Combination Chemotherapy With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for High Risk Stage II or Stage III Colon Cancer
Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT00112918
Collaborator
National Cancer Institute (NCI) (NIH)
3,451
1
3
90
38.3
Study Details
Study Description
Brief Summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab (Bv) may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving combination chemotherapy together with bevacizumab is more effective than combination chemotherapy alone in treating colon cancer in adjuvant setting.
PURPOSE: This randomized phase III trial is studying two different combination chemotherapy regimens with or without bevacizumab to compare how well they work in treating patients who have undergone surgery for high risk stage II or stage III colon cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
This was an open-label Phase III, multicenter, multinational, randomized, 3-arm study designed to evaluate the efficacy and safety of bevacizumab in combination with either intermittent fluorouracil/leucovorin with oxaliplatin (FOLFOX4) or capecitabine plus oxaliplatin (XELOX) versus FOLFOX4 regimen alone, as adjuvant chemotherapy in colon carcinoma.
The treatment phase consisted of two parts of 24 weeks for a total of 48 weeks. The first part (weeks 1 to 24) consisted of treatment with either FOLFOX4, FOLFOX4 in combination with bevacizumab, or XELOX in combination with bevacizumab. The second part (weeks 25 to 48) consisted of single-agent bevacizumab for patients randomized to either bevacizumab-containing arm, but was only an observation period for patients assigned to the FOLFOX4-alone arm.
Patients were to be followed for recurrence/new occurrence of colorectal cancer and survival. Patients who experienced a confirmed recurrence, occurrence of a new colorectal cancer during therapy, or experienced unacceptable toxicity were to be taken off study treatment but remain in study follow-up. Patients that came off therapy due to a confirmed recurrence/appearance of new colorectal cancer, were to be followed for survival until the end of the study follow-up period. The primary analysis was performed 36 months after the last patient has been randomized. After the primary analysis, patients continue to be followed for survival for at least a further 2 years ie, until all patients have been followed-up for at least 5 years following randomization.
Study Design
Study Type:
Interventional
Actual Enrollment
:
3451 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Three Arm Multinational Phase III Study to Investigate Bevacizumab (q3w or q2w) in Combination With Either Intermittent Capecitabine Plus Oxaliplatin (XELOX) (q3w) or Fluorouracil/Leucovorin With Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 Regimen Alone as Adjuvant Chemotherapy in Colon Carcinoma: The AVANT Study
Study Start Date
:
Dec 1, 2004
Actual Primary Completion Date
:
Jun 1, 2010
Actual Study Completion Date
:
Jun 1, 2012
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: FOLFOX4 Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. |
Drug: 5-Fluorouracil (5-FU)
Administered as either a bolus injection or continuous intravenous infusion over 22 hours.
Drug: Leucovorin calcium
Administered as a 200 mg/m^2 infusion over 2 hours.
Drug: Oxaliplatin
Administered as an intravenous infusion over 2 hours.
|
| Experimental: FOLFOX4 + Bv Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). |
Biological: Bevacizumab
Administered as an intravenous infusion over 30 - 90 minutes.
Drug: 5-Fluorouracil (5-FU)
Administered as either a bolus injection or continuous intravenous infusion over 22 hours.
Drug: Leucovorin calcium
Administered as a 200 mg/m^2 infusion over 2 hours.
Drug: Oxaliplatin
Administered as an intravenous infusion over 2 hours.
|
| Experimental: XELOX+Bv Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). |
Biological: Bevacizumab
Administered as an intravenous infusion over 30 - 90 minutes.
Drug: Capecitabine
Film-coated tablets
Other Names:
Drug: Oxaliplatin
Administered as an intravenous infusion over 2 hours.
|
Outcome Measures
Primary Outcome Measures
- Disease-free Survival in Stage III Cancer Patients - Time to Event [From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized).]
Disease-free survival (DFS) was defined as the time from the date of randomization to the time of a recurrence, a new occurrence of colorectal cancer or death due to any cause, whichever occurred first. Patients without an event were censored at the last date the patient was known to be disease-free. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Patients with no tumor assessments after baseline but still alive at the time of the clinical cut-off were censored at day 1.
- Disease-free Survival in Stage III Cancer Patients - Number of Events [From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized).]
A disease-free survival (DFS) event was composed of a recurrence, a new occurrence of colorectal cancer or death due to any cause. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Triggering events for DFS are reported; a patient can have both recurrence and a new occurrence of colon cancer.
Secondary Outcome Measures
- Overall Survival in Stage III Cancer Patients - Time to Event [From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized).]
Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the analysis were censored at the date they were last known to be alive.
- Overall Survival in Stage III Cancer Patients - Number of Events [From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized).]
An overall survival event was death due to any cause.
- Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis [From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized).]
Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the clinical cut-off date (30 June 2012) were censored at the date they were last known to be alive.
- Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis [From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized).]
An overall survival event was death due to any cause.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria
-
Signed written informed consent obtained prior to any study specific screening procedures.
-
Patient willing and able to comply with the protocol.
-
Age ≥ 18 years-of-age.
-
Histologically confirmed colon carcinoma, American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) Stage II or Stage III defined as a tumor location ≥ 15 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. The patient was not to be a candidate for (neo) adjuvant radiotherapy. Note: Stage II patients were to be considered as high-risk patients fulfilling one of the following criteria:
-
T4 tumours,
-
Patients presenting with bowel obstruction or perforation,
-
Histological signs of vascular invasion (i.e. blood and lymphatic vessels) or perineural invasion,
-
Patients aged less than 50 years,
-
Patients with sub-optimal surgery (less than 12 nodes analyzed).
-
Curative surgery not less than 4 and not more than 8 weeks prior to randomization.
-
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
-
Life expectancy of ≥ 5 years.
Exclusion Criteria
-
Macroscopic or microscopic evidence of remaining tumour. Patients should never have had any evidence of metastatic disease (including presence of tumour cells in the ascites). The isolated finding of cytokeratin positive cells in bone marrow is not considered evidence of metastatic disease for purposes of this study.
-
Carcinoembryonic antigen > 1.5 x upper limit of normal (ULN) after surgery (during screening period).
-
For patients with colostomy, unwilling to delay revision until at least 28 days after treatment completion.
-
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, not fully healed wounds, or anticipation of the need for major surgical procedure during the course of the study. Any central venous access device (CVAD) for chemotherapy administration must be inserted at least 2 days prior to treatment start.
-
Previous anti-angiogenic treatment for any malignancy; cytotoxic chemotherapy, radiotherapy or immunotherapy for colon cancer.
-
Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
-
Females with a positive or no pregnancy test (within 7 days before treatment start) unless childbearing potential can be otherwise excluded (postmenopausal i.e. amenorrheic for at least 2 years, hysterectomy or oophorectomy).
-
Lactating women.
-
Fertile women (< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.
-
History or evidence upon physical examination of central nervous disease (CNS) disease (eg, primary brain tumour, seizure not controlled with standard medical therapy, any brain metastases).
-
History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake.
-
Clinically significant (ie, active) cardiovascular disease. This includes, but is not limited to, the following examples: cerebrovascular accidents (≤ 6 months prior to randomization), myocardial infarction (≤ 1 year prior to randomization), uncontrolled hypertension (>150/100 mmHg) while receiving chronic medication, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, clinically significant electrocardiogram (ECG) findings (e.g. QTc ≥ 440 msecs [male] 460 msecs [female] or ≥ 2º atrioventricular block, etc.).
Patients who suffer from serious cardiac arrhythmia requiring medication can enter the study only if they are considered to be in a stable condition regarding both the arrhythmia and their medication. Patients with pacemakers are allowed to enter the study only if they are considered as being in a stable condition. In case of doubt, the investigator should obtain a consultation with a local cardiologist.
-
Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication.
-
Interstitial pneumonia or extensive symptomatic fibrosis of the lungs.
-
Known peripheral neuropathy ≥ Common terminology criteria for adverse events (CTCAE) version 3.0 Grade 1. Absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible.
-
Organ allografts requiring immunosuppressive therapy.
-
Serious, non-healing wound, ulcer, or bone fracture.
-
Evidence of bleeding diathesis or coagulopathy.
-
Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes.
-
Chronic, daily treatment with high-dose aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day).
-
Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
-
Serious intercurrent infections (uncontrolled or requiring treatment).
-
Known dihydropyrimidine dehydrogenase deficiency.
-
Current or recent (within the 28 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
-
Patients with known allergy to Chinese hamster ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of bevacizumab formulation, platinum compounds or to any other components of the study drugs.
-
History or presence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or patient at high risk from treatment complications.
-
Presence of proteinuria at baseline as defined by:
- Patients with > 1 g of protein/24 hour by a 24-hour urine collection.
- Any laboratory values at baseline are as follows:
Haematology:
-
Absolute neutrophil count (ANC) < 1.5 x 109/L
-
Platelet count < 100 x 10^9/L
-
Haemoglobin < 9 g/dL (may be transfused to maintain or exceed this level)
-
International normalized ratio (INR) > 1.5
-
Activated partial prothrombin time (APTT) ≥ 1.5 x ULN
Biochemistry:
-
Total bilirubin > 1.5 x ULN
-
aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) > 2.5 x ULN
-
Alkaline phosphatase (ALP) > 2.5 x ULN
-
Serum creatinine > 1.5 x ULN or creatinine clearance ≤ 50 mL/min (e.g. Cockcroft-Gault formula).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Jonsson Comprehensive Cancer Center at UCLA | Los Angeles | California | United States | 90095-1781 |
Sponsors and Collaborators
- Hoffmann-La Roche
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Joel Randolph Hecht, MD, Jonsson Comprehensive Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00112918
Other Study ID Numbers:
- CDR0000427299
- P30CA016042
- UCLA-0412086-01
- ROCHE-BO17920A
First Posted:
Jun 3, 2005
Last Update Posted:
Aug 27, 2013
Last Verified:
Jun 1, 2013
Keywords provided by Hoffmann-La Roche
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | Randomization was stratified according to geographic region and disease stage (high-risk stage II or stage III N1 or stage III N2). The primary analysis population consisted of patients with Stage III disease. |
| Arm/Group Title | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv |
|---|---|---|---|
| Arm/Group Description | Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-fluorouracil (5-FU), given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. | Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). |
| Period Title: Overall Study | |||
| STARTED | 1151 | 1155 | 1145 |
| Received Treatment | 1126 | 1145 | 1135 |
| Stage III Disease Population | 955 | 960 | 952 |
| COMPLETED | 854 | 810 | 846 |
| NOT COMPLETED | 297 | 345 | 299 |
Baseline Characteristics
| Arm/Group Title | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv | Total |
|---|---|---|---|---|
| Arm/Group Description | Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-fluorouracil (5-FU), given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. | Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Total of all reporting groups |
| Overall Participants | 955 | 960 | 952 | 2867 |
| Age, Customized (participants) [Number] | ||||
| <40 |
77
8.1%
|
74
7.7%
|
68
7.1%
|
219
7.6%
|
| 40-65 |
603
63.1%
|
625
65.1%
|
588
61.8%
|
1816
63.3%
|
| >=65 |
275
28.8%
|
261
27.2%
|
296
31.1%
|
832
29%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
425
44.5%
|
473
49.3%
|
432
45.4%
|
1330
46.4%
|
| Male |
530
55.5%
|
487
50.7%
|
520
54.6%
|
1537
53.6%
|
| Race/Ethnicity, Customized (participants) [Number] | ||||
| American Indian or Alaska Native |
1
0.1%
|
1
0.1%
|
0
0%
|
2
0.1%
|
| Asian |
139
14.6%
|
115
12%
|
123
12.9%
|
377
13.1%
|
| Black or African American |
6
0.6%
|
13
1.4%
|
14
1.5%
|
33
1.2%
|
| White |
791
82.8%
|
813
84.7%
|
795
83.5%
|
2399
83.7%
|
| Other |
18
1.9%
|
18
1.9%
|
20
2.1%
|
56
2%
|
Outcome Measures
| Title | Disease-free Survival in Stage III Cancer Patients - Time to Event |
|---|---|
| Description | Disease-free survival (DFS) was defined as the time from the date of randomization to the time of a recurrence, a new occurrence of colorectal cancer or death due to any cause, whichever occurred first. Patients without an event were censored at the last date the patient was known to be disease-free. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Patients with no tumor assessments after baseline but still alive at the time of the clinical cut-off were censored at day 1. |
| Time Frame | From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). |
Outcome Measure Data
| Analysis Population Description |
|---|
| The primary population for efficacy analyses was the intent to treat population (ITT; all randomized patients) with stage III disease. |
| Arm/Group Title | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv |
|---|---|---|---|
| Arm/Group Description | Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. | Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). |
| Measure Participants | 955 | 960 | 952 |
| Median (95% Confidence Interval) [months] |
NA
|
NA
|
NA
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | FOLFOX4, FOLFOX4 + Bv, XELOX+Bv |
|---|---|---|
| Comments | Adjustments for multiplicity was done using a closed test procedure which tests for differences between all three treatment groups at the 5% alpha level first. Only in case of a significant result, the pair-wise comparison between the control arm and each of the bevacizumab arm will be tested, again at the 5% alpha level. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2024 |
| Comments | ||
| Method | Closed test procedure | |
| Comments | ||
| Title | Overall Survival in Stage III Cancer Patients - Time to Event |
|---|---|
| Description | Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the analysis were censored at the date they were last known to be alive. |
| Time Frame | From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT patients with Stage III disease. |
| Arm/Group Title | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv |
|---|---|---|---|
| Arm/Group Description | Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. | Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). |
| Measure Participants | 955 | 960 | 952 |
| Median (95% Confidence Interval) [months] |
NA
|
NA
|
NA
|
| Title | Disease-free Survival in Stage III Cancer Patients - Number of Events |
|---|---|
| Description | A disease-free survival (DFS) event was composed of a recurrence, a new occurrence of colorectal cancer or death due to any cause. Recurrence and new occurrence of colorectal cancer were based on tumor assessments made by the investigator. Triggering events for DFS are reported; a patient can have both recurrence and a new occurrence of colon cancer. |
| Time Frame | From first patient randomized until the data cut-off date of 30 June 2010 (36 months after the last patient randomized). |
Outcome Measure Data
| Analysis Population Description |
|---|
| The primary population for efficacy analyses was the intent to treat population (ITT; all randomized patients) with stage III disease. |
| Arm/Group Title | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv |
|---|---|---|---|
| Arm/Group Description | Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. | Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). |
| Measure Participants | 955 | 960 | 952 |
| Patients with a DFS event |
237
24.8%
|
280
29.2%
|
253
26.6%
|
| Recurrence |
219
22.9%
|
253
26.4%
|
223
23.4%
|
| New Occurrence |
3
0.3%
|
8
0.8%
|
6
0.6%
|
| Death |
17
1.8%
|
21
2.2%
|
25
2.6%
|
| Patients without events |
718
75.2%
|
680
70.8%
|
699
73.4%
|
| Title | Overall Survival in Stage III Cancer Patients - Number of Events |
|---|---|
| Description | An overall survival event was death due to any cause. |
| Time Frame | From first patient randomized until the clinical data cut-off date of 30 June 2010 (36 months after the last patient randomized). |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT patients with Stage III disease. |
| Arm/Group Title | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv |
|---|---|---|---|
| Arm/Group Description | Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. | Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). |
| Measure Participants | 955 | 960 | 952 |
| Patients with events |
115
12%
|
151
15.7%
|
145
15.2%
|
| Patients without events |
840
88%
|
809
84.3%
|
807
84.8%
|
| Title | Overall Survival in Stage III Cancer Patients - Time to Event: Final Analysis |
|---|---|
| Description | Overall survival was defined as the time between date of randomization and date of death due to any cause. Patients not reported as having died at the time of the clinical cut-off date (30 June 2012) were censored at the date they were last known to be alive. |
| Time Frame | From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT patients with Stage III disease. |
| Arm/Group Title | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv |
|---|---|---|---|
| Arm/Group Description | Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. | Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). |
| Measure Participants | 955 | 960 | 952 |
| Median (95% Confidence Interval) [months] |
NA
|
NA
|
NA
|
| Title | Overall Survival in Stage III Cancer Patients - Number of Events: Final Analysis |
|---|---|
| Description | An overall survival event was death due to any cause. |
| Time Frame | From first patient randomized until the final data cut-off date of 30 June 2012 (5 years after the last patient randomized). |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT patients with Stage III disease. |
| Arm/Group Title | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv |
|---|---|---|---|
| Arm/Group Description | Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. | Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). |
| Measure Participants | 955 | 960 | 952 |
| Patients with events |
161
16.9%
|
202
21%
|
182
19.1%
|
| Patients without events |
794
83.1%
|
758
79%
|
770
80.9%
|
Adverse Events
| Time Frame | All adverse events occurring between the date of first drug intake and 28 days after last drug intake, regardless of which treatment group the patient was randomized to. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv | |||
| Arm/Group Description | Weeks 1-24: Oxaliplatin was administered as an 85 mg/m^2 intravenous infusion over 2 hours concomitantly with Leucovorin as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion were repeated on day 2. Cycle length was 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Observation only. | Weeks 1-24: Bevacizumab 5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin, administered as an 85 mg/m^2 intravenous infusion over 2 hours (on day 1 only) concomitantly with leucovorin, as a 200 mg/m^2 infusion over 2 hours, followed by 5-FU, given as a 400 mg/m^2 bolus injection, and then as a 600 mg/m^2 continuous infusion over 22 hours. Leucovorin 200 mg/m^2 (alone), followed by 5-FU 400 mg/m^2 bolus injection, and 5-FU 600 mg/m^2 continuous infusion are repeated on day 2. Cycle length is 2 weeks and cycles were repeated every second week for a total of 12 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | Weeks 1-24: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 - 90 minutes followed by oxaliplatin administered as a 130 mg/m^2 intravenous infusion over 2 hours (day 1 every 3 weeks) in combination with capecitabine, which was administered orally at a dose of 1000 mg/m^2 twice daily (equivalent to a total daily dose of 2000 mg/m^2), with first dose the evening of day 1 and last dose the morning of day 15, given as intermittent treatment (3-week cycles consisting of 2 weeks of treatment followed by 1 week without treatment), for a total of 8 cycles (24 weeks). Weeks 25-48: Bevacizumab 7.5 mg/kg was administered as an intravenous infusion over 30 minutes. Cycle length was 3 weeks. Cycles were repeated every 3 weeks for a total of 8 cycles (24 weeks). | |||
All Cause Mortality |
||||||
| FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 226/1126 (20.1%) | 297/1145 (25.9%) | 284/1135 (25%) | |||
| Blood and lymphatic system disorders | ||||||
| Neutropenia | 18/1126 (1.6%) | 18/1145 (1.6%) | 0/1135 (0%) | |||
| Febrile neutropenia | 14/1126 (1.2%) | 9/1145 (0.8%) | 2/1135 (0.2%) | |||
| Anaemia | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Idiopathic thrombocytopenia purpura | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Leukopenia | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Thrombocytopenia | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Cardiac disorders | ||||||
| Myocardial infarction | 1/1126 (0.1%) | 5/1145 (0.4%) | 1/1135 (0.1%) | |||
| Angina pectoris | 1/1126 (0.1%) | 1/1145 (0.1%) | 4/1135 (0.4%) | |||
| Coronary artery disease | 1/1126 (0.1%) | 2/1145 (0.2%) | 1/1135 (0.1%) | |||
| Myocardial ischaemia | 2/1126 (0.2%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Acute myocardial infarction | 1/1126 (0.1%) | 2/1145 (0.2%) | 0/1135 (0%) | |||
| Cardiac arrest | 0/1126 (0%) | 1/1145 (0.1%) | 2/1135 (0.2%) | |||
| Angina unstable | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Arteriospasm coronary | 1/1126 (0.1%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Atrial fibrillation | 2/1126 (0.2%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Acute coronary syndrome | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Cardiac asthma | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Cardiac failure | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Cardiac failure congestive | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Left ventricular dysfunction | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Mitral valve incompetence | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Palpitations | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Paroxysmal arrhythmia | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Pericardial haemorrhage | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Sinus arrest | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Ear and labyrinth disorders | ||||||
| Vertigo | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Endocrine disorders | ||||||
| Hypothyroidism | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Eye disorders | ||||||
| Retinal detachment | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Retinal vein thrombosis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Uveitis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Gastrointestinal disorders | ||||||
| Diarrhoea | 28/1126 (2.5%) | 28/1145 (2.4%) | 62/1135 (5.5%) | |||
| Abdominal pain | 11/1126 (1%) | 14/1145 (1.2%) | 18/1135 (1.6%) | |||
| Vomiting | 7/1126 (0.6%) | 11/1145 (1%) | 16/1135 (1.4%) | |||
| Intestinal obstruction | 6/1126 (0.5%) | 9/1145 (0.8%) | 7/1135 (0.6%) | |||
| Nausea | 0/1126 (0%) | 4/1145 (0.3%) | 7/1135 (0.6%) | |||
| Rectal haemorrhage | 1/1126 (0.1%) | 7/1145 (0.6%) | 3/1135 (0.3%) | |||
| Enteritis | 3/1126 (0.3%) | 0/1145 (0%) | 5/1135 (0.4%) | |||
| Small intestinal obstruction | 2/1126 (0.2%) | 2/1145 (0.2%) | 4/1135 (0.4%) | |||
| Constipation | 1/1126 (0.1%) | 4/1145 (0.3%) | 2/1135 (0.2%) | |||
| Subileus | 1/1126 (0.1%) | 4/1145 (0.3%) | 2/1135 (0.2%) | |||
| Colitis | 0/1126 (0%) | 1/1145 (0.1%) | 5/1135 (0.4%) | |||
| Abdominal adhesions | 2/1126 (0.2%) | 0/1145 (0%) | 2/1135 (0.2%) | |||
| Gastritis | 3/1126 (0.3%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Gastrointestinal haemorrhage | 0/1126 (0%) | 2/1145 (0.2%) | 2/1135 (0.2%) | |||
| Gastrointestinal obstruction | 0/1126 (0%) | 3/1145 (0.3%) | 1/1135 (0.1%) | |||
| Haemorrhoids | 1/1126 (0.1%) | 1/1145 (0.1%) | 2/1135 (0.2%) | |||
| Oesophagitis | 0/1126 (0%) | 2/1145 (0.2%) | 2/1135 (0.2%) | |||
| Small intestinal perforation | 0/1126 (0%) | 4/1145 (0.3%) | 0/1135 (0%) | |||
| Enterocolitis | 1/1126 (0.1%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Ileus paralytic | 0/1126 (0%) | 1/1145 (0.1%) | 2/1135 (0.2%) | |||
| Intestinal perforation | 1/1126 (0.1%) | 2/1145 (0.2%) | 0/1135 (0%) | |||
| Pancreatitis | 2/1126 (0.2%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Pancreatitis acute | 1/1126 (0.1%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Peritonitis | 0/1126 (0%) | 1/1145 (0.1%) | 2/1135 (0.2%) | |||
| Stomatitis | 1/1126 (0.1%) | 0/1145 (0%) | 2/1135 (0.2%) | |||
| Abdominal distension | 1/1126 (0.1%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Abdominal hernia | 2/1126 (0.2%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Anal fissure | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Anal fistula | 0/1126 (0%) | 2/1145 (0.2%) | 0/1135 (0%) | |||
| Gastrointestinal necrosis | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Haematemesis | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Haematochezia | 0/1126 (0%) | 0/1145 (0%) | 2/1135 (0.2%) | |||
| Ileus | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Mechanical ileus | 2/1126 (0.2%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Abdominal discomfort | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Abdominal pain lower | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Abdominal pain upper | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Abdominal rigidity | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Acute abdomen | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Caecitis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Colitis ulcerative | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Crohn's disease | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Duodenitis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Dyspepsia | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Enterocolitis haemorrhagic | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Erosive oesophagitis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Faecaloma | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Food poisoning | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Gastric ulcer | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Gastric volvulus | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Gastrointestinal perforation | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Gastrooesophageal reflux disease | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Hiatus hernia, obstructive | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Ileal perforation | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Intestinal angina | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Intestinal dilatation | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Intestinal fistula | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Intestinal ischaemia | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Intestinal prolapse | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Intestinal strangulation | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Large intestine perforation | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Lower gastrointestinal haemorrhage | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Mallory-Weiss syndrome | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Melaena | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Mesenteric vein thrombosis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Neutropenic colitis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Rectal perforation | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Umbilical hernia | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Upper gastrointestinal haemorrhage | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Volvulus of small bowel | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| General disorders | ||||||
| Pyrexia | 20/1126 (1.8%) | 10/1145 (0.9%) | 16/1135 (1.4%) | |||
| Non-cardiac chest pain | 1/1126 (0.1%) | 2/1145 (0.2%) | 5/1135 (0.4%) | |||
| Sudden death | 0/1126 (0%) | 2/1145 (0.2%) | 3/1135 (0.3%) | |||
| Asthenia | 0/1126 (0%) | 3/1145 (0.3%) | 1/1135 (0.1%) | |||
| Chest pain | 1/1126 (0.1%) | 2/1145 (0.2%) | 1/1135 (0.1%) | |||
| Extravasation | 0/1126 (0%) | 0/1145 (0%) | 2/1135 (0.2%) | |||
| Medical device complication | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Multi-organ failure | 2/1126 (0.2%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Thrombosis in device | 1/1126 (0.1%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Adhesion | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Catheter site pain | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Chills | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Device leakage | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Device malfunction | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| General physical health deterioration | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Hernia obstructive | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Hyperpyrexia | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Infusion site thrombosis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Malaise | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Pain | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Performance status decreased | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Sudden cardiac death | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Visceral pain | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Hepatobiliary disorders | ||||||
| Cholecystitis | 1/1126 (0.1%) | 1/1145 (0.1%) | 2/1135 (0.2%) | |||
| Portal vein thrombosis | 1/1126 (0.1%) | 2/1145 (0.2%) | 1/1135 (0.1%) | |||
| Cholangitis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Cholecystitis acute | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Cholelithiasis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Cytolytic hepatitis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Hepatic function abnormal | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Hepatitis toxic | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Hepatotoxicity | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Hyperbilirubinaemia | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Immune system disorders | ||||||
| Drug hypersensitivity | 5/1126 (0.4%) | 3/1145 (0.3%) | 1/1135 (0.1%) | |||
| Hypersensitivity | 3/1126 (0.3%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Anaphylactic reaction | 0/1126 (0%) | 3/1145 (0.3%) | 0/1135 (0%) | |||
| Anaphylactic shock | 2/1126 (0.2%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Anaphylactiod reaction | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Infections and infestations | ||||||
| Device related infection | 8/1126 (0.7%) | 12/1145 (1%) | 4/1135 (0.4%) | |||
| Pneumonia | 3/1126 (0.3%) | 4/1145 (0.3%) | 5/1135 (0.4%) | |||
| Urinary tract infection | 2/1126 (0.2%) | 5/1145 (0.4%) | 4/1135 (0.4%) | |||
| Sepsis | 4/1126 (0.4%) | 3/1145 (0.3%) | 3/1135 (0.3%) | |||
| Gastroenteritis | 1/1126 (0.1%) | 5/1145 (0.4%) | 3/1135 (0.3%) | |||
| Infection | 5/1126 (0.4%) | 3/1145 (0.3%) | 1/1135 (0.1%) | |||
| Abdominal abscess | 2/1126 (0.2%) | 4/1145 (0.3%) | 2/1135 (0.2%) | |||
| Catheter site infection | 4/1126 (0.4%) | 4/1145 (0.3%) | 0/1135 (0%) | |||
| Neutropenic sepsis | 4/1126 (0.4%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Lower respiratory tract infection | 3/1126 (0.3%) | 2/1145 (0.2%) | 0/1135 (0%) | |||
| Anal abscess | 0/1126 (0%) | 3/1145 (0.3%) | 1/1135 (0.1%) | |||
| Cellulitis | 3/1126 (0.3%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Abdominal wall abscess | 0/1126 (0%) | 2/1145 (0.2%) | 1/1135 (0.1%) | |||
| Device related sepsis | 1/1126 (0.1%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Staphylococcal sepsis | 1/1126 (0.1%) | 0/1145 (0%) | 2/1135 (0.2%) | |||
| Abscess | 0/1126 (0%) | 2/1145 (0.2%) | 0/1135 (0%) | |||
| Erysipelas | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Herpes zoster | 1/1126 (0.1%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Neutropenic infection | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Pelvic abscess | 0/1126 (0%) | 2/1145 (0.2%) | 0/1135 (0%) | |||
| Septic shock | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Upper respiratory tract infection | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Viral infection | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Abdominal infection | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Appendicitis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Appendicitis perforated | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Aspergillosis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Bacteraemia | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Bronchopneumonia | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Bronchopulmonary aspergillosis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Campylobacter infection | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Candida sepsis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Catheter site cellulitis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Cholecystitis infective | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Clostridial infection | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Clostridium difficile colitis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Diverticulitis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Enteritis infection | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Gastroenteritis norovirus | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Gastroenteritis viral | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Hepatitis viral | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Herpes zoster ophthalmic | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Incision site cellulitis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Intervertebral discitis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Intestinal fistual infection | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Klebsiella bacteraemia | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Klebsiella infection | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Lower respiratory tract infection viral | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Oral candidiasis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Orchitis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Overgrowth bacterial | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Perineal abscess | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Pharyngitis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Post procedural infection | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Postoperative abscess | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Psoas abscess | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Puncture site infection | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Respiratory tract infection | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Skin infection | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Staphylococcal bacteraemia | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Subcutaneous abscess | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Tooth abscess | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Tuberculosis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Wound abscess | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Wound infection | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Incisional hernia | 1/1126 (0.1%) | 2/1145 (0.2%) | 2/1135 (0.2%) | |||
| Procedural site reaction | 0/1126 (0%) | 0/1145 (0%) | 2/1135 (0.2%) | |||
| Accident at work | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Anastomotic stenosis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Brachial plexus injury | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Cervical vertebral fracture | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Drug toxicity | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Fall | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Foot fracture | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Femur fracture | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Head injury | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Joint dislocation | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Multiple fractures | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Post procedural fistula | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Post procedural haemorrhage | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Road traffic accident | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Subdural haematoma | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Thoracic vertebral fracture | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Tibia fracture | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Investigations | ||||||
| Blood lactate dehydrogenase increased | 1/1126 (0.1%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Blood creatinine increased | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Blood glucose fluctuation | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Weight increased | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Dehydration | 7/1126 (0.6%) | 10/1145 (0.9%) | 17/1135 (1.5%) | |||
| Hyperglycaemia | 3/1126 (0.3%) | 4/1145 (0.3%) | 2/1135 (0.2%) | |||
| Hypokalaemia | 2/1126 (0.2%) | 3/1145 (0.3%) | 2/1135 (0.2%) | |||
| Decreased appetite | 0/1126 (0%) | 1/1145 (0.1%) | 2/1135 (0.2%) | |||
| Hypertriglyceridaemia | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Hypocalcaemia | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Hyponatraemia | 0/1126 (0%) | 2/1145 (0.2%) | 0/1135 (0%) | |||
| Diabetes mellitus | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Diabetic ketoacidosis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Gout | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Hypercholesterolaemia | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Hypomagnesaemia | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Musculoskeletal pain | 1/1126 (0.1%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Intervertebral disc protusion | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Muscle spasms | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Muscular weakness | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Musculoskeletal chest pain | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Musculoskeletal disorder | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Myalgia | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Pain in extremity | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Breast cancer | 1/1126 (0.1%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Benign lung neoplasm | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Nervous system disorders | ||||||
| Syncope | 2/1126 (0.2%) | 5/1145 (0.4%) | 1/1135 (0.1%) | |||
| Transient ischaemic attack | 1/1126 (0.1%) | 3/1145 (0.3%) | 2/1135 (0.2%) | |||
| Cerebrovascular accident | 0/1126 (0%) | 2/1145 (0.2%) | 1/1135 (0.1%) | |||
| Neuropathy peripheral | 1/1126 (0.1%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Convulsion | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Dizziness | 2/1126 (0.2%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Epilepsy | 0/1126 (0%) | 0/1145 (0%) | 2/1135 (0.2%) | |||
| Headache | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Ischaemic stroke | 0/1126 (0%) | 0/1145 (0%) | 2/1135 (0.2%) | |||
| Peripheral sensory neuropathy | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Cerebral ischaemia | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Dysaesthesia | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Encephalopathy | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Leukoaraiosis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Loss of consciousness | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Migraine | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Monoparesis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Neurotoxicity | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Orthostatic intolerance | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Paraesthesia | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Post herpetic neuralgia | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Reversible ischaemic neurological deficit | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Reversible posterior leukoencephalopathy syndrome | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Sensory disturbance | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Somnolence | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Speech disorder | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Psychiatric disorders | ||||||
| Depression | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Alcoholism | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Anxiety | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Renal and urinary disorders | ||||||
| Hydronephrosis | 1/1126 (0.1%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Renal failure acute | 2/1126 (0.2%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Renal failure | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Renal impairment | 0/1126 (0%) | 1/1145 (0.1%) | 1/1135 (0.1%) | |||
| Ureteric stenosis | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Acute prerenal failure | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Calculus ureteric | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Calculus urinary | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Nephrogenic diabetes insipidus | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Nephrotic syndrome | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Reproductive system and breast disorders | ||||||
| Female genital tract fistula | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Prostatitis | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Vaginal haemorrhage | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Pulmonary embolism | 11/1126 (1%) | 15/1145 (1.3%) | 10/1135 (0.9%) | |||
| Dyspnoea | 2/1126 (0.2%) | 3/1145 (0.3%) | 2/1135 (0.2%) | |||
| Epistaxis | 0/1126 (0%) | 3/1145 (0.3%) | 1/1135 (0.1%) | |||
| Bronchospasm | 0/1126 (0%) | 1/1145 (0.1%) | 2/1135 (0.2%) | |||
| Dysaesthesia pharynx | 0/1126 (0%) | 0/1145 (0%) | 3/1135 (0.3%) | |||
| Laryngospasm | 0/1126 (0%) | 0/1145 (0%) | 3/1135 (0.3%) | |||
| Pneumothorax | 1/1126 (0.1%) | 2/1145 (0.2%) | 0/1135 (0%) | |||
| Respiratory failure | 0/1126 (0%) | 0/1145 (0%) | 2/1135 (0.2%) | |||
| Acute respiratory distress syndrome | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Interstitial lung disease | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Organising pneumonia | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Pneumonia aspiration | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Pulmonary artery thrombosis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Pulmonary oedema | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Angioedema | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Drug eruption | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Palmar-Plantar | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Swelling face | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Urticaria | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Social circumstances | ||||||
| Pregnancy of partner | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Surgical and medical procedures | ||||||
| Central venous catheter removal | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Vascular disorders | ||||||
| Deep vein thrombosis | 9/1126 (0.8%) | 16/1145 (1.4%) | 12/1135 (1.1%) | |||
| Hypertension | 1/1126 (0.1%) | 2/1145 (0.2%) | 13/1135 (1.1%) | |||
| Venous thrombosis | 3/1126 (0.3%) | 5/1145 (0.4%) | 1/1135 (0.1%) | |||
| Jugular vein thrombosis | 2/1126 (0.2%) | 3/1145 (0.3%) | 0/1135 (0%) | |||
| Subclavian vein thrombosis | 1/1126 (0.1%) | 2/1145 (0.2%) | 2/1135 (0.2%) | |||
| Venous thrombosis limb | 0/1126 (0%) | 3/1145 (0.3%) | 2/1135 (0.2%) | |||
| Hypertensive crisis | 0/1126 (0%) | 3/1145 (0.3%) | 1/1135 (0.1%) | |||
| Hypotension | 0/1126 (0%) | 2/1145 (0.2%) | 1/1135 (0.1%) | |||
| Thrombophlebitis | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Thrombosis | 1/1126 (0.1%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Arterial stenosis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Arterial thrombosis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Arterial thrombosis limb | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Axillary vein thrombosis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Pelvic venous thrombosis | 0/1126 (0%) | 0/1145 (0%) | 1/1135 (0.1%) | |||
| Peripheral ischaemia | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
| Phlebitis | 0/1126 (0%) | 1/1145 (0.1%) | 0/1135 (0%) | |||
| Thrombophlebitis superficial | 1/1126 (0.1%) | 0/1145 (0%) | 0/1135 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| FOLFOX4 | FOLFOX4 + Bv | XELOX+Bv | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1112/1126 (98.8%) | 1127/1145 (98.4%) | 1117/1135 (98.4%) | |||
| Blood and lymphatic system disorders | ||||||
| Neutropenia | 660/1126 (58.6%) | 567/1145 (49.5%) | 273/1135 (24.1%) | |||
| Thrombocytopenia | 331/1126 (29.4%) | 115/1145 (10%) | 99/1135 (8.7%) | |||
| Anaemia | 116/1126 (10.3%) | 89/1145 (7.8%) | 74/1135 (6.5%) | |||
| Leukopenia | 79/1126 (7%) | 55/1145 (4.8%) | 34/1135 (3%) | |||
| Eye disorders | ||||||
| Lacrimation increased | 70/1126 (6.2%) | 69/1145 (6%) | 35/1135 (3.1%) | |||
| Gastrointestinal disorders | ||||||
| Nausea | 725/1126 (64.4%) | 761/1145 (66.5%) | 720/1135 (63.4%) | |||
| Diarrhoea | 620/1126 (55.1%) | 699/1145 (61%) | 699/1135 (61.6%) | |||
| Vomiting | 385/1126 (34.2%) | 394/1145 (34.4%) | 460/1135 (40.5%) | |||
| Stomatitis | 310/1126 (27.5%) | 360/1145 (31.4%) | 246/1135 (21.7%) | |||
| Constipation | 308/1126 (27.4%) | 324/1145 (28.3%) | 219/1135 (19.3%) | |||
| Abdominal pain | 220/1126 (19.5%) | 227/1145 (19.8%) | 214/1135 (18.9%) | |||
| Dyspepsia | 126/1126 (11.2%) | 162/1145 (14.1%) | 84/1135 (7.4%) | |||
| Abdominal pain upper | 86/1126 (7.6%) | 118/1145 (10.3%) | 113/1135 (10%) | |||
| Haemorrhoids | 29/1126 (2.6%) | 68/1145 (5.9%) | 41/1135 (3.6%) | |||
| General disorders | ||||||
| Fatigue | 404/1126 (35.9%) | 425/1145 (37.1%) | 355/1135 (31.3%) | |||
| Asthenia | 241/1126 (21.4%) | 251/1145 (21.9%) | 250/1135 (22%) | |||
| Pyrexia | 186/1126 (16.5%) | 185/1145 (16.2%) | 106/1135 (9.3%) | |||
| Mucosal inflammation | 85/1126 (7.5%) | 85/1145 (7.4%) | 57/1135 (5%) | |||
| Temperature intolerance | 61/1126 (5.4%) | 61/1145 (5.3%) | 50/1135 (4.4%) | |||
| Oedema peripheral | 54/1126 (4.8%) | 62/1145 (5.4%) | 45/1135 (4%) | |||
| Immune system disorders | ||||||
| Drug hypersensitivity | 66/1126 (5.9%) | 72/1145 (6.3%) | 32/1135 (2.8%) | |||
| Infections and infestations | ||||||
| Nasopharyngitis | 76/1126 (6.7%) | 92/1145 (8%) | 70/1135 (6.2%) | |||
| Upper respiratory tract infection | 52/1126 (4.6%) | 87/1145 (7.6%) | 55/1135 (4.8%) | |||
| Investigations | ||||||
| Weight increased | 58/1126 (5.2%) | 81/1145 (7.1%) | 68/1135 (6%) | |||
| Weight decreased | 26/1126 (2.3%) | 56/1145 (4.9%) | 61/1135 (5.4%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 268/1126 (23.8%) | 324/1145 (28.3%) | 295/1135 (26%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 63/1126 (5.6%) | 140/1145 (12.2%) | 122/1135 (10.7%) | |||
| Pain in extremity | 63/1126 (5.6%) | 78/1145 (6.8%) | 116/1135 (10.2%) | |||
| Back pain | 79/1126 (7%) | 87/1145 (7.6%) | 66/1135 (5.8%) | |||
| Musculoskeletal pain | 35/1126 (3.1%) | 86/1145 (7.5%) | 46/1135 (4.1%) | |||
| Myalgia | 39/1126 (3.5%) | 70/1145 (6.1%) | 56/1135 (4.9%) | |||
| Nervous system disorders | ||||||
| Peripheral sensory neuropathy | 430/1126 (38.2%) | 430/1145 (37.6%) | 436/1135 (38.4%) | |||
| Paraesthesia | 310/1126 (27.5%) | 328/1145 (28.6%) | 314/1135 (27.7%) | |||
| Neuropathy peripheral | 252/1126 (22.4%) | 234/1145 (20.4%) | 204/1135 (18%) | |||
| Headache | 169/1126 (15%) | 284/1145 (24.8%) | 219/1135 (19.3%) | |||
| Dysgeusia | 237/1126 (21%) | 222/1145 (19.4%) | 152/1135 (13.4%) | |||
| Dysaesthesia | 128/1126 (11.4%) | 106/1145 (9.3%) | 128/1135 (11.3%) | |||
| Dizziness | 102/1126 (9.1%) | 117/1145 (10.2%) | 79/1135 (7%) | |||
| Neurotoxicity | 60/1126 (5.3%) | 69/1145 (6%) | 50/1135 (4.4%) | |||
| Lethargy | 44/1126 (3.9%) | 50/1145 (4.4%) | 59/1135 (5.2%) | |||
| Psychiatric disorders | ||||||
| Insomnia | 135/1126 (12%) | 132/1145 (11.5%) | 91/1135 (8%) | |||
| Anxiety | 45/1126 (4%) | 60/1145 (5.2%) | 61/1135 (5.4%) | |||
| Renal and urinary disorders | ||||||
| Proteinuria | 19/1126 (1.7%) | 73/1145 (6.4%) | 69/1135 (6.1%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Epistaxis | 228/1126 (20.2%) | 424/1145 (37%) | 216/1135 (19%) | |||
| Cough | 86/1126 (7.6%) | 120/1145 (10.5%) | 41/1135 (3.6%) | |||
| Dyspnoea | 57/1126 (5.1%) | 74/1145 (6.5%) | 73/1135 (6.4%) | |||
| Dysphonia | 17/1126 (1.5%) | 91/1145 (7.9%) | 74/1135 (6.5%) | |||
| Dysaesthesia pharynx | 37/1126 (3.3%) | 28/1145 (2.4%) | 79/1135 (7%) | |||
| Oropharyngeal pain | 52/1126 (4.6%) | 59/1145 (5.2%) | 33/1135 (2.9%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Palmar-Plantar Erythrodysaesthesia Syndrome | 98/1126 (8.7%) | 119/1145 (10.4%) | 435/1135 (38.3%) | |||
| Alopecia | 231/1126 (20.5%) | 241/1145 (21%) | 73/1135 (6.4%) | |||
| Rash | 114/1126 (10.1%) | 112/1145 (9.8%) | 110/1135 (9.7%) | |||
| Dry skin | 52/1126 (4.6%) | 66/1145 (5.8%) | 50/1135 (4.4%) | |||
| Pruritus | 36/1126 (3.2%) | 65/1145 (5.7%) | 28/1135 (2.5%) | |||
| Vascular disorders | ||||||
| Hypertension | 196/1126 (17.4%) | 472/1145 (41.2%) | 468/1135 (41.2%) | |||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
| Name/Title | Medical Communications |
|---|---|
| Organization | Hoffman-LaRoche |
| Phone | 800-821-8590 |
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00112918
Other Study ID Numbers:
- CDR0000427299
- P30CA016042
- UCLA-0412086-01
- ROCHE-BO17920A
First Posted:
Jun 3, 2005
Last Update Posted:
Aug 27, 2013
Last Verified:
Jun 1, 2013