Trial Outcomes & Findings for Parenteral Hydration in Advanced Cancer Patients (NCT NCT00423722)

Last Updated: 2024-03-12

Results Overview

Symptom burden, assessed using the Edmonton Symptom assessment scale, which has been validated in the cancer population. Participants are asked to rate the severity of their symptoms over the previous 24 hours using a numerical rating scale of 0-10, with 0 meaning that the symptom is absent and 10 meaning the worst possible symptom. The mean is a composite outcome where change in the sum of 4 dehydration symptoms (fatigue, myoclonus, sedation and hallucinations) between day 4 and baseline ranged from 0-40 daily. The reported value was the mean of average change in patients' scores per group.

Recruitment status

COMPLETED

Study phase

Target enrollment

262 participants

Primary outcome timeframe

From Baseline to 4 Days Later (Daily assessments at 2 hours [+/- 3 hours] after the completion of 4-Hour infusion)

Results posted on

2024-03-12

Participant Flow

Recruitment Period: 01/07/2007 - 05/02/2011. Participating sites included Silverado Hospice, Odyssey Hospice, Vitas Hospice, Houston Hospice and Christus Visiting Nurse Association (VNA) Hospice in the Greater Houston area.

Participant milestones

Participant milestones
Measure	Hydration: Normal Saline (Salt Water) Group 1: 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo: Lower Saline Group 2: Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.
Overall Study STARTED	63	66
Overall Study COMPLETED	49	53
Overall Study NOT COMPLETED	14	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Hydration: Normal Saline (Salt Water) Group 1: 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo: Lower Saline Group 2: Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.
Overall Study Death	4	4
Overall Study Declined to participate	2	3
Overall Study Unable to complete questionnaires	4	4
Overall Study Withdrawal by Subject	4	2

Baseline Characteristics

Parenteral Hydration in Advanced Cancer Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Hydration: Normal Saline (Salt Water) n=63 Participants Group 1: 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo: Lower Saline n=66 Participants Group 2: Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Total n=129 Participants Total of all reporting groups
Age, Continuous	67 years n=5 Participants	67 years n=7 Participants	67 years n=5 Participants
Age, Customized <=18 years	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Age, Customized Between 18 and 65 years	27 participants n=5 Participants	29 participants n=7 Participants	56 participants n=5 Participants
Age, Customized >=65 years	36 participants n=5 Participants	37 participants n=7 Participants	73 participants n=5 Participants
Sex: Female, Male Female	25 Participants n=5 Participants	36 Participants n=7 Participants	61 Participants n=5 Participants
Sex: Female, Male Male	38 Participants n=5 Participants	30 Participants n=7 Participants	68 Participants n=5 Participants
Region of Enrollment United States	63 participants n=5 Participants	66 participants n=7 Participants	129 participants n=5 Participants

PRIMARY outcome

Timeframe: From Baseline to 4 Days Later (Daily assessments at 2 hours [+/- 3 hours] after the completion of 4-Hour infusion)

Outcome measures

Outcome measures
Measure	Hydration n=49 Participants 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo n=53 Participants Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Hydration (Baseline and Day 7) 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo (Baseline and Day 7) Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.
Participant Reduced Symptom Burden	-3.3 units on a scale Standard Deviation 7.6	-2.8 units on a scale Standard Deviation 9.2	—	—

SECONDARY outcome

Timeframe: Baseline to Day 7

Participants rated delirium, quality of life, and overall survival using Richmond agitation sedition scale (RASS) where +4 is "Combative" to -5 is "Unarousable"; Memorial delirium assessment scale (MDAS), a ten-item, clinician-rated scale from 0 (none) to 3 (severe) for severity of delirium, for a total range of 0-30; and Unified Myoclonus Rating Scale (UMRS) 5-functional scores rated 0 to 4, for a total range of 0-20 where higher scores indicate more severe involuntary movements. Higher scores indicate worse outcomes for each scale, i.e. RASS more agitation, MDAS more delirium and UMRS more severe involuntary movements. The mean represents change in combined participant daily scores for each scale between Baseline and Day 4 assessments then separately Day 7 assessments. Reported value is mean of average change in patients' scores per group. Reported values reflect changes from baseline, either median decreases (less than 0), no change (0) or increases (greater than 0).

Outcome measures

Outcome measures
Measure	Hydration n=49 Participants 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo n=53 Participants Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Hydration (Baseline and Day 7) n=49 Participants 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo (Baseline and Day 7) n=53 Participants Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.
Reduced Symptom Burden as Measured by RASS, MDAS and UMRS RASS	0 units on a scale Interval -1.0 to 0.0	0 units on a scale Interval -2.0 to 0.0	0 units on a scale Interval -1.0 to 0.0	-1 units on a scale Interval -2.0 to 0.0
Reduced Symptom Burden as Measured by RASS, MDAS and UMRS MDAS	1 units on a scale Interval -2.0 to 5.8	3.5 units on a scale Interval -0.3 to 14.5	2 units on a scale Interval -2.0 to 10.0	2.5 units on a scale Interval -1.0 to 14.0
Reduced Symptom Burden as Measured by RASS, MDAS and UMRS UMRS	0 units on a scale Interval 0.0 to 3.0	0 units on a scale Interval 0.0 to 8.0	1 units on a scale Interval 0.0 to 5.8	0 units on a scale Interval 0.0 to 5.5

SECONDARY outcome

Timeframe: Baseline to Day 7

Change between Day 7 to Baseline in FACIT-F (Functional Assessment of Chronic illness Therapy-Fatigue) \& FACT-G (Functional Assessment of Cancer Therapy-General) scores. Participants rate quality of life using FACT-G consisting of 33 questions with 5 domains assessing physical and social, emotional \& functional well being \& relationship with physician, remaining 5 assess extent to which each domain affects overall quality of life on 5-point scale from 0 (not at all) to 4 (very much); total score obtained by summing individual subscale scores (0-132). FACIT-F consists of 13 items where participants rate intensity of fatigue \& its related symptoms on a scale of 0-4 from 0 "not at all" to 4 "very much." The responses to FACIT fatigue questionnaire are each measured on 4-point Likert scale with total score ranges from 0 to 52. High scores represent less fatigue. Reported is the mean change of the summed value of all reported scores for the FACT-G or the FACIT-F from baseline to Day 7.

Outcome measures

Outcome measures
Measure	Hydration n=44 Participants 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo n=49 Participants Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Hydration (Baseline and Day 7) 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo (Baseline and Day 7) Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.
Change in Quality of Life and Fatigue as Measured by FACIT-F and FACT-G From Baseline to Day 7 FACT-G	6.7 units on a scale Standard Deviation 11.2	2.6 units on a scale Standard Deviation 16.7	—	—
Change in Quality of Life and Fatigue as Measured by FACIT-F and FACT-G From Baseline to Day 7 FACIT-F	9.1 units on a scale Standard Deviation 17.9	1.4 units on a scale Standard Deviation 25.6	—	—

SECONDARY outcome

Timeframe: Baseline to Day 7 (Daily assessments at 2 hours [+/- 3 hours] after the completion of 4-Hour infusion)

Secondary outcomes included delirium, quality of life, and overall survival. The Nursing delirium screening scale (NuDESC) was used to assess delirium. NuDESC is a validated observational instrument conducted by research staff based on input from family caregivers. Five symptoms (disorientation, inappropriate behavior, inappropriate communication, illusions or hallucinations, and psychomotor retardation) are each given a score from 0 to 2, for a possible total score of 10. A higher NuDESC score indicates increased symptoms of delirium. It was observed a trend for lesser decline (delirium) in the hydration group, and significant worsening of night-time NuDESC scores in the placebo group.

Outcome measures

Outcome measures
Measure	Hydration n=49 Participants 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo n=53 Participants Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Hydration (Baseline and Day 7) n=49 Participants 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo (Baseline and Day 7) n=53 Participants Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.
Reduced Symptom Burden (From Baseline to 7 Days Post Infusion) NuDESC Day	0 units on a scale Interval -1.0 to 1.0	0 units on a scale Interval -1.0 to 2.0	0 units on a scale Interval 0.0 to 0.0	0 units on a scale Interval 0.0 to 1.0
Reduced Symptom Burden (From Baseline to 7 Days Post Infusion) NuDESC Evening	0 units on a scale Interval -1.0 to 1.0	0 units on a scale Interval -1.0 to 2.0	0 units on a scale Interval -1.0 to 1.0	0 units on a scale Interval -1.0 to 3.0
Reduced Symptom Burden (From Baseline to 7 Days Post Infusion) NuDESC Night	0 units on a scale Interval -1.0 to 0.0	0 units on a scale Interval -1.0 to 2.0	0 units on a scale Interval -1.0 to 1.0	0 units on a scale Interval -1.0 to 1.0

SECONDARY outcome

Timeframe: Baseline to Day 7

Dehydration was assessed by using the Dehydration Assessment Scale on the basis of three physical findings, moisture on the mucous membranes of the mouth (0=moist, 1=somewhat dry, 2=dry), axillary moisture (0=moist, 1=dry) and sunkenness of the eyes (0=normal, 1=slight sunken, 2=sunken). These signs are selected due to their significant correlations with biological dehydration, as previously confirmed by elderly patients. The dehydration score (range 0-7) is calculated as the total of these 3 scores, a higher score indicates a higher level of dehydration. The reported value was the mean of average change in patients' scores per group.

Outcome measures

Outcome measures
Measure	Hydration n=49 Participants 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo n=53 Participants Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Hydration (Baseline and Day 7) n=49 Participants 1,000 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.	Placebo (Baseline and Day 7) n=53 Participants Lower Amount of Normal Saline (salt water); 100 ml of normal saline (0.9% sodium chloride) parenterally over 4 hours daily.
Change in Dehydration as Measured by Dehydration Assessment Scale	-0.8 units on a scale Standard Deviation 1.5	-0.6 units on a scale Standard Deviation 1.4	-1.0 units on a scale Standard Deviation 1.7	-0.5 units on a scale Standard Deviation 1.4

Adverse Events

Hydration

Serious events: 18 serious events

Other events: 42 other events

Deaths: 0 deaths

Placebo

Serious events: 13 serious events

Other events: 48 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Eduardo Bruera, MD / Professor

UT MD Anderson Cancer Center

Phone: 713-792-6085

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Hydration n=63 participants at risk Change Between Day 4 and Baseline	Placebo n=66 participants at risk Change Between Day 4 and Baseline
Metabolism and nutrition disorders Anorexia	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Bone pain	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Blood and lymphatic system disorders BUN Increase	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Respiratory, thoracic and mediastinal disorders Dyspnea	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Fatigue	6.3% 4/63 • Number of events 4 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Involuntary Movement	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Nausea	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Pain	3.2% 2/63 • Number of events 2 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Psychiatric disorders Psychosis	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Seizures	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Somnolence	6.3% 4/63 • Number of events 4 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	4.5% 3/66 • Number of events 3 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Investigations Calcium, Serum-high	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Death NOS	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Disease Progression NOS	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.

Measure	Hydration n=63 participants at risk Change Between Day 4 and Baseline	Placebo n=66 participants at risk Change Between Day 4 and Baseline
Metabolism and nutrition disorders Anorexia	15.9% 10/63 • Number of events 11 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	6.1% 4/66 • Number of events 4 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Psychiatric disorders Anxiety	7.9% 5/63 • Number of events 7 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	6.1% 4/66 • Number of events 6 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Musculoskeletal and connective tissue disorders Bone Pain	3.2% 2/63 • Number of events 2 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	3.0% 2/66 • Number of events 2 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Injury, poisoning and procedural complications Bruising	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Blood and lymphatic system disorders BUN increase	3.2% 2/63 • Number of events 2 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	9.1% 6/66 • Number of events 6 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Cardiac disorders Cardiac Arrhytmia	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Psychiatric disorders Confusion	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	3.0% 2/66 • Number of events 3 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Constipation	7.9% 5/63 • Number of events 6 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	6.1% 4/66 • Number of events 5 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Investigations Creatine	1.6% 1/63 • Number of events 2 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Psychiatric disorders Depression	12.7% 8/63 • Number of events 8 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Dizziness	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	4.5% 3/66 • Number of events 3 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Dry mouth	6.3% 4/63 • Number of events 4 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	6.1% 4/66 • Number of events 4 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Dysphagia	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Respiratory, thoracic and mediastinal disorders Dyspnea	15.9% 10/63 • Number of events 12 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	9.1% 6/66 • Number of events 9 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Infections and infestations Dysuria	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	3.0% 2/66 • Number of events 2 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Edema	42.9% 27/63 • Number of events 151 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	37.9% 25/66 • Number of events 100 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Fatigue	20.6% 13/63 • Number of events 17 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	18.2% 12/66 • Number of events 13 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Fever	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Renal and urinary disorders Hematuria	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Hemorrhage	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Renal and urinary disorders Incontinence, Urinary	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Infections and infestations Infection	3.2% 2/63 • Number of events 3 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Involuntary Movement	7.9% 5/63 • Number of events 14 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	10.6% 7/66 • Number of events 7 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Investigations Metabolic/laboratory	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Psychiatric disorders Agitation	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	3.0% 2/66 • Number of events 3 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Nausea	22.2% 14/63 • Number of events 18 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	13.6% 9/66 • Number of events 16 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Neuropathy: Sensory	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
General disorders Pain	17.5% 11/63 • Number of events 20 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	15.2% 10/66 • Number of events 19 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Skin and subcutaneous tissue disorders Pruritus	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	3.0% 2/66 • Number of events 3 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Psychiatric disorders Psychosis	12.7% 8/63 • Number of events 12 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	10.6% 7/66 • Number of events 12 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Respiratory, thoracic and mediastinal disorders Respiratory Symptoms	1.6% 1/63 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	0.00% 0/66 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Somnolence	19.0% 12/63 • Number of events 20 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	22.7% 15/66 • Number of events 23 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Vomiting	6.3% 4/63 • Number of events 5 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	3.0% 2/66 • Number of events 2 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	4.5% 3/66 • Number of events 3 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Ascites	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Investigations Calcium-Serum high	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	3.0% 2/66 • Number of events 2 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Consciousness level depressed	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Diarrhea	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	4.5% 3/66 • Number of events 3 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Skin and subcutaneous tissue disorders Dry Skin	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Ear and labyrinth disorders Earache	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Skin and subcutaneous tissue disorders Erythema Multiforme	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Gastritis	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Hallucinations	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Heartburn	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Gastrointestinal disorders Hemorrhoids	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 3 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Respiratory, thoracic and mediastinal disorders Hiccoughs	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Psychiatric disorders Insomnia	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Blood and lymphatic system disorders Jaundice	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Musculoskeletal and connective tissue disorders Muscle weakness	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Nervous system disorders Neurology	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Skin and subcutaneous tissue disorders Rash/Desquamation	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 2 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.
Renal and urinary disorders Urine color change	0.00% 0/63 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.	1.5% 1/66 • Number of events 1 • Adverse event reporting collected an average of 7 days, up to 10 days for participant study period from January 2007 to May 2011.