Study to Evaluate the Efficacy and Safety of Eribulin Mesylate Administered Biweekly (Q2W) for Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Metastatic Breast Cancer

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02481050
• Collaborator: (none)
• Enrollment: 58
• Locations: 12
• Arm: 1
• Actual Duration (Months): 26.7
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a Phase 2, open-label, single arm, multicenter, 2-stage study of eribulin mesylate administered biweekly at 1.4 mg/m2 intravenously for the treatment of participants with HER2-negative metastatic breast cancer previously treated with 2 to 5 chemotherapy regimens.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Eribulin Mesylate	Phase 2

Detailed Description

This is a Phase 2, open-label, single arm, multicenter, 2-stage study of eribulin mesylate administered biweekly at 1.4 mg/m2 intravenously for the treatment of participants with HER2-negative metastatic breast cancer previously treated with 2 to 5 chemotherapy regimens. The study will be conducted in 3 Phases: a Pretreatment Phase (screening visit), a Treatment Phase (starting with Cycle 1 Day 1), and a Posttreatment Phase (End of treatment visit and survival follow up). Participants may remain on study drug as long as they demonstrate clinical benefit or until intercurrent illness, unacceptable toxicity, or disease progression occurs, until the participant withdraws consent, or death.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Eribulin Mesylate Administered Biweekly (Q2W) for Subjects With Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Metastatic Breast Cancer
• Actual Study Start Date: Jun 16, 2015
• Actual Primary Completion Date: Dec 31, 2016
• Actual Study Completion Date: Sep 5, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eribulin Mesylate Participants with metastatic HER2-negative breast cancer previously treated with 2 to 5 chemotherapy regimens.	Drug: Eribulin Mesylate; Eribulin Mesylate will be administered as a 1.4 mg/m2 intravenous (IV) injection over 2 to 5 minutes biweekly on Day 1 and Day 15 of each 28-day cycle.; Other Names: Halaven, E7389

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) by Investigator Assessment [From first dose of study drug until intercurrent illness, unacceptable toxicity, disease progression, or until the participant withdrew consent (approximately up to 2.3 years)]

   ORR was defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) measured by response evaluation criteria in solid tumors (RECIST) 1.1. CR defined as disappearance of all target lesions (a short diameter is less than [<] 10 millimeter [mm] if it exists in a lymph node). PR defined as at least 30 percent (%) decrease in the sum of the long diameter (LD) of all target lesions, as compared with Baseline summed LD.

2. Disease Control Rate (DCR) by Investigator Assessment [From first dose of study drug until intercurrent illness, unacceptable toxicity, disease progression, or until the participant withdrew consent (approximately up to 2.3 years)]

   DCR was defined as the percentage of participants who had BOR of CR, PR, or stable disease (SD) measured by RECIST 1.1. CR defined as disappearance of all target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD of all target lesions, as compared with Baseline summed LD. SD defined as reduction in tumor volume of less than 50% or an increase in the volume of 1 or more measurable lesions of less than 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to disease progression. SD must be achieved at greater than equal to (>=) 7 weeks after the first eribulin administration to be considered BOR.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) by Investigator Assessment [From first dose of study drug until intercurrent illness, unacceptable toxicity, disease progression, or until the participant withdrew consent (approximately up to 2.3 years)]

   PFS was defined as the time from date of first dose of study drug to the date of disease progression or death, whichever occurred first.

2. Overall Survival (OS) [From date of first dose of study drug administration until date of death from any cause (approximately up to 2.3 years)]

   OS was defined as the time from date of first dose of study drug until date of death from any cause.

3. Feasibility Rate [Cycle 2 Day 28 and Cycle 4 Day 28 ( cycle length=28 days)]

   Feasibility rate is defined as the percentage of participants completing the first 2 and 4 cycles (1 cycle = 28 days) of eribulin mesylate treatment (4 and 8 doses) without requiring dose delay greater than (>) 5 days or reduction due to adverse event (AE).

4. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 2.3 years)]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Histological or cytological adenocarcinoma of the breast.

2. Females, aged greater than or equal to 18 years at time of informed consent.

3. HER2-negative as determined by fluorescence in situ hybridization (FISH); or 0 or 1+ by immunohistochemistry (IHC) staining .

4. Participants with metastatic breast cancer who have received at least 2 and not more than 5 prior chemotherapy regimens.

5. Participants with at least one measurable lesion greater than or equal to 10 mm in the longest diameter for a non-lymph node or greater than or equal to 15 mm in the short-axis diameter for a lymph node as determined by investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).

6. Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 2.

7. Life expectancy of greater than or equal to 3 months.

8. Any neuropathy must recover to Grade less than or equal to 2 prior to enrollment.

9. Adequate renal function as evidenced by serum creatinine less than or equal to 1.5 mg/dL or calculated creatinine clearance greater than or equal to 50 mL/minute according to the Cockcroft and Gault formula.

10. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 X 10^{9/L, hemoglobin greater than or equal to 10.0 g/dL (can be corrected by growth factor or transfusion), and platelet count greater than or equal to 100 X 10}9/L.

11. Adequate liver function as evidenced by total bilirubin less than or equal to 1.5 X upper limit of normal (ULN), alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 X ULN (less than or equal to 5 X ULN in the case of liver metastases), unless there are bone metastases, in which case liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase.

12. Are willing and able to comply with all aspects of the treatment protocol.

13. Provide written informed consent.

Exclusion Criteria:

1. Previous treatment with eribulin.

2. Hypersensitivity to eribulin/excipients or halichondrin B or known intolerance of eribulin.

3. Current enrollment in another clinical study or used of any investigational drug or device within the past 28 days preceding informed consent.

4. Previous treatment with chemotherapy, radiation, biological, or targeted therapy within the last 2 weeks or 5 X half-life, whichever is longer, preceding informed consent.

5. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin ([B-hCG] test). A separate Baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.

6. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).

7. Females of childbearing potential who had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period or for 28 days after study drug discontinuation.

Females who are currently abstinent and do not agree to use a double barrier method as described above or to refrain from sexual activity during the study period or for 28 days after study drug discontinuation.

Females who are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study or for 28 days after study drug discontinuation.

1. Known central nervous system (CNS) disease, except for those participants with treated brain metastasis who are stable for at least 1 month with no evidence of progression or hemorrhage after treatment and no ongoing requirement for corticosteroids.

2. Known human immunodeficiency virus (HIV) positive.

3. Existing anticancer, therapy-related toxicities of Grades greater than or equal to 2, with the exception of alopecia.

4. A prior malignancy other than carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated greater than 5 years previously with no subsequent evidence of recurrence.

5. Clinically significant cardiovascular impairment (congestive heart failure of New York Heart Association [NYHA] Classification greater than II, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia).

6. Clinically significant ECG abnormality, including a marked Baseline prolonged QT/QTc interval (ie, a repeated demonstration of a QTc interval greater than 500 milliseconds).

7. Pulmonary lymphangitic involvement that resulted in pulmonary dysfunction requiring active treatment, including the use of oxygen.

8. History of concomitant medical condition(s) that, in the opinion of the investigator, would compromise the participant's ability to safely complete the study.

9. The investigator's belief that the participant is medically unfit to receive eribulin or unsuitable for any other reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Facility #1	Denver	Colorado	United States	80218
2	Facility #1	Columbia	Maryland	United States	21044
3	Facility #1	Omaha	Nebraska	United States	68130
4	Facility #1	Albany	New York	United States	12206
5	Facility #1	Portland	Oregon	United States	97213
6	Facility #1	Dallas	Texas	United States	75231
7	Facility #2	Dallas	Texas	United States	75246
8	Facility #1	Houston	Texas	United States	77024
9	Facility #1	San Antonio	Texas	United States	78217
10	Facility #1	Tyler	Texas	United States	75702
11	Facility #1	Leesburg	Virginia	United States	20176
12	Facility #1	Winchester	Virginia	United States	22601

Sponsors and Collaborators

• Eisai Inc.

Investigators

• Study Director: Sam Misir, Eisai Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT02481050
• Other Study ID Numbers: E7389-M001-216
• First Posted: Jun 25, 2015
• Last Update Posted: Nov 15, 2018
• Last Verified: Jan 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Keywords provided by Eisai Inc.: Eribulin Mesylate; Human Epidermal Growth Factor Receptor 2; Metastatic Breast Cancer; HER2-Negative
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 12 investigative sites in the United States from 16 June 2015 to 05 September 2017.
Pre-assignment Detail	A total of 74 participants were screened, of which 16 were screen failures and 58 were randomized to receive study treatment.

Arm/Group Title	Eribulin Mesylate 1.4 mg/m^2
Arm/Group Description	Participants with histologically confirmed human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) who were previously treated with 2 to 5 chemotherapy regimens received eribulin mesylate 1.4 milligram per square meter (mg/m^2), intravenous infusion over 2 to 5 minutes on Day 1 and Day 15 of each 28-days treatment cycle until intercurrent illness, unacceptable toxicity, disease progression occurred, or until the participant withdrew consent (up to 16 cycles).
Period Title: Overall Study
STARTED	58
COMPLETED	0
NOT COMPLETED	58

Baseline Characteristics

Arm/Group Title	Eribulin Mesylate 1.4 mg/m^2
Arm/Group Description	Participants with histologically confirmed HER2-negative MBC who were previously treated with 2 to 5 chemotherapy regimens received eribulin mesylate 1.4 mg/m^2, intravenous infusion over 2 to 5 minutes on Day 1 and Day 15 of each 28-days treatment cycle until intercurrent illness, unacceptable toxicity, disease progression occurred, or until the participant withdrew consent (up to 16 cycles).
Overall Participants	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.2 (9.08)
Sex: Female, Male (Count of Participants)
Female	58 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 6.9%
Not Hispanic or Latino	49 84.5%
Unknown or Not Reported	5 8.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.7%
Asian	3 5.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 8.6%
White	45 77.6%
More than one race	0 0%
Unknown or Not Reported	4 6.9%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR) by Investigator Assessment
Description	ORR was defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) measured by response evaluation criteria in solid tumors (RECIST) 1.1. CR defined as disappearance of all target lesions (a short diameter is less than [<] 10 millimeter [mm] if it exists in a lymph node). PR defined as at least 30 percent (%) decrease in the sum of the long diameter (LD) of all target lesions, as compared with Baseline summed LD.
Time Frame	From first dose of study drug until intercurrent illness, unacceptable toxicity, disease progression, or until the participant withdrew consent (approximately up to 2.3 years)

Outcome Measure Data

Analysis Population Description

The evaluable analysis set (EAS) included all participants who had both an evaluable baseline tumor assessment and an evaluable postbaseline tumor assessment, unless the participants discontinued because of disease progression or toxicity.

Arm/Group Title	Eribulin Mesylate 1.4 mg/m^2
Arm/Group Description	Participants with histologically confirmed HER2-negative MBC who were previously treated with 2 to 5 chemotherapy regimens received eribulin mesylate 1.4 mg/m^2, intravenous infusion over 2 to 5 minutes on Day 1 and Day 15 of each 28-days treatment cycle until intercurrent illness, unacceptable toxicity, disease progression occurred, or until the participant withdrew consent (up to 16 cycles).
Measure Participants	57
Number (95% Confidence Interval) [percentage of participants]	12.3 21.2%

2. Primary Outcome

Title	Disease Control Rate (DCR) by Investigator Assessment
Description	DCR was defined as the percentage of participants who had BOR of CR, PR, or stable disease (SD) measured by RECIST 1.1. CR defined as disappearance of all target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD of all target lesions, as compared with Baseline summed LD. SD defined as reduction in tumor volume of less than 50% or an increase in the volume of 1 or more measurable lesions of less than 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to disease progression. SD must be achieved at greater than equal to (>=) 7 weeks after the first eribulin administration to be considered BOR.
Time Frame	From first dose of study drug until intercurrent illness, unacceptable toxicity, disease progression, or until the participant withdrew consent (approximately up to 2.3 years)

Outcome Measure Data

Analysis Population Description

The EAS included all participants who had both an evaluable baseline tumor assessment and an evaluable postbaseline tumor assessment, unless the participants discontinued because of disease progression or toxicity.

Arm/Group Title	Eribulin Mesylate 1.4 mg/m^2
Arm/Group Description	Participants with histologically confirmed HER2-negative MBC who were previously treated with 2 to 5 chemotherapy regimens received eribulin mesylate 1.4 mg/m^2, intravenous infusion over 2 to 5 minutes on Day 1 and Day 15 of each 28-days treatment cycle until intercurrent illness, unacceptable toxicity, disease progression occurred, or until the participant withdrew consent (up to 16 cycles).
Measure Participants	57
Number (95% Confidence Interval) [percentage of participants]	64.9 111.9%

3. Secondary Outcome

Title	Progression-Free Survival (PFS) by Investigator Assessment
Description	PFS was defined as the time from date of first dose of study drug to the date of disease progression or death, whichever occurred first.
Time Frame	From first dose of study drug until intercurrent illness, unacceptable toxicity, disease progression, or until the participant withdrew consent (approximately up to 2.3 years)

Outcome Measure Data

Analysis Population Description

The FAS included all participants who received any amount of study drug.

Arm/Group Title	Eribulin Mesylate 1.4 mg/m^2
Arm/Group Description	Participants with histologically confirmed HER2-negative MBC who were previously treated with 2 to 5 chemotherapy regimens received eribulin mesylate 1.4 mg/m^2, intravenous infusion over 2 to 5 minutes on Day 1 and Day 15 of each 28-days treatment cycle until intercurrent illness, unacceptable toxicity, disease progression occurred, or until the participant withdrew consent (up to 16 cycles).
Measure Participants	58
Median (95% Confidence Interval) [months]	3.6

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from date of first dose of study drug until date of death from any cause.
Time Frame	From date of first dose of study drug administration until date of death from any cause (approximately up to 2.3 years)

Outcome Measure Data

Analysis Population Description

The FAS included all participants who received any amount of study drug.

Arm/Group Title	Eribulin Mesylate 1.4 mg/m^2
Arm/Group Description	Participants with histologically confirmed HER2-negative MBC who were previously treated with 2 to 5 chemotherapy regimens received eribulin mesylate 1.4 mg/m^2, intravenous infusion over 2 to 5 minutes on Day 1 and Day 15 of each 28-days treatment cycle until intercurrent illness, unacceptable toxicity, disease progression occurred, or until the participant withdrew consent (up to 16 cycles).
Measure Participants	58
Median (95% Confidence Interval) [months]	12.9

5. Secondary Outcome

Title	Feasibility Rate
Description	Feasibility rate is defined as the percentage of participants completing the first 2 and 4 cycles (1 cycle = 28 days) of eribulin mesylate treatment (4 and 8 doses) without requiring dose delay greater than (>) 5 days or reduction due to adverse event (AE).
Time Frame	Cycle 2 Day 28 and Cycle 4 Day 28 ( cycle length=28 days)

Outcome Measure Data

Analysis Population Description

The FAS included all participants who received any amount of study drug. The FAS where data at specified timepoints was available.

Arm/Group Title	Eribulin Mesylate 1.4 mg/m^2
Arm/Group Description	Participants with histologically confirmed HER2-negative MBC who were previously treated with 2 to 5 chemotherapy regimens received eribulin mesylate 1.4 mg/m^2, intravenous infusion over 2 to 5 minutes on Day 1 and Day 15 of each 28-days treatment cycle until intercurrent illness, unacceptable toxicity, disease progression occurred, or until the participant withdrew consent (up to 16 cycles).
Measure Participants	58
First 2 cycles	69.8 120.3%
First 4 cycles	50.0 86.2%

6. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame	From first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 2.3 years)

Outcome Measure Data

Analysis Population Description

The FAS included all participants who received any amount of study drug.

Arm/Group Title	Eribulin Mesylate 1.4 mg/m^2
Arm/Group Description	Participants with histologically confirmed HER2-negative MBC who were previously treated with 2 to 5 chemotherapy regimens received eribulin mesylate 1.4 mg/m^2, intravenous infusion over 2 to 5 minutes on Day 1 and Day 15 of each 28-days treatment cycle until intercurrent illness, unacceptable toxicity, disease progression occurred, or until the participant withdrew consent (up to 16 cycles).
Measure Participants	58
TEAE	58 100%
SAE	14 24.1%

Adverse Events

Time Frame	From first dose of study drug (Baseline) up to 30 days after last dose of study drug (approximately up to 2.3 years)
Arm/Group Title	Eribulin Mesylate 1.4 mg/m^2
Arm/Group Description	Participants with histologically confirmed HER2-negative MBC who were previously treated with 2 to 5 chemotherapy regimens received eribulin mesylate 1.4 mg/m^2, intravenous infusion over 2 to 5 minutes on Day 1 and Day 15 of each 28-days treatment cycle until intercurrent illness, unacceptable toxicity, disease progression occurred, or until the participant withdrew consent (up to 16 cycles).
All Cause Mortality
	Eribulin Mesylate 1.4 mg/m^2
	Affected / at Risk (%)	# Events
Total	40/58 (69%)
Serious Adverse Events
	Eribulin Mesylate 1.4 mg/m^2
	Affected / at Risk (%)	# Events
Total	14/58 (24.1%)
Gastrointestinal disorders
Constipation	1/58 (1.7%)
Vomiting	1/58 (1.7%)
Upper gastrointestinal haemorrhage	1/58 (1.7%)
General disorders
Asthenia	1/58 (1.7%)
Chest pain	1/58 (1.7%)
Pain	1/58 (1.7%)
Infections and infestations
Sepsis	2/58 (3.4%)
Injury, poisoning and procedural complications
Fall	1/58 (1.7%)
Spinal compression fracture	1/58 (1.7%)
Investigations
Neutrophil count decreased	1/58 (1.7%)
Metabolism and nutrition disorders
Dehydration	1/58 (1.7%)
Hypovolaemia	1/58 (1.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	2/58 (3.4%)
Nervous system disorders
Paraesthesia	1/58 (1.7%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/58 (1.7%)
Dyspnoea	1/58 (1.7%)
Pulmonary embolism	1/58 (1.7%)
Other (Not Including Serious) Adverse Events
	Eribulin Mesylate 1.4 mg/m^2
	Affected / at Risk (%)	# Events
Total	58/58 (100%)
Blood and lymphatic system disorders
Anaemia	6/58 (10.3%)
Leukopenia	3/58 (5.2%)
Neutropenia	25/58 (43.1%)
Thrombocytopenia	3/58 (5.2%)
Lymphadenopathy	1/58 (1.7%)
Cardiac disorders
Acute myocardial infarction	1/58 (1.7%)
Cardiac failure congestive	1/58 (1.7%)
Coronary artery disease	2/58 (3.4%)
Palpitations	3/58 (5.2%)
Tachycardia	1/58 (1.7%)
Ear and labyrinth disorders
Deafness unilateral	1/58 (1.7%)
Ear discomfort	1/58 (1.7%)
Ear pain	1/58 (1.7%)
Tinnitus	1/58 (1.7%)
Vestibular disorder	1/58 (1.7%)
Eye disorders
Cataract	1/58 (1.7%)
Conjunctival haemorrhage	1/58 (1.7%)
Eye irritation	1/58 (1.7%)
Eye swelling	1/58 (1.7%)
Eyelids pruritus	1/58 (1.7%)
Lacrimation increased	7/58 (12.1%)
Ocular hyperaemia	1/58 (1.7%)
Vision blurred	2/58 (3.4%)
Gastrointestinal disorders
Abdominal distension	3/58 (5.2%)
Abdominal pain	6/58 (10.3%)
Abdominal pain upper	4/58 (6.9%)
Constipation	22/58 (37.9%)
Diarrhoea	14/58 (24.1%)
Dry mouth	3/58 (5.2%)
Dyspepsia	6/58 (10.3%)
Gastritis	2/58 (3.4%)
Gastrointestinal pain	1/58 (1.7%)
Gastrooesophageal reflux disease	2/58 (3.4%)
Gingival pain	1/58 (1.7%)
Haemorrhoidal haemorrhage	1/58 (1.7%)
Loose tooth	2/58 (3.4%)
Mouth ulceration	1/58 (1.7%)
Nausea	17/58 (29.3%)
Stomatitis	14/58 (24.1%)
Toothache	3/58 (5.2%)
Vomiting	7/58 (12.1%)
Lip pain	1/58 (1.7%)
General disorders
Asthenia	2/58 (3.4%)
Chills	3/58 (5.2%)
Early satiety	2/58 (3.4%)
Face oedema	1/58 (1.7%)
Fatigue	32/58 (55.2%)
Gait disturbance	3/58 (5.2%)
Localised oedema	1/58 (1.7%)
Non-cardiac chest pain	1/58 (1.7%)
Oedema peripheral	8/58 (13.8%)
Pain	2/58 (3.4%)
Peripheral swelling	1/58 (1.7%)
Pyrexia	7/58 (12.1%)
Hepatobiliary disorders
Cholelithiasis	1/58 (1.7%)
Immune system disorders
Contrast media allergy	1/58 (1.7%)
Drug hypersensitivity	2/58 (3.4%)
Infections and infestations
Bronchitis viral	1/58 (1.7%)
Conjunctivitis	1/58 (1.7%)
Cystitis	1/58 (1.7%)
Diverticulitis	1/58 (1.7%)
Ear infection	1/58 (1.7%)
Eye infection	1/58 (1.7%)
Hepatitis B	1/58 (1.7%)
Herpes zoster	2/58 (3.4%)
Hordeolum	1/58 (1.7%)
Lung infection	1/58 (1.7%)
Nasopharyngitis	1/58 (1.7%)
Oral candidiasis	2/58 (3.4%)
Oral herpes	1/58 (1.7%)
Peritonitis	1/58 (1.7%)
Pneumonia	2/58 (3.4%)
Sinusitis	3/58 (5.2%)
Skin bacterial infection	1/58 (1.7%)
Tooth abscess	1/58 (1.7%)
Upper respiratory tract infection	4/58 (6.9%)
Urinary tract infection	6/58 (10.3%)
Injury, poisoning and procedural complications
Arthropod bite	1/58 (1.7%)
Contusion	1/58 (1.7%)
Fall	8/58 (13.8%)
Fibula fracture	1/58 (1.7%)
Foot fracture	1/58 (1.7%)
Joint injury	1/58 (1.7%)
Ligament sprain	1/58 (1.7%)
Patella fracture	2/58 (3.4%)
Upper limb fracture	2/58 (3.4%)
Investigations
Aspartate aminotransferase increased	1/58 (1.7%)
Blood alkaline phosphatase increased	2/58 (3.4%)
Blood bilirubin increased	1/58 (1.7%)
Blood pressure diastolic decreased	1/58 (1.7%)
Lymphocyte count decreased	1/58 (1.7%)
Neutrophil count decreased	22/58 (37.9%)
Platelet count decreased	2/58 (3.4%)
Troponin increased	1/58 (1.7%)
Weight decreased	5/58 (8.6%)
Weight increased	1/58 (1.7%)
White blood cell count decreased	4/58 (6.9%)
Metabolism and nutrition disorders
Decreased appetite	11/58 (19%)
Dehydration	4/58 (6.9%)
Hyperglycaemia	1/58 (1.7%)
Hyperkalaemia	1/58 (1.7%)
Hypermagnesaemia	1/58 (1.7%)
Hypoalbuminaemia	2/58 (3.4%)
Hypocalcaemia	1/58 (1.7%)
Hypokalaemia	4/58 (6.9%)
Hypomagnesaemia	8/58 (13.8%)
Hyponatraemia	1/58 (1.7%)
Lactic acidosis	2/58 (3.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/58 (13.8%)
Arthritis	1/58 (1.7%)
Back pain	7/58 (12.1%)
Bone pain	6/58 (10.3%)
Bursitis	1/58 (1.7%)
Intervertebral disc degeneration	1/58 (1.7%)
Joint swelling	1/58 (1.7%)
Muscle spasms	3/58 (5.2%)
Muscular weakness	5/58 (8.6%)
Musculoskeletal chest pain	6/58 (10.3%)
Musculoskeletal pain	10/58 (17.2%)
Myalgia	6/58 (10.3%)
Neck pain	3/58 (5.2%)
Pain in extremity	4/58 (6.9%)
Pain in jaw	1/58 (1.7%)
Temporomandibular joint syndrome	1/58 (1.7%)
Tendonitis	1/58 (1.7%)
Tenosynovitis stenosans	1/58 (1.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	2/58 (3.4%)
Malignant pleural effusion	2/58 (3.4%)
Nervous system disorders
Amnesia	2/58 (3.4%)
Balance disorder	1/58 (1.7%)
Disturbance in attention	1/58 (1.7%)
Dizziness	4/58 (6.9%)
Dysaesthesia	1/58 (1.7%)
Dysgeusia	6/58 (10.3%)
Headache	7/58 (12.1%)
Hypoaesthesia	4/58 (6.9%)
Neuralgia	2/58 (3.4%)
Peripheral motor neuropathy	2/58 (3.4%)
Peripheral sensorimotor neuropathy	1/58 (1.7%)
Peripheral sensory neuropathy	19/58 (32.8%)
Peroneal nerve palsy	1/58 (1.7%)
Psychomotor hyperactivity	2/58 (3.4%)
Syncope	1/58 (1.7%)
Product Issues
Device occlusion	1/58 (1.7%)
Psychiatric disorders
Anxiety	1/58 (1.7%)
Confusional state	1/58 (1.7%)
Depression	3/58 (5.2%)
Insomnia	3/58 (5.2%)
Panic attack	1/58 (1.7%)
Renal and urinary disorders
Acute kidney injury	1/58 (1.7%)
Bladder prolapse	2/58 (3.4%)
Dysuria	1/58 (1.7%)
Pollakiuria	1/58 (1.7%)
Proteinuria	1/58 (1.7%)
Urinary incontinence	1/58 (1.7%)
Reproductive system and breast disorders
Breast pain	1/58 (1.7%)
Respiratory, thoracic and mediastinal disorders
Cough	9/58 (15.5%)
Dysphonia	2/58 (3.4%)
Dyspnoea	11/58 (19%)
Dyspnoea exertional	2/58 (3.4%)
Epistaxis	3/58 (5.2%)
Oropharyngeal pain	3/58 (5.2%)
Paranasal sinus discomfort	1/58 (1.7%)
Pleural effusion	1/58 (1.7%)
Rhinitis allergic	1/58 (1.7%)
Rhinorrhoea	1/58 (1.7%)
Sinus congestion	1/58 (1.7%)
Upper-airway cough syndrome	1/58 (1.7%)
Wheezing	2/58 (3.4%)
Skin and subcutaneous tissue disorders
Alopecia	29/58 (50%)
Blister	1/58 (1.7%)
Dry skin	3/58 (5.2%)
Ecchymosis	2/58 (3.4%)
Erythema	2/58 (3.4%)
Erythema multiforme	1/58 (1.7%)
Nail discolouration	2/58 (3.4%)
Night sweats	2/58 (3.4%)
Onychoclasis	1/58 (1.7%)
Onychomadesis	1/58 (1.7%)
Palmar-plantar erythrodysaesthesia syndrome	1/58 (1.7%)
Pruritus	3/58 (5.2%)
Rash	1/58 (1.7%)
Rash maculo-papular	2/58 (3.4%)
Skin tightness	1/58 (1.7%)
Swelling face	1/58 (1.7%)
Vascular disorders
Flushing	1/58 (1.7%)
Hot flush	4/58 (6.9%)
Hypertension	3/58 (5.2%)
Thrombosis	1/58 (1.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.