A Multiple Myeloma Trial in Patients With Bone Metastases

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00104104
• Collaborator: (none)
• Enrollment: 179
• Locations: 68
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this trial is to study the safety of treating patients with multiple myeloma and at least one bone lesion with zoledronic acid 4mg intravenously (IV) every 3 - 4 weeks for 2 years. Patients will receive a zoledronic acid infusion for 15 minutes or 30 minutes.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: zoledronic acid	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 179 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter,Open Label, Randomized Trial Evaluating the Duration of Infusion of Zoledronic Acid 4 mg IV in Multiple Myeloma Patients With Bone Metastases
• Study Start Date: Oct 1, 2004
• Actual Primary Completion Date: Oct 1, 2007
• Actual Study Completion Date: Oct 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 15 Minute Infusion Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks	Drug: zoledronic acid; 4 mg zoledronic acid in 250 mL of calcium-free solution (i.e., 0.9% sodium chloride or 5% glucose) administered intravenously.; Other Names: ZOMETA®
Experimental: 30 Minute Infusion Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.	Drug: zoledronic acid; 4 mg zoledronic acid in 250 mL of calcium-free solution (i.e., 0.9% sodium chloride or 5% glucose) administered intravenously.; Other Names: ZOMETA®

Outcome Measures

Primary Outcome Measures

1. The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months [Baseline and 12 Months]

   The primary renal safety endpoint was the number of participants with a clinically relevant increase in serum creatinine at 12 months. Serum creatinine was determined prior to each zoledronic acid infusion for all Participants and was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value.

2. The Number of Participants With Disease Progression [24 Months]

Secondary Outcome Measures

1. The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months [Baseline and 24 Months]

   Serum Creatinine was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value.

2. Time to First Significant Increase in Serum Creatinine [Up to 24 months]

   Median time to event in participants who had a clinically relevant increase in serum creatinine.

3. Zoledronic Acid Concentrations [24 months]

   Samples for drug concentration analysis were drawn at 10 and 15 minutes into the infusion for participants in the 15-minute infusion group and at 25 and 30 minutes into the infusion for patients in the 30-minute infusion group. The mean and median zoledronic acid concentrations were greater in the 15-minute group than in the 30-minute group at both sampling timepoints.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients 18 years of age or older

• Confirmed diagnosis of Multiple Myeloma

• Stable renal function defined as two serum creatinine determinations of < 3 mg/dL

• Calculated creatinine clearance of greater than or equal to 30 mL/min

• ECOG Performance Status of 0 or 1

• Life expectancy of greater than or equal to 9 months

• If the patient is of child-bearing potential, a negative pregnancy test is required at screening, while postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.

• Ability to comply with trial requirements and give informed consent.

Exclusion Criteria:

• IV Bisphosphonate therapy for more than 3 years.

• Patients with a diagnosis of amyloidosis.

• Known hypersensitivity to zoledronic acid or other bisphosphonates

• Pregnant patients or lactating patients.

• Women of childbearing potential not on a medically recognized form of contraception

• Patients with uncontrolled cardiovascular disease, hypertension, and Type 2 diabetes mellitus.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hematology Oncology Specialists	Huntsville	Alabama	United States	35801
2	Palo Verde Hematology Oncology	Glendale	Arizona	United States	85304
3	US Oncology	Tucson	Arizona	United States	85710
4	Myeloma Institute For Research Therapy	Little Rock	Arkansas	United States	72205
5	University of Arkansas	Little Rock	Arkansas	United States	72205
6	Pacific Cancer Medical Center	Anaheim	California	United States	92801
7	Comprehensive Blood and Cancer Center	Bakersfield	California	United States	93309
8	Southbay Oncology Hematology Partners	Campbell	California	United States	95008
9	Bay Area Cancer Research Group	Concord	California	United States	94520
10	California Oncology of the Central Valley	Fresno	California	United States	93710
11	Dr. Robert P. Brouillard Inc.	LaJolla	California	United States	92037
12	Antelope Valley Cancer Center	Lancaster	California	United States	93534
13	Pacific Shores Medical Group	Long Beach	California	United States	90813
14	North Valley H/O	Mission Hills	California	United States	91345
15	Hematology/Oncology Group of Orange County	Orange	California	United States	92868
16	Desert Hematology Oncology Medical Group	Rancho Mirage	California	United States	92270
17	Camino Medical Group	Sunnyvale	California	United States	94086
18	Oncotherapeutics	West Hollywood	California	United States	90069
19	Greeley Medical Center	Greeley	Colorado	United States	80631
20	Florida Cancer Specialists	Fort Meyers	Florida	United States	33901
21	South Florida Oncology Hematology	Hollywood	Florida	United States	33021
22	Osceola Cancer Center	Kissimmee	Florida	United States	34741
23	Miami Cancer Care	Miami	Florida	United States	33133
24	Pasco Hernado Oncology	New Port Richey	Florida	United States	34652
25	MetCare Oncology	Ormond Beach	Florida	United States	32174
26	Hematology Oncology Associates PA	Pensacola	Florida	United States	32501
27	Hem/Onc Associates of Central Brevard	Rockledge	Florida	United States	32955
28	Augusta Oncology Associates	Augusta	Georgia	United States	30901
29	Georgia Cancer Specialists	Tucker	Georgia	United States	30084
30	Cancer Care Center	New Albany	Indiana	United States	47150
31	Hutchinson Clinic, PA	Hutchinson	Kansas	United States	67502
32	Hematology and Oncology Specialists	New Orleans	Louisiana	United States	70115
33	Maine Center for Cancer Medicine - Blood Disorders	Scarborough	Maine	United States	04074
34	Center for Cancer and Blood Disorders	Bethesda	Maryland	United States	20817
35	Oncology Hematology Associates, PA	Clinton	Maryland	United States	20735
36	Maryland Oncology-Hematology PA	Columbia	Maryland	United States	21044
37	Hematology Oncology Associates of Ohio & Michigan	Lambertville	Michigan	United States	48144
38	Providence Cancer Center, Clinical Trials Dept	Southfield	Michigan	United States	48075
39	Kansas City Cancer Center	Kansas City	Missouri	United States	64131
40	St. Joseph Oncology, Inc.	St. Joseph	Missouri	United States	64507
41	The Center for Cancer Care and Research	St. Louis	Missouri	United States	63141
42	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
43	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89109
44	Nevada Cancer Center	Las Vegas	Nevada	United States	89128
45	Center for Cancer & Hematology Disease	Cherry Hill	New Jersey	United States	08003
46	Central Jersey Oncology Center	East Brunswick	New Jersey	United States	08816
47	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
48	CINJ at Cooper University Hospital	Voorhees	New Jersey	United States	08043
49	New Mexico Cancer Care Associates	Santa Fe	New Mexico	United States	87505
50	Hematology Oncology of Western Suffolk	Bay Shore	New York	United States	11706
51	New York Presbyterian Hospital	New York	New York	United States	10021
52	Syracuse Hematology/Oncology PC	Syracuse	New York	United States	13210
53	Dayton Oncology & Hematology, PA	Kettering	Ohio	United States	45409
54	University of Pennsylvania, Philadelphia	Philadelphia	Pennsylvania	United States	19104
55	Pennsylvania Oncology Associates	Philadelphia	Pennsylvania	United States	19106
56	Berks Oncology and Hematology Associates	West Reading	Pennsylvania	United States	19611
57	Hematology & Oncology Associates of RI	Cranston	Rhode Island	United States	02920
58	Roger Williams Hospital Medical Center	Providence	Rhode Island	United States	02908
59	Charleston Hematology Oncology	Charleston	South Carolina	United States	29403
60	Baptist Regional Cancer Center	Knoxville	Tennessee	United States	37920
61	Center for Oncology Research & Treatment, PA	Dallas	Texas	United States	75230
62	UT Southwestern Medical Center	Dallas	Texas	United States	75390-9179
63	Joe Arrington Cancer Research and Treatment Center	Lubbock	Texas	United States	79410
64	Utah Hematology Oncology	Ogden	Utah	United States	84403
65	Oncology Hematology Associates of Southwest VA	Salem	Virginia	United States	24153
66	Western Washington Oncology	Lacey	Washington	United States	98503
67	Swedish Cancer Institute	Seattle	Washington	United States	98104
68	Fox Valley Hematology Oncology SC	Appleton	Wisconsin	United States	54915

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Chair: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00104104
• Other Study ID Numbers: CZOL446EUS97; US97
• First Posted: Feb 23, 2005
• Last Update Posted: Jun 29, 2011
• Last Verified: Jun 1, 2011

• Keywords provided by , ,: Z-MAX, multiple myeloma, zoledronic acid, bone metastases
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasm Metastasis; Zoledronic Acid

Study Results

Participant Flow

Arm/Group Title	15 - Minute Infusion	30 - Minute Infusion
Arm/Group Description	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.
Period Title: Overall Study
STARTED	90	89
Safety Population (Including Site 74)	88	88
Safety Population (Excluding Site 74)	85	84
COMPLETED	15	17
NOT COMPLETED	75	72

Baseline Characteristics

Arm/Group Title	15 - Minute Infusion	30 - Minute Infusion	Total
Arm/Group Description	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.	Total of all reporting groups
Overall Participants	88	88	176
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	39 44.3%	47 53.4%	86 48.9%
>=65 years	49 55.7%	41 46.6%	90 51.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.3 (11.95)	64.0 (11.54)	64.1 (11.7)
Sex: Female, Male (Count of Participants)
Female	32 36.4%	39 44.3%	71 40.3%
Male	56 63.6%	49 55.7%	105 59.7%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	70 79.5%	69 78.4%	139 79%
Black	9 10.2%	13 14.8%	22 12.5%
Asian	1 1.1%	1 1.1%	2 1.1%
Other	8 9.1%	5 5.7%	13 7.4%
Region of Enrollment (participants) [Number]
United States	88 100%	88 100%	176 100%
Time since diagnosis (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	12.5 (24.3)	9.7 (14.1)	11.1 (19.8)
Calculated creatinine clearance (mL/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min]	87.3 (32.6)	89.3 (39.5)	88.3 (36.1)

Outcome Measures

1. Primary Outcome

Title	The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months
Description	The primary renal safety endpoint was the number of participants with a clinically relevant increase in serum creatinine at 12 months. Serum creatinine was determined prior to each zoledronic acid infusion for all Participants and was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value.
Time Frame	Baseline and 12 Months

Outcome Measure Data

Analysis Population Description

Safety Population: enrolled patients who received at least one dose of study medication, exluding site 74.

Arm/Group Title	15 - Minute Infusion	30 - Minute Infusion
Arm/Group Description	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.
Measure Participants	85	84
Number [Participants]	17 19.3%	13 14.8%

2. Secondary Outcome

Title	The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months
Description	Serum Creatinine was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value.
Time Frame	Baseline and 24 Months

Outcome Measure Data

Analysis Population Description

Safety Population; enrolled patients who received at least one dose of study medication.

Arm/Group Title	15 - Minute Infusion	30 - Minute Infusion
Arm/Group Description	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.
Measure Participants	85	84
Number [Participants]	24 27.3%	23 26.1%

3. Secondary Outcome

Title	Time to First Significant Increase in Serum Creatinine
Description	Median time to event in participants who had a clinically relevant increase in serum creatinine.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

Safety Population; enrolled patients who received at least one dose of study medication. The medians shown are only for patients who had a significant increase by 24 months.

Arm/Group Title	15 - Minute Infusion	30 - Minute Infusion
Arm/Group Description	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.
Measure Participants	24	23
Median (Full Range) [weeks]	21.6 (19.88)	24.4 (31.48)

4. Secondary Outcome

Title	Zoledronic Acid Concentrations
Description	Samples for drug concentration analysis were drawn at 10 and 15 minutes into the infusion for participants in the 15-minute infusion group and at 25 and 30 minutes into the infusion for patients in the 30-minute infusion group. The mean and median zoledronic acid concentrations were greater in the 15-minute group than in the 30-minute group at both sampling timepoints.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population was analyzed for zoledronic acid concentration. Participants were considered to be in the PK population if they had evaluable PK data.

Arm/Group Title	15 - Minute Infusion	30 - Minute Infusion
Arm/Group Description	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.
Measure Participants	70	63
First Collection (10 minutes, 25 minutes)	231.1 (185.4)	186.3 (54.4)
Second Collection (15 minutes, 30 minutes)	248.8 (92.0)	172.0 (48.3)

5. Primary Outcome

Title	The Number of Participants With Disease Progression
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

Safety Population; enrolled patients who received at least one dose of study medication.

Arm/Group Title	15 - Minute Infusion	30 - Minute Infusion
Arm/Group Description	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.
Measure Participants	85	84
Number [Participants]	28 31.8%	20 22.7%

Adverse Events

Adverse Event Reporting Description	Because of GCP violations at Site 74, post-baseline data from that site are excluded from analyses, leaving 85 patients in the 15-minute infusion group and 84 patients in the 30-minute infusion group.
Arm/Group Title	15 - Minute Infusion		30 - Minute Infusion
Arm/Group Description	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.		Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.
All Cause Mortality
	15 - Minute Infusion		30 - Minute Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	15 - Minute Infusion		30 - Minute Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/85 (35.3%)		35/84 (41.7%)
Blood and lymphatic system disorders
Anaemia	5/85 (5.9%)		2/84 (2.4%)
Febrile neutropenia	1/85 (1.2%)		4/84 (4.8%)
Leukocytosis	1/85 (1.2%)		0/84 (0%)
Leukopenia	0/85 (0%)		1/84 (1.2%)
Pancytopenia	0/85 (0%)		1/84 (1.2%)
Thrombocytopenia	0/85 (0%)		3/84 (3.6%)
Cardiac disorders
Arteriosclerosis coronary artery	1/85 (1.2%)		0/84 (0%)
Atrial fibrillation	3/85 (3.5%)		1/84 (1.2%)
Atrioventricular block first degree	1/85 (1.2%)		0/84 (0%)
Bradycardia	1/85 (1.2%)		0/84 (0%)
Cardiac arrest	1/85 (1.2%)		1/84 (1.2%)
Cardiac failure	0/85 (0%)		1/84 (1.2%)
Cardiac failure congestive	1/85 (1.2%)		1/84 (1.2%)
Cardio-respiratory arrest	1/85 (1.2%)		1/84 (1.2%)
Cardiomyopathy	1/85 (1.2%)		0/84 (0%)
Left ventricular hypertrophy	1/85 (1.2%)		0/84 (0%)
Mitral valve disease	1/85 (1.2%)		0/84 (0%)
Mitral valve stenosis	0/85 (0%)		1/84 (1.2%)
Myocardial infarction	0/85 (0%)		1/84 (1.2%)
Palpitations	1/85 (1.2%)		0/84 (0%)
Right atrial dilatation	1/85 (1.2%)		0/84 (0%)
Sinus arrhythmia	1/85 (1.2%)		0/84 (0%)
Sinus tachycardia	1/85 (1.2%)		0/84 (0%)
Subendocardial ischaemia	0/85 (0%)		1/84 (1.2%)
Tachycardia	1/85 (1.2%)		0/84 (0%)
Endocrine disorders
Adrenocortical insufficiency acute	1/85 (1.2%)		0/84 (0%)
Gastrointestinal disorders
Diarrhoea	3/85 (3.5%)		4/84 (4.8%)
Diverticular perforation	1/85 (1.2%)		0/84 (0%)
Dysphagia	1/85 (1.2%)		1/84 (1.2%)
Faecal incontinence	0/85 (0%)		1/84 (1.2%)
Gastric ulcer	1/85 (1.2%)		0/84 (0%)
Gastrointestinal haemorrhage	1/85 (1.2%)		0/84 (0%)
Nausea	2/85 (2.4%)		3/84 (3.6%)
Small intestinal obstruction	0/85 (0%)		1/84 (1.2%)
Vomiting	2/85 (2.4%)		3/84 (3.6%)
General disorders
Asthenia	4/85 (4.7%)		4/84 (4.8%)
Chest discomfort	2/85 (2.4%)		0/84 (0%)
Chest pain	1/85 (1.2%)		3/84 (3.6%)
Chills	0/85 (0%)		1/84 (1.2%)
Inflammation	1/85 (1.2%)		0/84 (0%)
Influenza like illness	1/85 (1.2%)		0/84 (0%)
Mucosal inflammation	1/85 (1.2%)		0/84 (0%)
Oedema peripheral	0/85 (0%)		2/84 (2.4%)
Pain	1/85 (1.2%)		3/84 (3.6%)
Pyrexia	2/85 (2.4%)		3/84 (3.6%)
Suprapubic pain	0/85 (0%)		1/84 (1.2%)
Hepatobiliary disorders
Hepatic failure	0/85 (0%)		1/84 (1.2%)
Jaundice cholestatic	0/85 (0%)		1/84 (1.2%)
Liver disorder	0/85 (0%)		1/84 (1.2%)
Immune system disorders
Anaphylactic reaction	0/85 (0%)		1/84 (1.2%)
Infections and infestations
Abdominal abscess	1/85 (1.2%)		0/84 (0%)
Appendicitis	0/85 (0%)		1/84 (1.2%)
Bacteraemia	0/85 (0%)		2/84 (2.4%)
Bronchitis	0/85 (0%)		1/84 (1.2%)
Cellulitis	0/85 (0%)		3/84 (3.6%)
Clostridium difficile colitis	1/85 (1.2%)		0/84 (0%)
Diverticulitis	0/85 (0%)		1/84 (1.2%)
Infection	0/85 (0%)		1/84 (1.2%)
Meningitis bacterial	0/85 (0%)		1/84 (1.2%)
Oral candidiasis	1/85 (1.2%)		0/84 (0%)
Pneumonia	7/85 (8.2%)		2/84 (2.4%)
Pneumonia bacterial	0/85 (0%)		1/84 (1.2%)
Sepsis	2/85 (2.4%)		2/84 (2.4%)
Septic shock	1/85 (1.2%)		0/84 (0%)
Staphylococcal sepsis	1/85 (1.2%)		0/84 (0%)
Urinary tract infection	1/85 (1.2%)		1/84 (1.2%)
Injury, poisoning and procedural complications
Compression fracture	0/85 (0%)		1/84 (1.2%)
Fall	0/85 (0%)		1/84 (1.2%)
Fractured sacrum	1/85 (1.2%)		0/84 (0%)
Ilium fracture	1/85 (1.2%)		0/84 (0%)
Spinal compression fracture	3/85 (3.5%)		2/84 (2.4%)
Investigations
Blood bilirubin increased	0/85 (0%)		1/84 (1.2%)
Blood calcium abnormal	1/85 (1.2%)		0/84 (0%)
Blood creatinine abnormal	1/85 (1.2%)		0/84 (0%)
Blood creatinine increased	0/85 (0%)		1/84 (1.2%)
Blood potassium abnormal	1/85 (1.2%)		0/84 (0%)
Blood pressure increased	1/85 (1.2%)		0/84 (0%)
Blood urea abnormal	1/85 (1.2%)		0/84 (0%)
Brain natriuretic peptide increased	1/85 (1.2%)		0/84 (0%)
Ejection fraction abnormal	1/85 (1.2%)		0/84 (0%)
Electrocardiogram ST segment elevation	1/85 (1.2%)		0/84 (0%)
Hepatic enzyme increased	1/85 (1.2%)		0/84 (0%)
Platelet count decreased	1/85 (1.2%)		0/84 (0%)
Metabolism and nutrition disorders
Acidosis	1/85 (1.2%)		0/84 (0%)
Decreased appetite	1/85 (1.2%)		1/84 (1.2%)
Dehydration	2/85 (2.4%)		6/84 (7.1%)
Diabetic ketoacidosis	1/85 (1.2%)		0/84 (0%)
Electrolyte imbalance	1/85 (1.2%)		0/84 (0%)
Hypercalcaemia	3/85 (3.5%)		0/84 (0%)
Hyperglycaemia	1/85 (1.2%)		0/84 (0%)
Hyperkalaemia	0/85 (0%)		1/84 (1.2%)
Hypocalcaemia	0/85 (0%)		1/84 (1.2%)
Hypoglycaemia	0/85 (0%)		1/84 (1.2%)
Hypokalaemia	4/85 (4.7%)		0/84 (0%)
Hyponatraemia	1/85 (1.2%)		0/84 (0%)
Hypovolaemia	2/85 (2.4%)		0/84 (0%)
Malnutrition	1/85 (1.2%)		0/84 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/85 (1.2%)		0/84 (0%)
Back pain	2/85 (2.4%)		4/84 (4.8%)
Groin pain	1/85 (1.2%)		0/84 (0%)
Muscular weakness	1/85 (1.2%)		1/84 (1.2%)
Musculoskeletal chest pain	1/85 (1.2%)		1/84 (1.2%)
Neck pain	1/85 (1.2%)		0/84 (0%)
Osteolysis	1/85 (1.2%)		1/84 (1.2%)
Osteonecrosis	1/85 (1.2%)		0/84 (0%)
Pain in extremity	1/85 (1.2%)		4/84 (4.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia	1/85 (1.2%)		0/84 (0%)
Pancreatic carcinoma	0/85 (0%)		1/84 (1.2%)
Nervous system disorders
Brain oedema	0/85 (0%)		1/84 (1.2%)
Carotid artery stenosis	0/85 (0%)		1/84 (1.2%)
Cerebral haemorrhage	0/85 (0%)		1/84 (1.2%)
Cerebral ischaemia	0/85 (0%)		1/84 (1.2%)
Depressed level of consciousness	0/85 (0%)		1/84 (1.2%)
Dizziness	1/85 (1.2%)		0/84 (0%)
Encephalopathy	0/85 (0%)		2/84 (2.4%)
Hydrocephalus	0/85 (0%)		1/84 (1.2%)
Lethargy	1/85 (1.2%)		1/84 (1.2%)
Loss of consciousness	0/85 (0%)		1/84 (1.2%)
Metabolic encephalopathy	0/85 (0%)		1/84 (1.2%)
Syncope	2/85 (2.4%)		2/84 (2.4%)
Psychiatric disorders
Confusional state	2/85 (2.4%)		0/84 (0%)
Depression	1/85 (1.2%)		0/84 (0%)
Mental status changes	0/85 (0%)		2/84 (2.4%)
Suicide attempt	1/85 (1.2%)		0/84 (0%)
Renal and urinary disorders
Acute prerenal failure	1/85 (1.2%)		0/84 (0%)
Hydronephrosis	0/85 (0%)		1/84 (1.2%)
Renal failure	2/85 (2.4%)		2/84 (2.4%)
Renal failure acute	4/85 (4.7%)		0/84 (0%)
Renal failure chronic	1/85 (1.2%)		0/84 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/85 (0%)		1/84 (1.2%)
Atelectasis	1/85 (1.2%)		0/84 (0%)
Cough	0/85 (0%)		1/84 (1.2%)
Dyspnoea	8/85 (9.4%)		1/84 (1.2%)
Dyspnoea exertional	0/85 (0%)		1/84 (1.2%)
Hypoxia	1/85 (1.2%)		2/84 (2.4%)
Lung infiltration	2/85 (2.4%)		0/84 (0%)
Orthopnoea	0/85 (0%)		1/84 (1.2%)
Pleural effusion	0/85 (0%)		1/84 (1.2%)
Pleuritic pain	1/85 (1.2%)		1/84 (1.2%)
Pneumonia aspiration	0/85 (0%)		1/84 (1.2%)
Productive cough	0/85 (0%)		1/84 (1.2%)
Pulmonary embolism	1/85 (1.2%)		1/84 (1.2%)
Pulmonary hypertension	0/85 (0%)		1/84 (1.2%)
Pulmonary mass	0/85 (0%)		1/84 (1.2%)
Pulmonary oedema	0/85 (0%)		1/84 (1.2%)
Respiratory arrest	1/85 (1.2%)		0/84 (0%)
Respiratory failure	0/85 (0%)		1/84 (1.2%)
Skin and subcutaneous tissue disorders
Skin lesion	0/85 (0%)		1/84 (1.2%)
Vascular disorders
Deep vein thrombosis	1/85 (1.2%)		4/84 (4.8%)
Hypotension	3/85 (3.5%)		1/84 (1.2%)
Jugular vein distension	0/85 (0%)		1/84 (1.2%)
Jugular vein thrombosis	1/85 (1.2%)		1/84 (1.2%)
Other (Not Including Serious) Adverse Events
	15 - Minute Infusion		30 - Minute Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	74/85 (87.1%)		76/84 (90.5%)
Blood and lymphatic system disorders
Anaemia	16/85 (18.8%)		26/84 (31%)
Neutropenia	6/85 (7.1%)		12/84 (14.3%)
Thrombocytopenia	4/85 (4.7%)		11/84 (13.1%)
Gastrointestinal disorders
Abdominal pain	6/85 (7.1%)		5/84 (6%)
Constipation	20/85 (23.5%)		21/84 (25%)
Diarrhoea	11/85 (12.9%)		19/84 (22.6%)
Dyspepsia	5/85 (5.9%)		5/84 (6%)
Nausea	16/85 (18.8%)		25/84 (29.8%)
Vomiting	8/85 (9.4%)		12/84 (14.3%)
General disorders
Asthenia	5/85 (5.9%)		10/84 (11.9%)
Chills	6/85 (7.1%)		7/84 (8.3%)
Fatigue	30/85 (35.3%)		41/84 (48.8%)
Oedema	5/85 (5.9%)		5/84 (6%)
Oedema peripheral	13/85 (15.3%)		19/84 (22.6%)
Pain	6/85 (7.1%)		7/84 (8.3%)
Pyrexia	14/85 (16.5%)		16/84 (19%)
Infections and infestations
Bronchitis	3/85 (3.5%)		5/84 (6%)
Herpes zoster	6/85 (7.1%)		6/84 (7.1%)
Pneumonia	5/85 (5.9%)		5/84 (6%)
Sinusitis	7/85 (8.2%)		8/84 (9.5%)
Upper respiratory tract infection	13/85 (15.3%)		13/84 (15.5%)
Injury, poisoning and procedural complications
Contusion	3/85 (3.5%)		7/84 (8.3%)
Investigations
Weight decreased	6/85 (7.1%)		3/84 (3.6%)
Metabolism and nutrition disorders
Anorexia	8/85 (9.4%)		9/84 (10.7%)
Decreased appetite	6/85 (7.1%)		5/84 (6%)
Dehydration	2/85 (2.4%)		5/84 (6%)
Hyperglycaemia	7/85 (8.2%)		7/84 (8.3%)
Hypokalaemia	8/85 (9.4%)		13/84 (15.5%)
Hypomagnesaemia	0/85 (0%)		6/84 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/85 (11.8%)		16/84 (19%)
Back pain	17/85 (20%)		16/84 (19%)
Bone pain	10/85 (11.8%)		11/84 (13.1%)
Muscle spasms	4/85 (4.7%)		6/84 (7.1%)
Muscular weakness	5/85 (5.9%)		7/84 (8.3%)
Musculoskeletal chest pain	2/85 (2.4%)		6/84 (7.1%)
Musculoskeletal pain	7/85 (8.2%)		6/84 (7.1%)
Myalgia	3/85 (3.5%)		6/84 (7.1%)
Pain in extremity	13/85 (15.3%)		12/84 (14.3%)
Pain in jaw	2/85 (2.4%)		5/84 (6%)
Nervous system disorders
Dizziness	10/85 (11.8%)		10/84 (11.9%)
Dysgeusia	4/85 (4.7%)		6/84 (7.1%)
Headache	8/85 (9.4%)		8/84 (9.5%)
Hypoaesthesia	10/85 (11.8%)		3/84 (3.6%)
Neuropathy	9/85 (10.6%)		6/84 (7.1%)
Neuropathy peripheral	7/85 (8.2%)		15/84 (17.9%)
Tremor	2/85 (2.4%)		5/84 (6%)
Psychiatric disorders
Anxiety	6/85 (7.1%)		4/84 (4.8%)
Depression	9/85 (10.6%)		5/84 (6%)
Insomnia	10/85 (11.8%)		14/84 (16.7%)
Respiratory, thoracic and mediastinal disorders
Cough	13/85 (15.3%)		14/84 (16.7%)
Dyspnoea	10/85 (11.8%)		16/84 (19%)
Epistaxis	3/85 (3.5%)		7/84 (8.3%)
Pharyngolaryngeal pain	5/85 (5.9%)		5/84 (6%)
Skin and subcutaneous tissue disorders
Rash	9/85 (10.6%)		12/84 (14.3%)
Vascular disorders
Hot flush	3/85 (3.5%)		6/84 (7.1%)
Hypertension	2/85 (2.4%)		6/84 (7.1%)
Hypotension	4/85 (4.7%)		7/84 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial; or disclosure of the trial results in their entirety.