decrease dose-level per protocol. Totals are based on number of patients and not on dose-level cohort. Patients can appear in more than one dose-level cohort. | |||||||||||||||||||||
Arm/Group Title | Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD | |||||||||||
Arm/Group Description | Patients self-administered orally 75 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 125 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 100 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 200 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 250 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 400 mg of NS-018 twice daily (BID) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | Patients self-administered orally 300 mg of NS-018 once daily (QD) in cycles of 28 days in duration (4 weeks) for Cycles 1, 2, 3, 4, 5, 6, 7 and until the patient experiences unacceptable toxicity that precludes any further treatment, disease progression, and/or as long as the patient is benefiting from treatment. | |||||||||||
All Cause Mortality |
||||||||||||||||||||||
Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD | ||||||||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Serious Adverse Events |
||||||||||||||||||||||
Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD | ||||||||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 2/3 (66.7%) | 2/4 (50%) | 2/10 (20%) | 6/15 (40%) | 1/4 (25%) | 1/5 (20%) | 4/13 (30.8%) | 3/8 (37.5%) | 4/12 (33.3%) | 3/8 (37.5%) | 13/29 (44.8%) | |||||||||||
Blood and lymphatic system disorders | ||||||||||||||||||||||
Anaemia | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Thrombocytopenia | 1/3 (33.3%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Haemolysis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Haemolytic anaemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Splenic infarction | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Splenomegaly | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Splenic infarction | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Cardiac disorders | ||||||||||||||||||||||
Angina pectoris | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Acute coronary syndrome | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Coronary artery occlusion | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Myocardial infarction | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Sinus node dysfunction | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Left ventricular failure | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Acute myocardial infarction | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Cardiac failure acute | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Cardiac failure congestive | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Gastrointestinal disorders | ||||||||||||||||||||||
Abdominal pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Diarrhoea | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Dysphagia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Enterocolitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Gastrointestinal haemorrhage | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Vomiting | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Mallory-Weiss syndrome | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Pancreatitis acute | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
General disorders | ||||||||||||||||||||||
Chest pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Generalised oedema | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Non-cardiac chest pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hepatobiliary disorders | ||||||||||||||||||||||
Hepatosplenomegaly | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Infections and infestations | ||||||||||||||||||||||
Pneumonia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 3/15 (20%) | 0/4 (0%) | 0/5 (0%) | 2/13 (15.4%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Sepsis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Appendicitis perforated | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Arthritis infective | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Cellulitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Influenza | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Urinary tract infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Urosepsis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Acute sinusitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Bacteraemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Bronchitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Clostridium difficile infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Otitis externa | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Otitis media | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Parainfluenzae virus infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Upper respiratory tract infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Vulval cellulitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Injury, poisoning and procedural complications | ||||||||||||||||||||||
Postoperative ileus | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Tibia fracture | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Investigations | ||||||||||||||||||||||
Lipase increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Alanine aminotransferase increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
N-terminal prohormone brain natriuretic peptide increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Metabolism and nutrition disorders | ||||||||||||||||||||||
Steroid diabetes | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Tumour lysis syndrome | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Musculoskeletal and connective tissue disorders | ||||||||||||||||||||||
Bursitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Muscular weakness | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Spinal stenosis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Groin pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Haematoma muscle | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Lumbar spinal stenosis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Osteoarthritis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||||||||
Glioblastoma multiforme | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Lung adenocarcinoma | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Nervous system disorders | ||||||||||||||||||||||
Dizziness | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Hypoaesthesia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Paraesthesia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Seizure | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Syncope | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Encephalopathy | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Psychiatric disorders | ||||||||||||||||||||||
Confusional state | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Suicide attempt | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Renal and urinary disorders | ||||||||||||||||||||||
Renal failure | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Acute kidney injury | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||||
Chronic obstructive pulmonary disease | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Epistaxis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Lung infiltration | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Pulmonary oedema | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Acute respiratory failure | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Hypoxia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Vascular disorders | ||||||||||||||||||||||
Hypertension | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||||||||||
Part 1: 75 mg QD | Part 1: 125 mg QD | Part 1: 200 mg QD | Part 1: 300 mg QD | Part 1: 400 mg QD | Part 1: 100 mg BID | Part 1: 200 mg BID | Part 1: 250 mg BID | Part 1: 300 mg BID | Part 1: 400 mg BID | Part 2: 300 mg QD | ||||||||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 3/3 (100%) | 4/4 (100%) | 9/10 (90%) | 14/15 (93.3%) | 4/4 (100%) | 4/5 (80%) | 11/13 (84.6%) | 8/8 (100%) | 12/12 (100%) | 7/8 (87.5%) | 29/29 (100%) | |||||||||||
Blood and lymphatic system disorders | ||||||||||||||||||||||
Anaemia | 2/3 (66.7%) | 0/4 (0%) | 4/10 (40%) | 3/15 (20%) | 1/4 (25%) | 2/5 (40%) | 5/13 (38.5%) | 2/8 (25%) | 6/12 (50%) | 3/8 (37.5%) | 12/29 (41.4%) | |||||||||||
Thrombocytopenia | 1/3 (33.3%) | 0/4 (0%) | 1/10 (10%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 3/8 (37.5%) | 3/12 (25%) | 1/8 (12.5%) | 4/29 (13.8%) | |||||||||||
Increased tendency to bruise | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Hypoprothrombinaemia | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Lymphadenopathy | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Neutropenia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Lymphopenia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Cardiac disorders | ||||||||||||||||||||||
Palpitations | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 2/13 (15.4%) | 0/8 (0%) | 3/12 (25%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Arrhythmia | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Cardiac flutter | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Sinus bradycardia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Tachycardia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Ear and labyrinth disorders | ||||||||||||||||||||||
Tinnitus | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 1/12 (8.3%) | 2/8 (25%) | 3/29 (10.3%) | |||||||||||
Vertigo | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 1/8 (12.5%) | 1/29 (3.4%) | |||||||||||
Ear pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hypoacusis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Eye disorders | ||||||||||||||||||||||
Vision blurred | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Cataract | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Glaucoma | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Blepharitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Dry eye | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Eye swelling | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Eyelid irritation | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Lacrimation increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Meibomian gland dysfunction | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Photophobia | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Strabismus | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Gastrointestinal disorders | ||||||||||||||||||||||
Diarrhoea | 0/3 (0%) | 0/4 (0%) | 3/10 (30%) | 6/15 (40%) | 1/4 (25%) | 1/5 (20%) | 3/13 (23.1%) | 1/8 (12.5%) | 4/12 (33.3%) | 3/8 (37.5%) | 11/29 (37.9%) | |||||||||||
Nausea | 0/3 (0%) | 0/4 (0%) | 2/10 (20%) | 3/15 (20%) | 1/4 (25%) | 0/5 (0%) | 2/13 (15.4%) | 3/8 (37.5%) | 7/12 (58.3%) | 1/8 (12.5%) | 10/29 (34.5%) | |||||||||||
Abdominal pain | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 3/15 (20%) | 0/4 (0%) | 1/5 (20%) | 2/13 (15.4%) | 3/8 (37.5%) | 2/12 (16.7%) | 0/8 (0%) | 4/29 (13.8%) | |||||||||||
Vomiting | 0/3 (0%) | 0/4 (0%) | 4/10 (40%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 2/8 (25%) | 2/12 (16.7%) | 1/8 (12.5%) | 4/29 (13.8%) | |||||||||||
Abdominal distension | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 8/29 (27.6%) | |||||||||||
Constipation | 0/3 (0%) | 1/4 (25%) | 1/10 (10%) | 1/15 (6.7%) | 1/4 (25%) | 0/5 (0%) | 1/13 (7.7%) | 2/8 (25%) | 5/12 (41.7%) | 1/8 (12.5%) | 6/29 (20.7%) | |||||||||||
Abdominal discomfort | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 3/15 (20%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 2/12 (16.7%) | 1/8 (12.5%) | 1/29 (3.4%) | |||||||||||
Gastrooesophageal reflux disease | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Dyspepsia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 2/12 (16.7%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Ascites | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Abdominal hernia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Abdominal pain upper | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Anal pruritus | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Anal sphincter atony | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Dysphagia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Faeces discoloured | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Flatulence | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Haematochezia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Haemorrhoids | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hypoaesthesia oral | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Oesophageal ulcer | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Oral discomfort | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Oral pain | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Umbilical hernia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
General disorders | ||||||||||||||||||||||
Fatigue | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 6/15 (40%) | 1/4 (25%) | 2/5 (40%) | 3/13 (23.1%) | 2/8 (25%) | 4/12 (33.3%) | 2/8 (25%) | 11/29 (37.9%) | |||||||||||
Oedema peripheral | 1/3 (33.3%) | 0/4 (0%) | 2/10 (20%) | 5/15 (33.3%) | 0/4 (0%) | 2/5 (40%) | 1/13 (7.7%) | 2/8 (25%) | 1/12 (8.3%) | 0/8 (0%) | 10/29 (34.5%) | |||||||||||
Pyrexia | 1/3 (33.3%) | 1/4 (25%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 2/8 (25%) | 2/12 (16.7%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Chills | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 2/13 (15.4%) | 0/8 (0%) | 1/12 (8.3%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Chest discomfort | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 1/15 (6.7%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Influenza like illness | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 1/8 (12.5%) | 2/29 (6.9%) | |||||||||||
Asthenia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Early satiety | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Gait disturbance | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 2/8 (25%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Non-cardiac chest pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 3/29 (10.3%) | |||||||||||
Oedema | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Thirst | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Adverse drug reaction | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Chest pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Cyst | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Drug withdrawal syndrome | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Face oedema | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Generalised oedema | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Localised oedema | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Malaise | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Nodule | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Peripheral swelling | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Hepatobiliary disorders | ||||||||||||||||||||||
Hepatic pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hepatomegaly | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Jaundice | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Infections and infestations | ||||||||||||||||||||||
Upper respiratory tract infection | 0/3 (0%) | 0/4 (0%) | 2/10 (20%) | 5/15 (33.3%) | 0/4 (0%) | 1/5 (20%) | 2/13 (15.4%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Urinary tract infection | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 1/4 (25%) | 1/5 (20%) | 2/13 (15.4%) | 0/8 (0%) | 1/12 (8.3%) | 1/8 (12.5%) | 1/29 (3.4%) | |||||||||||
Nasopharyngitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 2/5 (40%) | 2/13 (15.4%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Bronchitis | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Oral candidiasis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 2/13 (15.4%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Influenza | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Pneumonia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 1/29 (3.4%) | |||||||||||
Sinusitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Acute sinusitis | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Body tinea | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Cellulitis | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Ear infection | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Fungal infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Genital abscess | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hordeolum | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Infected seroma | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Lip infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Localised infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Molluscum contagiosum | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Otitis media | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Rectal abscess | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Rhinovirus infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Skin infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Subcutaneous abscess | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Tinea pedis | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Wound infection | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Injury, poisoning and procedural complications | ||||||||||||||||||||||
Contusion | 0/3 (0%) | 1/4 (25%) | 1/10 (10%) | 2/15 (13.3%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 1/8 (12.5%) | 2/29 (6.9%) | |||||||||||
Fall | 0/3 (0%) | 1/4 (25%) | 2/10 (20%) | 3/15 (20%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Animal bite | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Animal scratch | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Foreign body | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Incision site pain | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Ligament injury | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Muscle strain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Rib fracture | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Skin abrasion | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Skin wound | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Ligament sprain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Investigations | ||||||||||||||||||||||
Platelet count decreased | 0/3 (0%) | 1/4 (25%) | 1/10 (10%) | 2/15 (13.3%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 1/8 (12.5%) | 2/12 (16.7%) | 1/8 (12.5%) | 2/29 (6.9%) | |||||||||||
Blood alkaline phosphatase increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 3/15 (20%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 2/8 (25%) | 2/12 (16.7%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Weight increased | 0/3 (0%) | 0/4 (0%) | 2/10 (20%) | 1/15 (6.7%) | 1/4 (25%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Alanine aminotransferase increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 2/13 (15.4%) | 0/8 (0%) | 2/12 (16.7%) | 1/8 (12.5%) | 3/29 (10.3%) | |||||||||||
Blood bilirubin increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 2/8 (25%) | 2/12 (16.7%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Lymphocyte count decreased | 0/3 (0%) | 1/4 (25%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
White blood cell count decreased | 1/3 (33.3%) | 0/4 (0%) | 1/10 (10%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Amylase increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 2/12 (16.7%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Blood creatinine increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Electrocardiogram QT prolonged | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Aspartate aminotransferase increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 2/12 (16.7%) | 0/8 (0%) | 4/29 (13.8%) | |||||||||||
Blood potassium increased | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Cardiac murmur | 0/3 (0%) | 1/4 (25%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Lipase increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Neutrophil count decreased | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Physical examination abnormal | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Serum ferritin increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Blast cell count increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Blood cholesterol increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Blood urea increased | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Blood uric acid increased | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Gamma-glutamyltransferase increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Heart rate abnormal | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Red blood cell count increased | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Troponin I increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Vitamin B1 decreased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
White blood cell count increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Blood lactate dehydrogenase increased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Weight decreased | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 3/15 (20%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Metabolism and nutrition disorders | ||||||||||||||||||||||
Hyperglycaemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 1/4 (25%) | 1/5 (20%) | 4/13 (30.8%) | 2/8 (25%) | 1/12 (8.3%) | 1/8 (12.5%) | 7/29 (24.1%) | |||||||||||
Hypocalcaemia | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 2/8 (25%) | 2/12 (16.7%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hyperkalaemia | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 1/15 (6.7%) | 0/4 (0%) | 1/5 (20%) | 1/13 (7.7%) | 1/8 (12.5%) | 0/12 (0%) | 1/8 (12.5%) | 2/29 (6.9%) | |||||||||||
Hyperuricaemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 3/15 (20%) | 0/4 (0%) | 1/5 (20%) | 2/13 (15.4%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 4/29 (13.8%) | |||||||||||
Hypokalaemia | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 2/8 (25%) | 1/12 (8.3%) | 1/8 (12.5%) | 2/29 (6.9%) | |||||||||||
Decreased appetite | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Dehydration | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hypoalbuminaemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 0/12 (0%) | 1/8 (12.5%) | 2/29 (6.9%) | |||||||||||
Hyponatraemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 2/12 (16.7%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Hyperphosphataemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hypomagnesaemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Diabetes mellitus | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Gout | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hyperlipidaemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hypermagnesaemia | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Iron deficiency | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Steroid diabetes | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Fluid overload | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Hypoglycaemia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Musculoskeletal and connective tissue disorders | ||||||||||||||||||||||
Arthralgia | 0/3 (0%) | 2/4 (50%) | 2/10 (20%) | 3/15 (20%) | 0/4 (0%) | 1/5 (20%) | 1/13 (7.7%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 7/29 (24.1%) | |||||||||||
Musculoskeletal pain | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 3/15 (20%) | 0/4 (0%) | 1/5 (20%) | 1/13 (7.7%) | 1/8 (12.5%) | 2/12 (16.7%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Pain in extremity | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 1/5 (20%) | 3/13 (23.1%) | 1/8 (12.5%) | 2/12 (16.7%) | 0/8 (0%) | 4/29 (13.8%) | |||||||||||
Back pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 5/15 (33.3%) | 0/4 (0%) | 0/5 (0%) | 2/13 (15.4%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 5/29 (17.2%) | |||||||||||
Muscle spasms | 0/3 (0%) | 1/4 (25%) | 1/10 (10%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 5/29 (17.2%) | |||||||||||
Muscular weakness | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 2/12 (16.7%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Bone pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Musculoskeletal chest pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 1/13 (7.7%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Myalgia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Flank pain | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Arthritis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Bursitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Chondrocalcinosis pyrophosphate | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Fibromyalgia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Joint effusion | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Limb discomfort | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Lumbar spinal stenosis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Musculoskeletal stiffness | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Neck pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Osteoarthritis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Rheumatoid arthritis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Soft tissue mass | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Spinal stenosis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Synovial cyst | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||||||||
Basal cell carcinoma | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Bone neoplasm | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Muscle neoplasm | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Neoplasm | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Skin cancer | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Transitional cell carcinoma | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Nervous system disorders | ||||||||||||||||||||||
Dizziness | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 5/15 (33.3%) | 2/4 (50%) | 2/5 (40%) | 3/13 (23.1%) | 3/8 (37.5%) | 6/12 (50%) | 2/8 (25%) | 8/29 (27.6%) | |||||||||||
Headache | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 4/15 (26.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 5/12 (41.7%) | 1/8 (12.5%) | 11/29 (37.9%) | |||||||||||
Dysgeusia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 2/12 (16.7%) | 2/8 (25%) | 0/29 (0%) | |||||||||||
Paraesthesia | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 1/15 (6.7%) | 2/4 (50%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Neuropathy peripheral | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 2/12 (16.7%) | 2/8 (25%) | 3/29 (10.3%) | |||||||||||
Balance disorder | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Disturbance in attention | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Hypoaesthesia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Memory impairment | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Dizziness postural | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Somnolence | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Aphasia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Ataxia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Cognitive disorder | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Dysaesthesia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Dysarthria | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Lethargy | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Migraine | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Muscle contractions involuntary | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Neuralgia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Peripheral sensory neuropathy | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Sciatica | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Sensory disturbance | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Transient ischaemic attack | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Tremor | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Pregnancy, puerperium and perinatal conditions | ||||||||||||||||||||||
Pelvic girdle pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Psychiatric disorders | ||||||||||||||||||||||
Insomnia | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 4/8 (50%) | 1/12 (8.3%) | 0/8 (0%) | 4/29 (13.8%) | |||||||||||
Depression | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Agitation | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Anxiety | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 3/29 (10.3%) | |||||||||||
Depressed mood | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Mental disorder | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Alcohol withdrawal syndrome | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Claustrophobia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Confusional state | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Emotional distress | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Mental status changes | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Sleep terror | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Tobacco withdrawal symptoms | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Renal and urinary disorders | ||||||||||||||||||||||
Chromaturia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 2/8 (25%) | 0/29 (0%) | |||||||||||
Dysuria | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Haematuria | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Nocturia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Urinary retention | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Acute kidney injury | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Pollakiuria | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Urinary incontinence | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Urinary tract pain | 0/3 (0%) | 1/4 (25%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Reproductive system and breast disorders | ||||||||||||||||||||||
Benign prostatic hyperplasia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Breast cyst | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Erectile dysfunction | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Menorrhagia | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Oedema genital | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Penis disorder | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||||
Cough | 0/3 (0%) | 1/4 (25%) | 1/10 (10%) | 5/15 (33.3%) | 1/4 (25%) | 1/5 (20%) | 4/13 (30.8%) | 4/8 (50%) | 3/12 (25%) | 2/8 (25%) | 7/29 (24.1%) | |||||||||||
Dyspnoea | 0/3 (0%) | 1/4 (25%) | 2/10 (20%) | 5/15 (33.3%) | 0/4 (0%) | 2/5 (40%) | 2/13 (15.4%) | 1/8 (12.5%) | 4/12 (33.3%) | 2/8 (25%) | 13/29 (44.8%) | |||||||||||
Dyspnoea exertional | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 2/15 (13.3%) | 1/4 (25%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 6/29 (20.7%) | |||||||||||
Nasal congestion | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 1/12 (8.3%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Epistaxis | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 3/15 (20%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Pleural effusion | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Wheezing | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 1/5 (20%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Hypoxia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Oropharyngeal pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Atelectasis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Bronchospasm | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Chronic obstructive pulmonary disease | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Dysphonia | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Interstitial lung disease | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Laryngeal inflammation | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Pleuritic pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Pulmonary mass | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Pulmonary oedema | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Rales | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Rhinorrhoea | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 1/29 (3.4%) | |||||||||||
Sinus pain | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Sleep apnoea syndrome | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Upper-airway cough syndrome | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Skin and subcutaneous tissue disorders | ||||||||||||||||||||||
Pruritus | 0/3 (0%) | 1/4 (25%) | 2/10 (20%) | 3/15 (20%) | 1/4 (25%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 4/29 (13.8%) | |||||||||||
Hyperhidrosis | 0/3 (0%) | 0/4 (0%) | 1/10 (10%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 2/12 (16.7%) | 1/8 (12.5%) | 3/29 (10.3%) | |||||||||||
Night sweats | 0/3 (0%) | 1/4 (25%) | 1/10 (10%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 0/12 (0%) | 0/8 (0%) | 4/29 (13.8%) | |||||||||||
Ecchymosis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Rash maculo-papular | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 1/8 (12.5%) | 1/12 (8.3%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Skin lesion | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 1/5 (20%) | 2/13 (15.4%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Acne | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 1/8 (12.5%) | 0/29 (0%) | |||||||||||
Petechiae | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 2/15 (13.3%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Rash | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 1/12 (8.3%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Decubitus ulcer | 1/3 (33.3%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Dermatitis | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) | |||||||||||
Erythema | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/4 (0%) | 0/5 (0%) | 0/13 (0%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 2/29 (6.9%) | |||||||||||
Macule | 0/3 (0%) | 0/4 (0%) | 0/10 (0%) | 0/15 (0%) | 0/4 (0%) | 0/5 (0%) | 1/13 (7.7%) | 0/8 (0%) | 0/12 (0%) | 0/8 (0%) | 0/29 (0%) |