VALOR: Study of Vosaroxin or Placebo in Combination With Cytarabine in Patients With First Relapsed or Refractory AML

• Sponsor: Sunesis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01191801
• Collaborator: (none)
• Enrollment: 711
• Locations: 124
• Arms: 2
• Duration (Months): 74.4
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study compared treatment groups of patients treated with vosaroxin and cytarabine versus patients treated with placebo and cytarabine.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: vosaroxin + cytarabine; Drug: placebo + cytarabine	Phase 3

Detailed Description

The study includes additional objectives to ones listed above as Outcome Measures. These additional objectives also compared treatment groups in the following:

CR + CRp rate, defined as CR + CRp based on modified IWG response criteria.

Combined CR rate (CR+CRp+CRi).

Percentage of patients who have post-treatment (subsequent) transplantation.

Percentage of patients who received subsequent non-protocol therapy (including transplantation).

Safety and tolerability.

In keeping with FDA guidance for adaptive trial designs, the study incorporated an independent DSMB (Drug Safety Monitoring Board) to address potential uncertainty concerning the true treatment affect between the treatment groups and to address a deterioration of power from a small difference. Sunesis remained blinded and had no involvement in the interim data analysis, interpretation, or adaptive design. Based on the results of the interim data analysis the DSMB recommended an increase in the target number of deaths from 375 in 450 patients to 562 in 675 patients which based on a 5% dropout rate increased enrollment from 475 to 712.

The primary analysis was performed when the target number of deaths had been achieved based on a permuted block randomization procedure, stratified by disease status (refractory, first relapse with duration of first CR or CRp ≥ 90 days and < 12 months, or first relapse with duration of first CR or CRp ≥ 12 months and ≤ 24 months), age (< 60 years or ≥ 60 years), and geographic location (US or outside US). The study included periods of screening, treatment / hematologic recovery, post-treatment follow-up, and long-term follow-up for survival.

Follow-up was monthly during the first year, every 2 months during the second year, and every 3 months thereafter until death, withdrawal of consent, or loss to follow-up, whichever occurred first. Long-term follow-up began for all patients when the required number of deaths for primary analysis had been met; thereafter, survival data were collected every 4 months until death, withdrawal of consent, or loss to follow-up, whichever occurred first.

The long term follow-up for this study continues at this time and the September 2014 date reflects database lock for primary analyses reflected in the Results Section. During long term follow-up Sunesis is not collecting Adverse Events.

Study Design

• Study Type: Interventional
• Actual Enrollment: 711 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Controlled, Double-Blind, Multinational Clinical Study of the Efficacy and Safety of Vosaroxin and Cytarabine Versus Placebo and Cytarabine in Patients With First Relapsed or Refractory Acute Myeloid Leukemia (VALOR)
• Study Start Date: Dec 17, 2010
• Actual Primary Completion Date: Sep 26, 2014
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A: vosaroxin + cytarabine vosaroxin (short IV infusion within 10 minutes) on days 1 and 4: cytarabine on days 1 through 5; a maximum of 2 cycles of Induction and 2 cycles for Consolidation	Drug: vosaroxin + cytarabine; Vosaroxin days 1 and 4: 90 mg/m2 for induction 1; 70 mg/m2 for all other cycles Cytarabine 1 g/m2 daily on days 1-5 (IDAC)
Placebo Comparator: Group B: placebo + cytarabine placebo (short IV infusion within 10 minutes and volume matched to vosaroxin) on days 1 and 4: cytarabine on days 1 through 5; a maximum of 2 cycles of Induction and 2 cycles for Consolidation	Drug: placebo + cytarabine; Placebo days 1 and 4: volume matched to vosaroxin Cytarabine 1 g/m2 daily on days 1-5 (IDAC); Other Names: control

Outcome Measures

Primary Outcome Measures

1. Overall Survival [Up to 5 years or duration of study]

   Vosaroxin + cytarabine patient survival versus placebo + cytarabine patient survival

Secondary Outcome Measures

1. Complete Remission (CR) Rate Based on Modified International Working Group (IWG) Criteria. [Up to 5 years or duration of study]

   Group A (Vosaroxin + cytarabine) patient CR as compared to Group B (placebo + cytarabine) patient CR. Complete remission (CR) is typically defined using IWG criteria as bone marrow blast count of less than 5% with adequate recovery of peripheral blood counts.

2. All Cause Mortality [30 Days]

   Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality

3. All Cause Mortality [60 Days]

   Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality

Other Outcome Measures

1. Overall Remission (OR) Rate Based on the IWG Response Criteria [Up to 5 years or the duration of the study]

   Group A patient OR compared to Group B patient OR Overall Remission includes Complete Remission (CR), Complete Remission with incomplete platelet recovery (CRp), Complete Remission with incomplete blood count recovery (CRi), and Partial Remission (PR). Complete remission means bone marrow blast count of less than 5% with adequate recovery of peripheral blood counts as typically defined by the IWG. Both CRi and CRp refer complete remission but with incomplete blood count and platelet recovery, respectively. PR, or partial remission, refers to remission in which bone marrow contains blast counts between 5 and 25 percent.

2. Event Free Survival (EFS) [Up to 5 years or duration of study]

3. Leukemia-Free Survival (LFS) [Up to 5 years or the duration of the study]

   Durability of remission (CR) assessed by LFS

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provided signed, written informed consent

• At least 18 years of age

• Had a diagnosis of AML according to World Health Organization (WHO) classification

• First relapsed or refractory AML (refractory to initial induction therapy) with at least 5% blasts by bone marrow or aspirate or 1% blasts in peripheral blood with additional requirements for relapsed or refractory

• Had an ECOG score of 0-2

• Had adequate liver and renal function as indicated by certain laboratory values

• Had adequate cardiac function (left ventricular ejection fraction at least 40% by multiple gated acquisition scan or ECG)

• Nonfertile or agreed to use an adequate method of contraception until 30 days after the last treatment

• Had any clinically significant nonhematologic toxicity after prior chemotherapy recovered to Grade 1 per NCI-CTCAE

Exclusion Criteria:

• Had acute promyelocytic leukemia

• Had more than 2 cycles of induction therapy for AML

• Had completed a single cycle of treatment containing a total dose of 5 g/m2 or more of cytarabine within 90 days before randomization

• Refractory to or relapsed within the previous 3 months after therapy with an IDAC- or HIDAC-containing regimen

• Had received a hematopoietic stem cell transplant (HSCT) within the previous 90 days

• Had received active immunosuppressive therapy for graft-versus-host disease (GVHD) within 2 weeks before study start

• Had any other severe concurrent disease, or have a history of serious disease involving the heart, kidney, liver, or other organ system

• Had evidence of central nervous system involvement of active AML

• Had other active malignancies (including other hematologic malignancies) or been diagnosed with other malignancies within the last 12 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia

• Had an active, uncontrolled infection

• Had received any other investigational therapy within 14 days or not recovered from acute affects of the other investigational therapy

• Had received prior or current hydroxyurea or medications to reduce blast count within 24 hours before randomization

• Had received previous treatment with vosaroxin

• Pregnant or lactating

• Had any other medical, psychological, or social condition that may interfere with consent, study participation, or follow-up

• Had known HIV seropositivity

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Moores UCSD Cancer Center	La Jolla	California	United States	92093
2	UCLA Division of Hematology/Oncology	Los Angeles	California	United States	90095
3	Sharp Clinical Oncology Research	San Diego	California	United States	92123
4	University of California San Francisco	San Francisco	California	United States	94143
5	HCA HealthONE - Rocky Mountain Blood and Marrow Transplant Program	Denver	Colorado	United States	80218
6	George Washington University-Medical Faculty Associates	Washington	District of Columbia	United States	20037
7	Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
8	Baptist Cancer Institute	Jacksonville	Florida	United States	32207
9	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612
10	Georgia Health Sciences University	Augusta	Georgia	United States	30912
11	Rush University Medical Center, Division of Hematology/Oncology	Chicago	Illinois	United States	60612
12	University of Chicago	Chicago	Illinois	United States	60637
13	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
14	St. Francis Medical Group Oncology and Hematology Specialists	Indianapolis	Indiana	United States	46237
15	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
16	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
17	University of Michigan	Ann Arbor	Michigan	United States	48109
18	Henry Ford Health System	Detroit	Michigan	United States	48202
19	Ellis Fischel Cancer Center, University of Missouri Health Care	Columbia	Missouri	United States	65203
20	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
21	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
22	North Shore Long Island Jewish Health System	Lake Success	New York	United States	11042
23	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	100065
24	Weill Cornell Medical College	New York	New York	United States	10065
25	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
26	New York Medical College, Division of Oncology/Hematology	Valhalla	New York	United States	10595
27	Mecklenburg Medical Group	Charlotte	North Carolina	United States	28204
28	Duke University Medical Center	Durham	North Carolina	United States	27710
29	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
30	University Hospitals fo Cleveland	Cleveland	Ohio	United States	44106
31	Medical University of South Carolina	Charleston	South Carolina	United States	29425
32	Family Cancer Center	Memphis	Tennessee	United States	38119
33	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37203
34	Henry-Joyce Cancer Clinic	Nashville	Tennessee	United States	37232
35	UT Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390
36	The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia	Houston	Texas	United States	77030
37	Cancer Care Centers of South Texas	San Antonio	Texas	United States	78229
38	Department of Medicine Section of Hematology/Oncology, West Virginia University Hospitals, Mary Babb Randolph Cancer Center, West Virginia University	Morgantown	West Virginia	United States	26506
39	The Canberra Hospital	Garran	Australian Capital Territory	Australia	2605
40	Concord Repatriation General Hospital	Concord	New South Wales	Australia	2139
41	Haematology Department, Gosford Hospital	Gosford	New South Wales	Australia	2250
42	Westmead Hospital	Westmead	New South Wales	Australia	2145
43	Royal Brisbane and Women's Hospital	Brisbane	Queensland	Australia	4029
44	Haematology and Bone Marrow Transplant Unit, Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
45	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
46	Andrew Love Cancer Center, Geelong Hospital, Barwon Health	Geelong	Victoria	Australia	3220
47	The Alfred Hospital	Melbourne	Victoria	Australia	3004
48	Department of Clinical Haematology and BMT Service, Royal Melbourne Hospital	Parkville	Victoria	Australia	3050
49	Royal Perth Hospital	Perth	Western Australia	Australia	6000
50	Universitatsklinik Graz, Universitatsklinik fur Innere Medizin, Abteilung fur Hamatologie	Graz		Austria	8036
51	University Hospital for Internal Medicine V, Innsbruck Medical University	Innsbruck		Austria	6020
52	Landeskrankenhaus Salzburg, Universitaetsklinik fur innere Medizin lll, Universitaetsklinikum der PMU	Salzburg		Austria	5020
53	AKH Wien / MedUniWien Universtatsklinik fur Innere Medizin 1	Wien		Austria	1090
54	ZNA Middleheim Lindendreef 1	Antwerpen		Belgium	2020
55	ZNA Stuivenberg, Lange Beeldekensstraat 267	Antwerpen		Belgium
56	AZ St.-Jan Brugge-Oostende AV	Brugge		Belgium	8000
57	Cliniques Universitaires Saint Luc	Brussels		Belgium	1200
58	UZ Leuven, campus Gasthuisberg, Department of Haematology	Leuven		Belgium	B 3000
59	H.-Hartziekenhuis Roeselare - Menen vzw	Roeselare		Belgium	8800
60	Division of Hematology, Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
61	Saint John Regional Hospital	Saint John	New Brunswick	Canada	E2L 4L2
62	Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 2Y9
63	University Health Network, Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
64	Charles LeMoyne Hospital	Greenfield Park	Quebec	Canada	J4V 2H1
65	Fakultni nemocnice Kralovske Vinohrady, Oddeleni klinicke hematologie	Praha	Srobarova	Czechia	100 34 Praha 10
66	Fakultni nemocnice Brno, Interni hematoonkologicka klinika	Brno		Czechia	625 00
67	Fakultni nemocnice Hradec Kralove, 2. Interni klinika-oddeleni klinicke hematologie	Hradec Kralove		Czechia	500 05
68	CHU Lille, Service des maladies du sang, Hopital Huriez	Lille	Lille Cedex	France	59037
69	CHU Angers, Service des maladies du sang	Angers Cedex 01		France	49033
70	Hopital Avicenne- Departement Onco-hematologie	Bobigny		France	93000
71	Hopital Mignot	Le Chesnay		France	78157
72	Institut Paoli Calmettes	Marseille		France	13009
73	CHU Nantes Hotel Dieu, Service d'hematologie clinique	Nantes		France	44093
74	CHU de Bordeaux- Hopital Haut-Leveque, Centre Francois Magendle	Pessac		France	33604
75	Centre Hospitalier Lyon Sud - Service d'Hematologie - Pavillon Marcel Berard - Bat. 1G - 1er etage, 165 Chemin du grand Revoyet	Pierre Benite		France	69495
76	Service d'hematologie- Hopital Purpan- CHU de Toulouse	Toulouse		France	31059
77	St. Johannes-Hospital	Duisburg		Germany	47166
78	Klinikum Frankfurt am Main-Hochst, Department of Hematology and Oncology, Klinikum Frankfurt Academic Hospital of the University of Frankfurt	Frankfurt		Germany	65929
79	Universitatsklinikum Hamburg-Eppendorf; ll. Medizinische Klinik und Poliklinik; Onkologie, Hamatologie und Knochenmarktransplantation	Hamburg		Germany	20246
80	Medizinische Hochschule Hannover, Abteilung Hamatologie	Hannover		Germany	30625
81	SLK-Kliniken Heilbronn GmbH, Medizinische Klinik	Heilbronn		Germany	74078
82	Staedtisches Krankenhaus Kiel GmbH, Infektionsambulanz der 2. Medizinischen Klinik	Kiel		Germany	24116
83	Klinikum St. Georg gGmbH; Klinik fur Internistische Onkologie/Hamatologie	Leipzig		Germany	04129
84	University Hospital of Muenster	Muenster		Germany	48149
85	Klinikum rechts der Isar der Technischen Universitat Munchen lll, Medizinische Klinik	Munich		Germany	81675
86	University of Debrecen Medical and Health Sciences Center	Debrecen		Hungary	H-4030
87	Petz Aladar County Hospital	Gyor		Hungary	H-9024
88	kaposi Mor Oktato Korhaz Belgyogyaszati Osztaly	Kaposvar		Hungary	H-7400
89	Szegedi Tudomanyegyetem, 11. Belgyogyaszati Klinika	Szeged		Hungary	H-6720
90	Ospedale "A. Perrino", U.O. Compessa di Ematologia	Brindisi		Italy	72100
91	Azienda Ospedaliero-Universitaria Sant'Anna, Sezione di Ematologia, Dipartmento di Science Biomediche e Terapie Avanzate	Ferrara		Italy	44121
92	Ospedaliera Universitaria San Martino di Genova	Genova		Italy	16132
93	Ospedale "Vito Fazzi", U.O Ematologia	Lecce		Italy	73100
94	AORN "A. Cardarelli", U.O.S.C. Ematologia con TMO	Napoli		Italy	80131
95	Azienda Ospedaliero-Universitaria Maggiore Della Carita, Struttura Complessa Direzione Universitaria Ematologia	Novara		Italy	28100
96	Fondazione IRCCS, Policlinico S. Matteo - Dipartimento di Ematologia	Pavia		Italy	27100
97	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
98	Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine	Seoul		Korea, Republic of	135-710
99	Seoul St. Mary's Hospital	Seoul		Korea, Republic of	137-701
100	Dept. of Hematology, Asan Medical Center	Seoul		Korea, Republic of	138-736
101	Haematology Research, Auckland District Health Board, Auckland City Hospital	Grafton	Auckland	New Zealand	1023
102	Canterbury Health Laboratories	Christchurch		New Zealand	8011
103	Department of Haematology, Waikato Hospital	Hamilton		New Zealand	3240
104	Regional Cancer Treatment Service, Palmerston North Hospital	Palmerston North		New Zealand	4414
105	Uniwersyteckle Centrum Kliniczne	Gdansk		Poland	80-952
106	Klinika Hematologii i Chorob Rozrostowych Ukladu Krwiotworczego, Szpital Kliniczny Przemiemienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu	Poznan		Poland	60-569
107	Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw		Poland	50-369
108	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain	08025
109	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
110	Hospital Universitari Germans Trias i Pujol	Barcelona		Spain	08916
111	Hospital del Mar	Barcelona		Spain
112	Centro Oncologico MD Anderson International Espana	Madrid		Spain	28033
113	Hospital Universitario La Paz	Madrid		Spain	28046
114	Hospital Sont Llatzer	Palma de Mallorca		Spain	07198
115	Hospital Universitario de Salamanca	Salamanca		Spain	37007
116	Hospital Universitari Politecnic la Fe Hematology Department	Valencia		Spain	46026
117	Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Foundation Trust	Blackpool		United Kingdom	FY3 8NR
118	Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital	Cambridge		United Kingdom	CB2 0QQ
119	Department of Haematology, University Hospital of Wales	Cardiff		United Kingdom	CF14 4XW
120	Queen's Centre for Oncology and Hematology, Castle Hill Hospital	Cottingham		United Kingdom	GY16 5JQ
121	Leicester Royal Infirmary, University Hospitals of Leicester, NHS Trust	Leicester		United Kingdom	LE1 5WW
122	Department of Haematology, Royal Liverpool University Hospital	Liverpool		United Kingdom	L7 8XP
123	Department of Haematology, Guy's Hospital	London		United Kingdom	SE1 9RT
124	Central Manchester University Hospitals NHS Trust, Manchester Royal Infirmary	Manchester		United Kingdom	M13 9WL

Sponsors and Collaborators

• Sunesis Pharmaceuticals

Investigators

• Study Director: Linda Neuman, MD, Sunesis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sunesis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01191801
• Other Study ID Numbers: VOS-AML-301; 2010-021961-61
• First Posted: Aug 31, 2010
• Last Update Posted: Aug 22, 2018
• Last Verified: Mar 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Sunesis Pharmaceuticals: Leukemia; Acute Myeloid Leukemia; Hematologic; Hematologic diseases; Blood; Cancer; Malignancy; Vosaroxin; Cytarabine; First Relapsed AML; Refractory AML; VALOR; Sunesis; Voreloxin; SNS-595
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine

Study Results

Participant Flow

Recruitment Details	320 patients enrolled in 30 US sites:391 patients enrolled at 71 sites outside of the US (Canada, Europe, Australia, New Zealand, and Republic of Korea)
Pre-assignment Detail	Six patients were randomized but never received treatment due to death prior to beginning treatment: 4 assigned to receive vosaroxin/cytarabine; 2 assigned to receive placebo/cytarabine.

Arm/Group Title	Group A (Vosaroxin/Cytarabine)	Group B (Placebo/Cytarabine)
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5	Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5
Period Title: Overall Study
STARTED	356	355
COMPLETED	40	18
NOT COMPLETED	316	337

Baseline Characteristics

Arm/Group Title	Group A (Vosaroxin/Cytarabine)	Group B (Placebo/Cytarabine)	Total
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5	Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5	Total of all reporting groups
Overall Participants	356	355	711
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (11.51)	60.2 (12.49)	60.6 (12.01)
Sex: Female, Male (Count of Participants)
Female	154 43.3%	163 45.9%	317 44.6%
Male	202 56.7%	192 54.1%	394 55.4%
Region of Enrollment (participants) [Number]
Hungary	8 2.2%	11 3.1%	19 2.7%
United States	161 45.2%	159 44.8%	320 45%
United Kingdom	15 4.2%	10 2.8%	25 3.5%
Spain	9 2.5%	8 2.3%	17 2.4%
New Zealand	4 1.1%	3 0.8%	7 1%
Canada	10 2.8%	10 2.8%	20 2.8%
Czech Republic	5 1.4%	6 1.7%	11 1.5%
Austria	4 1.1%	4 1.1%	8 1.1%
Belgium	17 4.8%	19 5.4%	36 5.1%
Poland	3 0.8%	1 0.3%	4 0.6%
Korea, Republic of	10 2.8%	5 1.4%	15 2.1%
Italy	20 5.6%	18 5.1%	38 5.3%
Australia	25 7%	20 5.6%	45 6.3%
France	38 10.7%	50 14.1%	88 12.4%
Germany	27 7.6%	31 8.7%	58 8.2%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Vosaroxin + cytarabine patient survival versus placebo + cytarabine patient survival
Time Frame	Up to 5 years or duration of study

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population which consists of all patients enrolled (randomly assigned to treatment group).

Arm/Group Title	Group A (Vosaroxin/Cytarabine)	Group B (Placebo/Cytarabine)
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5	Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5
Measure Participants	356	355
Median (95% Confidence Interval) [Months]	7.5	6.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A (Vosaroxin/Cytarabine), Group B (Placebo/Cytarabine)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0305
	Comments	Unstratified one sided P-Value
	Method	Unstratified Log Rank
	Comments	Since the sample size was increased, the primary analysis used the weighted statistic proposed by Cui, Hung, and Wang (Cui 1999).
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.87
	Confidence Interval	(1-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Complete Remission (CR) Rate Based on Modified International Working Group (IWG) Criteria.
Description	Group A (Vosaroxin + cytarabine) patient CR as compared to Group B (placebo + cytarabine) patient CR. Complete remission (CR) is typically defined using IWG criteria as bone marrow blast count of less than 5% with adequate recovery of peripheral blood counts.
Time Frame	Up to 5 years or duration of study

Outcome Measure Data

Analysis Population Description

The percentage of patients who achieved CR was adjudicated by the CPARR (Central Pathology and Response Review) panel using modified IWG response criteria. The outcome measure reflects the Intent to Treat Population.

Arm/Group Title	Group A (Vosaroxin/Cytarabine)	Group B (Placebo/Cytarabine)
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5	Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5
Measure Participants	356	355
Number (95% Confidence Interval) [percentage of particpants]	30.1	16.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A (Vosaroxin/Cytarabine), Group B (Placebo/Cytarabine)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Two sided P-Value
	Method	Chi-squared
	Comments

3. Secondary Outcome

Title	All Cause Mortality
Description	Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality
Time Frame	30 Days

Outcome Measure Data

Analysis Population Description

Safety Population (705)

Arm/Group Title	Group A (Vosaroxin/Cytarabine)	Group B (Placebo/Cytarabine)
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5	Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5
Measure Participants	355	350
Number (95% Confidence Interval) [percentage of Participants in the Group]	7.9 2.2%	6.6 1.9%

4. Secondary Outcome

Title	All Cause Mortality
Description	Vosaroxin + cytarabine mortality versus placebo + cytarabine mortality
Time Frame	60 Days

Outcome Measure Data

Analysis Population Description

Safety Population (705)

Arm/Group Title	Group A (Vosaroxin/Cytarabine)	Group B (Placebo/Cytarabine)
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5	Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5
Measure Participants	355	350
Number (95% Confidence Interval) [percentage of Participants]	19.7 5.5%	19.4 5.5%

5. Other Pre-specified Outcome

Title	Overall Remission (OR) Rate Based on the IWG Response Criteria
Description	Group A patient OR compared to Group B patient OR Overall Remission includes Complete Remission (CR), Complete Remission with incomplete platelet recovery (CRp), Complete Remission with incomplete blood count recovery (CRi), and Partial Remission (PR). Complete remission means bone marrow blast count of less than 5% with adequate recovery of peripheral blood counts as typically defined by the IWG. Both CRi and CRp refer complete remission but with incomplete blood count and platelet recovery, respectively. PR, or partial remission, refers to remission in which bone marrow contains blast counts between 5 and 25 percent.
Time Frame	Up to 5 years or the duration of the study

Outcome Measure Data

Analysis Population Description

Intent to Treat Population

Arm/Group Title	Group A (Vosaroxin/Cytarabine)	Group B (Placebo/Cytarabine)
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5	Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5
Measure Participants	356	355
Number (95% Confidence Interval) [percentage of participants]	37.9 10.6%	18.9 5.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A (Vosaroxin/Cytarabine), Group B (Placebo/Cytarabine)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Two sided P-Value
	Method	Chi-squared
	Comments

6. Other Pre-specified Outcome

Title	Event Free Survival (EFS)
Time Frame	Up to 5 years or duration of study

Outcome Measure Data

Analysis Population Description

Intent to Treat Population

Arm/Group Title	Group A (Vosaroxin/Cytarabine)	Group B (Placebo/Cytarabine)
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5	Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5
Measure Participants	356	355
Median (95% Confidence Interval) [months]	1.9	1.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A (Vosaroxin/Cytarabine), Group B (Placebo/Cytarabine)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unstratified one-sided P-Value
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(1-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Other Pre-specified Outcome

Title	Leukemia-Free Survival (LFS)
Description	Durability of remission (CR) assessed by LFS
Time Frame	Up to 5 years or the duration of the study

Outcome Measure Data

Analysis Population Description

Subset of Intent to Treat patients that have a Measured CR

Arm/Group Title	Group A (Vosaroxin/Cytarabine)	Group B (Placebo/Cytarabine)
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5	Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5
Measure Participants	107	58
Median (95% Confidence Interval) [Months]	11	8.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A (Vosaroxin/Cytarabine), Group B (Placebo/Cytarabine)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3134
	Comments	One sided P-Value
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse Event reported below reflects time from first patient randomization 17 December 2010 to database lock for primary analysis 26 September 2014. The Tables show Incidence of Treatment Emergent Adverse Events.
Arm/Group Title	Group A (Vosaroxin/Cytarabine)		Group B (Placebo/Cytarabine)
Arm/Group Description	Vosaroxin on Days 1 and 4 (90 mg/m2 induction 1; 70 mg/m2 all other cycles); cytarabine 1 g/m2 daily on Days 1 through 5		Placebo (volume matched to vosaroxin) on Days 1 and 4; cytarabine 1 g/m2 daily on Days 1 through 5
All Cause Mortality
	Group A (Vosaroxin/Cytarabine)		Group B (Placebo/Cytarabine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	273/355 (76.9%)		288/350 (82.3%)
Serious Adverse Events
	Group A (Vosaroxin/Cytarabine)		Group B (Placebo/Cytarabine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	197/355 (55.5%)		125/350 (35.7%)
Blood and lymphatic system disorders
Anaemia	0/355 (0%)		2/350 (0.6%)
Disseminated intravascular coagulation	1/355 (0.3%)		0/350 (0%)
Febrile neutropenia	40/355 (11.3%)		26/350 (7.4%)
Neutropenia	0/355 (0%)		1/350 (0.3%)
Pancytopenia	2/355 (0.6%)		0/350 (0%)
Pure white cell aplasia	1/355 (0.3%)		0/350 (0%)
Thrombocytopenia	1/355 (0.3%)		1/350 (0.3%)
Cardiac disorders
Atrial fibrillation	2/355 (0.6%)		1/350 (0.3%)
Atrial flutter	1/355 (0.3%)		1/350 (0.3%)
Cardiac failure congestive	0/355 (0%)		1/350 (0.3%)
Cardiomyopathy	0/355 (0%)		1/350 (0.3%)
Diastolic dysfunction	1/355 (0.3%)		0/350 (0%)
Left ventricular dysfunction	1/355 (0.3%)		0/350 (0%)
Myocardial infarction	1/355 (0.3%)		0/350 (0%)
Myocardial ischaemia	1/355 (0.3%)		0/350 (0%)
Myopericarditis	0/355 (0%)		1/350 (0.3%)
Tachycardia	0/355 (0%)		1/350 (0.3%)
Endocrine disorders
Diabetes insipidus	1/355 (0.3%)		0/350 (0%)
Eye disorders
Conjunctivitis	0/355 (0%)		1/350 (0.3%)
Vitreous haemorrhage	1/355 (0.3%)		0/350 (0%)
Gastrointestinal disorders
Anal fistula	1/355 (0.3%)		0/350 (0%)
Caecitis	1/355 (0.3%)		0/350 (0%)
Colitis	5/355 (1.4%)		0/350 (0%)
Diarrhoea	1/355 (0.3%)		1/350 (0.3%)
Enteritis	2/355 (0.6%)		0/350 (0%)
Enterocolitis	1/355 (0.3%)		0/350 (0%)
Gastric ulcer perforation	0/355 (0%)		1/350 (0.3%)
Gastritis	1/355 (0.3%)		0/350 (0%)
Gastrointestinal haemorrhage	2/355 (0.6%)		1/350 (0.3%)
Gastrointestinal inflammation	1/355 (0.3%)		0/350 (0%)
Haemorrhoidal haemorrhage	1/355 (0.3%)		1/350 (0.3%)
Haemorrhoids	0/355 (0%)		2/350 (0.6%)
Ileitis	0/355 (0%)		1/350 (0.3%)
Ileus	1/355 (0.3%)		1/350 (0.3%)
Nausea	1/355 (0.3%)		1/350 (0.3%)
Neutropenic colitis	1/355 (0.3%)		1/350 (0.3%)
Oesophagitis	3/355 (0.8%)		0/350 (0%)
Periodontitis	0/355 (0%)		1/350 (0.3%)
Stomatitis	12/355 (3.4%)		5/350 (1.4%)
General disorders
Asthenia	1/355 (0.3%)		0/350 (0%)
Infusion site extravasation	0/355 (0%)		1/350 (0.3%)
Medical device complication	0/355 (0%)		1/350 (0.3%)
Multi-organ failure	1/355 (0.3%)		0/350 (0%)
Non-cardiac chest pain	1/355 (0.3%)		0/350 (0%)
Pain	1/355 (0.3%)		0/350 (0%)
Pyrexia	3/355 (0.8%)		3/350 (0.9%)
Sudden death	1/355 (0.3%)		0/350 (0%)
Hepatobiliary disorders
Biliary colic	1/355 (0.3%)		0/350 (0%)
Cholecystitis	1/355 (0.3%)		0/350 (0%)
Cholestasis	1/355 (0.3%)		1/350 (0.3%)
Cytolytic hepatitis	1/355 (0.3%)		2/350 (0.6%)
Hepatic function abnormal	1/355 (0.3%)		0/350 (0%)
Infections and infestations
Abscess neck	0/355 (0%)		1/350 (0.3%)
Anal abscess	1/355 (0.3%)		2/350 (0.6%)
Anorectal cellulitis	1/355 (0.3%)		0/350 (0%)
Appendicitis perforated	0/355 (0%)		1/350 (0.3%)
Aspergilloma	1/355 (0.3%)		0/350 (0%)
Aspergillosis	2/355 (0.6%)		1/350 (0.3%)
Bacteraemia	30/355 (8.5%)		10/350 (2.9%)
Bronchiolitis	1/355 (0.3%)		0/350 (0%)
Bronchopneumonia	1/355 (0.3%)		1/350 (0.3%)
Bronchopulmonary aspergillosis	2/355 (0.6%)		1/350 (0.3%)
Cellulitis	4/355 (1.1%)		1/350 (0.3%)
Clostridial infection	1/355 (0.3%)		1/350 (0.3%)
Clostridium difficile colitis	0/355 (0%)		1/350 (0.3%)
Device related infection	1/355 (0.3%)		0/350 (0%)
Device related sepsis	0/355 (0%)		1/350 (0.3%)
Diverticulitis	0/355 (0%)		1/350 (0.3%)
Enterobacter infection	1/355 (0.3%)		0/350 (0%)
Enterobacter sepsis	1/355 (0.3%)		0/350 (0%)
Enterococcal infection	1/355 (0.3%)		0/350 (0%)
Enterococcal sepsis	2/355 (0.6%)		0/350 (0%)
Enterocolitis bacterial	1/355 (0.3%)		0/350 (0%)
Enterocolitis infectious	1/355 (0.3%)		0/350 (0%)
Escherichia bacteraemia	1/355 (0.3%)		1/350 (0.3%)
Escherichia sepsis	1/355 (0.3%)		1/350 (0.3%)
Folliculitis	0/355 (0%)		1/350 (0.3%)
Fungaemia	1/355 (0.3%)		0/350 (0%)
Fungal infection	2/355 (0.6%)		2/350 (0.6%)
Fungal sepsis	1/355 (0.3%)		0/350 (0%)
Gastroenteritis	1/355 (0.3%)		0/350 (0%)
Gastrointestinal infection	1/355 (0.3%)		0/350 (0%)
Infection	1/355 (0.3%)		0/350 (0%)
Infusion site cellulitis	1/355 (0.3%)		0/350 (0%)
Klebsiella bacteraemia	0/355 (0%)		1/350 (0.3%)
Klebsiella infection	1/355 (0.3%)		0/350 (0%)
Klebsiella sepsis	1/355 (0.3%)		1/350 (0.3%)
Localised infection	0/355 (0%)		1/350 (0.3%)
Lower respiratory tract infection	0/355 (0%)		1/350 (0.3%)
Neutropenic sepsis	9/355 (2.5%)		7/350 (2%)
Perirectal abscess	3/355 (0.8%)		0/350 (0%)
Pharyngitis	0/355 (0%)		1/350 (0.3%)
Pneumonia	27/355 (7.6%)		17/350 (4.9%)
Pneumonia fungal	7/355 (2%)		2/350 (0.6%)
Pneumonia staphylococcal	1/355 (0.3%)		0/350 (0%)
Pseudomonal sepsis	1/355 (0.3%)		1/350 (0.3%)
Pseudomonas infection	1/355 (0.3%)		2/350 (0.6%)
Pulmonary mycosis	1/355 (0.3%)		0/350 (0%)
Pulmonary sepsis	2/355 (0.6%)		0/350 (0%)
Pulmonary tuberculosis	1/355 (0.3%)		0/350 (0%)
Respiratory syncytial virus infection	0/355 (0%)		1/350 (0.3%)
Sepsis	31/355 (8.7%)		15/350 (4.3%)
Septic embolus	1/355 (0.3%)		0/350 (0%)
Septic shock	7/355 (2%)		6/350 (1.7%)
Sinusitis	0/355 (0%)		1/350 (0.3%)
Sinusitis aspergillus	0/355 (0%)		1/350 (0.3%)
Sinusitis fungal	1/355 (0.3%)		0/350 (0%)
Staphylococcal bacteraemia	1/355 (0.3%)		2/350 (0.6%)
Staphylococcal infection	4/355 (1.1%)		1/350 (0.3%)
Streptococcal bacteraemia	3/355 (0.8%)		0/350 (0%)
Systemic candida	1/355 (0.3%)		2/350 (0.6%)
Thrombophlebitis septic	1/355 (0.3%)		0/350 (0%)
Tooth abscess	0/355 (0%)		4/350 (1.1%)
Urinary tract infection	0/355 (0%)		4/350 (1.1%)
Urinary tract infection enterococcal	1/355 (0.3%)		1/350 (0.3%)
Urosepsis	1/355 (0.3%)		0/350 (0%)
Viral pericarditis	1/355 (0.3%)		0/350 (0%)
Vulval abscess	1/355 (0.3%)		0/350 (0%)
Vulval cellulitis	0/355 (0%)		1/350 (0.3%)
Vulvovaginitis	1/355 (0.3%)		0/350 (0%)
Injury, poisoning and procedural complications
Fall	1/355 (0.3%)		1/350 (0.3%)
Febrile nonhaemolytic transfusion reaction	1/355 (0.3%)		0/350 (0%)
Foot fracture	1/355 (0.3%)		0/350 (0%)
Subdural haematoma	0/355 (0%)		2/350 (0.6%)
Transfusion reaction	1/355 (0.3%)		0/350 (0%)
Investigations
Blood pressure increased	1/355 (0.3%)		0/350 (0%)
Hepatic enzyme increased	1/355 (0.3%)		0/350 (0%)
Lipase increased	1/355 (0.3%)		0/350 (0%)
Transaminases increased	0/355 (0%)		1/350 (0.3%)
Metabolism and nutrition disorders
Dehydration	2/355 (0.6%)		0/350 (0%)
Diabetic ketoacidosis	0/355 (0%)		1/350 (0.3%)
Failure to thrive	1/355 (0.3%)		1/350 (0.3%)
Hypernatraemia	1/355 (0.3%)		0/350 (0%)
Hyponatraemia	0/355 (0%)		1/350 (0.3%)
Nervous system disorders
Coma	1/355 (0.3%)		0/350 (0%)
Haemorrhage intracranial	0/355 (0%)		1/350 (0.3%)
Headache	0/355 (0%)		1/350 (0.3%)
Intracranial pressure increased	1/355 (0.3%)		0/350 (0%)
Ischaemic cerebral infarction	0/355 (0%)		1/350 (0.3%)
Ischaemic stroke	0/355 (0%)		2/350 (0.6%)
Neurotoxicity	0/355 (0%)		1/350 (0.3%)
Presyncope	2/355 (0.6%)		0/350 (0%)
Subarachnoid haemorrhage	1/355 (0.3%)		0/350 (0%)
Psychiatric disorders
Confusional state	0/355 (0%)		2/350 (0.6%)
Renal and urinary disorders
Acute prerenal failure	1/355 (0.3%)		0/350 (0%)
Haematuria	1/355 (0.3%)		0/350 (0%)
Nephrolithiasis	1/355 (0.3%)		0/350 (0%)
Renal failure	1/355 (0.3%)		0/350 (0%)
Renal failure acute	1/355 (0.3%)		0/350 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/355 (0%)		1/350 (0.3%)
Epistaxis	0/355 (0%)		4/350 (1.1%)
Haemothorax	1/355 (0.3%)		1/350 (0.3%)
Lung disorder	1/355 (0.3%)		0/350 (0%)
Lung infiltration	0/355 (0%)		1/350 (0.3%)
Pleural effusion	1/355 (0.3%)		0/350 (0%)
Pneumonitis	2/355 (0.6%)		0/350 (0%)
Pneumothorax	1/355 (0.3%)		0/350 (0%)
Pulmonary haemorrhage	2/355 (0.6%)		0/350 (0%)
Pulmonary oedema	1/355 (0.3%)		0/350 (0%)
Respiratory failure	2/355 (0.6%)		0/350 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/355 (0.3%)		0/350 (0%)
Skin nodule	0/355 (0%)		1/350 (0.3%)
Vascular disorders
Deep vein thrombosis	0/355 (0%)		1/350 (0.3%)
Embolism arterial	1/355 (0.3%)		0/350 (0%)
Hypotension	1/355 (0.3%)		0/350 (0%)
Hypovolaemic shock	1/355 (0.3%)		0/350 (0%)
Shock	2/355 (0.6%)		0/350 (0%)
Vena cava thrombosis	1/355 (0.3%)		0/350 (0%)
Venous thrombosis	0/355 (0%)		1/350 (0.3%)
Other (Not Including Serious) Adverse Events
	Group A (Vosaroxin/Cytarabine)		Group B (Placebo/Cytarabine)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	354/355 (99.7%)		349/350 (99.7%)
Blood and lymphatic system disorders
Anaemia	95/355 (26.8%)		104/350 (29.7%)
Febrile neutropenia	143/355 (40.3%)		97/350 (27.7%)
Neutropenia	70/355 (19.7%)		50/350 (14.3%)
Thrombocytopenia	88/355 (24.8%)		90/350 (25.7%)
Cardiac disorders
Atrial fibrillation	22/355 (6.2%)		16/350 (4.6%)
Tachycardia	32/355 (9%)		29/350 (8.3%)
Gastrointestinal disorders
Abdominal distension	20/355 (5.6%)		10/350 (2.9%)
Abdominal pain	79/355 (22.3%)		46/350 (13.1%)
Abdominal pain upper	31/355 (8.7%)		33/350 (9.4%)
Constipation	136/355 (38.3%)		141/350 (40.3%)
Diarrhoea	243/355 (68.5%)		121/350 (34.6%)
Dry mouth	22/355 (6.2%)		12/350 (3.4%)
Dyspepsia	46/355 (13%)		17/350 (4.9%)
Dysphagia	20/355 (5.6%)		7/350 (2%)
Haemorrhoids	30/355 (8.5%)		14/350 (4%)
Nausea	218/355 (61.4%)		167/350 (47.7%)
Oral pain	21/355 (5.9%)		6/350 (1.7%)
Stomatitis	169/355 (47.6%)		64/350 (18.3%)
Vomiting	135/355 (38%)		73/350 (20.9%)
General disorders
Asthenia	60/355 (16.9%)		43/350 (12.3%)
Chest pain	29/355 (8.2%)		19/350 (5.4%)
Chills	61/355 (17.2%)		46/350 (13.1%)
Fatigue	107/355 (30.1%)		94/350 (26.9%)
Oedema peripheral	96/355 (27%)		69/350 (19.7%)
Pain	21/355 (5.9%)		32/350 (9.1%)
Pyrexia	118/355 (33.2%)		106/350 (30.3%)
Infections and infestations
Bacteraemia	18/355 (5.1%)		6/350 (1.7%)
Oral candidiasis	18/355 (5.1%)		16/350 (4.6%)
Oral herpes	23/355 (6.5%)		4/350 (1.1%)
Pneumonia	22/355 (6.2%)		19/350 (5.4%)
Injury, poisoning and procedural complications
Procedural pain	8/355 (2.3%)		20/350 (5.7%)
Transfusion reaction	18/355 (5.1%)		16/350 (4.6%)
Investigations
Alanine aminotransferase increased	29/355 (8.2%)		17/350 (4.9%)
Aspartate aminotransferase increased	24/355 (6.8%)		16/350 (4.6%)
Blood creatinine increased	18/355 (5.1%)		10/350 (2.9%)
Platelet count decreased	23/355 (6.5%)		29/350 (8.3%)
White blood cell count decreased	24/355 (6.8%)		21/350 (6%)
Metabolism and nutrition disorders
Decreased appetite	126/355 (35.5%)		59/350 (16.9%)
Fluid overload	18/355 (5.1%)		16/350 (4.6%)
Fluid retention	19/355 (5.4%)		23/350 (6.6%)
Hyperglycaemia	43/355 (12.1%)		33/350 (9.4%)
Hypoalbuminaemia	30/355 (8.5%)		20/350 (5.7%)
Hypocalcaemia	49/355 (13.8%)		25/350 (7.1%)
Hypokalaemia	170/355 (47.9%)		102/350 (29.1%)
Hypomagnesaemia	95/355 (26.8%)		58/350 (16.6%)
Hyponatraemia	31/355 (8.7%)		20/350 (5.7%)
Hypophosphataemia	56/355 (15.8%)		26/350 (7.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	24/355 (6.8%)		27/350 (7.7%)
Back pain	35/355 (9.9%)		38/350 (10.9%)
Bone pain	21/355 (5.9%)		18/350 (5.1%)
Musculoskeletal pain	16/355 (4.5%)		22/350 (6.3%)
Pain in extremity	34/355 (9.6%)		44/350 (12.6%)
Nervous system disorders
Dizziness	32/355 (9%)		35/350 (10%)
Dysgeusia	25/355 (7%)		7/350 (2%)
Headache	103/355 (29%)		93/350 (26.6%)
Psychiatric disorders
Anxiety	43/355 (12.1%)		56/350 (16%)
Confusional state	25/355 (7%)		19/350 (5.4%)
Depression	30/355 (8.5%)		22/350 (6.3%)
Insomnia	78/355 (22%)		70/350 (20%)
Respiratory, thoracic and mediastinal disorders
Cough	71/355 (20%)		44/350 (12.6%)
Dyspnoea	63/355 (17.7%)		44/350 (12.6%)
Epistaxis	56/355 (15.8%)		55/350 (15.7%)
Hiccups	23/355 (6.5%)		8/350 (2.3%)
Oropharyngeal pain	46/355 (13%)		41/350 (11.7%)
Pleural effusion	26/355 (7.3%)		12/350 (3.4%)
Skin and subcutaneous tissue disorders
Alopecia	28/355 (7.9%)		9/350 (2.6%)
Erythema	25/355 (7%)		16/350 (4.6%)
Petechiae	27/355 (7.6%)		23/350 (6.6%)
Pruritus	41/355 (11.5%)		28/350 (8%)
Rash	53/355 (14.9%)		37/350 (10.6%)
Rash maculo-papular	21/355 (5.9%)		10/350 (2.9%)
Vascular disorders
Hypertension	40/355 (11.3%)		32/350 (9.1%)
Hypotension	66/355 (18.6%)		50/350 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.