Trial Outcomes & Findings for Acupuncture-Like Transcutaneous Electrical Nerve Stimulation (ALTENS) or Pilocarpine in Treating Early Dry Mouth in Patients Undergoing Radiation Therapy for Head and Neck Cancer (NCT NCT00656513)

Last Updated: 2019-11-19

Results Overview

Patients completing at least 19 out of 24 ALTENS therapy sessions were categorized as compliant. Fleming's two-stage was used, assuming a successful target compliance rate of 80%, statistical power of 0.87, and a type I error rate of 0.13. If fewer than 9 of the first 13 patients were compliant, then treatment delivery will be deemed not feasible. If there were between 9-12 compliant patients, the second stage analysis would be required to determine feasibility of treatment delivery. If all 13 patients are compliant, treatment delivery will immediately be deemed feasible. The second stage analysis required at least 31 compliant out of 39 overall patients for the treatment delivery to be deemed feasible.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

196 participants

Primary outcome timeframe

Randomization to 12 weeks

Results posted on

2019-11-19

Participant Flow

Participant milestones

Participant milestones
Measure	ALTENS: Phase II Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	Pilocarpine: Phase III 5mg pilocarpine by mouth 3 times a day for 12 weeks	ALTENS: Phase III Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Overall Study STARTED	48	73	75
Overall Study COMPLETED	44	43	53
Overall Study NOT COMPLETED	4	30	22

Reasons for withdrawal

Reasons for withdrawal
Measure	ALTENS: Phase II Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	Pilocarpine: Phase III 5mg pilocarpine by mouth 3 times a day for 12 weeks	ALTENS: Phase III Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Overall Study Protocol Violation	1	0	2
Overall Study Withdrawal by Subject	0	11	4
Overall Study Death	0	0	1
Overall Study Missing data	0	11	9
Overall Study Incomplete treatment	3	0	0
Overall Study Treatment completed outside of timeframe	0	3	1
Overall Study Missing baseline form	0	5	5

Baseline Characteristics

Acupuncture-Like Transcutaneous Electrical Nerve Stimulation (ALTENS) or Pilocarpine in Treating Early Dry Mouth in Patients Undergoing Radiation Therapy for Head and Neck Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ALTENS: Phase II n=47 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	Pilocarpine: Phase III n=73 Participants 5mg pilocarpine by mouth 3 times a day for 12 weeks	ALTENS: Phase III n=73 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	Total n=193 Participants Total of all reporting groups
Age, Continuous	60 years n=5 Participants	59 years n=7 Participants	58 years n=5 Participants	58 years n=4 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	10 Participants n=7 Participants	11 Participants n=5 Participants	28 Participants n=4 Participants
Sex: Female, Male Male	40 Participants n=5 Participants	63 Participants n=7 Participants	62 Participants n=5 Participants	165 Participants n=4 Participants

PRIMARY outcome

Timeframe: Randomization to 12 weeks

Population: Eligible patients starting protocol treatment

Outcome measures

Outcome measures
Measure	ALTENS: Phase II n=47 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	ALTENS: Phase III Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Phase II: Treatment Compliance (Number of Compliant Patients) First Stage	12 Participants	—
Phase II: Treatment Compliance (Number of Compliant Patients) Second Stage (Overall)	44 Participants	—

PRIMARY outcome

Timeframe: Baseline (randomization) and 9 months

Population: Eligible randomized patients with both baseline and 9 month XeQOLS scores

Xerostomia burden is measured by the University of Michigan Xerostomia Related Quality of Life Scale (XeQOLS). The XeQOLS is a validated patient-reported 15-item assessment scale with 4 domains: physical functioning,pain/discomfort, personal/psychologic functioning, and social functioning.The score is the average of all responses of all domains and can range from 0 to 4, with higher scores indicating increased xerostomia burden. Change in xerostomia burden is calculated by subtracting the baseline score from the 9-month score such that a negative change indicates an improvement of the xerostomia burden.

Outcome measures

Outcome measures
Measure	ALTENS: Phase II n=43 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	ALTENS: Phase III n=53 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Phase III: Change From Baseline in Overall Xerostomia Burden at 9 Months	-0.27 units on a scale Interval -1.06 to 0.0	-0.53 units on a scale Interval -0.87 to -0.2

SECONDARY outcome

Timeframe: Pre-treatment and 6 months from registration

Population: Eligible patients who started treatment and have both baseline and 6-month XeQOLS scores

This secondary objective was to evaluate the effect of ALTENS treatment on overall radiation-induced xerostomia burden by looking at treatment response. Treatment response was determined by a reduction of at least 20% from baseline to 6 months in the University of Michigan Xerostomia Related Quality of Life Scale (XeQOLS). The XeQOLS is a validated patient-reported 15-item assessment scale with 4 domains: physical functioning,pain/discomfort, personal/psychologic functioning, and social functioning.The score is the average of all responses of all domains and can range from 0 to 4. Higher scores indicate increased xerostomia burden. This scale has high reproducibility and sensitivity. For the first and second stage analyses, 4 and 10 patients, respectively, must respond to treatment in order to proceed to the phase III component.

Outcome measures

Outcome measures
Measure	ALTENS: Phase II n=35 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	ALTENS: Phase III Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Phase II: Pecentage of Patients With Beneficial Treatment Response	85.7 percentage of participants Interval 84.9 to 86.5	—

SECONDARY outcome

Timeframe: Baseline, 4, 6, and 15 months from randomization

Population: Eligible patients with both baseline and respective follow-up (4,6,15 months) XeQOLS scores.

Outcome measures

Outcome measures
Measure	ALTENS: Phase II n=67 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	ALTENS: Phase III n=63 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Change From Baseline in Overall Xerostomia Burden at 4, 6, and 15 Months (Phase III) 4 months	-0.27 units on a scale Interval -0.6 to 0.0	-0.47 units on a scale Interval -0.8 to -0.13
Change From Baseline in Overall Xerostomia Burden at 4, 6, and 15 Months (Phase III) 6 months	-0.33 units on a scale Interval -0.73 to -0.2	-0.4 units on a scale Interval -0.87 to -0.14
Change From Baseline in Overall Xerostomia Burden at 4, 6, and 15 Months (Phase III) 15 months	-0.47 units on a scale Interval -0.87 to -0.07	-0.6 units on a scale Interval -1.0 to -0.2

SECONDARY outcome

Timeframe: Baseline, 4, 6, 9 and 15 months from randomization

Population: Eligible patients with both baseline and respective follow-up (4,6, 9,15 months) XeQOLS scores.

Symptom burden is measured by the University of Michigan Xerostomia Related Quality of Life Scale (XeQOLS). The XeQOLS is a validated patient-reported 15-item assessment scale with 4 domains: physical functioning,pain/discomfort, personal/psychologic functioning, and social functioning. The domain score is the average of all responses on a given domain and can range from 0 to 4, with higher scores indicating increased symptom burden. Change in symptom burden is calculated by subtracting the baseline score from the 9-month score such that a negative change indicates an improvement of the symptom burden.

Outcome measures

Outcome measures
Measure	ALTENS: Phase II n=67 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	ALTENS: Phase III n=63 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 9-month Personal/Psychological Functioning	-0.5 units on a scale Interval -1.0 to 0.25	-0.75 units on a scale Interval -1.0 to -0.25
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 9-month Social Functioning	-0.66 units on a scale Interval -1.0 to 0.33	-0.33 units on a scale Interval -0.67 to 0.0
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 15-month Physical Functioning	-0.5 units on a scale Interval -1.0 to 0.0	-0.75 units on a scale Interval -1.25 to -0.25
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 4-month Physical Functioning	-0.5 units on a scale Interval -0.75 to 0.0	-0.5 units on a scale Interval -0.75 to 0.0
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 4-month Pain/Discomfort	-0.25 units on a scale Interval -0.75 to 0.0	-0.375 units on a scale Interval -1.0 to 0.125
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 4-month Personal/Psychological Functioning	-0.25 units on a scale Interval -0.5 to 0.25	-0.5 units on a scale Interval -0.875 to -0.125
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 4-month Social Functioning	0 units on a scale Interval -0.67 to 0.33	-0.33 units on a scale Interval -0.835 to 0.0
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 6-month Physical Functioning	-0.5 units on a scale Interval -1.0 to 0.0	-0.5 units on a scale Interval -1.0 to 0.0
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 6-month Pain/Discomfort	-0.25 units on a scale Interval -0.5 to 0.0	-0.5 units on a scale Interval -1.0 to 0.0
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 15-month Pain/Discomfort	-0.5 units on a scale Interval -1.0 to 0.0	-0.5 units on a scale Interval -1.0 to 0.0
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 15-month Personal/Psychological Functioning	-0.5 units on a scale Interval -1.0 to 0.0	-0.75 units on a scale Interval -1.25 to -0.25
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 15-month Social Functioning	0 units on a scale Interval -1.0 to 0.33	-0.33 units on a scale Interval -0.67 to 0.0
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 6-month Personal/Psychological Functioning	-0.25 units on a scale Interval -0.75 to 0.0	-0.5 units on a scale Interval -1.0 to -0.25
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 6-month Social Functioning	-0.33 units on a scale Interval -0.67 to 0.66	-0.33 units on a scale Interval -0.67 to 0.0
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 9-month Physical Functioning	-0.5 units on a scale Interval -1.25 to 0.0	-0.5 units on a scale Interval -1.0 to -0.25
Change From Baseline in Symptom Burden at 4, 6, 9 and 15 Months (Phase III) 9-month Pain/Discomfort	-0.25 units on a scale Interval -0.5 to 0.0	-0.5 units on a scale Interval -1.0 to 0.0

SECONDARY outcome

Timeframe: Baseline, 4, 6, 9 and 15 months from randomization

Population: Eligible patients with both baseline and respective follow-up (4,6, 9,15 months) WSP measurements.

Stimulated (citric acid primed) whole salivary production (WSP) was measured by expectoration weight, with one gram of saliva produced considered as one ml of saliva. WSP is expressed in ml/min calculated by dividing the measured weight or volume of WSP by five. Procedure: Patients refrain from eating, drinking, and smoking at least two hours prior to each measurement. Stimulation is elicited by asking patients to rinse 5 ml of 2% citric acid solution in the mouth for 15 seconds and then completely expectorating the citric acid. For each measurement, patients are asked to expectorate continuously into a pre-weighed dry plastic container over a 5-minute period without swallowing. The collected saliva with the plastic container will be weighed (total weight) immediately after each collection. The total weight minus the weight of the container is the weight or volume of whole saliva collected.

Outcome measures

Outcome measures
Measure	ALTENS: Phase II n=73 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	ALTENS: Phase III n=73 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Change From Baseline in Stimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) 4 months	0.03 ml/min Interval -0.12 to 1.4	0.2 ml/min Interval -0.2 to 0.9
Change From Baseline in Stimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) 6 months	0.2 ml/min Interval -0.27 to 1.33	0.40 ml/min Interval -0.3 to 1.07
Change From Baseline in Stimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) 9 months	0.99 ml/min Interval 0.0 to 1.9	0.60 ml/min Interval -0.17 to 1.44
Change From Baseline in Stimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) 15 months	0.3 ml/min Interval -0.3 to 1.7	0.20 ml/min Interval -0.13 to 2.0

SECONDARY outcome

Timeframe: Pre-treatment to 4, 6, 9 and 15 months from randomization

Population: Eligible randomized patients with both baseline and respective follow-up (4,6, 9,15 months) WSP measurements.

Basal whole salivary production (WSP) was measured by expectoration weight, with one gram of saliva produced considered as one ml of saliva. WSP is expressed in ml/min calculated by dividing the measured weight or volume of WSP by five. Procedure: Patients refrain from eating, drinking, and smoking at least two hours prior to each measurement. For each measurement, patients are asked to expectorate continuously into a pre-weighed dry plastic container over a 5-minute period without swallowing. The collected saliva with the plastic container will be weighed (total weight) immediately after each collection. The total weight minus the weight of the container is the weight or volume of whole saliva collected.

Outcome measures

Outcome measures
Measure	ALTENS: Phase II n=73 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	ALTENS: Phase III n=73 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Change From Baseline in Unstimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) 4 months	0 ml/min Interval -0.3 to 0.29	0 ml/min Interval -0.28 to 0.38
Change From Baseline in Unstimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) 6 months	0 ml/min Interval -0.3 to 0.7	0.02 ml/min Interval -0.32 to 0.46
Change From Baseline in Unstimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) 9 months	0.056 ml/min Interval -0.1 to 0.9	0.04 ml/min Interval -0.2 to 0.587
Change From Baseline in Unstimulated Whole Salivary Production (WSP) at 4, 6, 9 and 15 Months (Phase III) 15 months	0.13 ml/min Interval 0.0 to 0.9	0.192 ml/min Interval -0.2 to 0.8

SECONDARY outcome

Timeframe: Baseline and 9 months from randomization.

Population: Eligible randomized patients with both baseline and 9-month UWHNSS total scores.

The UWHNSS includes ten categories-pain, disfigurement, activity, recreation/entertainment, employment, eating, saliva, taste, speech, mucus/phlegm. Patient scores on the UWHNSS range from 0 to 100 with higher scores indicating declining quality of life. Change in total score was calculated by subtracting baseline from follow-up , thus a positive change score indicates a worsening while a negative change score indicates an improvement.

Outcome measures

Outcome measures
Measure	ALTENS: Phase II n=43 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	ALTENS: Phase III n=51 Participants Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Quality of Life (QOL) as Measured by the University of Washington Head and Neck Questionnaire (UWHNSS) Phase III	-3.64 units on a scale Interval -9.09 to 1.82	-7.27 units on a scale Interval -12.73 to -1.81

Adverse Events

ALTENS: Phase II

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

Pilocarpine: Phase III

Serious events: 0 serious events

Other events: 51 other events

Deaths: 0 deaths

ALTENS: Phase III

Serious events: 1 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	ALTENS: Phase II n=47 participants at risk Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	Pilocarpine: Phase III n=73 participants at risk 5mg pilocarpine by mouth 3 times a day for 12 weeks	ALTENS: Phase III n=72 participants at risk Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Gastrointestinal disorders Gastrointestinal disorder	2.1% 1/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Infections and infestations Appendicitis perforated	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	1.4% 1/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.

Other adverse events

Additional Information

Wendy Seiferheld, M.S.

NRG Oncology

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.
Publication restrictions are in place

Restriction type: OTHER

Measure	ALTENS: Phase II n=47 participants at risk Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit	Pilocarpine: Phase III n=73 participants at risk 5mg pilocarpine by mouth 3 times a day for 12 weeks	ALTENS: Phase III n=72 participants at risk Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) twice weekly for 12 weeks via a Codetron unit
Ear and labyrinth disorders Tinnitus	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	5.5% 4/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.8% 2/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Eye disorders Vision blurred	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.8% 5/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Constipation	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	5.5% 4/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	1.4% 1/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Diarrhea	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.8% 5/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	1.4% 1/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Dry mouth	10.6% 5/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	30.1% 22/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	25.0% 18/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Gastrointestinal disorders Dysphagia	2.1% 1/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	13.7% 10/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	12.5% 9/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Chills	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.8% 5/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Fatigue	2.1% 1/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	9.6% 7/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	8.3% 6/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
General disorders Localized edema [head and neck]	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	1.4% 1/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	5.6% 4/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.1% 3/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	5.6% 4/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Nervous system disorders Dizziness	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.8% 5/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.2% 3/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Nervous system disorders Headache	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	19.2% 14/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.8% 2/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Nervous system disorders Taste alteration	2.1% 1/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.8% 5/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	5.6% 4/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Psychiatric disorders Insomnia	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	5.5% 4/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.8% 2/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Renal and urinary disorders Urinary frequency	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	6.8% 5/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	11.0% 8/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	2.8% 2/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Skin and subcutaneous tissue disorders Skin induration	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	4.1% 3/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	8.3% 6/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Skin and subcutaneous tissue disorders Sweating	0.00% 0/47 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	32.9% 24/73 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.	0.00% 0/72 Adverse events are reported for all eligible patients who started protocol treatment. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.