A Phase III Prospective Randomized Trial of Acupuncture for Treatment of Radiation-Induced Xerostomia in Patients With Head and Neck Cancer
Phase: NA
Conditions: Radiation-Induced Xerostomia, Head and Neck Cancer, Radiation Toxicity, Oral Complications of Chemotherapy and Head/Neck Radiation
Sponsor: Wake Forest University Health Sciences

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CI Protocol #:     
 
WF 97115 
WFU Protocol #:    
 
97115 
IND# (if applicable):    
NA 
 
 
PROTOCOL TITLE:     
A Phase III Prospective Randomized Trial of Acupuncture for 
Treatment of Radiation-Induced Xerostomia in Patients with Head 
and Neck Cancer 
 
 
Consortium Name: 
 
Wake Forest NCORP Research Base  
Name of Consortium Multi-  
 
Glenn Lesser, MD 
Principal Investigator: 
       Wake Forest School of Medicine 
 
 
Department of Internal Medicine 
 
 
Section on Hematology and Oncology 
 
 
Medical Center Boulevard 
 
 
Winston-Salem, NC 27157 
Telephone (336) 716-0891 
Fax: (336) 716-6275 
Email: glesser@wakehealth.edu 
 
Consortium Name: 
 
 
Wake Forest NCORP Research Base 
Name of Consortium Multi- 
 
Kathryn Weaver, PhD, MPH  
Principal Investigator: 
 
Associate Professor of Public Health Sciences 
 
 
Department of Social Sciences & Health Policy   
 
 
Medical Center Boulevard  
 
 
Winston-Salem, NC 27157  
 
 
Telephone: (336) 713-5062  
 
 
Fax: (336) 716-7554  
 
 
 
 
 
Email: keweaver@wakehealth.edu 
 
Organization Name: 
 
Wake Forest School of Medicine 
Protocol Principal Investigator: 
Suzanne C. Danhauer, PhD 
 
       Department of Social Sciences & Health Policy 
 
 
Division of Public Health Sciences 
 
 
Medical Center Boulevard 
 
 
Winston-Salem, NC 27157 
 
 
Telephone (336) 716-7402 
 
 
Fax (336) 716-7554 
 
 
Email: danhauer@wakehealth.edu 
 
Coordinating Center:  
 
Wake Forest NCORP Research Base 
Department of Social Sciences & Health Policy 
 
 
Medical Center Boulevard, 525 @ Vine 4th Floor (Box 573152) 
 
 
Winston-Salem, NC 27157 
 
 
Telephone:  (336) 716-0891 
 
 
Fax: (336) 716-6275 
 
 
Email:  resbase@wakehealth.edu 
 
Protocol Chairman: 
 
Lorenzo Cohen, PhD 
 The University of Texas MD Anderson Cancer Center 
1400 Holcombe Blvd., Unit 0462 
 
Houston, Texas 77030-4009 
 
PH:   (713) 745-4260 
 
FAX: (713) 745-2437 
 
Email: lcohen@mdanderson.org 
 
 

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Protocol Co-Chair: 
Mark Chambers, DMD, MS 
The University of Texas MD Anderson Cancer Center 1515 
Holcombe Blvd., Unit 1445 
 
Houston, Texas 77030-4009 
 
PH:  (713) 745-2672 
 
FAX: (713) 794-4662 
 
Email: mchamber@mdanderson.org 
 
Collaborators: 
M. Kay Garcia, DrPH, MSN, RN, LAc 
The University of Texas MD Anderson Cancer 
Center 1400 Holcombe Blvd., Unit 462 
Houston, Texas 77030-4009 
PH:   (713) 563-7413 
FAX: (713) 745-2437 
Email: kaygarcia@mdanderson.org 
 
Joseph S. Chiang, MD 
The University of Texas MD Anderson Cancer 
Center 1400 Holcombe Blvd., Unit 0409 
Houston, Texas 77030-4009 
PH:   (713) 794-5363 
FAX: (713) 563-9335 
Email: jchiang@mdanderson.org 
 
 
David Rosenthal, MD 
The University of Texas MD Anderson Cancer 
Center 1515 Holcombe Blvd., Unit 0097 
Houston, Texas 77030-4009 
PH:  (713) 563-2300 
FAX: (713) 563-2366 
Email: dirosenthal@mdanderson.org 
 
Peiying Yang, PhD 
The University of Texas MD Anderson Cancer 
Center 1400 Holcombe Blvd., Unit 0462 
Houston, Texas 77030-4009 
PH:   (713) 563-7531 
FAX: (713) 745-2437 
Email: pyang@mdanderson.org 
 
Statistician: 
Emily V. Dressler, PhD 
Department of Public Health Sciences 
Department of Biostatistics and Data Science 
Wake Forest University School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC  27157 
PH:   (336) 713-0917 
FAX: (336) 716-6427 
Email:  edressle@wakehealth.edu 
 
 
 

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Grant: 5UG1CA189824 (NCI) 
5R01CA148707 (NCI) 
 
Agent(s)/Supplier: N/A  
Protocol Amendment #: 14 
Protocol Version Date: 12/26/2019 
 
Amendments Numbers & IRB Approval Dates: Amend 2: 08/13/15 (Initial)  
Amend 3: 02/11/16 (Personnel Change)  
Amend 4: 02/11/16 (WF Change Only)  
Amend 5: Withdrawn  
Amend 6: 03/03/16 (WF Change Only)  
Amend 7: 03/08/16 (Personnel Change) 
 
 
 
Amend 8: 05/12/16 (Personnel Change) 
Amend 9: 05/15/16 
 
 
 
Amend 10: 04/26/17 
 
 
Amend 11: 05/01/18 
 
 
Amend 12: 07/01/19 
 
 
Amend 13: 10/17/2019  
 
 
Amend 14: [enter IRB approval date prior to distributing 
to sites] 
 
 
 
 
 
 
 
 
 
 
 
Participating Organizations 
 
WAKE/ Wake Forest NCORP Research Base 
 

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ACUPUNCTURE – SCHEMA 
 
 
 
 
Accrual Goal: 240 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1.0 OBJECTIVES  ................................................................................................................ 7 
1.1 Primary Objective ...................................................................................................... 7 
1.2 Secondary Objective .................................................................................................. 7 
2.0 BACKGROUND .............................................................................................................. 7 
2.1 Rationale ................................................................................................................... 7 
3.0 PATIENT SELECTION .................................................................................................. 11 
3.1 Inclusion Criteria ...................................................................................................... 11 
3.2 Exclusion Criteria ..................................................................................................... 12 
3.3 Study Population ..................................................................................................... 12 
4.0 STUDY DESIGN ........................................................................................................... 12 
4.1 Enrollment Procedures ............................................................................................ 12 
4.2 Stratification/Randomization Procedures ................................................................. 12 
5.0 TREATMENT PLAN ..................................................................................................... 13 
5.1 Acupuncture ............................................................................................................ 13 
5.2 Sham Treatment ...................................................................................................... 15 
5.3 Standard of Care ..................................................................................................... 16 
5.4 Needling/Training Procedures ................................................................................. 16 
6.0 STUDY REQUIREMENTS ............................................................................................. 17 
6.1 Study Plan ............................................................................................................... 17 
6.2 Baseline Assessments ............................................................................................. 18 
6.3 On-Study Assessments ........................................................................................... 18 
6.4 Off-Study Assessments ........................................................................................... 19 
6.5 Study Compliance ................................................................................................... 19 
6.6 Intervention Delay .................................................................................................... 19 
6.7 Study Follow-Up ...................................................................................................... 20 
7.0 MEASUREMENT OF EFFECT ...................................................................................... 20 
7.1 Xerostomia Questionnaire (XQ) ............................................................................... 20 
7.2 MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN) ............ 20 
7.3 The Functional Assessment of Cancer Therapy (FACT-G) ...................................... 20 
7.4 Acupuncture Expectancy Scale (AES) ..................................................................... 20 
7.5 Study Calendar of Events ........................................................................................ 22 
8.0 SIALOMETRY ............................................................................................................... 23 
8.1 Saliva Flow Examination .......................................................................................... 23 
8.2 Saliva Constituent Analyses .................................................................................... 23 
9.0 ADVERSE EVENTS AND REPORTING REQUIREMENTS .......................................... 23 
9.1 Protocol Specific Reporting for Adverse Events (AEs) ............................................. 24 
9.2 Protocol Specific Reporting for Serious Adverse Events (SAEs) .............................. 24 
9.3 Guidelines to Determine Grade and Severity of AEs and/or SAEs ........................... 25 
9.4 Follow-Up of SAEs................................................................................................... 25 
10.0 STASTICAL CONSIDERATIONS ............................................................................... 26 
11.0 STUDY ACCRUAL ...................................................................................................... 27 
12.0 DATA MANAGEMENT ............................................................................................... 27 
13.0 DATA MONITORING COMMITTEE ............................................................................ 28 
14.0 SITE REGISTRATION………………………………………………………………………..28  
15.0 REFERENCES ............................................................................................................ 30 
 
Consent 
 
 
 

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Appendix 1 - Data Submission Checklist 
Appendix 2 - Eligibility Checklist/Enrollment Form 
Appendix 3 - FACT-G 
Appendix 4 - MDASI-HN 
Appendix 5 - Xerostomia Questionnaire 
Appendix 6 - Flow Sheet/Addenda 
Appendix 7 - Acupuncture Expectancy Scale 
Appendix 8 - Oral Hygiene Instructions  
Appendix 9 - Screening Log  
Appendix 10 - Sialometry  
Appendix 11 - Toxicity/Adverse Events Report Form  
Appendix 12 - Concomitant Medications  
Appendix 13 - TAT  
Appendix 14 - SAT 
Appendix 15 - Patient Status Form  
Appendix 16 - Stored Saliva Sample Transmittal Form

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1.0 
OBJECTIVES 
 
1.1 Primary Objective 
1. To determine whether or not acupuncture can symptomatically improve moderate or 
severe xerostomia (grade 2 or 3) due to head/neck radiotherapy. 
 
1.2 Secondary Objective 
1. To explore the duration of response (up to a maximum of 6 months) in the subgroup 
of patients who report a response to the acupuncture intervention. 
2. Examine group differences in saliva flow using unstimulated and stimulated whole 
salivary flow rates. 
3. Examine whether true acupuncture results in better overall QOL than sham 
acupuncture or standard of care. 
4. Determine  the  effects  of  acupuncture  on  saliva-based  factors  including  pH, 
buffering capacity, and viscosity as well as levels of total protein, calcitonin-gene 
related peptide, and vasoactive intestinal polypeptide. 
5. Examine the role of expectancy for the benefits of acupuncture in predicting outcomes. 
The role of expectancy as a moderator of the effects of treatment will be thoroughly 
examined. 
 
2.0 
BACKGROUND 
 
2.1 Rationale 
 
Xerostomia is a major quality-of-life (QOL) limiting problem among cancer patients who have 
received radiation treatment to the head and neck area. The impact of xerostomia on QOL 
among cancer patients is well established1-4.  Patients suffer from a decreased or total lack 
of saliva secretion leading to the subjective discomfort of dry mouth as well as other clinical 
problems such as difficulty speaking, eating, swallowing, taste aberration, insufficient 
nutritional intake, weight loss, ulceration, mucositis, pain, fungal infection, gingivitis and tooth 
structure deterioration.  A recent study by Lin and colleagues5 found quality of life scores 
were significantly correlated with xerostomia scores. 
 
It is estimated more than 40,000 patients are diagnosed annually with head and neck 
cancer6.  Approximately 80% will receive radiotherapy and xerostomia is a common sequela 
of treatment 7. The pathology and course of xerostomia is not well described, and several 
approaches to treatment, including saliva substitutes, chewing gum, lozenges, pilocarpine, 
nicotinamide, and amifostine, have been attempted with limited results. Thus far, the few 
available therapies have demonstrated a low success rate or low acceptance by patients due 
to unpleasant side effects. Currently, the most widely used treatment is orally administered 
pilocarpine hydrochloride. The limited positive response is short lived and the 
cholinomimetic effect such as sweating, rhinitis, headaches, nausea and urinary frequency 
significantly limit its application.  In addition to pharmaceutical stimulation, many mechanical 
devices have been offered ranging from electrical stimulation to the tongue and palate to the 
extreme hyperbaric oxygen therapy.  Each has limited and short-lasting results8. 
 
Several encouraging reports have been published using acupuncture to stimulate saliva flow 
among radiation induced xerostomia patients 9-15.  These studies were conducted in different 
countries, by different investigators, using different acupuncture points, yet all produced 
similar positive results. One study demonstrated long-term effect (>3 years) of saliva 
production11.  An additional study revealed a significant

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increase in the blood flux in the skin of the cheek of xerostomia patients 16.  This increase 
in blood flow may affect the metabolism of the salivary gland causing increased salivary 
secretion.  Other plausible hypotheses suggest increase production of certain 
neuropeptides after acupuncture stimulation that may cause vasodilation and an increase 
of microcirculation13,14,17. 
 
A recently completed, non-randomized, single-arm pilot study 18 at MD Anderson assessed 
whether radiation-induced xerostomia could be reversed using acupuncture. Quantification of 
response was measured both subjectively and objectively. Subjective measures based on 
self-assessment of individual symptoms associated with dry mouth were collected using the 
Xerostomia Inventory (XI) and the Patient Benefit Questionnaire (PBQ).  Objective measures 
were performed using both unstimulated whole salivary flow rates (UWSFRs) and stimulated 
salivary flow rates (SSFRs).  A total of 20 patients received 8 acupuncture treatments over 4 
weeks with follow-up assessments at week 5 and week 8 (1-month). 
 
Tables 1 & 2 provide results from both subjective measures. For the XI (high score = 
increased severity of xerostomia), differences between baseline and end of acupuncture 
treatment (week 4) and 1 month follow-up (week 8) were highly statistically significant (p = 
0.0004 and p = 0.0001, respectively).  Mean scores declined from 36.3 at baseline to 31.6 and 
29.9 at weeks 4 and 8 respectively.  For the PBQ (low score = increased severity of 
xerostomia), differences between baseline and end of acupuncture treatment (week 4) and 1 
month follow-up (week 8) were also very highly significant (p = 0.0004 and p = 0.0011, 
respectively).  Mean PBQ scores increased from 43.94 at baseline to 56.85 at week 4 and 
56.10 at 1-month.  In Tables 1 and 2 the standard deviations presented are for the single time 
point measures and the p values were obtained from Wilcoxon signed-rank test, which used 
the change from baseline for each individual as the outcome measure. 
 
Table 1. XI scores compared to baseline 
Week 
Mean 
SD 
P value 
Baseline 
36.3 
7.71 
--- 
Week 1 
36.0 
7.01 
0.4708 
Week 2 
34.1 
7.27 
0.0067 
Week 3 
32.9 
7.32 
0.0187 
Week 4 
31.6 
6.66 
0.0004 
Week 5 
31.4 
6.80 
0.0007 
Week 8 (1-month) 
29.9 
7.96 
0.0001 
 
Table 2. PBQ scores compared to baseline 
Week 
Mean 
SD 
P value 
Baseline 
43.94 
12.93 
--- 
Week 1 
47.10 
14.33 
0.0675 
Week 2 
50.10 
13.42 
0.0029 
Week 3 
53.60 
13.11 
0.0010 
Week 4 
56.85 
13.22 
0.0004 
Week 5 
57.78 
14.53 
<0.0001 
Week 8 (1-month) 
56.10 
12.92 
0.0011 

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For objective measures, no significant differences were found for either UWSFRs or SSFRs; 
however, mean saliva output did increase from baseline to end of follow-up at 1 month.  For 
UWSFRs, mean saliva at baseline was 0.67g and increased slightly to 0.77g at 1-month, 
with the greatest difference occurring at week 1 (0.99g, p=0.08).  For SSFRs, mean saliva 
output increased from 1.92g at baseline to 1.94g at week 8, with the most change also 
occurring at week 1 (2.59g, p=0.13). Tables 3 & 4 provide sialometry results. 
 
Table 3. UWSFR compared to baseline 
Week 
Mean 
SD 
P value 
Baseline 
0.67 
0.62 
--- 
Week 1 
0.99 
0.88 
0.08 
Week 2 
0.71 
0.73 
0.65 
Week 3 
0.87 
0.88 
0.27 
Week 4 
0.79 
0.79 
0.54 
Week 5 
0.68 
0.72 
0.57 
Week 8 (1-month) 
0.77 
0.81 
0.46 
 
Table 4. SSFR compared to baseline 
Week 
Mean 
SD 
P value 
Baseline 
1.92 
1.70 
--- 
Week 1 
2.59 
2.29 
0.13 
Week 2 
2.24 
1.86 
0.26 
Week 3 
2.01 
1.55 
0.40 
Week 4 
2.12 
1.48 
0.26 
Week 5 
2.08 
1.46 
0.21 
Week 8 (1-month) 
1.94 
1.38 
0.62 
 
Both basal and stimulated salivary flow rates vary significantly among individuals. UWSFRs 
have been reported to range from 0.08 to 1.83 mL/min, a difference of more than 20 fold. 
SSFRs vary even more, from 0.2 to 5.7 mL/min. Within this wide range, subjective 
perception of dry mouth and objective signs of salivary gland dysfunction do not always 
correlate. Subjective feelings of oral dryness (xerostomia) are not reliable indicators of flow 
rate. Impaired salivary gland function can exist without xerostomia, which can, conversely, 
exist with normal salivary gland function. Thus, difficulty lies in the fact that there is no 
definitive threshold of increased saliva output that results in a clear clinical benefit. 
 
Because the FDA uses subjective outcomes as the standard for drug approval in treating 
xerostomia, summed XI scores were used to determine clinical significance. A partial 
response (PR) was defined as a difference on the XI > 6 points from baseline or 30% of 
starting score if baseline <20; however, no patients in this population had a baseline score 
< 20 points.  A minor response (MR) was defined as a difference < 6 points but at least 3 
points from baseline, and no response (NR) was defined as the absence of either PR or 
MR. 

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The overall expected response rate was 40%.  At the end of acupuncture treatment on 
week 4, 44.44% of participants achieved a PR, and on week 8, 55.56% had achieved a 
PR.  These results are provided in Table 5. 
 
Table 5.  Clinical significance as determined by XI scores 
Week 
NR (n / %) 
MR (n / %) 
PR (n / %) 
Week 1 
13 / 68.42 
5 / 26.32 
1 / 5.26 
Week 2 
10 / 58.82 
4 / 23.53 
3 / 17.65 
Week 3 
7 / 38.89 
5 / 27.78 
6 / 33.33 
Week 4 
5 / 27.78 
5 / 27.78 
8 / 44.44 
Week 5 
6 / 33.33 
2 / 11.11 
10 / 55.56 
Week 8 
3 / 16.67 
5 / 27.78 
10 / 55.56 
 
This small pilot study is viewed as a positive trial.  However, since completion of the trial, a 
new instrument has become available that covers questions from both the XI and the PBQ. 
Thus, for the proposed study, we will use the Xerostomia Questionnaire (XQ) as the 
subjective measure in place of the XI and the PBQ. This will reduce the time burden placed 
on patients while providing the same information. The XQ questionnaire has been validated 
in patients with head and neck cancer 7,19. 
 
Recently, we also completed a randomized xerostomia prevention trial in Shanghai, China 
where patients were randomly assigned to undergo acupuncture (n = 39) or usual care (n = 
46) throughout their 7 weeks of radiotherapy.  Similar, but not  identical, acupuncture points 
were used. There where statistically and clinically significant group differences in subjective 
outcomes (general QOL and xerostomia) and saliva flow rates starting as early as 3 weeks 
into the 7 weeks of radiotherapy.  The group differences remained 1 and 6 months after the 
end of radiotherapy.  The placebo procedure has also been tested in a small pilot trial 
conducted in Shanghai, China.  Twenty patients undergoing radiotherapy to the head and 
neck were randomized to either real or sham acupuncture. Patients were asked at week 4 
and  at the end of week 7 whether they thought they were in the true or sham group or 
uncertain and whether they thought the acupuncture was helpful for their dry mouth (yes/no).  
All patients thought they were in the true acupuncture group, and all thought the treatment 
was useful for their dry mouth. Group differences did not reach statistical significance (which 
is not surprising due to the small sample size), but differences in XQ scores by week 4 were 
greater than 10 points, suggesting the differences were clinically significant [week 4 mean 
(SD): true = 23.6 (8.8) vs sham = 
36.1 (13.2)].  Importantly, the means and standard deviations were similar to those in the 
previous larger completed study that compared acupuncture to standard care. 
 
Finally, in the proposed trial, we will evaluate participant expectations on outcomes. This will 
allow further exploration of how psychological phenomena may be related to outcomes in 
acupuncture research.  Although well-conducted, placebo-controlled clinical trials have 
offered insights into the efficacy of acupuncture, the substantial effect seen in many placebo 
acupuncture groups presents a significant challenge in interpreting treatment results.  Many 
studies, including several meta-analyses20-26, have found that both real and placebo 
acupuncture produce statistically and clinically significant changes when compared to no 
treatment or standard/enhanced medical care. These findings suggest that the effect found 
in placebo acupuncture groups cannot be entirely attributed to either regression to the mean 
or natural disease

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processes; thus, the “non-specific” effect of acupuncture must be responsible in part for 
patients’ clinical response.  Nevertheless, until we can parse the components that make up 
the “non-specific” effect, this effect, powerful as it may be, is likely to be discarded from a 
scientific standpoint.  Years of psychological research has found that expectancy is one of 
the central pieces in this so-called “non-specific” effect. In particular, response expectancy, 
a form of outcome expectancy defined as “expectations held by the individual about one’s 
own emotional and physiological response” related to a situation or therapy, may produce 
important clinical changes28. In a systematic review, Crow et al.28 showed that when 
clinicians stated positive outcome expectations as opposed to uncertain expectations, most 
studies found improvements in patient self-reports of anxiety, pain, and distress. 
 
A few studies have explored the association between expectancy and clinical outcomes in 
the context of acupuncture29,30. While these studies provided preliminary evidence that 
greater expectancy may produce better clinical response, none used a validated instrument 
to measure expectancy.  In this study, we will use an Acupuncture Expectancy questionnaire 
that has been validated in both English and Mandarin31. We will also use the MD Anderson 
Symptom Inventory for Head and Neck Cancer (MDASI-HN) and the Functional Assessment 
of Cancer Therapy (FACT-G) questionnaires to collect quality of life information. 
 
Investigating expectancy and quality of life as part of the complex mind-body interactions of 
acupuncture care will likely yield important knowledge that is both scientifically sound and 
clinically meaningful to patients who suffer from xerostomia and other distressing symptoms. 
 
3.0 
PATIENT SELECTION 
 
3.1 Inclusion Criteria 
1. Must be at least 18 years of age and able to give informed consent. 
2. Must be able to read, write and understand English. 
3. Must have a diagnosis of head/neck cancer. 
4. Must have received bilateral radiation therapy,  and subsequently developed 
grade 2 or 3 xerostomia, according to modified RTOG scale: 
 
 
Grade 0 – None 
 
Grade 1 – Slight dryness of mouth (good response on stimulation and 
no significant dietary alterations necessary) 
 
Grade 2 – Moderate dryness of mouth (poor response on stimulation and 
altered oral intake required such as frequent water, oral lubricants, or soft-
moist foods) 
 
Grade 3 – Complete dryness of mouth (no response on stimulation 
and difficult oral alimentation; IV fluids, pureed diet or tube feedings 
may be required) 
 
Grade 4 – Fibrosis  
 
5. Must have received external beam radiation with curative intent.  
6. Must have completed radiotherapy at least 12 months prior to entry. 
7. Must have anatomically intact parotid glands and at least one submandibular 
gland. A focused (head/neck) history and exam conducted by a physician or 
dentist within the past year is required.  
8. Have never had acupuncture for xerostomia. 
9. Must have ECOG performance status of 0-2.  
 

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3.2 Exclusion Criteria 
1. History of xerostomia, Sjogren’s disease or other illness known to affect 
salivation prior to head/neck radiation. 
2. Suspected or known closure of salivary gland ducts on either side. (Patients 
addressed in inclusion criteria 7 (i.e. those who have had one submandibular gland 
removed) are expected to have closure of the duct to the removed submandibular 
gland and will be exempt from this exclusion criteria.) 
3. Currently receiving or planning to receive other xerostomia treatment, including 
drugs, herbs or devices.  All other treatments known to affect salivation should be 
stopped at least 14 days prior to enrollment. 
4. Have received any investigational new drug within the past 30 days or 
planning to receive such during the study period. 
5. Active systemic infection or skin infection at or near the acupuncture sites. 
6. Receiving chemotherapy during study period.   
 
3.3 Study Population 
This study will enroll both male and female patients who have received radiation for 
the treatment of head and neck cancer.  A study recruitment letter is located on the 
WF NCORP Research Base website for submission to your IRB for approval should 
the site decide to use as a mail out for recruitment purposes. 
 
The MD Anderson Integrative Medicine Program’s recommended safety guidelines 
for patients receiving acupuncture are provided as a helpful guide on the WF 
NCORP Research Base website.  
 
4.0 
STUDY DESIGN 
 
4.1 Enrollment Procedure 
Eligible and consented patients will be enrolled only after the enrolling institution submits a 
completed IRB approval letter to the Wake Forest NCORP Research Base. IRB approval 
will be verified. Patients must meet all inclusion/exclusion criteria to be eligible for the 
protocol. Any patient who does not satisfy all eligibility requirements cannot be entered onto 
the protocol.  Screening logs (Appendix 9) should be kept on all patients screened 
(approached, accrued, failed) for this trial.  Logs should be made readily available for review 
and data collection if requested. 
 
Once the patient’s eligibility is confirmed and the patient has been consented, the baseline 
assessments should be completed (see Section 6.2). Then the patient can be enrolled to 
the study using the WFNCORP RB website enrollment system.  A unique case number and 
blinded study arm assignment will be given to each patient.  A confirmation of patient 
enrollment will be generated and conveyed to the enrolling institution for verification 
purposes. If the patient is randomized to an acupuncture arm, the Research Base will relay 
the arm assignment to the participating acupuncturist(s) for that site. 
 
4.2 Stratification/Randomization Procedure 
Patients who have met all eligibility criteria will be randomized at the time of enrollment to 
standard oral hygiene, standard oral hygiene + true acupuncture twice weekly for 4 weeks, 
or standard oral hygiene + sham acupuncture twice weekly for 4 weeks by a form of 
adaptive randomization, called minimization, because simple randomization could result in 
covariate imbalances 33. Statistical adjustment of covariates can take imbalances into 
consideration, but results are generally more credible when they are obtained from groups 
with comparable baseline distributions. In minimization, group assignment is done 

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sequentially.  Before a participant is assigned to a group, the number of already randomized 
participants with similar covariate characteristics is totaled. The totals are computed based 
on marginal sums so that each covariate is considered separately. The treatment 
assignment for a participant is then based on which treatment group assignment would 
produce the best overall balance with respect to the covariate characteristics.  Minimization 
is similar to stratification in that participant characteristics are used to assign participants to 
the treatment conditions.  Minimization, however, results in better group balance and does 
not suffer from the limitations of stratification, especially when several participant factors are 
used.  In this study, the patient characteristics used for group assignment will be stage of 
disease (for staging questions please contact the Research Base for assistance), age, sex, 
time since the end of radiotherapy,  the mean parotid radiotherapy doses received (left and 
right side calculated separately and balanced between groups),  and baseline XQ scores. 
Randomization will be conducted by using a centralized website to ensure equal distribution 
across all groups and balance at each site.  All sites and study staff and patients will be 
blinded to randomization of the acupuncture arms. At the time of enrollment, the site will be 
automatically notified of blinded group assignment by the Research Base.  The Research 
Base will provide acupuncturists with unblinded group information.  
 
5.0 
TREATMENT PLAN 
 
5.1 Acupuncture 
The acupuncture points will be at three sites on each ear (Shenmen, Point Zero, Salivary 
Gland 2-prime), a site on the chin (CV24), a site on each forearm (Lu7), a site on each hand 
(LI 1-prime), a site on each leg (K6), and one placebo needle at Gb32 for a total of 14 sites. 
All sites will be applied for 20 minutes.  For body points, standardized techniques for 
location will be utilized, which are based on anatomical landmarks as well as proportional 
measurements using the patient’s own body.  For example, finger breadth is based on each 
patient’s middle finger, and the proportional unit of measure, the “cun,” is defined as the 
distance between the two medial ends of the creases of the interphalangeal joints when the 
middle finger is flexed34.  Earpoint locations will mimic standard practice and be identified by 
the acupuncturists. 
 
The specific acupoints to be used were selected based on:  1) previous published studies 
4,9,35 showing successful results of reversing xerostomia; 2) indications according to the 
classical theory of Traditional Chinese Medicine (TCM)34,36, and; 3) current understanding 
of the various anatomical locations and neurovascular tissues.  Although many point 
combinations could be used, the investigators have attempted to identify a set of acupoints 
that integrates TCM and biomedicine.  The sites are summarized below: 
 
CV 24: Above the chin, in the depression in the centre of the mentolabial groove 
(approximately midway between the chin and lower lip). This point is supplied by 
branches of the inferior labial artery and vein and the mental nerve. 
 
The Chinese name for this point is Chengjiang (translated as “container of fluids.”) It 
is a point where 3 other channels meet (Du, LI, and St). The CV channel winds 
around the mouth and terminates under the eyes. According to TCM theory, body 
fluids are considered Yin. Thus, xerostomia is a form of Yin deficiency, and the CV 
channel is one of the most important channels for tonifying and nourishing Yin. 
 
Although this point has not been closely investigated for the treatment of  xerostomia, 
several clinicians and renowned researchers in this area recommend its inclusion 
based on their clinical experience. 

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Lu 7: This point is located superior to the styloid process of the radius, 1.5 cun above 
the transverse crease of the wrist. If the index finger is placed in the anatomical 
"snuffbox" located at the radial aspect of the wrist (i.e., LI 5) and moved proximally over 
the styloid process of the radius, the point is located in the depression in the cleft 
between the tendons of brachioradialis and abductor pollicis longus, 1.5 cun proximal 
to the transverse wrist crease. This point is supplied by the cephalic vein and branches 
of the radial artery and vein. It is innervated by the lateral antebrachial cutaneous nerve 
and the superficial ramus of the radial nerve. 
 
In TCM, Lu 7 is known as the Gao Wu command point for the head and neck area. 
The lungs in TCM are also responsible for water metabolism, and the lung channel 
ascends to the throat. Lu 7 is a paired confluent point with K6 and indicated for dry 
throat. For this function, it is needled proximally towards the elbow. It is also 
considered a confluent point of the conception vessel (CV) and has the additional 
function of supporting CV 24 in this study. 
 
K 6: This point is located in the depression 1 cun below the prominence of the medial 
malleolus in the groove formed by the 2 ligamentous bundles. It is supplied by the 
posterior tibial artery and vein. It is innervated by the medial crural cutaneous nerve 
and the deeper tibial nerve. 
 
In TCM, K 6 is known as the "shining sea" point. When paired with its confluent 
point Lu 7, one of its primary functions is to nourish yin and clear heat from the 
throat. In addition, by activating 2 channels (i.e., Kidney channel and Yin Motility 
channel), K 6 is a main distal point for treating Yin deficiency and dryness of the 
throat. 
 
LI 1-prime: This point is located slightly medial and distal to the traditional jing well 
point, LI 1.  It is on the radial side of the index finger, at the edge of the nail and 
approximately 0.1 cun distal and slightly medial to LI 1. 
 
Prior studies 4,9,35 have investigated the use of this point in the treatment of 
xerostomia.  From a TCM perspective, it is considered a modification of LI 1, a Jing 
Well point.  According to TCM theory, all Jing Well points “clear heat.” In the case of 
this patient population, “excess heat” is produced by the radiation therapy. 
 
Ear:  Points on the ear include Shenmen, Point Zero, and Salivary Gland 2-prime. 
These points have been found to be effective in the treatment of xerostomia in prior 
studies 4,9,35. Shenmen is used to alleviate pain, reduce inflammation, and calm the 
mind. The area where it is located is supplied by a mixed branch of the vagus, facial, 
and trigeminal nerves and the cervical plexus. Point Zero is also known as the vagus 
nerve point and is used to regulate various organ functions. Salivary Gland 2-prime is 
used to regulate salivary function and is supplied by the auriculotemporal branch of 
the trigeminal nerve as well as a mixed branch of the vagus, facial, and trigeminal 
nerves and the cervical plexus. 
 
Treatment Group (active acupuncture) 
 
36 gauge x 30 mm acupuncture needles at the following body points:  CV24, K6 
(bilateral), Lu7 (bilateral). 
 

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40 gauge x 15 mm acupuncture needles at LI 1-prime (bilateral) and the following ear 
points:  Shenmen (bilateral), Point Zero (bilateral), and Salivary Gland 2-prime 
(bilateral) 
 
One placebo needle at Gb 32 above the right knee (Note: This is intended to 
provide participants in the active treatment group with a stimulus that will not elicit de 
qi sensation). 
 
5.2 Sham Treatment 
Well-designed clinical acupuncture trials require a sham procedure that is indistinguishable 
from the real treatment, yet inactive.  Some authors have concluded that needling anywhere 
on the ear may cause a physiologic response and may not be an inert procedure.  
Nevertheless, Usichenko and colleagues have used 3 points on the helix of the ear ipsilateral 
to the site of injury with success in 3 different studies 37-39.  Fixed sham points on each ear 
will be used as shown below.  These points are located  in the middle of the ear helix and are 
known as Helix 2, Helix 3, and Helix 4 40.  
 
 
 
By having a placebo needle in the active group and having a real body point needle and 
real ear needles in the placebo group, participants will be unable to identify their group 
assignment. In addition, as patients will be acupuncture naïve they do not know what the 
“correct” feeling should be. The procedure in this trial is similar to that used by Dr. Brian 
Berman and colleagues for a trial that examined acupuncture for osteoarthritis of the knee 
20. However, in the Berman study although the blinding was effective in terms of the 
treatment procedures, the lack of benefit in terms of pain control in the placebo group 
increased the rate of accurate guesses in the placebo group; in essence resulting in an 
unblinded study. This is an inherent problem with any placebo controlled trial and especially 
problematic with acupuncture trials. In order to avoid this risk, patients will be told that we 
are examining two different forms of acupuncture compared to a usual care group. In the 
consent form, patients are told there are two acupuncture groups using different 
acupuncture points. This will help to diminish any of the demand characteristics associated 
with knowing they could be in a true acupuncture or sham acupuncture group. In our 
study, the "sham" group is getting real needles inserted at real points along with sham 
needles at sham points. Therefore, it is not deception to say they are getting acupuncture. 
Moreover, trials that have compared real and sham acupuncture versus standard care 
have found similar benefits of both treatments over usual care. Therefore, sham 
acupuncture, in this case real needles at real points, may in fact be a form of 

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acupuncture that results in similar outcomes to the “real” acupuncture. The design of the 
protocol keeps the participants blind to group assignment.   Both groups are getting real and 
sham needles.  The protocol is not compromised if the patients know they are in Group 1 
versus Group 2. We will also be able to examine expectations of the benefits of the 
intervention at baseline and at mid- treatment. We are using this exact same technique 
currently in a large, multi-center, NCI R01 funded trial being conducted in Shanghai, China 
and at MD Anderson.  
 
Although no “gold standard” has been established for placebo controls in acupuncture 
trials, ideally, non-penetrating needles placed at inactive points should be used. Park and 
colleagues validated a non-penetrating, telescoping needle with a separate device that 
attaches it to the skin 41,42. This device is too heavy and bulky for use on auricular points, 
but will be used on body points in this study. 
 
The sham treatment will be given according to the same schedule as the active 
acupuncture treatment. Participants in both groups will be placed in a comfortable 
supine position. Each point will be identified and marked on the skin. A total of 14 points 
will be used in both groups.   The sham procedure for body points is outlined 
below: 
 
Sham Group (inactive acupuncture) 
 
Sham Location 1 - placebo needle at inactive point located 0.5 cun below and 0.5 
cun lateral to CV 24 on the chin 
 
Sham Location 2 - placebo needle at inactive point located 0.5 cun radial and 0.5 
cun proximal to SJ 6 between SJ and LI Channels (bilateral UE) 
 
Sham Location 3 - placebo needle at inactive point located 2 cun above Sham 
Location 2 between SJ and LI Channels and between LI7 and LI8 (bilateral UE) 
 
Sham Location 4 - placebo needle at inactive point located 1.0 cun below and 0.5 
cun lateral to St 36, between St and Gb Channels (bilateral LE) 
 
One 32 gauge x 30mm acupuncture needle at GB32 above the right knee (Note: 
This point is not indicated for dry mouth and is used to elicit de qi sensation in the 
control group.) 
 
5.3 Standard of Care 
All patients will receive standard oral hygiene patient teaching information that includes 
instructions regarding mouth rinses, use of lip balms, use of mild fluoride toothpaste, the 
importance of adequate oral hydration, and other standard advice. All patients should 
continue with standard oral hygiene throughout the study. Each participating site determines 
the standard oral hygiene recommendations used at their site. All efforts should be made 
to ensure standard oral hygiene remains consistent across patients enrolled at the 
participating site. 
 
5.4 Needling/Training Procedures 
The acupuncture needles are made by Seirin, Kyoto, Japan. The manufacturer conforms to 
the requirements of the ISO 9002, EN46002 and CE.U.S. Food and Drug 
Administration’s International Good Manufacturing Practices (GMP) and the World Health 
Organization’s standards for quality and safety. The stainless steel needles used in the ear 

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and for one body point (LI 1-prime) are 40 gauge in diameter x 15mm in length, and the 
needles used for all other body points are 36 gauge x 30 mm in length. The needles with 
guide tubes are provided in individual sterile packages. 
 
Acupuncture will be performed by a certified acupuncturist designated by the NCORP site. 
The acupuncturists who participate in this study will meet the local state acupuncture 
licensing requirements and have passed the National Certification Commission for 
Acupuncture and Oriental Medicine (NCCAOM) examination if required by state 
regulations. Acupuncturists in states that do not require NCCAOM certification who 
meet requirements to practice in their state will be allowed to participate upon 
submission of a copy of their state license and resume/CV. These are the accepted 
standards for acupuncturists and will insure their qualifications. To further ensure their 
acupuncture experience, they will also need to provide proof of CPR certification valid 
within two years, and at least one year of clinical acupuncture practice experience. All 
acupuncturists involved in this study will participate in a video-based training program 
found on the Wake Forest NCORP website and all will be required to provide evidence of 
certification of training in human subject protection. 
 
The acupuncture points selected in this protocol are common and widely used for many 
other treatments.  A properly trained and experienced acupuncturist should have no problem 
locating them accurately. Training courses and teaching materials will be supplied to the 
acupuncturists by MD Anderson Cancer Center. The training course will be concentrated on 
this particular protocol procedure including point selection, acupuncture needle application, 
length of treatment, frequency of treatment and, other protocol guidelines. For reference 
purposes, training materials will be made available online to participating acupuncturists.   
 
The participating acupuncturists, who meet all of the above criteria (state acupuncture 
license, NCCAOM exam or meet state regulatory requirements, one year of acupuncture 
experience, attended MDACC training course, CPR certification, and human subject 
protection training), will be approved by the NCORP Research Base for acupuncture 
research participation. The participating acupuncturists may be an employee of the 
participating site or may be contracted through the participating site.  Acupuncture 
treatments may be conducted on-site or in a private practice setting by the selected trained 
acupuncturist(s) that meet the above requirements. 
 
If all requirements are met, chiropractors and licensed physicians with acupuncture 
credentialing may be considered for participation in the trial on an individual basis. These 
individuals may also be an employee of the participating site or may be contracted through 
the participating site. 
 
6.0 
STUDY REQUIREMENTS 
 
6.1 Study Plan 
All patients will receive standard oral hygiene instructions and complete the baseline 
assessments: the Xerostomia Questionnaire (XQ), the MD Anderson Symptom Inventory 
for Head and Neck Cancer (MDASI-HN) questionnaire,  The Functional Assessment of 
Cancer Therapy (FACT-G), and the Acupuncture Expectancy Scale (AES) before 
enrollment and randomization occurs. 
 
All patients in all groups will complete the XQ, MDASI-HN, and the FACT-G again at week 4 
(±1 week). Participants in the active and sham acupuncture groups will complete the AES 
again at week 4. If patients have a minor response (10-19 point decrease in XQ score from 

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baseline), they will continue their assigned acupuncture treatment for an additional 4 weeks.  
Patients who have no response (increase in XQ score or decrease of <10 points from 
baseline), partial response (20 or more point decrease in XQ score from baseline), or 
complete response (XQ score = 0) will receive no further acupuncture treatment. 
 
All patients (i.e., Standard Oral Hygiene group, and complete, minor, partial, and non- 
responders of the acupuncture groups) will complete the XQ, MDASI-HN, and FACT-G 
again at weeks 8  (±1 week), 12  (±2 weeks), and a final time at the 6 month follow-up  (±1 
month), and then will be taken off study.  All patients will also have sialometry collection at 
all timepoints as well. 
 
Patients in the Standard Oral Hygiene group or the sham acupuncture group who have 
completed study participation and are taken off-study will have the opportunity to receive 3 
sessions of true acupuncture at no cost. These 3 sessions will be conducted in the same 
manner as the active true acupuncture arm using the same acupoints. These 3 free sessions 
will occur after the 6 month follow-up has been completed. There is no collection of patient 
data for these 3 free sessions. 
 
6.2 Baseline Assessments 
After the patient has signed consent and all eligibility requirements are met, the patient will 
complete the following before being enrolled and randomized to 1 of 3 study arms: 
 
• 
Xerostomia Questionnaire (XQ) 
• 
MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-
HN) questionnaire 
• 
The Functional Assessment of Cancer Therapy (FACT-G) 
• 
Acupuncture Expectancy Scale (AES) 
• 
Sialometry 
• 
Concomitant Medications 
 
6.3 On-Study Assessments 
 
Please see Patient Study Calendar (Section 7.5) for complete schedule of events. 
 
All patients will have study visits at the end of week 4 (±1 week), week 8 (±1 week), week 
12 (±2 weeks) and a follow-up visit at 6 months (±1 month) after treatment (i.e. last 
acupuncture session received) for patients randomized to either acupuncture group or 
7. 5 months (±1 month) after consent for those randomized to the standard oral hygiene 
group. These study visits will be conducted to assess response. 
 
A study visit should also be completed if the patient terminates from the study early. 
 
Standard Oral Hygiene Arm: 
Patients randomized to the Standard Oral Hygiene arm will receive standard care only. 
Patients will complete the following at each study visit as defined above: 
 
• 
Xerostomia Questionnaire (by phone if patient is unable to come to clinic for 
Response assessment) 
• 
MDASI-HN Questionnaire 
• 
FACT-G questionnaire 
• 
Sialometry 

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• 
Concomitant Medications 
 
True Acupuncture and Sham Acupuncture Arms: 
Patients randomized to the true acupuncture and sham acupuncture arms will receive 
standard care in regards to their xerostomia. In addition, patients will receive either true or 
sham acupuncture twice weekly for four weeks. 
 
The following will be completed at each acupuncture visit: 
• 
Vital signs 
• 
Review of adverse events 
• 
Review of concomitant medications 
• 
TAT or SAT 
 
At the end of week 4 patients will complete: 
• 
Xerostomia Questionnaire (by phone if patient is unable to come to clinic for 
Response assessment) 
• 
MDASI-HN Questionnaire 
• 
FACT-G questionnaire 
• 
AES Questionnaire (week 4 only) 
• 
Sialometry 
• 
Adverse Events 
• 
Concomitant Medications 
 
At 8 and 12 weeks and at 6 months after treatment, all acupuncture patients will complete the 
following: 
 
• 
Xerostomia Questionnaire (by phone if patient is unable to come to clinic for 
Response assessment) 
• 
MDASI-HN Questionnaire 
• 
FACT-G Questionnaire 
• 
Sialometry 
• 
Adverse Events 
• 
Concomitant Medications 
 
6.4 Off-Study Assessments 
All patients taken off-study at the 6 month follow-up visit, or any other time during the study 
should have a final study visit and complete the XQ, MDASI-HN, FACT-G, and sialometry 
prior to being removed from study. 
 
6.5 Study Compliance 
Compliance is a key factor in analyzing the information collected in this trial.  Patients should 
remain compliant with study requirements to the very best of their ability.  Patients should be 
counseled on compliance issues and encouraged to follow the protocol as outlined.  
Telephone calls reminding patients of their assessment appointments should be made.  
Reminders should include information on the time and date of study visit, the completion of 
forms, and sialometry collection.  Study calendars, diaries, AE assessment forms, and any 
other forms used to assess and collect research data should also be mentioned. 
 
6.6 Intervention Delay 
Patients who miss acupuncture sessions may have sessions made up. The sessions should 
be rescheduled as close as possible and no more than 4 days after the missed session.   If 
the missed session cannot be rescheduled within 4 days, it will not be made up and the 

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patient will move on to the next scheduled subsequent session unless the missed session 
was their last protocol required session. If 2 consecutive sessions or a total of 3 or more 
sessions during the first 4 weeks of treatment are missed, patients will be taken off-study. 
 
6.7 Study Follow-Up 
There is no other required follow-up for this trial after the 6 month follow-up visit.  However, if 
the treating physician feels that a follow-up is necessary on a patient, the patient may be 
taken off-treatment and followed until no longer felt necessary, then taken off-study. 
 
7.0 
MEASUREMENT OF EFFECT 
 
7.1 Xerostomia Questionnaire (XQ)  
The XQ is an 9-item questionnaire that has been validated in several cohorts 7,19.  Subjects 
rate each symptom on an 11-point ordinal Likert scale from 0 to 10, with higher scores 
indicating greater dryness or discomfort due to dryness. The questions are equally divided into 
4 items about oral dryness while eating or chewing and 4 items about dryness while not eating 
or chewing.  The 9th item (first question) asks about oral comfort with dentures and does not 
apply to the majority of patients. The XQ will be scored at the end of 4 weeks of treatment to 
determine response. This will be done as follows: add response values for questions 2-9 and 
divide by 8 to calculate mean. Then, multiply by 10 for a final summary score ranging 
between 0 and 100, with higher scores representing more xerostomia. See below for 
response definitions. 
 
7.2 MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN) 
Symptoms will be systematically assessed using the validated MDASI-HN 32,43. The MDASI 
has been used in Phase I though Phase IV trials in the U.S. and in Europe. This tool can be 
easily used in clinical and research settings. The MDASI measures, on a numeric rating 
scale of 0-10, both the severity of symptoms and the interference symptoms cause in 
patients’ daily activities. The 13 core MDASI symptom items are based on extensive 
evaluation of symptoms common to cancer and cancer treatment. Symptoms on the core 
MDASI include pain, fatigue, and appetite changes that the head and neck cancer 
population typically experiences. Patients easily complete it as a self- report tool. 
 
The MDASI was developed so that items relevant to specific cancers and cancer treatments 
identified through focus groups could be added. The MDASI-HN includes 9 head and neck–
specific items. The instrument was validated in a cohort of more than 200 patients and 
found to be highly reliable 32. 
 
 
7.3 The Functional Assessment of Cancer Therapy (FACT-G)   
Health-related quality of life will be assessed with the FACT-G 44. This instrument is able to 
discriminate between individuals with metastatic and non-metastatic disease, as well as 
between patients at different stages of illness. The scale has been found to have good 
concurrent validity, high internal consistency (0.89), and good test-re-test reliability (0.82 to 
0.88). 
 
7.4 Acupuncture Expectancy Scale (AES)   
To determine the relationship between outcome expectancy related to acupuncture and 
clinical response, we will use the Acupuncture Expectancy Scale. This 4-item instrument 
was developed by Mao et al. and found to be reliable (Cronbach’s α of 0.82) and valid by 
positive correlation with patient self-reported efficacy and satisfaction 31. The scale was 
further validated among cancer patients who were mostly acupuncture naïve27.  Expectancy 
of a benefit from acupuncture appeared to be increased by educating patients on the 

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scientific theory and clinical evidence of acupuncture.  Higher expectancy was also found in 
patients who had previously participated in an acupuncture trial compared with those who 
had not participated in an acupuncture trial27.  In the proposed study, we will evaluate 
expectancy as a predictor of response to acupuncture. 
 
Response Assessment for Xerostomia Questionnaire (XQ)Patient response will be 
assessed by determining XQ scores at baseline and at 4 weeks after beginning treatment.  
Response after 4 weeks of treatment will be calculated based on XQ score at baseline minus 
XQ score at 4 weeks. Duration of response will be assessed by determining XQ scores at 8 
and 12 weeks and the 6 month follow-up.  Patients will circle the appropriate response to the 
question and the corresponding numbers will be used to determine the response. The 
corresponding numbers will be totaled giving the patient’s score. 
 
Protocol responses are listed below: 
 
No Response:  Xerostomia worsening or decrease of < 10 points in score from 
baseline. 
 
Minor Response:  10 – 19 point decrease in score from baseline score. 
 
Partial Response:  20 point or higher decrease in score from baseline score. 
 
Complete Response:  Complete resolution of all xerostomia as reported by the patient 
on the XQ with a score of 0

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7.5 
Study Calendar of Events 
 
 
 
Acupuncture treatment must begin within 30 days of Baseline data collection and enrollment. 
Coordinators should complete a MedWatch only for Grades 4 and 5—definitely related, probably related or possibly related to the intervention and 
submit to the RB DMC. 

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8.0 
SIALOMETRY 
 
8.1 Saliva Flow Examination 
Unstimulated Whole Saliva (USFR): Patients are instructed to refrain from eating, drinking, 
and dental hygiene for a minimum of 60 minutes before saliva collection. The patient is 
seated upright in a quiet area where he/she will remain undisturbed and is told to minimize 
orofacial movements. The patient will relax in the designated area for 15 minutes before 
saliva collection.  Patients are instructed not to attempt to increase or control salivation 
actively (such as sucking or swallowing) but to simply relax.  A collection vial (including seal 
and cover) will be weighed on a calibrated balance with accuracy to 0.01 gm. The patient is 
instructed to first clear his/her mouth by swallowing. Then, with the head held slightly 
forward, the patient is instructed not to talk or swallow during the 5-minute collection but to 
allow saliva to collect in the floor of the mouth. The 5-minute collection time is initiated on a 
digital timer and in view of the patient. The patient should then expectorate the accumulated 
saliva into the pre-weighed vial after 60 seconds. The patient should repeat this procedure 4 
more times for a total collection time of 5 minutes.  Patients are reminded not to swallow or 
talk during the entire collection period.  At the end of the 5 minutes, the collection vial is 
promptly sealed, weighed, placed on ice and transported to the laboratory. 
 
Stimulated Whole Saliva (SSFR): Patients are to rest for 5 minutes prior to stimulated 
saliva collection.  The exogenous stimulant will be a neutral chewing gum from Wrigley 
(unflavored gum base) used previously for SSFR. The patient will chew the gum for 3 
minutes, then expectorate the gum and saliva into a disposable cup. Next, the patient 
should swallow to clear the mouth. The patient’s saliva will then be collected in the vial for 5 
minutes using a method identical to USFR collection. After a 5 minute rest period, repeat 
(i.e. chew gum for 3 minutes, expectorate gum and saliva into a disposable cup, swallow, 
then collect saliva for 5 minutes as above.) 
 
8.2 Saliva Constituent Analyses 
We will determine acupuncture’s effects on saliva-based factors including pH, buffering 
capacity, and viscosity, as well as levels of total protein, CGRP and VIP from SSFR collected 
at baseline, week 4, week 8, week 12 and 6 months. The value of pH and buffering capacity 
will be measured using a portable pH meter with micro electroprobe. Buffering capacity will 
be measured using the method previously described by Siqueria  et al. (79). All salivary 
outcomes will be measured at MD Anderson from frozen samples assayed in batch to 
decrease variance. Viscosity of the saliva (0.5 ml) will be determined using LVT Wells-
Brookfield cone-and-plate digital viscometer (Brookfield Engineering Laboratory) (80). The 
total amount of protein in each saliva sample will be determined using the Bradford assay 
(Biorad protein assay kit). Levels of CGRP and VIP will be quantified using neuropeptide-
specific RIA kits (Peninsula-Bachem) (81). The concentration of peptides will be normalized 
by the amount of protein in each sample. All assays will be conducted in the laboratory of Dr. 
Peiying Yang. Once the saliva samples have been assayed they will be destroyed. 
 
9.0 
ADVERSE EVENTS AND REPORTING REQUIREMENTS 
 
 
Adverse Event/Serious Adverse Event reporting begins after the informed consent is 
signed. 
 
Serious Adverse Events occurring within 30 days of study completion must be reported 
via FDA Form 3500 (MedWatch). 
 
 
 

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9.1 Protocol Specific Reporting for Adverse Events (AEs) 
 
o DEFINITION: An adverse event (AE) is any untoward medical occurrence in a study 
participant.   
 
o Grades 1, 2, and 3 expected (solicited) and unexpected (unsolicited) AEs that meet 
the above definition for an AE and are ONLY definitely related, possibly related or 
probably related to the intervention should be reported to the RB DMC using the 
Toxicity Assessment Sheet. 
 
o Hospitalizations for routine scheduled procedures and treatments do not need to be 
reported. Example: Patient admitted for gall bladder surgery.  
  
9.2 Protocol Specific Reporting for Serious Adverse Events (SAEs) 
 
DEFINITION: ICH Guideline E2A and Fed. Reg. 62, Oct. 7, 1997 define serious adverse 
events as those events which meet any of the following criteria? 
 
Results in death 
 
Is life threatening (Note: the term life-threatening refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 
Is a congenital abnormality/birth defect 
 
Events that may not meet these criteria, but which the investigator finds very 
unusual and/or potentially serious, will also be reported in the same manner. 
  
 
Grades 3, 4, and 5 expected (solicited) and unexpected (unsolicited) SAEs that 
meet the above definition for SAEs and/or regardless of attribution (i.e. 
regardless of whether they are related to this study intervention or not) should 
be reported to the RB DMC using the FDA Form 3500 (MedWatch).  
 
 
Site staff and/or Principal Investigators will report to the RB Data Management Staff 
within 24 hours of discovering the details of all unexpected severe, life-threatening 
(grade 4) and/or fatal adverse events (grade 5) if there is reasonable suspicion that 
the event was definitely, probably, or possibly related to the study intervention.  
 
Otherwise, the MedWatch should be sent to the RB DMC by fax or email within 10 working 
days of discovering the details of the SAE. 
 
Data Elements to include on the MedWatch are: 
 
SAE reported date 
 
CTCAE Term (v5.0) 
 
Event onset date and event ended date 
 
Severity grade (use table provided in Section 9.3 below) 
 
Attribution to study intervention (relatedness) 
 
Action taken with the study participant and intervention 
 
Outcome of the event 
 
Comments 
 

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9.3 Guidelines to Determine Grade and Severity of AEs and/or SAEs 
 
 
 
The active version of the CTCAE is identified and located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Identify the adverse event using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0.  The CTCAE provides descriptive terminology and a grading scale for 
each adverse event listed.  A copy of the CTCAE can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
AEs will be assessed according to the CTCAE grade associated with the AE term.  AEs that 
do not have a corresponding CTCAE term will be assessed according to the general 
guidelines for grading used in the CTCAE v5.0. as stated below. 
 
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental ADL*. 
3 
Severe 
Severe or medically significant but not immediately life-
threatening; 
Hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL**. 
4 
Life threatening 
Life-threatening consequences; urgent intervention 
indicated. 
5 
Fatal 
Death related to AE. 
 
 
Activities of Daily Living (ADL) 
* 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
The Research Base Grant PI, Safety and Toxicity Review Committee and/or Study Chair will 
take appropriate action to inform the membership and statistical personnel of any protocol 
modifications and/or precautionary measures, if this is warranted. 
 
The RB DMC is responsible for communicating AEs/SAEs to the FDA, the drug sponsor, WF 
IRB, the WF Safety and Toxicity Review Committee (STRC) and/or other regulatory agencies 
as appropriate per agency reporting requirements. 
 
Institutions must comply with their individual Institutional Review Board (IRB) policy regarding 
submission of documentation of adverse events. All MedWatch reports should be sent to the 
local IRB in accordance with the local IRB policies. 
 
9.4 Follow-up of SAEs  
 
Site staff should send follow-up reports as requested when additional information is available.  
Additional information should be entered on the MedWatch form in the appropriate format.  
Follow-up information should be sent to the RB Data Management Center as soon as 
available. 

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SAEs (Grade 4 and/or Grade 5) for this protocol should be followed for those related to the 
study intervention.  Documentation should include: 
 
 
PID 
 
Date of SAE 
 
Description of the event  
 
Relationship of the SAE to the study intervention 
 
Severity 
 
Intervention/Resolution 
 
If the AE is attributed to anything other than study therapy, it should be assigned the 
attribution of “not related”. The study team will work with the acupuncturist in gathering AEs 
between study visits.  Acupuncturists will record AEs on the provided SAT/TAT forms and 
study staff will speak with the acupuncturist regarding AEs in order to determine grade and 
attribution. The study staff may also contact the patient directly to gather more information 
regarding the event. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
The primary objective will be assessed by determining the Xerostomia Questionnaire score 
before and 4 weeks after starting acupuncture. The Xerostomia Questionnaire is an 9-item 
survey with each item scored between 0 and 10 then the final score normalized to a 0-100 
scale, and has been validated in several cohorts 19,45. 
 
 
We will compare the three groups using analysis of covariance (ANCOVA) adjusting for 
the baseline XQ score. If the test for the overall comparison is significant (p<0.05), we 
will then perform pairwise comparisons, each at a 5%/3 = 1.33% significance level, to 
control for the overall type I error rate. We have powered the study to be able to detect a 
difference of 10 points between each pair of groups on a 0 to 100 scale for the XQ. In order 
to detect this difference we will require 64 patients per group. This assumes a t-test with a 
two-sided significance level of1.33% and 84% power, and that the standard deviation of 
responses is about 16 46. Our actual ANCOVA analysis is expected to yield higher power of 
detecting the same differences due to the potentially reduced within-group SD of the response 
after controlling for the baseline XQ score. We will, in general, have higher power to detect 
clinically significant changes/differences in individual group XQ scores over time if these 
changes range, as expected, from 15-20 points 47, depending on the level of correlation 
between the baseline and 4-week XQ scores. 
 
In order to allow for up to a 20% drop out rate, a total of 240 patients will be entered into this 
study, or 80 per group. Similar analyses will be conducted for the outcomes of MDASI-HN 
and FACT-G. 
 
In patients who report a response to the acupuncture intervention at 8 weeks, an additional 
assessment will be made for all three instruments (XQ, MDASI-HN and FACT-G) at week 12 
and 6 months after treatment (i.e. last acupuncture session received) to estimate the 
response. This analysis will be exploratory and its outcomes will be estimates of responses 
and variability of responses between patients (mean ± standard deviations) for XQ, MDASI- 
HN and FACT-G. 
 
When applicable, we will also conduct linear mixed model analysis to assess the group 
differences over time as well as the interaction effects between group and time, controlling for 

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the appropriate baseline outcomes. 
 
Analysis for the secondary objectives. Objective 1. 
We will also summarize the duration of response up to a maximum of 6 months after 
treatment (i.e. last acupuncture session received) in the subgroup of patients who report a 
response to the acupuncture intervention and will test for differences between groups.  
 
Objective 2-4. Analyses for these objectives will be similar to those for assessing the primary 
objective, except using different outcomes. 
 
Objective 5. To assess this objective, we will preliminarily test for the interaction effects 
between treatment group and expectancy. 
 
Acupuncture Expectancy Scale (AES): We will also explore the association between 
expectancy and outcomes using information from the Acupuncture Expectancy Scale (AES). 
Expectancy will be assessed among all participants using the AES at baseline.  For patients 
randomized to either acupuncture group, it will be assessed again at week 4. The AES 
assessment will be correlated with severity of xerostomia using the XQ (and other 
continuous variables).  More complex analyses will also evaluate whether expectancy 
moderates outcomes. Following the procedures of Baron and Kenny48, the evaluation of 
moderation involves examining the interaction between intervention condition and baseline 
expectancy.  In a series of mixed model analyses, tests of the interaction of intervention 
condition with expectancy will be evaluated to determine whether baseline expectancy 
changes the impact of acupuncture condition on the outcome measures [i.e., determine 
whether acupuncture (active or inactive) is more effective based on baseline expectancy]. 
 
Changes in xerostomia symptoms will also be examined as a possible mediator of the 
effects of acupuncture on QOL outcomes following the procedures of Baron and Kenny48 
using generalized linear mixed model regression. The mediation effect estimate will be 
computed according to MacKinnon49, who describes mediation as the difference of the 
intervention effect on outcome with and without the presence of the mediators, or 
alternatively, the product of the effect of the intervention on the mediators and the effect of 
the mediators on the outcome controlling for the intervention condition. 
  
11.0 
STUDY ACCRUAL 
 
240 participants are expected to be enrolled on this trial. It is expected that 5-7 
participants will be enrolled each month.  An accrual of 5-7 patients per month is expected 
since 1) certified acupuncturists are available at most of our NCORP sites, 2) interest in 
applying acupuncture to western medicine is escalating, 3) objective benefits of 
acupuncture for xerostomia have been reported, and 4) the condition lacks any significant 
treatment. Accrual for the trial would thus be expected to take 1.8 to 2.5 years. 
  
12.0 
DATA MANAGEMENT 
 
Case report form submission guidelines are: 
 
• Enrollment documents including eligibility checklist prior to enrollment 
• Baseline forms within 14 days of enrollment 
• Serious adverse events (SAE) within 24 hours of event and/or knowledge 
of event 
• Course/cycle information within 14 days of completing course/cycle 

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• Other case report forms within 14 days of event. 
 
NCORP site staff will electronically enroll their study participants in the WF NCORP RB 
database website, CCRBIS, at https://ccrbis.phs.wakehealth.edu  
 
 
Log in to the database website using your CCRBIS username and password. 
 
In the drop-down menu next to Enroll Patient/Patient Info select 97115, then click 
Enroll Patient/Patient Info. 
 
Click on Enroll New Patient. 
 
Complete the Eligibility Checklist/Enrollment Form then click Submit. 
 
Following successful submission, a confirmation page will appear with the assigned 
PID, print this page for your records. 
 
Submit a copy of the signed informed consent form to the WF NCORP Data 
Management Center (DMC) by fax at (336) 713-6476 or mail to: 
 
WF NCORP Research Base Data Management Center 
Wake Forest Baptist Medical Center 
Building 525@Vine, 4th floor Medical Center Boulevard 
 
 
 
 
 
Winston-Salem, NC 27157 
 
If you have questions related to the subject enrollment process or require assistance with 
enrollment, please contact the WF NCORP Research Base DMC between 8:00am and 
5:00pm EST, Monday through Friday at (336) 706-0891. 
 
 
13.0 
DATA MONITORING COMMITTEE 
 
The Wake Forest NCORP Research Base has established a Data Safety Monitoring 
Board (DSMB) that is independent of study leadership, is free of conflicts of interest, 
and has formal policies and procedures approved by the NCI. The main objective of the 
DSMB is to: 
 
• 
Ensure that patients in the clinical trial are protected 
• 
Ensure that evaluation of interim results and decisions about continuing, modifying, 
or terminating a clinical trial and reporting results are made competently 
• 
Ensure that the credibility of clinical trial reports and the ethics of clinical trial 
conduct are above reproach. 
 
This DSMB will review the data from this protocol every 6 months or as requested. 
 
14.0 
SITE REGISTRATION 
 
IRB Approval: 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept the 
NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB review will 
continue to be accepted for studies that are not reviewed by the CIRB, or if the study was 
previously open at the site under the local IRB. International sites should continue to submit 
Research Ethics Board (REB) approval to the CTSU Regulatory Office following country-

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specific regulations.  
Sites using their local IRB or REB, must submit their approval via email to the Lead Protocol 
Office, the Wake Forest NCORP Research Base to NCORP@wakehealth.edu.  
 
Additional Requirements: 
 
Additional requirements to obtain an approved site registration status include: 
 
An active Federal Wide Assurance (FWA) number; 
 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
 
Compliance with all protocol-specific requirements (PSRs) 
 

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