An Ascending Dose Study of KW-2449 in Acute Leukemias, Myelodysplastic Syndromes, and Chronic Myelogenous Leukemia

Sponsor

Kyowa Kirin, Inc. (Industry)

Overall Status

Terminated

CT.gov ID

NCT00346632

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

9.3

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Non-randomized, open, dose ranging and dose scheduling study of ascending doses of KW-2449 in subjects with AML, ALL, MDS and CML.

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndromes Chronic Myelogenous Leukemia	Drug: KW-2449	Phase 1

Detailed Description

This is a Phase I open-label dose escalation study of KW-2449 in subjects with acute leukemias, high risk MDS, and CML who are not candidates for approved therapy. Over an 18-month period, the investigative sites collectively will enroll up to a total of 96 subjects. Subjects will be enrolled sequentially into 1 of 7 dose groups to evaluate 2 dosing schedules (Arm A = 14 consecutive days of dosing followed by a 7-28 day rest period as determined by recovery from any acute hematologic and non-hematologic toxicities, or Arm B = 28 consecutive days of dosing followed by a 7-28 day rest period, as determined by recovery from any acute hematologic and non-hematologic toxicities). The safety of a dose level in Arm A (14-day dosing regimen) will be established prior to enrollment of subjects in the same dose level in Arm B (28-day dosing regimen).

In April 2007 the protocol was amended to discontinue Arm B (28 consecutive days of dosing). The protocol will continue as planned for Arm A (14 days of consecutive dosing).

Enrollment will proceed until a maximum tolerated dose (MTD) has been established for each study Arm. Once the MTD has been reached, 12 additional subjects, with 1 or more of the hematologic conditions included in this study, may be enrolled at the MTD as an expanded safety cohort.

Study Design

Study Type:

Interventional

Actual Enrollment :

37 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of KW-2449 in Acute Leukemias (AML), Myelodysplastic Syndromes (MDS), and Chronic Myelogenous Leukemia (CML)

Study Start Date :

Jun 1, 2006

Actual Primary Completion Date :

Apr 1, 2008

Actual Study Completion Date :

Apr 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: KW-2449 Treatment with ascending doses of KW-2449	Drug: KW-2449 Sequential ascending oral doses of KW-2449 given for 14 or 28 days (modified by protocol amendment to only 14 days dosing).

Arm

Intervention/Treatment

Experimental: KW-2449

Treatment with ascending doses of KW-2449

Drug: KW-2449

Sequential ascending oral doses of KW-2449 given for 14 or 28 days (modified by protocol amendment to only 14 days dosing).

Outcome Measures

Primary Outcome Measures

Safety of KW-2449 - Number of Participants With Treatment-related Adverse Events (TEAEs) as Assessed by NCI-CTCAE v3.0 [Baseline up to Cycle 2, Day 1]
In addition to the number of TEAEs, the number of serious TEAEs, the number of related TEAEs, the number of Grade 3-4 TEAEs, and the number of subjects who died or discontinued due to TEAEs were also assessed. The maximally tolerated dose (MTD) was also to be determined, but it was not actually reached in either arm.

Secondary Outcome Measures

Observed Peak Plasma Concentration (Cmax) [Days 1 and 14 (and Day 28 for Arm B) of Cycle 1]
Time to Peak Plasma Concentration (Tmax) [Days 1 and 14 (and Day 28 for Arm B) of Cycle 1]
Area Under the Plasma Concentration-time Curve From 0 to Tau (AUC (0-tau, Tau is the Dosing Interval)) [Days 1 and 14 (and Day 28 for Arm B) of Cycle 1]
Terminal Half Life (t 1/2) [Days 1 and 14 (and Day 28 for Arm B) of Cycle 1]
Accumulation Ratio (AUC 0-tau Day 14 or 28 / AUC 0-tau Day 1) [Day 1 and either Day 14 or Day 28 of Cycle 1]
Disease Response [Day 14 (Arm A) or Day 28 (Arm B) for all cycles]
Disease response (i.e., complete or partial remission) based on standard criteria: Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-4649. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000 Dec 1;96(12):3671-3674. VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. Criteria for use of Imatinib Mesylate (Gleevec®) [updated March 2002; cited 2005 Nov 16]. Available from: http://www.pbm.va.gov/archive/imatinibcriteria.pdf

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed diagnosis of:

AML (including APL refractory to all-trans retinoic acid and arsenic) that has relapsed or was not responsive to prior chemotherapy;
Relapsed/refractory ALL;
CML that has failed to respond or has lost a response to imatinib; and
Advanced MDS (INT-2 and High risk by IPSS) with failure or intolerance to approved therapy.

ECOG Performance Status score of 0, 1, or 2;
Male or female, at least 18 years of age;
Signed written informed consent;
Serum creatinine ≤ 2.0 mg/dL;
Serum SGOT (AST) and SGPT (ALT) ≤ 5x ULN; serum bilirubin ≤ 2 mg/dL (serum bilirubin may be ≤ 3.0 mg/dL in any subject with Gilbert's Syndrome); and
For females of childbearing potential, a negative serum pregnancy test. Subjects, of childbearing potential, must use an Investigator-approved method of birth control.

Exclusion Criteria:

Candidates for approved therapies;
Concomitant treatment with any investigational agent, chemotherapy, radiotherapy, or immunotherapy;
Active CNS leukemia;
Previous or concurrent malignancy except noninvasive non-melanomatous skin cancer, in situ carcinoma of the cervix, or other solid tumor treated curatively, and without evidence of recurrence for at least 2 years prior to study entry;
Uncontrolled systemic infection (viral, bacterial, or fungal);
Uncontrollable disseminated intravascular coagulation;
Major surgery within the 28 days preceding the first dose KW-2449;
Radiotherapy, or lack of recovery of any radiotherapy-related acute toxicity, within the 28 days preceding the first dose KW-2449;
Treatment with systemic therapy for the underlying hematologic condition, or lack of recovery of toxicity from such treatment, within 28 days of the first dose of KW-2449, with the following exceptions: hydroxyurea for treatment of hyperleukocytosis (discontinued for at least 48 hours prior to the first dose of KW-2449); imatinib (discontinued for at least 48 hours prior to the first dose of KW-2449); and interferon (discontinued for at least 7 days prior to the first dose of KW-2449);
Treatment with any other investigational agent, or lack of recovery of toxicity from such treatment, within the 28 days preceding the first dose of KW-2449;
Positive serology for HIV;
Clinically significant cardiac dysfunction (New York Heart Association Class 3 or 4) at the time of screening, or a history of myocardial infarction or heart failure within 3 months preceding the first dose of KW-2449;
Any evidence of chronic Graft versus Host Disease;
Active autoimmune disease requiring immunosuppressive therapy;
Female subjects who are pregnant or breast feeding;
Subjects of childbearing potential, unwilling to use an approved, effective means of contraception in accordance with the institution's standards;
Known current drug or alcohol abuse;
Other severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may compromise the safety of the subject during the study, affect the subject's ability to complete the study, or interfere with interpretation of study results; or
For any reason is judged by the Investigator to be inappropriate for study participation, including an inability to communicate or cooperate with the Investigator.
Hematopoietic growth factors (i.e., such as erythropoietin or darbepoetin alpha, filgrastim [granulocyte colony-stimulating factor ], sargramostim [granulocyte-macrophage colony-stimulating factor ], or other thrombopoietic agents) and corticosteroids within 14 days of study entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
2	Contact Kyowa	Princeton	New Jersey	United States	08540
3	Weill Cornell/New York Presbyterian Hospital	New York	New York	United States	10021
4	M.D. Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

Kyowa Kirin, Inc.

Investigators

Study Director: Matt Fujimori, MD, Kyowa Kirin, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Kyowa Kirin, Inc.

ClinicalTrials.gov Identifier:

NCT00346632

Other Study ID Numbers:

2449-US-001

First Posted:

Jun 30, 2006

Last Update Posted:

Sep 28, 2016

Last Verified:

Aug 1, 2016

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Keywords provided by Kyowa Kirin, Inc.

Additional relevant MeSH terms:

Leukemia

Preleukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Leukemia, Myeloid, Acute

Myelodysplastic Syndromes

Syndrome

Study Results

Participant Flow

Recruitment Details	Four study centers in the US
Pre-assignment Detail

Arm/Group Title	25 mg/Day KW-2449 14-day Regimen (Arm A)	50 mg/Day KW-2449 14-day Regimen (Arm A)	100 mg/Day KW-2449 14-day Regimen (Arm A)	200 mg/Day KW-2449 14-day Regimen (Arm A)	300 mg/Day KW-2449 14-day Regimen (Arm A)	400 mg/Day KW-2449 14-day Regimen (Arm A)	500 mg/Day KW-2449 14-day Regimen (Arm A)	25 mg/Day KW-2449 28-day Regimen (Arm B)	50 mg/Day KW-2449 28-day Regimen (Arm B)	100 mg/Day KW-2449 28-day Regimen (Arm B)
Arm/Group Description	Arm A has sequential ascending oral doses of KW-2449 given for 14-day cycles	Arm A has sequential ascending oral doses of KW-2449 given for 14-day cycles	Arm A has sequential ascending oral doses of KW-2449 given for 14-day cycles	Arm A has sequential ascending oral doses of KW-2449 given for 14-day cycles	Arm A has sequential ascending oral doses of KW-2449 given for 14-day cycles	Arm A has sequential ascending oral doses of KW-2449 given for 14-day cycles	Arm A has sequential ascending oral doses of KW-2449 given for 14-day cycles	Arm B has sequential ascending oral doses of KW-2449 given for 28-day cycles	Arm B has sequential ascending oral doses of KW-2449 given for 28-day cycles	Arm B has sequential ascending oral doses of KW-2449 given for 28-day cycles
Period Title: Overall Study
STARTED	3	3	6	3	4	2	5	4	4	3
COMPLETED	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	3	3	6	3	4	2	5	4	4	3

Baseline Characteristics

Arm/Group Title	Arm A: KW-2449 14-day Regimen	Arm B: KW-2449 28-day Regimen	Total
Arm/Group Description	Sequential ascending oral doses of KW-2449 given for 14-day cycles	Sequential ascending oral doses of KW-2449 given for 28-day cycles	Total of all reporting groups
Overall Participants	26	11	37
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	18 69.2%	5 45.5%	23 62.2%
>=65 years	8 30.8%	6 54.5%	14 37.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.4 (15.48)	62.1 (17.22)	61.6 (12.0)
Sex: Female, Male (Count of Participants)
Female	15 57.7%	6 54.5%	21 56.8%
Male	11 42.3%	5 45.5%	16 43.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 3.8%	0 0%	1 2.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 7.7%	1 9.1%	3 8.1%
White	23 88.5%	10 90.9%	33 89.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	26 100%	11 100%	37 100%

Outcome Measures

1. Primary Outcome

Title	Safety of KW-2449 - Number of Participants With Treatment-related Adverse Events (TEAEs) as Assessed by NCI-CTCAE v3.0
Description	In addition to the number of TEAEs, the number of serious TEAEs, the number of related TEAEs, the number of Grade 3-4 TEAEs, and the number of subjects who died or discontinued due to TEAEs were also assessed. The maximally tolerated dose (MTD) was also to be determined, but it was not actually reached in either arm.
Time Frame	Baseline up to Cycle 2, Day 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm A - 25 mg/Day	Arm A - 50 mg/Day	Arm A - 100 mg/Day	Arm A - 200 mg/Day	Arm A - 300 mg/Day	Arm A - 400 mg/Day	Arm A - 500 mg/Day	Arm A - Total	Arm B - 25 mg/Day	Arm B - 50 mg/Day	Arm B - 100 mg/Day	Arm B - Total
Arm/Group Description	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	Total Patients in Treatment Arm A	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm B)	Total Patients in Treatment Arm B
Measure Participants	3	3	6	3	4	2	5	26	4	4	3	11
Subjects with any TEAE	3 11.5%	3 27.3%	6 16.2%	3 NaN	4 NaN	2 NaN	5 NaN	26 NaN	4 NaN	4 NaN	3 NaN	11 NaN
Subjects with any serious TEAE	2 7.7%	2 18.2%	5 13.5%	2 NaN	4 NaN	1 NaN	3 NaN	19 NaN	2 NaN	3 NaN	3 NaN	8 NaN
Subjects with TEAE related to study drug	1 3.8%	3 27.3%	6 16.2%	3 NaN	4 NaN	2 NaN	3 NaN	22 NaN	3 NaN	3 NaN	3 NaN	9 NaN
Subjects with TEAE of Grade 3 or above	2 7.7%	2 18.2%	6 16.2%	2 NaN	4 NaN	2 NaN	3 NaN	21 NaN	1 NaN	3 NaN	3 NaN	7 NaN
Subjects who discontinued the study due to TEA	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN
Subjects who died	1 3.8%	0 0%	5 13.5%	1 NaN	3 NaN	0 NaN	1 NaN	11 NaN	0 NaN	1 NaN	0 NaN	1 NaN

2. Secondary Outcome

Title	Observed Peak Plasma Concentration (Cmax)
Description
Time Frame	Days 1 and 14 (and Day 28 for Arm B) of Cycle 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm A - 25 mg/Day: Day 1	Arm A - 25 mg/Day: Day 14	Arm A - 50 mg/Day: Day 1	Arm A - 50 mg/Day: Day 14	Arm A - 100 mg/Day: Day 1	Arm A - 100 mg/Day: Day 14	Arm A - 200 mg/Day: Day 1	Arm A - 200 mg/Day: Day 14	Arm A - 300 mg/Day: Day 1	Arm A - 300 mg/Day: Day 14	Arm A - 400 mg/Day: Day 1	Arm A - 400 mg/Day: Day 14	Arm A - 500 mg/Day: Day 1	Arm A - 500 mg/Day: Day 14	Arm B - 25 mg/Day: Day 1	Arm B - 25 mg/Day: Day 14	Arm B - 25 mg/Day: Day 28	Arm B - 50 mg/Day: Day 1	Arm B - 50 mg/Day: Day 14	Arm B - 50 mg/Day: Day 28	Arm B - 100 mg.Day: Day 1	Arm B - 100 mg/Day: Day 14	Arm B - 100 mg/Day: Day 28
Arm/Group Description	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm B)
Measure Participants	3	3	3	3	6	6	3	3	4	4	2	2	5	5	4	4	4	4	4	4	3	3	3
Mean (Standard Deviation) [ng/mL]	6.35 (0.754)	7.94 (3.06)	10.5 (3.49)	18.6 (3.10)	34.4 (15.7)	38.8 (16.1)	31.3 (17.8)	83.7 (97.4)	97.5 (18.6)	147 (77.1)	151 (52.3)	198 (23.3)	180 (125)	371 (129)	7.05 (4.85)	8.39 (1.70)	4.49 (1.97)	8.20 (4.11)	12.7 (4.73)	15.6 (9.43)	20.9 (9.66)	36.3 (15.1)	32.5 (24.6)

3. Secondary Outcome

Title	Time to Peak Plasma Concentration (Tmax)
Description
Time Frame	Days 1 and 14 (and Day 28 for Arm B) of Cycle 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm A - 25 mg/Day: Day 1	Arm A - 25 mg/Day: Day 14	Arm A - 50 mg/Day: Day 1	Arm A - 50 mg/Day: Day 14	Arm A - 100 mg/Day: Day 1	Arm A - 100 mg/Day: Day 14	Arm A - 200 mg/Day: Day 1	Arm A - 200 mg/Day: Day 14	Arm A - 300 mg/Day: Day 1	Arm A - 300 mg/Day: Day 14	Arm A - 400 mg/Day: Day 1	Arm A - 400 mg/Day: Day 14	Arm A - 500 mg/Day: Day 1	Arm A - 500 mg/Day: Day 14	Arm B - 25 mg/Day: Day 1	Arm B - 25 mg/Day: Day 14	Arm B - 25 mg/Day: Day 28	Arm B - 50 mg/Day: Day 1	Arm B - 50 mg/Day: Day 14	Arm B - 50 mg/Day: Day 28	Arm B - 100 mg.Day: Day 1	Arm B - 100 mg/Day: Day 14	Arm B - 100 mg/Day: Day 28
Arm/Group Description	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm B)
Measure Participants	3	3	3	3	6	6	3	3	4	4	2	2	5	5	4	4	4	4	4	4	3	3	3
Mean (Standard Deviation) [hours]	1.51 (0.508)	1.83 (1.18)	1.67 (0.577)	2.06 (0.0962)	1.31 (0.386)	0.979 (0.728)	2.97 (1.71)	2.68 (1.36)	1.67 (0.577)	1.50 (0.707)	2.00 (0.00)	1.57 (0.613)	2.27 (1.23)	1.50 (0.707)	2.27 (1.28)	1.14 (0.177)	1.33 (0.583)	1.26 (0.506)	1.26 (0.492)	1.44 (0.509)	1.34 (0.587)	2.00 (1.73)	1.54 (0.766)

4. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From 0 to Tau (AUC (0-tau, Tau is the Dosing Interval))
Description
Time Frame	Days 1 and 14 (and Day 28 for Arm B) of Cycle 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm A - 25 mg/Day: Day 1	Arm A - 25 mg/Day: Day 14	Arm A - 50 mg/Day: Day 1	Arm A - 50 mg/Day: Day 14	Arm A - 100 mg/Day: Day 1	Arm A - 100 mg/Day: Day 14	Arm A - 200 mg/Day: Day 1	Arm A - 200 mg/Day: Day 14	Arm A - 300 mg/Day: Day 1	Arm A - 300 mg/Day: Day 14	Arm A - 400 mg/Day: Day 1	Arm A - 400 mg/Day: Day 14	Arm A - 500 mg/Day: Day 1	Arm A - 500 mg/Day: Day 14	Arm B - 25 mg/Day: Day 1	Arm B - 25 mg/Day: Day 14	Arm B - 25 mg/Day: Day 28	Arm B - 50 mg/Day: Day 1	Arm B - 50 mg/Day: Day 14	Arm B - 50 mg/Day: Day 28	Arm B - 100 mg.Day: Day 1	Arm B - 100 mg/Day: Day 14	Arm B - 100 mg/Day: Day 28
Arm/Group Description	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm B)
Measure Participants	3	3	3	3	6	6	3	3	4	4	2	2	5	5	4	4	4	4	4	4	3	3	3
Mean (Standard Deviation) [hr*ng/mL]	23.6 (8.56)	30.9 (NA)	46.7 (11.1)	77.9 (29.7)	138 (41.8)	162 (28.7)	173 (90.5)	647 (665)	428 (192)	626 (310)	647 (73.5)	1060 (300)	822 (463)	1200 (180)	38.0 (18.0)	35.3 (8.76)	28.8 (7.36)	36.3 (18.1)	58.7 (21.7)	60.3 (23.6)	107 (31.2)	158 (58.8)	147 (90.9)

5. Secondary Outcome

Title	Terminal Half Life (t 1/2)
Description
Time Frame	Days 1 and 14 (and Day 28 for Arm B) of Cycle 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm A - 25 mg/Day: Day 1	Arm A - 25 mg/Day: Day 14	Arm A - 50 mg/Day: Day 1	Arm A - 50 mg/Day: Day 14	Arm A - 100 mg/Day: Day 1	Arm A - 100 mg/Day: Day 14	Arm A - 200 mg/Day: Day 1	Arm A - 200 mg/Day: Day 14	Arm A - 300 mg/Day: Day 1	Arm A - 300 mg/Day: Day 14	Arm A - 400 mg/Day: Day 1	Arm A - 400 mg/Day: Day 14	Arm A - 500 mg/Day: Day 1	Arm A - 500 mg/Day: Day 14	Arm B - 25 mg/Day: Day 1	Arm B - 25 mg/Day: Day 14	Arm B - 25 mg/Day: Day 28	Arm B - 50 mg/Day: Day 1	Arm B - 50 mg/Day: Day 14	Arm B - 50 mg/Day: Day 28	Arm B - 100 mg.Day: Day 1	Arm B - 100 mg/Day: Day 14	Arm B - 100 mg/Day: Day 28
Arm/Group Description	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm B)
Measure Participants	3	3	3	3	6	6	3	3	4	4	2	2	5	5	4	4	4	4	4	4	3	3	3
Mean (Standard Deviation) [hours]	2.96 (1.42)	3.36 (NA)	2.67 (0.435)	3.26 (0.631)	3.11 (0.310)	2.80 (0.187)	3.27 (NA)	3.04 (0.715)	2.48 (0.158)	2.44 (0.149)	2.42 (0.06)	2.83 (0.0806)	2.93 (1.01)	2.47 (0.105)	2.78 (0.108)	3.00 (0.453)	3.35 (0.443)	3.90 (1.43)	3.32 (0.383)	3.88 (1.64)	2.97 (0.471)	3.90 (1.62)	3.16 (NA)

6. Secondary Outcome

Title	Accumulation Ratio (AUC 0-tau Day 14 or 28 / AUC 0-tau Day 1)
Description
Time Frame	Day 1 and either Day 14 or Day 28 of Cycle 1

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm A - 25 mg/Day: Day 14	Arm A - 50 mg/Day: Day 14	Arm A - 100 mg/Day: Day 14	Arm A - 200 mg/Day: Day 14	Arm A - 300 mg/Day: Day 14	Arm A - 400 mg/Day: Day 14	Arm A - 500 mg/Day: Day 14	Arm B - 25 mg/Day: Day 14	Arm B - 25 mg/Day: Day 28	Arm B - 50 mg/Day: Day 14	Arm B - 50 mg/Day: Day 28	Arm B - 100 mg/Day: Day 14	Arm B - 100 mg/Day: Day 28
Arm/Group Description	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm B)
Measure Participants	3	3	6	3	4	2	5	4	4	4	4	3	3
Mean (Standard Deviation) [Ratio of hr*ng/mL]	1.50 (NA)	1.66 (0.389)	1.50 (0.459)	3.37 (1.45)	1.28 (0.0271)	1.68 (0.654)	0.846 (NA)	0.953 (0.181)	0.906 (0.622)	1.42 (0.331)	1.44 (0.180)	1.50 (0.187)	1.60 (NA)

7. Secondary Outcome

Title	Disease Response
Description	Disease response (i.e., complete or partial remission) based on standard criteria: Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-4649. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000 Dec 1;96(12):3671-3674. VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. Criteria for use of Imatinib Mesylate (Gleevec®) [updated March 2002; cited 2005 Nov 16]. Available from: http://www.pbm.va.gov/archive/imatinibcriteria.pdf
Time Frame	Day 14 (Arm A) or Day 28 (Arm B) for all cycles

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Arm A - 25 mg/Day	Arm A - 50 mg/Day	Arm A - 100 mg/Day	Arm A - 200 mg/Day	Arm A - 300 mg/Day	Arm A - 400 mg/Day	Arm A - 500 mg/Day	Arm A - Total	Arm B - 25 mg/Day	Arm B - 50 mg/Day	Arm B - 100 mg/Day	Arm B - Total
Arm/Group Description	KW2449-001 25 mg/day (Treatment Arm A)	KW2449-001 50 mg/day (Treatment Arm A)	KW2449-001 100 mg/day (Treatment Arm A)	KW2449-001 200 mg/day (Treatment Arm A)	KW2449-001 300 mg/day (Treatment Arm A)	KW2449-001 400 mg/day (Treatment Arm A)	KW2449-001 500 mg/day (Treatment Arm A)	Total Patients in Treatment Arm A	KW2449-001 25 mg/day (Treatment Arm B)	KW2449-001 50 mg/day (Treatment Arm B)	KW2449-001 100 mg/day (Treatment Arm B)	Total Patients in Treatment Arm B
Measure Participants	3	3	6	3	4	2	5	26	4	4	3	11
Number [number of responders]	0	0	0	0	0	0	0	0	0	0	0	0

Adverse Events

	Arm A - 25 mg/Day		Arm A - 50 mg/Day		Arm A - 100 mg/Day		Arm A - 200 mg/Day		Arm A - 300 mg/Day		Arm A - 400 mg/Day		Arm A - 500 mg/Day		Arm A - Total		Arm B - 25 mg/Day		Arm B - 50 mg/Day		Arm B - 100 mg/Day		Arm B - Total
Time Frame
Adverse Event Reporting Description

Arm/Group Title	Arm A - 25 mg/Day		Arm A - 50 mg/Day		Arm A - 100 mg/Day		Arm A - 200 mg/Day		Arm A - 300 mg/Day		Arm A - 400 mg/Day		Arm A - 500 mg/Day		Arm A - Total		Arm B - 25 mg/Day		Arm B - 50 mg/Day		Arm B - 100 mg/Day		Arm B - Total
Arm/Group Description	KW2449-001 25 mg/day (Treatment Arm A)		KW2449-001 50 mg/day (Treatment Arm A)		KW2449-001 100 mg/day (Treatment Arm A)		KW2449-001 200 mg/day (Treatment Arm A)		KW2449-001 300 mg/day (Treatment Arm A)		KW2449-001 400 mg/day (Treatment Arm A)		KW2449-001 500 mg/day (Treatment Arm A)		Total Patients in Treatment Arm A		KW2449-001 25 mg/day (Treatment Arm B)		KW2449-001 50 mg/day (Treatment Arm B)		KW2449-001 100 mg/day (Treatment Arm B)		Total Patients in Treatment Arm B
All Cause Mortality
	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	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A - 25 mg/Day		Arm A - 50 mg/Day		Arm A - 100 mg/Day		Arm A - 200 mg/Day		Arm A - 300 mg/Day		Arm A - 400 mg/Day		Arm A - 500 mg/Day		Arm A - Total		Arm B - 25 mg/Day		Arm B - 50 mg/Day		Arm B - 100 mg/Day		Arm B - Total
	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	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		2/3 (66.7%)		5/6 (83.3%)		2/3 (66.7%)		4/4 (100%)		1/2 (50%)		3/5 (60%)		19/26 (73.1%)		2/4 (50%)		3/4 (75%)		3/3 (100%)		8/11 (72.7%)
Blood and lymphatic system disorders
Febrile neutropenia	1/3 (33.3%)	1	0/3 (0%)	0	3/6 (50%)	3	1/3 (33.3%)	1	1/4 (25%)	1	0/2 (0%)	0	2/5 (40%)	2	8/26 (30.8%)	8	1/4 (25%)	1	1/4 (25%)	1	0/3 (0%)	0	2/11 (18.2%)	2
Thrombocytopenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Cardiac disorders
Atrial fibrillation	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Atrial flutter	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Gastrointestinal disorders
Abdominal pain	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Nausea	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Rectal haemorrhage	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Vomiting	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
General disorders
Catheter related complication	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Chest pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Death	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	1/5 (20%)	1	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Disease progression	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	1/3 (33.3%)	1	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	4/26 (15.4%)	4	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Injection site haemorrhage	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Pyrexia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	1/4 (25%)	1	0/4 (0%)	0	1/3 (33.3%)	1	2/11 (18.2%)	2
Infections and infestations
Appendicitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Catheter related infection	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Diverticulitis	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Escherichia sepsis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	2	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Localised infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Pneumonia	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	3	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	1/5 (20%)	1	4/26 (15.4%)	5	0/4 (0%)	0	3/4 (75%)	3	0/3 (0%)	0	3/11 (27.3%)	3
Pneumonia fungal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Sepsis	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	3/26 (11.5%)	3	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Urinary tract infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Investigations
Haemoglobin decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Metabolism and nutrition disorders
Dehydration	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Hyponatraemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Bone pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Pain in extremity	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Tumour lysis syndrome	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Nervous system disorders
Brain stem haemorrhage	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Cerebrovascular accident	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Subarachnoid haemorrhage	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Renal and urinary disorders
Renal failure	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Renal failure acute	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Reproductive system and breast disorders
Pelvic pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Pleural effusion	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Pneumonitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A - 25 mg/Day		Arm A - 50 mg/Day		Arm A - 100 mg/Day		Arm A - 200 mg/Day		Arm A - 300 mg/Day		Arm A - 400 mg/Day		Arm A - 500 mg/Day		Arm A - Total		Arm B - 25 mg/Day		Arm B - 50 mg/Day		Arm B - 100 mg/Day		Arm B - Total
	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	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		6/6 (100%)		3/3 (100%)		4/4 (100%)		2/2 (100%)		5/5 (100%)		26/26 (100%)		4/4 (100%)		4/4 (100%)		3/3 (100%)		11/11 (100%)
Blood and lymphatic system disorders
Anaemia	0/3 (0%)	0	1/3 (33.3%)	5	2/6 (33.3%)	4	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	3/26 (11.5%)	9	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Febrile neutropenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Haemorrhagic diathesis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Leukocytosis	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	3/26 (11.5%)	3	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Lymphadenopathy	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Neutropenia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	2/4 (50%)	2	0/3 (0%)	0	2/11 (18.2%)	2
Splenomegaly	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Thrombocytopenia	0/3 (0%)	0	1/3 (33.3%)	2	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	3/26 (11.5%)	4	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Cardiac disorders
Angina pectoris	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Bundle branch block right	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Palpitations	1/3 (33.3%)	1	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Sinus tachycardia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Tachycardia	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	1/5 (20%)	1	3/26 (11.5%)	3	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Ventricular extrasystoles	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Congenital, familial and genetic disorders
Congenital jaw malformation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Ear and labyrinth disorders
Ear haemorrhage	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Ear pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	3	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	3	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Eye disorders
Conjunctival hyperaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Dry eye	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Eye pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	2	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Keratoconjunctivitis sicca	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Macular degeneration	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Ocular hyperaemia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Pupillary reflex impaired	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Scleral discolouration	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Visual disturbance	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Vitreous floaters	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Abdominal pain	0/3 (0%)	0	1/3 (33.3%)	3	1/6 (16.7%)	1	1/3 (33.3%)	2	1/4 (25%)	4	0/2 (0%)	0	1/5 (20%)	1	5/26 (19.2%)	11	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Abdominal pain upper	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Constipation	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	2/3 (66.7%)	3	0/4 (0%)	0	2/2 (100%)	2	0/5 (0%)	0	5/26 (19.2%)	6	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Diarrhoea	0/3 (0%)	0	1/3 (33.3%)	2	0/6 (0%)	0	1/3 (33.3%)	1	3/4 (75%)	3	1/2 (50%)	2	2/5 (40%)	2	8/26 (30.8%)	10	1/4 (25%)	2	2/4 (50%)	3	2/3 (66.7%)	2	5/11 (45.5%)	7
Dry mouth	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	2	1/4 (25%)	1	0/2 (0%)	0	1/5 (20%)	1	3/26 (11.5%)	4	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Dyspepsia	1/3 (33.3%)	1	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	3/26 (11.5%)	3	0/4 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	2	2/11 (18.2%)	3
Dysphagia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Faecal incontinence	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Flatulence	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	1/5 (20%)	1	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Gastrointestinal inflammation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Gastrooesophageal reflux disease	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	1/5 (20%)	1	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Gingival bleeding	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Gingival pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	1/4 (25%)	1	0/3 (0%)	0	2/11 (18.2%)	2
Haemorrhoidal haemorrhage	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Haemorrhoids	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Inguinal hernia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Melaena	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Nausea	2/3 (66.7%)	2	2/3 (66.7%)	2	3/6 (50%)	3	3/3 (100%)	3	3/4 (75%)	7	1/2 (50%)	1	3/5 (60%)	3	17/26 (65.4%)	21	1/4 (25%)	2	2/4 (50%)	3	2/3 (66.7%)	2	5/11 (45.5%)	7
Odynophagia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Oral mucosal petechiae	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	2/4 (50%)	2	0/4 (0%)	0	0/3 (0%)	0	2/11 (18.2%)	2
Salivary gland enlargement	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Stomatitis	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Tongue coated	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Tongue disorder	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Toothache	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	2/4 (50%)	2	0/3 (0%)	0	2/11 (18.2%)	2
Vomiting	2/3 (66.7%)	2	2/3 (66.7%)	3	2/6 (33.3%)	2	2/3 (66.7%)	4	2/4 (50%)	2	2/2 (100%)	3	2/5 (40%)	3	14/26 (53.8%)	19	1/4 (25%)	1	2/4 (50%)	3	1/3 (33.3%)	1	4/11 (36.4%)	5
General disorders
Asthenia	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	2	0/2 (0%)	0	1/5 (20%)	1	3/26 (11.5%)	4	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Catheter site bruise	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Catheter site haemorrhage	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Catheter site oedema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Catheter site pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Catheter site related reaction	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Chest pain	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Chills	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	1/5 (20%)	1	2/26 (7.7%)	2	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Fatigue	0/3 (0%)	0	2/3 (66.7%)	4	4/6 (66.7%)	4	0/3 (0%)	0	2/4 (50%)	2	1/2 (50%)	1	2/5 (40%)	3	11/26 (42.3%)	14	2/4 (50%)	4	1/4 (25%)	1	2/3 (66.7%)	6	5/11 (45.5%)	11
Gait disturbance	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Inflammation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Injection site reaction	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Local swelling	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Localised oedema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Malaise	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Mucosa vesicle	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Nodule	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Oedema	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Oedema peripheral	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/4 (25%)	1	1/2 (50%)	1	1/5 (20%)	1	5/26 (19.2%)	5	1/4 (25%)	2	2/4 (50%)	5	2/3 (66.7%)	3	5/11 (45.5%)	10
Pain	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Pyrexia	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/2 (0%)	0	2/5 (40%)	4	5/26 (19.2%)	7	0/4 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	2/11 (18.2%)	2
Hepatobiliary disorders
Hepatomegaly	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Hyperbilirubinaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	3	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	3	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Portal vein thrombosis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Infections and infestations
Candidiasis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Catheter site infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Cellulitis	1/3 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	3	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Enterococcal infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Herpes zoster	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Oral candidiasis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Otitis externa	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Pneumonia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Pneumonia fungal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Sinusitis	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Subcutaneous abscess	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Tooth abscess	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	3	0/3 (0%)	0	1/11 (9.1%)	3
Tooth infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Upper respiratory tract infection	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	1/26 (3.8%)	1	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Transfusion reaction	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Investigations
Aspartate aminotransferase increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Blood alkaline phosphatase increased	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Blood glucose increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Blood magnesium decreased	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Breath sounds abnormal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	1/5 (20%)	1	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Cardiac murmur	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Electrocardiogram ST-T change	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Full blood count decreased	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Heart sounds abnormal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	2	0/5 (0%)	0	1/26 (3.8%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Spleen palpable	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Sputum abnormal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Troponin increased	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Weight decreased	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	2/26 (7.7%)	2	1/4 (25%)	1	0/4 (0%)	0	1/3 (33.3%)	1	2/11 (18.2%)	2
Metabolism and nutrition disorders
Anorexia	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/2 (0%)	0	1/5 (20%)	1	4/26 (15.4%)	4	1/4 (25%)	1	2/4 (50%)	3	0/3 (0%)	0	3/11 (27.3%)	4
Appetite disorder	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Decreased appetite	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Dehydration	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Gout	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Hyperglycaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Hypermagnesaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Hyperphosphataemia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	2	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	3	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Hyperuricaemia	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	1/5 (20%)	1	3/26 (11.5%)	3	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Hypokalaemia	0/3 (0%)	0	2/3 (66.7%)	3	2/6 (33.3%)	3	0/3 (0%)	0	1/4 (25%)	2	0/2 (0%)	0	1/5 (20%)	1	6/26 (23.1%)	9	0/4 (0%)	0	0/4 (0%)	0	2/3 (66.7%)	2	2/11 (18.2%)	2
Hypomagnesaemia	0/3 (0%)	0	2/3 (66.7%)	2	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	3/26 (11.5%)	3	2/4 (50%)	2	0/4 (0%)	0	1/3 (33.3%)	1	3/11 (27.3%)	3
Increased appetite	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Weight fluctuation	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/3 (33.3%)	1	1/3 (33.3%)	3	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	2/2 (100%)	4	1/5 (20%)	1	6/26 (23.1%)	10	3/4 (75%)	3	1/4 (25%)	1	0/3 (0%)	0	4/11 (36.4%)	4
Back pain	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/4 (25%)	1	1/2 (50%)	1	1/5 (20%)	1	4/26 (15.4%)	4	0/4 (0%)	0	2/4 (50%)	3	0/3 (0%)	0	2/11 (18.2%)	3
Flank pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Joint effusion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Joint swelling	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Muscle spasms	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Muscular weakness	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Musculoskeletal pain	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Myalgia	0/3 (0%)	0	2/3 (66.7%)	2	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	3/26 (11.5%)	3	0/4 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	2/11 (18.2%)	2
Neck pain	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	2/4 (50%)	2	0/2 (0%)	0	0/5 (0%)	0	3/26 (11.5%)	3	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Osteitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Pain in extremity	1/3 (33.3%)	1	0/3 (0%)	0	3/6 (50%)	3	1/3 (33.3%)	1	1/4 (25%)	1	1/2 (50%)	1	1/5 (20%)	1	8/26 (30.8%)	8	0/4 (0%)	0	2/4 (50%)	2	1/3 (33.3%)	1	3/11 (27.3%)	3
Pain in jaw	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Sacral pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Shoulder pain	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	2/3 (66.7%)	2	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	4/26 (15.4%)	4	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	2	1/11 (9.1%)	2
Nervous system disorders
Balance disorder	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Coordination abnormal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Dizziness	1/3 (33.3%)	2	1/3 (33.3%)	1	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	3/26 (11.5%)	4	0/4 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	2/11 (18.2%)	2
Drooling	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Dysarthria	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	2/26 (7.7%)	3	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Dysgeusia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Facial palsy	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Headache	1/3 (33.3%)	1	1/3 (33.3%)	2	3/6 (50%)	3	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	5/26 (19.2%)	6	0/4 (0%)	0	2/4 (50%)	2	1/3 (33.3%)	1	3/11 (27.3%)	3
Hemiparesis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Hypoaesthesia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	2	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	3	0/4 (0%)	0	1/4 (25%)	2	0/3 (0%)	0	1/11 (9.1%)	2
Lethargy	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Peripheral motor neuropathy	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Restless legs syndrome	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	2	0/3 (0%)	0	1/11 (9.1%)	2
Sensory disturbance	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Sinus headache	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Syncope	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Transient ischaemic attack	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Unresponsive to verbal stimuli	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	2	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Psychiatric disorders
Agitation	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Anxiety	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Confusional state	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Delirium	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Depressed mood	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Eating disorder	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Hallucination, visual	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Insomnia	0/3 (0%)	0	1/3 (33.3%)	2	2/6 (33.3%)	2	1/3 (33.3%)	1	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	5/26 (19.2%)	6	0/4 (0%)	0	2/4 (50%)	2	1/3 (33.3%)	1	3/11 (27.3%)	3
Renal and urinary disorders
Micturition urgency	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Renal failure	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Urinary hesitation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Urinary incontinence	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Reproductive system and breast disorders
Pelvic pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Cough	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	3/26 (11.5%)	3	1/4 (25%)	1	1/4 (25%)	1	0/3 (0%)	0	2/11 (18.2%)	2
Dysphonia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Dyspnoea	2/3 (66.7%)	4	0/3 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	2/4 (50%)	2	0/2 (0%)	0	1/5 (20%)	1	7/26 (26.9%)	9	2/4 (50%)	2	1/4 (25%)	1	1/3 (33.3%)	3	4/11 (36.4%)	6
Epistaxis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	1/4 (25%)	1	1/4 (25%)	1	0/3 (0%)	0	2/11 (18.2%)	2
Haemoptysis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	1/4 (25%)	1	2/4 (50%)	2	0/3 (0%)	0	3/11 (27.3%)	3
Hypoxia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Increased upper airway secretion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Laryngeal haemorrhage	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Nasal congestion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	2/4 (50%)	2	0/4 (0%)	0	0/3 (0%)	0	2/11 (18.2%)	2
Pharyngeal erythema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Pharyngolaryngeal pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	2	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Pleuritic pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Productive cough	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Pulmonary congestion	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Pulmonary oedema	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	2	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Rales	2/3 (66.7%)	2	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/2 (50%)	1	0/5 (0%)	0	3/26 (11.5%)	3	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Rhinitis allergic	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Tachypnoea	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Throat irritation	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Wheezing	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Skin and subcutaneous tissue disorders
Actinic keratosis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Blister	0/3 (0%)	0	1/3 (33.3%)	4	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	4	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Blood blister	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Dermatitis exfoliative	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Dry skin	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	2/26 (7.7%)	2	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Ecchymosis	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	2/4 (50%)	2	1/4 (25%)	1	1/3 (33.3%)	1	4/11 (36.4%)	4
Erythema	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Excoriation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Hyperhidrosis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Increased tendency to bruise	1/3 (33.3%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Night sweats	1/3 (33.3%)	2	1/3 (33.3%)	1	0/6 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	3/26 (11.5%)	4	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Palmar erythema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Periorbital oedema	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Petechiae	0/3 (0%)	0	2/3 (66.7%)	2	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	1/5 (20%)	1	3/26 (11.5%)	3	0/4 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	1/11 (9.1%)	1
Pruritus	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Rash	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	2/5 (40%)	2	3/26 (11.5%)	3	0/4 (0%)	0	1/4 (25%)	1	1/3 (33.3%)	1	2/11 (18.2%)	2
Rash macular	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Rash pruritic	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Skin lesion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Skin ulcer	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	1/4 (25%)	1	0/4 (0%)	0	1/3 (33.3%)	1	2/11 (18.2%)	2
Swelling face	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	1/3 (33.3%)	1	1/11 (9.1%)	1
Urticaria	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/26 (0%)	0	1/4 (25%)	1	1/4 (25%)	1	0/3 (0%)	0	2/11 (18.2%)	2
Vascular disorders
Hypertension	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/4 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	1/26 (3.8%)	1	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0
Hypotension	0/3 (0%)	0	2/3 (66.7%)	2	0/6 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/2 (0%)	0	1/5 (20%)	1	4/26 (15.4%)	4	1/4 (25%)	1	0/4 (0%)	0	0/3 (0%)	0	1/11 (9.1%)	1
Orthostatic hypotension	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	0/2 (0%)	0	0/5 (0%)	0	2/26 (7.7%)	2	0/4 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/11 (0%)	0

Limitations/Caveats

[Not Specified]

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

Results Point of Contact

Name/Title	Project Leader
Organization	Kyowa Kirin Pharmaceutical Development, Inc.
Phone	6099191100
Email	clinical.info@kyowakirin.com

Responsible Party:

Kyowa Kirin, Inc.

ClinicalTrials.gov Identifier:

NCT00346632

Other Study ID Numbers:

2449-US-001

First Posted:

Jun 30, 2006

Last Update Posted:

Sep 28, 2016

Last Verified:

Aug 1, 2016

An Ascending Dose Study of KW-2449 in Acute Leukemias, Myelodysplastic Syndromes, and Chronic Myelogenous Leukemia

Study Details

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Detailed Description

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

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Inclusion Criteria:

Exclusion Criteria:

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Locations

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Investigators

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Study Results

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Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

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Certain Agreements

Results Point of Contact