Opioid-Sparing Pain Treatment In Myeloma And Lymphoma Patients Undergoing High-Dose Chemotherapy (OPTIMAL-HiChemo): Randomized Controlled Trial
Phase: PHASE3
Conditions: Multiple Myeloma, Hodgkin Disease, Non-Hodgkin Lymphoma
Sponsor: Memorial Sloan Kettering Cancer Center

 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
Page 1 of 34 
 
MSK PROTOCOL COVER SHEET 
 
Opioid-Sparing Pain Treatment In Myeloma And Lymphoma Patients Undergoing High-
Dose Chemotherapy (OPTIMAL-HiChemo) 
 
Principal Investigator/Department:  
Gary E Deng, MD, PhD/Medicine/Integrative Medicine Service 
 
Memorial Sloan Kettering Cancer Center
IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
Page 2 of 34 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 4 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................ 8 
4.1 
Design ................................................................................................................................. 8 
4.2 
Intervention ......................................................................................................................... 8 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS ............. 9 
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY ........................................................................ 9 
6.1 
Participant Inclusion Criteria .............................................................................................. 10 
6.2 
Participant Exclusion Criteria ............................................................................................. 10 
7.0 
RECRUITMENT PLAN ......................................................................................................... 10 
7.1 
Research Participant Registration ..................................................................................... 11 
7.2 
Randomization .................................................................................................................. 12 
8.0     INFORMED CONSENT PROCEDURES ............................................................................... 12 
9.0 
PRE-TREATMENT/INTERVENTION  ................................................................................... 15 
10.0 TREATMENT/INTERVENTION PLAN .................................................................................. 15 
11.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 16 
12.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 17 
13.0    CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY ................. 17 
14.0 BIOSTATISTICS .................................................................................................................. 20 
15.0 TOXICITIES/RISKS/SIDE EFFECTS .................................................................................... 25 
15.1 Serious Adverse Event (SAE) Reporting ........................................................................... 26 
16.0 PROTECTION OF HUMAN PARTICIPANTS ....................................................................... 27 
16.1 Privacy .............................................................................................................................. 26 
16.2 Data Management  .............................................................................................................. 28 
16.3 Quality Assurance ............................................................................................................. 29 
16.4 Data and Safety Monitoring ............................................................................................... 29 
17.0    REFERENCES ..................................................................................................................... 30 
18.0    APPENDICES ...................................................................................................................... 34 
 
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IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
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Page 3 of 34 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Study Title 
Opioid-sparing Pain Treatment In Myeloma And Lymphoma Patients 
Undergoing High-Dose Chemotherapy (OPTIMAL-HiChemo) 
Objective 
To investigate how to optimize pain management during cancer 
treatment by combining nonpharmacologic and pharmacologic 
interventions: whether using acupuncture to prevent onset of severe 
pain, with opioids as backup, leads to lower risk of opioid use without 
compromising pain management and lower symptom burden, when 
compared to opioids as first line treatment. 
Specific Aims 
1: To determine the comparative effectiveness of ACU (acupuncture 
and opioids, further defined below) versus OPI (opioids only) in reducing 
opioid use during and after HiChemo among patients who do not use 
opioids at baseline before HiChemo and in reducing their symptom 
burden during HiChemo.   
 
2: To determine the short-term (Day 7) and long-term (Day 90) effects of 
ACU compared to OPI on patient-reported pain, opioid side effects (e.g. 
drowsiness, constipation, nausea), and quality of life among the above 
study population.  
 
Exploratory: (1) Explore whether the effect of ACU treatment on Day 90 
opioid use is mediated by its effect on Day 7 opioid use.   
(2) Explore potential heterogeneity of treatment effect (HTE) by various 
factors. 
Study Design 
A multicenter, 2-arm, parallel group, individual randomized (1:1 ratio) 
controlled trial comparing two pain management interventions. 
Study Sites 
Memorial Sloan Kettering Cancer Center, New York (MSK) 
Seattle Cancer Care Alliance (SCCA), Fred Hutchinson Cancer 
Research Center (Fred Hutch) 
Interventions 
and 
Comparators 
A) Acupuncture as a first-line pain preventive measure during HiChemo 
with opioids as back-up pain treatment (ACU), and B) opioids as first-
line pain treatment (OPI). Every study patient will receive the same 
usual care for opioid administration, initiated and adjusted according to 
their pain levels as in standard of care. 
Study 
Population 
Opioid-naïve (defined as not using opioids in the week before 
enrollment) adult multiple myeloma, Hodgkin disease, and non-Hodgkin 
lymphoma patients undergoing HiChemo followed by hematopoietic 
stem cell transplantation (HSCT)  
Total 
Enrollment 
300 
Time to 
Completion 
36 months 
Outcomes 
The following will be assessed at baseline and days 7, 15, 30, and 90 
after the first dose of HiChemo (Day 0):  
 
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Primary outcomes: opioid use, and symptom burden measured by M. D. 
Anderson Symptom Inventory – Bone Marrow Transplantation (MDASI-
BMT). 
 
Secondary outcomes: Brief Pain Inventory–Short Form, Patient-
Reported Oral Mucositis Symptom Scale, Pain Medication Side Effects 
Questionnaire quality of life measured by Patient-Reported Outcomes 
Measurement Information System – 29 Items (PROMIS-29). 
 
Other outcomes: opioid dose, clinical features (diagnosis and disease 
status), Common Terminology Criteria for Adverse Events Version 5.0 
(CTC-AE v5.0), Opioid Risk Tool, Acupuncture Expectancy, use of 
health care resources (length of hospital stays during HSCT, transfers to 
the intensive care unit (ICU) while hospitalized, urgent care/emergency 
room visits, and readmission rates during the first 30 days post-HSCT). 
Analytic 
Methods 
All analyses will be by intent-to-treat, with patients entered into analysis 
as randomized, irrespective of treatment actually received. For Aim 1 
opioid use, we will utilize logistic regression to model the probability of 
opioid use at specific time points (i.e., day 7 and 90, separately), and 
generalized linear mixed models to model the probability of opioid use 
across all time points (i.e. days 7, 15, 30, and 90), as a function of study 
arm (ACU vs. OPI), time, and randomization stratification variables. For 
Aim 1 symptom burden and Aim 2 pain, side effects and QOL , we 
will use linear mixed models to similarly model those continuous 
endpoints over time. We will also explore potential causal mechanisms 
by testing mediation hypotheses (e.g. test whether the effect of 
treatment on Day 90 opioid use is mediated through the effect of 
treatment on Day 7 opioid use). 
Funding Source 
Peer-reviewed Patient-Centered Outcomes Research Institute 
(PCORI) contract 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Opioids are often used to treat acute pain during cancer treatment, yet this exposure to 
opioids is a risk factor for patients to become long-term opioid users. Cancer survivors have 
a higher risk for opioid use, with an odds ratio up to 2.55. Clinical practice guidelines all 
recommend a combination of pharmacologic and non-pharmacologic modalities for treatment 
of acute pain. But, currently there is no strong evidence guiding clinicians or patients on how 
best to combine the two. The proposed study in 300 patients undergoing high-dose 
chemotherapy (HiChemo) will generate high quality evidence to support clinicians and 
patients in making patient-centered decisions on the optimal management of acute pain 
during cancer treatment.  
Memorial Sloan Kettering Cancer Center
IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
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New York, New York 10065 
 
Page 5 of 34 
 
The overall objective is to investigate how to optimize pain management during cancer 
treatment by combining nonpharmacologic and pharmacologic interventions: does using 
acupuncture to prevent onset of severe pain, with opioids as backup, lead to lower risk of 
opioid use without compromising pain management and lower symptom burden, when 
compared to opioids as first line treatment. 
Specific Aim 1: To determine the comparative effectiveness of ACU versus OPI in reducing 
opioid use during and after HiChemo among patients who do not use opioids at baseline 
before HiChemo and in reducing their symptom burden during HiChemo. Hypothesis 1 (a): 
ACU during HiChemo will significantly reduce the proportion of short-term opioid users (at 
Day 7 after HiChemo) when compared to OPI. Hypothesis 1 (b): ACU during HiChemo will 
significantly reduce the proportion of long-term opioid user (at Day 90 after HiChemo) when 
compared to OPI. Hypothesis 1 (c): ACU during HiChemo will significantly reduce the 
MDASI-BMT Total Symptom Severity score at Day 7 when compared to OPI.  
Specific Aim 2: To determine the short-term (Day 7) and long-term (Day 90) effects of ACU 
compared to OPI on patient-reported pain, opioid side effects (e.g. drowsiness, constipation, 
nausea), and quality of life among the above study population. Hypothesis 2(a): ACU is not 
inferior to OPI in maintaining a low pain score at Day 7 and 90 after HiChemo. Hypothesis 
2(b): ACU will reduce symptoms of drowsiness, constipation, nausea, and improve mental 
and physical quality of life at day 7 and 90 after HiChemo. 
Exploratory Aim 1: Explore whether the effect of ACU treatment on Day 90 opioid use is 
mediated by its effect on Day 7 opioid use.   
Exploratory Aim 2: Explore whether sex, race, ethnicity, gender, primary cancer diagnosis 
(MM versus HD versus NHL), Opioid Risk Tool (ORT), Acupuncture Expectancy Scale (AES) 
score, or concurrent use of other medications with analgesic effects influence response to 
interventions in this population (i.e., heterogeneity of treatment effect, HTE). 
 
3.0 
BACKGROUND AND RATIONALE 
In 2018, an estimated 1.7 million new cases of cancer will be diagnosed in the U.S. and 0.6 
million people will die from the disease. Among patients with cancer, pain is one of the most 
common, burdensome, and feared symptoms.1 A meta-analysis of 122 studies (N=4,199) 
showed that about 55% of patients experience pain during cancer treatment; 40% 
experience pain after curative treatment.1 Opioids are necessary and appropriate for patients 
with advanced cancer and intractable pain, but cancer survivors with no active cancer should 
not be using opioids unnecessarily. Cancer survivors have a higher risk for opiod use. A 
recent study using SEER and Medicare data of 46,789 older cancer survivors and 138,136 
noncancer controls shows a significantly higher chronic opioid use in cancer survivors who 
had a higher pain burden during cancer treatment (colorectal cancer: odds ratio (OR) 1.34; 
95% CI, 1.22 to 1.47; lung cancer: OR 2.55; 95% CI, 2.34 to 2.77). It takes six years for 
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IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
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Page 6 of 34 
 
opioid use to return to the level of controls.2 Other studies showed the exposure to opioids 
during treatment for acute pain is a strong risk factor for patients to become long-term opioid 
users even when the acute pain has subsided and opioids are no longer appropriate.3-6 The 
largest increments in probability of long-term opioid use were observed after the 5th and 31st 
days on short-term use.7 Unnecessary use of opioids presents problems beyond the medical 
field, such as effects on mental health, impact on family members, financial costs, opioid 
misuse disorder, especially in light of the current opioid crisis. 
Autologous hematopoietic stem cell transplantation (auto-HSCT) is a treatment for multiple 
myeloma (MM), Hodgkin disease (HD), and non-Hodgkin lymphoma (NHL). Patients receive 
high-dose chemotherapy (HiChemo) followed by infusion of hematopoietic stem cells days 
later. Pain is rated one of the top five symptoms during this treatment.8 Oral mucositis from 
HiChemo is the main source of severe acute pain and the main reason patients are initiated 
on opioids. Between 30-43% of patients undergoing HiChemo and auto-HSCT experience 
severe (grade 3 or 4) mucositis which creates distress and interferes with eating and 
drinking. Mucositis pain follows a predictable course, usually starting shortly after HiChemo 
and peaking around day 7 after initiation of HiChemo. It begins to subside around days 15, 
and has usually resolved by Day 30. By Day 90, there should be no residual pain caused 
directly by HSCT. The pain can lead to periods of difficulty eating, malnutrition, dehydration, 
weight loss, depression, and impaired quality of life.9-12 Opioids are usually used to manage 
the pain. Although effective, opioids are often associated with side effects like constipation, 
nausea, sedation, and delirium.13-20 After mucositis has subsided, some patients may have 
become accustomed to opioids and use them chronically for other pain. The intensity of pain 
during HiChemo, the high incidence of opioid use in this population, and the predictable 
clinical course make HiChemo/HSCT an excellent model to study the effects of pain control 
interventions during cancer treatment on short- and long-term opioid use.  
Pain management during cancer treatment presents patients and clinicians with a decision 
dilemma. The Joint Commission,21 American College of Physicians (ACP),22,23 National 
Comprehensive Cancer Network (NCCN)24,25 and American Society of Clinical Oncology 
(ASCO)26 guidelines all recommend a combination of pharmacologic (mainly opioids during 
HiChemo) and non-pharmacologic modalities. However there is currently no strong evidence 
guiding clinicians or patients on how to combine non-pharmacologic and pharmacologic 
interventions to manage the pain patients experience during cancer treatment. In particular, 
there is a lack of evidence that considers what patients perceive as important, e.g. side 
effects and risk of long-term opioid use.24-26  
Acupuncture is a non-pharmacologic modality that involves insertion of filiform needles into 
certain points on the body, followed by manual manipulation, heat, or electrical stimulation to 
elicit therapeutic effects. Numerous randomized controlled trials have shown its effectiveness 
in pain management.27-29 A systematic review of 17 trials (N= 2,027) showed that 
acupuncture reduced the intensity of acute and chronic low back pain more than sham 
acupuncture, leading ACP’s clinical practice guidelines to recommend acupuncture.23 In a 
meta-analysis of 20,827 patients from 39 RCTs, the analgesic effect size of acupuncture was 
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IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
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1275 York Avenue 
New York, New York 10065 
 
Page 7 of 34 
 
0.5 SDs compared with no acupuncture control and close to 0.2 SDs compared with sham.29 
Neuroscience research has shown that acupuncture increases production of endogenous 
analgesic neurotransmitters, such as endorphins and adenosine.30-35 In January 2020, 
Centers for Medicare & Medicaid Services (CMS) finalized a decision to cover acupuncture 
for Medicare patients with chronic low back pain. We conducted a pilot randomized study 
showing that acupuncture during HiChemo/HSCT has the potential to be an opioid-sparing 
non-pharmacologic therapy that significantly reduces opioid use and opioid side effects 
without compromising pain control.36 We found that patients in the sham acupuncture group 
had greater than five times the odds of increasing pain medications from baseline compared 
with those in the true acupuncture group (OR 5.31, 95% Confidence Interval (CI) 1.35 to 
20.93, P=0.017). The effect was most pronounced among patients who were not taking 
opioids at baseline (“opioid-naïve”). In those patients, any increase in opioid use was due to 
the pain induced by HiChemo/HSCT, rather than from pre-existing pain. Among opioid-naïve 
patients, 20% (4 of 20) of those who received sham acupuncture started to use opioids 
during HiChemo/HSCT (Day 5), 40% around Day 30, and 25% became long-term opioid 
users (Day 90). In contrast, among the 15 patients who received true acupuncture, none 
needed to use opioids on Day 5 (p=0.119) or Day 30 (p=0.006), and only one (7%) became a 
long-term opioid user (Day 90, p=0.365).36 Acupuncture also reduces symptoms commonly 
associated with opioid use, such as nausea, poor appetite and drowsiness. The proposed 
study expands on that research and uses a patient-centered approach to address this gap in 
the evidence.  
Patients and stakeholders took part in the formulation of the research question and the 
design of the study. We formed a Patient/Stakeholder Advisory Committee (PSAC) which 
consists of 3 patients who participated in the previous pilot study, a future HSCT patient, a 
patient caregiver, a representative from advocacy organization, 2 clinicians and 2 
researchers. The PSAC helped with study design and development of patient-centered 
recruitment/retention strategies. One patient from the pilot study and one patient who is likely 
to receive HSCT in the near future will serve as consultants for the duration of the study.  
The proposed study takes advantage of a highly efficient clinical pain model. Pain and other 
symptoms during HiChemo/HSCT follows a very predictable clinical course. This reduces 
variability and increases the statistical power of the study under a given sample size. It 
allows for a longitudinal evaluation of the transition from acute opioid use to chronic opioid 
use in each patient. The decision-making dilemma addressed by the study is commonly 
faced by patients and clinicians in clinical practice. The outcomes evaluated are all related to 
improving cancer care and patient-centered. The interventions are easy to implement. 
Patients, caregivers, clinicians and hospitals have a keen interest in incorporating non-drug-
based pain management to reduced unnecessary opioid use. Such interest facilitates future 
dissemination of findings from this study. Thus, the proposed study will generate high quality 
evidence and potentially improve clinical practice. 
 
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IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
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1275 York Avenue 
New York, New York 10065 
 
Page 8 of 34 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
The study is a prospective, multicenter, two-arm parallel group, individual randomized (at 1:1 
ratio) controlled trial with two pain management interventions as comparators. We chose this 
design because it helps balance the variables between treatment arms, therefore providing 
stronger causal inference than an observational or non-randomized design. It also reduces 
bias during analysis of heterogeneity of treatment effects. The multicenter design enhances 
diversity of the study population and the generalizability of study results. There have been 
many randomized controlled trials comparing acupuncture to sham acupuncture. Its efficacy 
in pain control is well established. In addition, PCORI is most interested in the pragmatic 
aspect of clincal interventions that improve patient-centered outcomes. Thus the control 
group in this study is usual care, not sham acupuncture. 
4.2 
Intervention 
All patients in the study will receive usual HSCT care. Patients in both the ACU group and 
the OPI group will receive the 
same usual care for opioid 
administration, initiated and 
adjusted according to their 
pain levels as in standard of 
care in the study institutions. In 
addition, patients in the ACU 
group will receive acupuncture 
treatment as detailed in 
Section 10.0. The conceptual 
framework is shown in the 
diagram in this section. 
 
The schema of interventions and outcome assessment is as follows. 
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New York, New York 10065 
 
Page 9 of 34 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS 
Acupuncture is a non-pharmacologic modality that involves insertion of single-use disposable 
filiform needles into certain points on the body, followed by manual manipulation, heat, or 
electrical stimulation to elicit therapeutic effects. Acupuncture has been provided in both 
inpatient and outpatient settings at MSKCC for more than 15 years, as part of standard 
clinical services provided to MSKCC patients. Acupuncture the modality itself is not 
investigational. Its integration to symptom management in this clinical setting is the subject of 
investigation. 
Seirin acupuncture needles at 30mm or 40mm and 0.16mm - 0.25 mm gauge will be used in 
this study. The needles are purchased and distributed from Seirin® in the United States 
(http://www.seirinamerica.com ). Seirin acupuncture needles are approved by the FDA 
(http://www.accessdata.fda.gov/cdrh_docs/pdf/K962809.pdf ). 
Participants in the OPI group will receive pain management with opioids administered per 
institutional standards.  
6.0 
CRITERIA FOR PARTICIPANT ELIGIBILITY 
We will conduct the study in “opioid-naïve” multiple myeloma (MM), Hodgkin disease (HD), 
and non-Hodgkin lymphoma (NHL) patients who are undergoing HiChemo and autologous 
HSCT. In this study, “opioid-naïve” patients are defined as those who have not been taking 
opioids regularly in the week preceding registration to the study, not literally as those who 
never have taken opioids. We are targeting pain caused by chemotherapy, not severe 
preexisting pain caused by cancer that requires pain medication prior to HiChemo. Our 
preliminary data showed that those who are not taking opioids for preexisting pain before 
HiChemo benefitted the most from acupuncture. One-time dosing of opioids in that period for 
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IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
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New York, New York 10065 
 
Page 10 of 34 
 
a painful procedure (e.g. placement of a venous port) is allowed. Patients undergoing 
allogeneic HSCT (allo-HSCT) are not included. They tend to have more variable clinical 
courses and higher incidence of post-HSCT complications (infection, engraftment failure, 
disease relapse, or graft versus host disease). 
6.1 
Participant Inclusion Criteria 
 
age 18 or older 
 
pathological diagnosis of MM, HD or NHL 
 
scheduled for high dose chemotherapy for auto-HSCT in the following month (30 
days) 
 
not taking opioids regularly in the week prior to consent (one-time dosing of opioids 
for a painful procedure is allowed) 
6.2 
Participant Exclusion Criteria 
 
absolute neutrophil count (ANC) of <500/µl, platelet count of <20,000/ µl or INR >2.0 
 
acupuncture within two weeks prior to HiChemo (to avoid residual effects of 
acupuncture)  
 
unable to provide informed consent  
 
7.0 
RECRUITMENT PLAN 
All MM, HD, and NHL patients who are scheduled to receive auto-HSCT at the Adult Bone 
Marrow Transplantation (BMT) Service at a participating study site will be screened for 
eligibility by the clinical and/or research staff in the study. All such patients will be screened 
and enrolled, if eligible, regardless of their gender or ethnicity/race. 
Potential research subjects will be identified by a member of the patient’s treatment team, a 
protocol investigator, or research staff.  If the investigator is a member of the treatment team, 
s/he will screen their patient’s medical records for suitable research study participants and 
discuss the study and their potential for enrolling in the research study.  Potential subjects 
contacted by their treating physician will be referred to the investigator/research staff of the 
study. The principal investigator and research staff may also screen the medical records of 
patients with whom they do not have a treatment relationship for the limited purpose of 
identifying patients who would be eligible to enroll in the study and to record appropriate 
contact information in order to approach these patients regarding the possibility of enrolling in 
the study.   
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process.  The investigator/research staff may also review 
portions of their medical records in order to further assess eligibility.  They will use the 
information provided by the patient and/or medical record to confirm that the patient is 
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Page 11 of 34 
 
eligible and to contact the patient regarding study enrollment.  If the patient turns out to be 
ineligible for the research study, the research staff will destroy all information collected on the 
patient during the initial conversation and medical records review, except for any information 
that must be maintained for screening log purposes.    
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment 
team.  The recruitment process outlined presents no more than minimal risk to the privacy of 
the patients who are screened and minimal PHI will be maintained as part of a screening log.  
For these reasons, MSK and participating sites seek a (partial) limited waiver of authorization 
for the purposes of (1) reviewing medical records to identify potential research subjects and 
obtain information relevant to the enrollment process; (2) conversing with patients regarding 
possible enrollment; (3) handling of PHI contained within those records and provided by the 
potential subjects; and (4) maintaining information in a screening log of patients approached 
(if applicable).  
The research staff in conjunction with the clinical staff will explain to an eligible patient the 
study, potential risks and benefits of participating in the study, that participation in the 
research study is completely voluntary, and that they have the right to refuse participation or 
withdraw at any point in the study without influencing any aspect of their medical treatment. 
Once a patient is deemed eligible, they may be enrolled through an in-person consent 
appointment, econsent or by a verbal consent conducted over the phone. For patients 
interested in consenting remotely, they may be enrolled through MSK eConsent modules to 
conduct electronic consent as in Section 8.0. Patients who do not have a desktop or laptop 
computer capable of a remote econsent and who cannot travel to study sites may be 
consented using a verbal consent. 
Similarily, at participating sites, each week, study staff will review new incoming BMT patients 
for eligibility.  Staff will receive a list of new patients every week and will screen for eligibility 
using available electronic health records.  If a patient is eligible based upon medical record 
review, a consent coordinator on the patient’s medical team and/or the research coordinator 
will provide the patient with initial study information either virtually (via Zoom) or in person at 
the SCCA clinic.  If the patient is interested and eligible, study staff will consent the 
participant and enroll them into the study prior to initiation of BMT treatment. 
7.1 
Research Participant Registration  
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. Written documentation of consent form and authorization will be waived for 
verbal consent. See Section 8.0 for Informed Consent procedures. During the registration 
process registering individuals will be required to complete a protocol specific Eligibility 
Checklist. The individual signing the Eligibility Checklist is confirming whether the participant 
is eligible to enroll in the study. Study staff are responsible for ensuring that all institutional 
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requirements necessary to enroll a participant to the study have been completed. See related 
Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 
 
7.2 
Randomization 
After registration, research staff will randomize patients via MSK's secure Clinical Research 
Database (CRDB) using permuted blocks of random length. The allocation ratio will be 1:1 
for ACU:OPI. Using the institutional randomization standard procedure with random blocks 
for RCTs will ensure full allocation concealment. Randomization will be stratified by study 
site, primary cancer diagnosis (MM versus HD versus NHL) and transplantation setting 
(inpatient versus outpatient) to ensure these characteristics are comparably distributed 
between the two study arms. 
 
8.0     INFORMED CONSENT PROCEDURES 
 
Scenario 1: Standard written consent scenario 
The consent form/research authorization meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form will 
include the following: 
1. The nature, objectives, potential risks, and benefits of the intended study. 
2. The length of study, what it entails, and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to withdraw 
from participation at any time. 
6. How the participants’ data will be protected, who will have access to their PHI, and what data will 
be disclosed for research purposes 
Prior to inclusion in the study and before protocol-specified procedures are carried out, the 
consenting professionals will explain the details of the protocol as outlined in the consent and 
research authorization to the participants/LARs. The participant/LAR will also be informed that they 
are free to withdraw from the study at any time. The consent discussion may occur in person or 
remotely via teleconference, telephone, or videoconference. 
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All participants/LARs must sign an IRB/PB-approved consent form/research authorization indicating 
their consent to participate. Each participant/LAR and consenting professional will sign and date the 
consent form. The participant/LAR must receive a copy of the signed informed consent form. 
Scenario 2: Documentation of consent waived (e.g.,, verbal consent, only consenting professional 
signs) 
The verbal informed consent/research authorization meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent/research 
authorization script will include the following: 
1. The nature, objectives, potential risks, and benefits of the intended study. 
2. The length of study, what it entails, and the likely follow-up required. 
3. Alternatives to the proposed study. 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to withdraw 
from participation at any time. 
6. How the participants’ data will be protected, who will have access to their PHI, and what data will 
be disclosed for research purposes. 
Prior to inclusion in the study and before protocol-specified procedures are carried out, consenting 
professionals will explain the details of the protocol to participants/LARs. Participants/LARs will also 
be informed that they are free to withdraw from the study at any time. The consent discussion may 
occur in person or remotely via teleconference, telephone, or videoconference. 
The consenting professional must sign an IRB/PB-approved consent /research authorization script 
to document the consent discussion and the participant’s agreement. 
In following the Code of Federal Regulations Title 45, Part 46, Subpart A, the IRB is waiving the 
requirement for an investigator to obtain a signed consent form from the participant as the research: 
· presents no more than minimal risk of harm to participants, and 
· involves no procedures for which written consent is normally required outside of the research 
context. 
In following the Code of Federal Regulations Title 45, Part 164, Subpart E, IRB/PB is waiving the 
requirement for the investigator to obtain signed research authorization from the participant as: 
· the use or disclosure of the PHI involves no more than minimal risk to the privacy of the individuals, 
based on the following elements: 
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o An adequate plan to protect identifiers from improper use and disclosure; 
o An adequate plan to destroy the identifiers at the earliest opportunity consistent with conduct of the 
research (unless there is a health or research justification for retaining the identifiers, or such 
retention is otherwise required by law); and 
o Adequate written assurances that the PHI will not be reused or re-disclosed to any other person or 
entity, except as required by law, for authorized oversight of the research project, or for other 
research for which the use of disclosure of PHI would be permitted by HIPAA. 
· The research could not be practicably conducted without access to and use of the PHI. 
· The research could not practicably be conducted without the waiver. 
 
 
If a verbal consent is being conducted, the consenting professional will use the IRB/PB-approved 
verbal informed consent script when calling patients. If the patient agrees to participate, the 
consenting professional will sign and date the verbal consent, and a copy will be sent to the patient. 
A verbal consent would be used in cases where individuals do not have access to a computer and 
those who are unable to travel to study sites for an in-person consent appointment. This research 
involves no more than minimal risk to participants and use of a verbal consent would not adversely 
affect the rights and welfare of the research participants. 
 
Informed consent can be obtained remotely with a telehealth platform and through an electronic-
consenting process, using the MSK eConsent module. Electronic consent will be made available to 
potential patients who wish to enroll using the MSK eConsent modules. At participating sites, 
electronic consent will be made available to potential patients who wish to enroll using MSK’s 
REDCap eConsent platform. FH/SCCA may use MSK’s REDCap eConsent platform to electronically 
consent potential patients, and the MSK study team will maintain the REDCap eConsents. All 
participants/LARs must sign an IRB/PB-approved consent form via REDCap indicating their consent 
to participate. A consenting professional signature is not required as noted in IRB SOP IC-706. The 
participant/LAR must receive a copy of the signed informed consent form. Consenting professionals 
will perform the informed consent procedures using a telehealth audio/video platform. A copy of the 
written informed consent with standard research authorization document will be available as a file 
download for the patient’s reference. Contact information for the study team will also be available 
should participants need to reach out with any questions. Patients interested in study participation 
will be able to sign the electronic consent once they have reviewed the consent form in its entirety 
and discussed the study with the consenting professional. Those who decline participation will not 
be contacted further. Reasons for refusal to take part in the study will be tracked if provided. Once 
consented, a PDF copy of the electronic consent form will be stored in the project’s file repository 
survey archive. This document will record the date stamp, participant identifier information, IP 
address and the consent version number. A copy of the consent will be sent to the participant via 
email or standard mail based on his/her preference.  
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MSK may verbally consent patients, whereas FH/SCCA will always obtain written consent.The 
participant must receive a copy of the signed or verbal informed consent form, and a copy of the 
signed or verbal consent form will be sent to the patient’s EMR. 
 
 
9.0 
PRE-TREATMENT/INTERVENTION  
Enrolled patients will receive the following baseline assessments within 4 weeks before the 
first dose of HiChemo. Detailed descriptions of each assessment are in Section 11.0 and 
13.1. 
 
Demographic and Clinical Features 
 
Symptom Burden (MDASI-BMT), paper or electronic 
 
Brief Pain Inventory – Short Form (BPI), paper or electronic 
 
Patient-Reported Oral Mucositis Symptom Scale (PROMS) ,paper or electronic 
 
Pain Medication Side Effects Questionnaire,paper or electronic 
 
Quality of Life (PROMIS-29), paper or electronic 
 
Adverse Events (CTCAE v5) 
 
Opioid Risk Tool (ORT), paper or electronic 
 
Acupuncture Expectancy Scale (AES), paper or electronic 
 
10.0 TREATMENT/INTERVENTION PLAN 
All study patients will receive the usual HSCT care and pain management regimens as per 
standard practice at the study institution. For patients randomized to the ACU group, they will 
receive acupuncture as follows. 
In addition to usual care, patients in the ACU group will receive acupuncture treatments. 
Acupuncture treatments will be scheduled to cover the period of high symptom burden. 
Acupuncture will start on Day 0 and continue once daily to Day 15, as long as the patient is 
inpatient or comes to the clinic for post-transplantation follow-up. For myeloma patients 
getting melphalan, the day of melphalan infusion is counted as Day 0 in the study. For 
lymphoma patients getting BEAM (carmustine, etoposide, cytarabine, melphalan), the day of 
melphalan infusion is counted as Day 0. For lymphoma patients getting TBC (thiotepa, 
busulfan and cyclophosphamide), the day of thiotepa infusion is counted as Day 0. For the 
occasional patients on investigational conditioning chemotherapy regimen, Day 0 will be 
determined by the BMT physician and the PI.  
Acupuncture will not be done on days patients are neutropenic (absolute neutrophil counts 
<500/microliter) or thrombocytopenic (platelet counts <20,000/microliter). Acupuncture does 
not have to be done on days when acupuncturists are not available, for example during 
weekend days or on days there is a staff shortage, or when a patient declines an 
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acupuncture treatment. The total number of acupuncture treatment a patient has received 
will be recorded. Patients will be instructed to do self-acupressure at LI-4 and PC-6 
acupuncture points when they experience pain or nausea. 
Patients in the OPI group will receive usual care and will not receive acupuncture. 
In this study, acupuncture needles will be inserted at bilateral PC6, LI4, ST36, SP6, KI3, 
LR3, and ear shenmen acupuncture points and unilateral GV20 and Ex-HN3 points. The 
needles will be manualy manipulated for deqi and left in place for 20 minutes before removal. 
Electrical stimulation (e-acupuncture) may be applied to the ST36 and SP6 points when 
appropriate as per standard acupuncture practice. 
Prior to acupuncture, the acupuncturist will check the patient’s Complete Blood Counts 
(CBC) from the same day (HSCT patients have daily CBCs and will not provide the treatment 
if the patient’s absolute neutrophil counts are less than 500/microliter or platelet counts less 
than 20,000/microliter.  If an acupuncture point falls on an area of skin that is not safe to do 
acupuncture (e.g. wound or skin infection), the point will not be used and the deviation from 
point prescription will be recorded. A needle counting will be performed at the end of the 
treatment to ensure all needles are removed. Any adverse event noted during or immediately 
after acupuncture will be address according to standards in the profession of acupuncture 
and documented in the research record. Any serious adverse event will be reported to the 
study PI or a co-I immediately. 
Participants will be asked to complete patient reported outcomes assessments online using 
REDCap or, If they prefer, via pencil and paper or over the phone with a Clinical Research 
Coordinator to reduce participant burden and ensure timely completion. 
 
11.0 EVALUATION DURING TREATMENT/INTERVENTION 
We will assess all study participants for the study outcomes at baseline (within 4 weeks 
before HiChemo) and on or about days 7, 15, 30, and 90 after the first dose of HiChemo 
(See Schema in Section 4.0). The total burden in time to patients is about 30-45 minutes at 
each time point.  
The following outcome measurements will be carried out on and about Day 7, 15, 30 and 90 
(Day 0 being the day of first dose of HiChemo), either in the Integrative Medicine or BMT 
clinic in order to minimize unnecessary visits. The instruments are attached in appendices, 
and may be administered electronically (on a tablet if in clinic, via secure link if at home) or 
on paper. 
 
Opioid Use (drug administration record while inpatient and pill count while outpatient)  
 
Symptom Burden (MDASI-BMT) 
 
Brief Pain Inventory – Short Form (BPI) 
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 
Patient-Reported Oral Mucositis Symptom Scale (PROMS) 
 
Pain Medication Side Effects Questionnaire 
 
Quality of Life (PROMIS-29) 
 
Adverse Events (CTCAE v5) 
Collection of demographic and clinical features (diagnosis, disease status, chemotherapy 
regimen and mortality) data and assessement of use of healthcare resources will also be 
carried out on and about Day 90. Use of healthcare resources includes the length of hospital 
stays and transfers to the intensive care unit during HSCT, and total inpatient days, 
emergency room visits and readmissions during the first 30 days post-HSCT.  
Schema of Data Collection 
By Patient vs. By Study 
Team (ST) 
Baseline 
Day 7  
 (± 2 day) 
Day 15  
(± 3 days ) 
Day 30 
(± 7 days ) 
Day 90  
(± 14 days ) 
Demographic and Clinical Features 
ST 
X 
 
 
 
X 
Opioid Use (Primary Outcome) 
Patient and ST 
X 
X 
X 
X 
X 
Symptom Burden (MDASI-BMT) 
Patient 
X 
X 
X 
X 
X 
Brief Pain Inventory – Short Form (BPI) 
Patient 
X 
X 
X 
X 
X 
Patient-Reported Oral Mucositis 
Symptom Scale (PROMS) 
Patient 
X 
X 
X 
X 
X 
Pain Medication Side Effects 
Questionnaire 
Patient 
X 
X 
X 
X 
X 
Quality of Life (PROMIS-29) 
Patient 
X 
X 
X 
X 
X 
Adverse Events (CTCAE v5) 
ST 
X 
X 
X 
X 
X 
Opioid Risk Tool (ORT) 
Patient 
X 
 
 
 
 
Acupuncture Expectancy Scale (AES) 
Patient (ACU) 
X 
 
 
 
 
Use of Health Care Resources 
ST 
 
 
 
 
X 
*Day 0 = Day of the first dose of high dose chemotherapy 
 
12.0 CRITERIA FOR REMOVAL FROM STUDY 
Patients will be considered off-study upon completion of Day 90 assessments. Study 
intervention will be discontinued if severe, unexpected adverse events attributable to 
acupuncture has occurred or discontinuation is deemed by the principal investigator to be in 
the best interest of the patient. Those patients will remain in the study for outcome 
assessments. Patients will be removed from the study if the patient wishes to withdraw from 
the study. Removed patients will continue to be evaluated for outcomes if they give 
permission for us to do so. 
 
13.0    CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY 
 
13.1 Criteria for Therapeutic Response/Outcome Assessment  
Demographic data (age, gender, race, ethnicity, height and weight) and clinical features 
(cancer diagnosis, disease status, and regimen of the high-dose chemotherapy) will be 
collected. 
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Our first primary outcome is the proportion of patients who are opioid users (the number of 
patients using opioids at a given time divided by the total number of patients randomized to 
that group at Day 7 and Day 90). In this study, we define opioid user as a patient who uses 
any opioids during the seven days preceding the day of assessment. At baseline, patients 
will be asked whether they have a prescription for any opioids, any access to non-
prescription opioids and whether they used any opioids in the preceding seven days. During 
an inpatient period, all administrations of pain medications are recorded on hospital drug 
administration records, which will serve as our primary data source. For outpatient, we will 
use pill-counting to collect this data and data on opioid dose actually consumed by the 
patient in the week prior to the time point (Appendix 2).37-39 Pill-counting can be done 
remotely with a telehealth platform. 
 
Our second primary outcome is the symptom burden at Day 7, measured by the MDASI-BMT 
Total Symptom Severity score. MDASI-BMT (M.D.Anderson Symptom Inventory – Blood and 
Marrow Transplantation) is a 24-item multi-symptom patient-reported outcome (PRO) 
measure for clinical and research use.40 The MDASI-BMT consists of the core MDASI plus 5 
items specific to BMT patients. It assesses 13 core symptoms common across cancer types 
and treatments (pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, difficulty 
remembering, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and 
numbness/tingling).  In addition to the 13 core symptom items, it has 6 items that assess 
symptom-related interference. The MDASI has several advantages over other symptom-
assessment scales in that it applies broadly across cancer types and treatments, is easy for 
patients to complete, includes items related to symptom interference with daily life, and it is 
easily translated into other languages. It takes five minutes to complete and has a Cronbach 
alpha reliability range from 0.82 to 0.94. For MDASI-BMT, five additional symptoms important 
to this population were added. The BMT symptoms rated are feeling physically sick, weak, 
diarrhea, mouth sores, and bleeding. All symptoms are rated with reference to “the last 24 
hours” on 0–10 numeric scales from “not present” to “as bad as you can imagine.” Patients 
also rate the amount of interference with daily activities caused by symptoms on 0–10 
numeric scales from “did not interfere” to “interfered completely.” The MDASI-BMT has 
demonstrated good internal reliability in prior studies.41,42  Three symptom and one 
interference subscale scores can be calculated from the MDASI-BMT items by taking the 
means of particular item subsets: Core Symptom Severity (13 core MDASI items), BMT 
Symptom Severity (5 BMT-specific items), Total Symptom Severity (13 core plus 5 BMT-
specific items), and Interference (6 interference items). The subscale scores may be 
calculated when more than half of the items on a subscale have valid, non-missing 
responses, and should otherwise be considered missing.  In the current study, the MDASI-
BMT Total Symptom Severity score will serve as the symptom burden primary endpoint.  
 
The Brief Pain Inventory–Short Form (BPI, internal consistency Cronbach's α of 0.77–0.91) is 
a well-validated and widely used instrument to assess pain in cancer patients.43 It uses 
numerical rating scales (NRS) to quantify pain intensity and patient interference. The BPI 
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contains 4 pain severity items and 7 pain interference items, all rated on a scale from 0 to 10 
(higher ratings indicate worse pain intensity/interference). A pain interference subscale can 
be computed by taking the average rating of the 7 pain interference items. A pain severity 
subscale score can similarly be computed for the 4 pain severity items; however, the Worst 
Pain severity item and the Average Pain severity item are often examined separately from 
the pain intensity subscale in clinical research because they tend to be more sensitive 
indicators of changes in patients’ perceived pain. As such, the primary outcome of this study 
will be the patient’s rating of their Worst Pain in the past week with response choices of 0 “no 
pain” to 10 “pain as bad as you can imagine.” The Average Pain rating in the past week and 
the pain interference subscale will be used as secondary pain outcomes. This takes 5 
minutes to complete.  
 
Because the main source of pain in the study population is mucositis caused by high-dose 
chemotherapy, we will complement the BPI with an instrument that specifically assesses 
mucositis pain. We will use the PROMS (Patient-Reported Oral Mucositis Symptom) scale,11 
which was developed using HSCT patients from baseline to 60 days post-HSCT (similar to 
our study population), has excellent psychometric properties, and is easy to administer. The 
PROMS scale has ten items, each quantified through a 100-mm Visual Analog Scale (VAS), 
and a Cronbach's α of 0.86–0.98. This takes 3 minutes to complete.  
 
Side effects are a major concern for patients using opioids.18,44 There is currently no gold 
standard instrument for specifically evaluating opioid side effects.45-47 We will use the method 
from Martel et al., which is specific for opioids side effects.48 Patients will be asked to 
complete a questionnaire in which they rate the intensity of each of the following symptoms 
in the last 24 hours on a visual analog scale (VAS) that ranges from 0 (minimum) to 10 
(maximum): 1) nausea, 2) constipation, 3) headaches, 4) dry mouth, 5) itching, 6) sneezing, 
7) sweating, 8) weakness, 9) dizziness, 10) confusion, 11) memory problems, and 12) visual 
problems. This takes 2 minutes to complete.  
 
We will assess patients’ overall quality of life (QOL) using the Patient-Reported Outcomes 
Measurement Information System 29 Items (PROMIS-29), which resulted from a National 
Institutes of Health initiative to develop state-of-the-science self-report measures to assess 
functioning and well-being in physical, mental and social domains of health. The PROMIS-29 
v2.0 profile measure is analogous to the most widely used profile measure to date, the SF-
36. But the PROMIS-29 v2.0 profile items were selected from PROMIS item banks calibrated 
using item response theory (IRT) analyses and all items in a domain are scored on the same 
underlying metric.49 This takes 10 minutes to complete.  
 
We will monitor and record adverse events (AEs) as per the Common Terminology Criteria 
for Adverse Events Version 5.0 (CTC-AE v5.0). The adverse events will be collected by the 
study team, and assessed (grade/attribution) by the clinician. The Opioid Risk Tool (ORT) is 
a brief, self-report screening tool designed for use with adult patients to assess risk for opioid 
abuse.50 It is recommended by the National Institute on Drug Abuse (NIDA) as an instrument 
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to screen for opioid misuse risk, and takes 2 minutes to complete. This data will be collected 
at baseline and used in Heterogeneity of Treatment Effect (HTE) analysis to assess whether 
it influences the effects of acupuncture. Expectancy for acupuncture may influence its clinical 
effects.51-54 We will assess patients at baseline using the Acupuncture Expectancy Scale 
(AES). This is a validated instrument (takes about 3 minutes to complete) with an internal 
consistency (Cronbach's α) of 0.95 and test-retest reliability of 0.62 over four weeks without 
acupuncture treatment.55,56 This data will be used as a variable in HTE analyses for predictor 
to response and sensitivity analyses. We will also track use of healthcare resources, such as 
the length of hospital stays and transfers to the intensive care unit during HSCT, and 
emergency room visits and readmission during the first 30 days post-HSCT. These are 
exploratory endpoints to generate preliminary data about impact on the health care system, 
e.g. iatrogenic adverse events from opioids and delayed discharge from opioid side effects. 
 
All patient-reported measures will be administered either electronically (on a tablet if in clinic, 
via secure link if at home) or on paper. 
 
13.2 Criteria for Study Endpoint Evaluability 
All patients who are randomized and who have their opioid use evaluated at Day 7 will be 
considered evaluable for the Day 7 opioid primary endpoint. Similarly, patients who have 
their opioid use evaluated at Day 90 will be evaluable for the Day 90 opioid primary endpoint. 
For the Day 7 symptom burden primary endpoint, all patients who are randomized and who 
have at least a baseline MDASI-BMT Total Symptom Severity score will be considered 
evaluable. In general, patients will be considered evaluable for continuous study endpoints 
as long as they have at least the baseline measurement.  No patient will be replaced after 
randomization. All randomized patients meeting these additional evaluability criteria will be 
included in the analyses using the modified intention-to-treat (ITT) principle (i.e. participants 
will be analyzed according to the treatment group to which they will be randomly allocated 
regardless of treatment adherence status).  
 
14.0 BIOSTATISTICS 
This is a multicenter, two-arm randomized controlled trial to compare the effects of two pain 
management strategies on opioid use, symptom burden, and other patient-reported 
outcomes among patients receiving high-dose chemotherapy (HiChemo) followed by HSCT. 
Opioid-naïve adult multiple myeloma, Hodgkin disease, and non-Hodgkin lymphoma patients 
undergoing HiChemo followed by HSCT will be randomized (at 1:1 ratio, see Section 7.2) to 
receive either acupuncture as a first-line pain preventive measure during HiChemo with 
opioids as back-up pain treatment (ACU), or opioids as first-line pain treatment (OPI).  Study 
outcomes will be measured at pre-HiChemo baseline and at Days 7, 15, 30, and 90 after the 
first dose of HiChemo, with the Day 7 (short-term) and Day 90 (long-term) outcomes of 
particular interest.  We expect to accrue approximately 12 patients per month, and we 
anticipate the study will be open to enrollment for approximately 30 months. We expect the 
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total study duration to be 3 years.   
14.1. Sample Size Considerations. This study has 3 primary endpoints: opioid use at Day 
7, opioid use at Day 90, and symptom burden at Day 7. The statistical plan takes that into 
consideration. Our overall Type I error rate for testing these 3 primary endpoints is set to 
alpha = 0.05.  To maintain this Type I error rate, we will allocate alpha = 0.02 to each of the 
tests of opioid use at Day 7 and at Day 90, and we will allocate alpha = 0.01 to the test of 
symptom burden at Day 7.  
In our pilot study, among “opioid-naïve” patients, 25% of sham acupuncture (SA) patients 
and 7% of true acupuncture (TA) patients were opioid users at Day 90. For our sample 
size/power estimates for Aim 1, we conservatively assume that patients in the OPI arm will 
have similar Day 90 opioid usage (25%) as the SA patients in our prior study, and that 10% 
of patients in the ACU arm will be using opioids at Day 90 (slightly higher than the TA arm in 
our pilot study). This translates to a relative reduction of 60% fewer opioid users in the ACU 
arm, and an odds ratio of 0.33, which would be considered clinically meaningful. The attrition 
rate was only 5% in our pilot study. However, we will conservatively plan for a high 10% 
attrition rate by randomizing 300 patients (150 per arm) in order to obtain 270 patients (135 
per arm) with evaluable Day 90 endpoints. With an initial sample size of 300 patients and a 
10% attrition rate, we will have 81% statistical power to detect this Day 90 difference 
between the two arms (i.e. 10% vs 25%) at a significance threshold of p<0.02 using logistic 
regression analysis and a two-sided significance test. It is possible that the OPI group will 
have higher opioid use than the SA patients in our pilot study, as sham acupuncture is known 
to have some placebo effect.23,28 We therefore expect a larger effect size than we observed 
in the pilot study where true acupuncture was compared to sham acupuncture. In that 
scenario, assuming 30% in the OPI group use opioids versus 10% in ACU group, our power 
will increase to 96%.  
We based our sample size exclusively on having adequate power for the Day 90 comparison 
of opioid use.  This was due to the high public health priority to find pain interventions that 
can reduce long-term opioid use.  That said, we expect the Day 7 comparison to have similar 
power as the Day 90 comparison.  We believe this is a conservative assumption, and that we 
most likely have higher power at Day 7 due to lower attrition and potentially a larger effect 
size at Day 7 relative to Day 90.  For example, in our pilot study, 20% of sham acupuncture 
(SA) patients were using opioids at Day 5 (opioid usage not collected at Day 7) compared to 
none of the true acupuncture (TA) patients. 
For our sample size/power considerations for comparing symptom burden between ACU vs. 
OPI at Day 7, we calculated the smallest standardized effect size (aka, Cohen’s d) we will be 
able to detect with 80% power, given our sample sizes of 150 in each of the two arms. To 
estimate this smallest detectable effect size, we used the methods of Lu, Luo, & Chen 
(2008),57 which describes sample size calculations for a class of analyses called the “mixed 
model for repeated measures” (MMRM) in randomized clinical trials with participant attrition. 
Our LMM analyses fall under this MMRM class of analyses. Using the “power.mmrm” 
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function from the R package “longpower”, we applied the formulas in Lu et al. (2008) to our 
study design and assumptions to derive the smallest detectable effect size for the coefficient 
of the time-by-arm interaction term in our LMM (with time including only the Day 0 and Day 7 
assessments, see Section 14.2), which we transformed to represent the standardized mean 
difference (aka, Cohen’s d) of the changes in symptom burden from baseline between the 
two arms at Day 7 post-HSCT.  With 150 participants in each of the two arms, we will have 
power of 0.80 to detect an effect size for symptom burden as small as 0.41 (standardized 
difference, Cohen’s d) at Day 7 between acupuncture vs. usual care, assuming 10% attrition, 
correlation between baseline and Day 7 symptom burden scores of 0.50, and two-sided 
alpha of 0.01. The MDASI-BMT Total Symptom Severity score does not have an empirically-
established minimum clinically important difference (MCID).  A research-based rule-of-thumb 
for PRO instruments lacking empirical MCIDs is to adopt a standardized difference of 0.50 as 
the MCID.58 Given our detectable effect size of 0.41, we will be able to detect a MCID in 
symptom burden between the two arms.   
For Aim 2, we will test whether mean ACU pain scores are non-inferior to mean OPI pain 
scores at two timepoints, Day 7 and Day 90.  To limit the type I error rate for this family of 
two tests to 0.05, we will use a significance threshold for each test of 0.025. The Aim 2 key 
endpoint is Day 7 pain scores, since pain due to HiChemo is expected to peak around Day 7 
and resolve well before Day 90 for both study arms.  We present power considerations below 
for the Day 7 non-inferiority test.  The same assumptions apply to the Day 90 test; however, 
we expect ACU pain scores to be well within our non-inferiority margin by Day 90.  WeWe 
will have 80% power to find mean ACU pain scores non-inferior to mean OPI pain scores 
within a non-inferiority margin of 0.34 standard deviations (SD), assuming 300 patients, 10% 
attrition, and one-sided significance threshold of 0.025. Our non-inferiority margin (0.34 SD) 
is smaller than the typical minimum clinically important difference (MCID) for self-report 
measures (i.e., MCID = 0.50 SD for BPI59). Therefore, this margin represents an acceptable 
pain control benchmark for ACU in comparison to OPI.  
14.2. Statistical Methods.  
14.2.1. General Approaches. All analyses will be by intent-to-treat, with patients analyzed 
as randomized, irrespective of treatment actually received. Demographics and other relevant 
variables (e.g., number of acupuncture sessions received in the ACU arm) will be 
summarized by treatment arm using standard descriptive statistics. All data at all assessment 
time points will be summarized by treatment arm using standard descriptive statistics and 
plotted to visually assess trajectories over time. In the following subsections, we present 
specific analysis plans that are tailored to address our specific aim hypotheses, focus on 
single assessment time points, have relatively straightforward interpretations, and will be 
used to draw our primary conclusions regarding the Aims of this trial. However, our more 
general analysis approach will use more complex models to capitalize on the longitudinal 
nature of the study design and allow us to examine plots of the model-based trajectories of 
our outcome measures over time by study arm, giving us a visual overview of each outcome 
measure that incorporates all of the available data. For Aim 1, we will utilize generalized 
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linear mixed models (GLMM) to model the probability of opioid use across all time points (i.e. 
Day 7, 15, 30, and 90) as a function of study arm (ACU vs. OPI), time, the arm-by-time 
interaction, and randomization stratification variables.. For Aim 1 symptom burden, and for 
the continuous Aim 2 outcome measures, we will use linear mixed models (LMM) to similarly 
model those continuous endpoints over time. For both the GLMM and LMM analyses, we will 
use interaction terms between time and study arm to allow us to plot the arm-specific 
outcome trajectories over time. These statistical procedures (GLMM and LMM) account for 
within-subject correlations from repeated measurements in the same subjects and allow 
estimation of between-group differences without necessitating exclusion of participants with 
missing data.  
14.2.2. Specific Aim 1 Analysis Methods. To test Aim 1 hypotheses, we will test whether 
ACU has fewer opioid users compared to OPI at Day 7 (Hypothesis 1a) and at Day 90 
(Hypothesis 1b) using separate but similar logistic regression models.  Each model will 
predict opioid use at the given time point as a function of treatment arm (ACU vs. OPI), 
controlling for the randomization stratification variables (study site and cancer diagnosis). To 
test whether ACU reduces symptom burden at Day 7 compared to OPI (Hypothesis 1c), we 
will use a LMM to model the baseline and Day 7 MDASI-BMT Total Symptom Severity 
scores as a function of study arm (ACU vs. OPI), time (Day 0 and Day 7), and the arm-by-
time interaction (coefficient of interest), controlling for the randomization stratification 
variables.   
14.2.3. Specific Aim 2 Analysis Methods. For the Aim 2 hypotheses we will first test 
(Hypothesis 2a) whether mean pain scores among ACU patients were non-inferior to those 
among OPI patients (within a non-inferiority margin of 0.34 standard deviations) at Day 7 
(key Aim 2 endpoint) using a LMM containing arm, time (Days 0 and 7), and the arm-by-time 
interaction as predictors, controlling for the randomization stratification factors. That is, if the 
mean Day 7 pain score in the ACU arm is not significantly (p < 0.025) more than 0.34 
standard deviations higher than the mean OPI pain score, then we will consider ACU to be 
non-inferior to OPI with respect to Day 7 pain control. A similar analysis will be performed for 
the Day 90 pain scores.  For Hypothesis 2b, we will estimate mean differences (and 95% 
confidence intervals) between ACU vs. OPI side effect ratings, PROMIS-29 scores, and 
PROMS scores using separate linear mixed models for the Day 7 and Day 90 outcomes, 
controlling for the randomization stratification variables and baseline score (when relevant). 
We will have 80% power to detect unadjusted differences between study arms on these 
outcomes as small as 0.34 SD (i.e., Cohen’s d = 0.34) using two-sided tests and p<0.05. By 
convention, this effect size is between a small (i.e., d=0.20) and moderate (d= 0.50) effect 
size. We will have power to detect smaller effect sizes in the covariate-adjusted regression 
analyses described above, but we have insufficient preliminary data on which to base 
estimates of these adjusted effect sizes. 
We will adjust all comparisons between the two treatment arms for the randomization 
stratification factors - study site and primary cancer diagnosis (MM versus HD versus NHL) - 
by including them as fixed effects in our statistical models. 
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IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
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14.2.4. Exploratory Aim 1, Mediation. We will explore potential causal mechanisms by 
testing mediation hypotheses60 (e.g. test whether the effect of treatment on Day 90 opioid 
use is mediated through the effect of treatment on Day 7 opioid use).  We will use the 
approach to testing mediation hypotheses outlined in Imai, Keele, & Tingley (2010)60 in which 
a series of models are fit that allow estimation of the total, direct, and indirect (i.e., through 
the mediator) effects of treatment arm on Day 90 opioid use.   
14.2.5. Exploratory Aim 2, Heterogeneity of Treatment Effect (HTE). We expect patients 
will respond differently to study interventions but we do not have enough preliminary to data 
to generate hypotheses. Our HTE analyses will be exploratory and hypothesis-generating. 
We will explore whether sex, race, ethnicity, gender, primary cancer diagnosis (MM versus 
HD versus NHL), Opioid Risk Tool (ORT), Acupuncture Expectancy Scale (AES) score, or 
concurrent use of other medications with analgesic effects influence response to 
interventions in this population. We will add these variables and variable-by-arm interaction 
terms to our Day 7 and Day 90 logistic and linear regression models to identify potential 
patient-level factors associated with differential responses to treatment with respect to our 
primary and secondary outcomes. Each variable of interest will be assessed for HTE in a 
separate model. We will guard against inflated type I errors due to multiple testing by 
adjusting the variable-by-intervention interaction p-values for the false discovery rate.61,62 We 
intend to approach the evaluation of HTE based on existing literature and patient/clinician 
input. Our current focus on evaluating and reporting HTE will be based on the approach 
proposed by Kent et al.63 However we will also apply promising emerging Bayesian64,65 and 
machine learning66,67 methods, which can identify HTE and subgroups based on multiple 
variables simultaneously and are potentially more powerful than traditional univariate 
methods. We recognize that these types of sub-group analyses, although patient-centered, 
may need to be interpreted with caution and cannot replace the primary analyses. 
14.3. Missing Data. We will first explore whether missingness is associated with observed 
variables (particularly randomization arm and the baseline outcome measures) by comparing 
patients with complete and incomplete data. Of note, our general longitudinal data analysis 
approaches described above (GLMM and LMM) validly include patients with incomplete data 
under the missing at random assumption. However, our exploration of the data may deem 
the missing at random assumption to be inappropriate, and not all our hypotheses will be 
tested using these longitudinal modeling approaches. In these cases, we will use well-
established methods such as multiple imputation and pattern mixture models to help us deal 
with these issues.68,69 We will perform sensitivity analyses to evaluate the robustness of our 
main findings by using multiple imputation to impute the missing outcomes (particularly for 
Day 7 and Day 90) and duplicating the analyses using the multiply imputed data sets. 
14.4 Populations for Analyses  
 
Modified Intention-to-Treat Analysis Dataset, Opioid Use: For the Day 7 analysis, this will 
include all randomized patients who have Day 7 opioid use assessed.  For the Day 90 
analysis, this will include all randomized patients who have Day 90 opioid use assessed.    
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IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
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New York, New York 10065 
 
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 
Modified Intention-to-Treat Analysis Dataset, Symptom Burden: This will include all 
randomized patients who have, at least, a valid baseline MDASI-BMT Total Symptom 
Severity score.   
 
Modified Intention-to-Treat Analysis Dataset, Other Continuous Endpoints: For a given 
continuous endpoint, this will include all randomized patients who have, at least, a valid 
baseline endpoint measurement.  
 
15.0 TOXICITIES/RISKS/SIDE EFFECTS 
Potential Risks. All potential risks that might occur as a result of participation will be detailed 
in an informed consent form, and will also be fully discussed with each subject prior to 
enrollment. We will also explain to each subject that in the unlikely event of an injury directly 
resulting from the research procedures, every effort will be made to make the facilities and 
professional skills of our institutions available to them. While some risks are unpredictable, 
we will take every precaution consistent with the best medical practices to protect the health 
and safety of subjects. We will document all adverse event (AEs) attributed to acupuncture 
and report them to the IRB in regular continuing review forms.  
Physical Risks: Acupuncture has a known safety record.70 According to data from 97,733 
patients and more than 760,000 treatments, the most common AEs (in around 7% 
treatments) were pain experienced during needling and loss of blood when the acupuncture 
needle was removed, all grade 1 and self-limiting. In clinical trial settings, SAEs are rare and 
found to be at a rate of around 0.005% of patients and 0.0008% of treatments.71 In our pilot 
study, no SAEs from acupuncture were encountered.72 Adverse effects of opioids include dry 
mouth (42%), constipation (20–41%), sweating (34%), weight gain (29%), somnolence (14–
29%), problems with sleep (25%), memory deficits (24%), loss of appetite (23%), nausea 
(17–33%), concentration deficits (19%), fatigue (19%), sexual dysfunction (18%), dizziness 
(12–22%), vomiting (11–15%), pruritus/dry skin (10%) and urinary retention,14-20 with as 
many as 80% patients experience at least one adverse event.73 Serious adverse effects are 
uncommon (around 0.60% of admission) and include altered mentation, cardiovascular 
depression, respiratory depression and even death.74 Psychological Risks:  It is possible that 
a patient may experience psychological distress when completing the Patient Reported 
Outcome (PRO) measurements.  
Financial and Legal Risks:  There are no financial or legal risks to the study patients. All 
research interventions and evaluations are provided free of charge to study participants.  
Privacy and/or Confidentiality Risks: Information about study subjects may be inadvertently 
disclosed to a person not authorized to access such information.  
Alternative Treatments: The alternative to participating in the study is receiving standard 
HSCT care without participating in the study. Patients may receive opioid-based pain 
management and/or acupuncture depending on their treating clinician’s clinical judgment. 
During the informed consent process, study candidates will be informed of this alternative, 
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New York, New York 10065 
 
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that their participation in the study is entirely voluntary, and that their care will not be affected 
in any way if they decide not to participate in the study. 
CTCAE Version 5 will be utilized for toxicity evaluation.  
15.1 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes:  
 
Death  
 
A life-threatening adverse event  
 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
A congenital anomaly/birth defect 
 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. Hospital admission as part of standard hematopoietic stem cell transplantation care 
and attributable as unrelated to acupuncture is not considered an SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention.  SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported.  
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event.  All other SAEs must be submitted within 30 calendar 
days of the event.   
The report should contain the following information: 
 
The date the adverse event occurred 
 
The adverse event 
 
The grade of the event  
 
Relationship of the adverse event to the treatment(s)  
 
If the AE was expected 
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Approval date: 21-Dec-2022

 
 
 
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New York, New York 10065 
 
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 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
 
If an amendment will need to be made to the protocol and/or consent form 
 
If the SAE is an Unanticipated Problem  
 
 
16.0 PROTECTION OF HUMAN PARTICIPANTS 
Protection Against Physical Risks. To reduce risks associated with acupuncture, we will 
exclude patients in whom acupuncture may not be safe - those with neutropenia (absolute 
neutrophil counts less than 500/microliter) or thrombocytopenia (platelet counts less than 
20,000/microliter). We will also not perform acupuncture on patients who become 
neutropenic or thrombocytopenic during the study. HSCT patients have daily complete blood 
counts (CBC) during the transplantation period. The acupuncturists will check a patient’s 
CBC before giving them acupuncture. Our acupuncturists have been trained to recognize 
AEs that occur during or immediately after acupuncture treatment. They will exercise safety 
precautions as is standard in their professional discipline and inform the primary oncology 
team when an AE is deemed unusual or beyond what is expected for acupuncture.  
Protection Against Psychological Risks. If a Research Assistant (RA) observes a patient 
displaying elevated psychological distress during an assessment, the RA will inform the site 
PI so that s/he can assess the situation and potentially refer the patient to psychiatric care, if 
clinically warranted. In the unlikely event of significant acute distress, patients will be referred 
for urgent evaluation by psychiatry at the study institution. 
Protection Against Privacy and/or Confidentiality Risks. Information about study subjects 
will be kept confidential and managed according to the HIPAA requirements. The paper data 
files will be kept in locked cabinets and electronic files will be kept in password-protected 
computers that only personnel with a need-to-know can access. The data will be disclosed to 
the IRB upon request for data safety monitoring. We will not attempt secondary use of the 
data after the study ends without subsequent IRB approval. 
Vulnerable Subjects. No specific class, such as fetuses, neonates, pregnant women, 
children, prisoners, institutionalized individuals, or others who may be considered vulnerable 
populations, will be included in the study.  
Potential Benefits of the Proposed Research to Research Participants and Others. Our 
preliminary research suggests that acupuncture may reduce pain medication use and some 
side effects commonly associated with pain medication use without compromising pain 
management in HiChemo/HSCT patients. Patients in the proposed study may experience the 
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IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022

 
 
 
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New York, New York 10065 
 
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same benefits. If confirmed by the proposed research, future HiChemo patients may have an 
additional tool for pain management available to them and may experience fewer symptoms 
and better quality of life during their cancer treatment. The risks to subjects are small in 
comparison to the scientific information and potential benefit to cancer patients that may 
result from the conduct of this study. Patients will receive the following payments for their 
time and effort while participating this study: $40 upon completion of Day 30 assessments, 
and $60 upon completion of Day 90 assessments.  
Alternative to Participation. The alternative to participating in the study is to receive 
standard HSCT care without acupuncture or receive these therapies outside of this study. 
During the informed consent process, potential study participants will be informed of this 
alternative, that their participation in the study is entirely voluntary, and that their care will not 
be affected in any way if they decide not to participate in the study. 
16.1 
Privacy 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals/entities described in the 
Research Authorization form. A Research Authorization form must be approved by the IRB 
and Privacy Board (IRB/PB).  
The consent indicates that individualized de-identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other at the 
time of study publication. 
 
16.2 
Data Management  
The Clinical Research Coordinator(s) (CRC(s)) assigned to this study will be responsible for 
project compliance, data collection, abstraction and entry, data reporting, regulatory and 
quality control monitoring, problem identification, and prioritization. Coordination of the study 
team activities will be the responsibility of our Clinical Research Supervisor (CRS) and/or 
Clinical Research Manager (CRM). The CRS and CRM will work with the CRC on problem 
resolution, organization, and quality control. We hold regular meetings attended by the 
research staff and the Principal Investigator to review study progress and to manage any 
difficulties encountered. For any communication with participants, all security precautions will 
be taken, including making sure to activate MSKSecure in e-mail correspondences. 
Registration and patient study status will be entered into CTMS per institution requirement.  
CRDB will be utilized for randomization. Subject recruitment will be tracked in Excel. Other 
study-related data will be in REDCap. Participants will be asked to complete patient reported 
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Approval date: 21-Dec-2022

 
 
 
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New York, New York 10065 
 
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outcomes assessments online using REDCap, as described below. If they prefer, patients 
will have the option to complete the measures via pencil and paper or over the phone with a 
CRC to reduce participant burden and ensure timely completion. 
REDCap (Research Electronic Data Capture) is a data management software system 
supported by the Clinical Research Administration (CRA) at MSK. Members of the CRA 
supporting the REDCap software will have access to REDCap projects hosted by MSK’s 
servers for the purpose of ensuring the proper functioning of the database and the overall 
software system. REDCap is a tool for the creation of customized, secure data management 
systems including web-based data entry forms, reporting tools, and a full array of security 
features including user- and group-based privileges with a full audit trail of data manipulation 
and export procedures. REDCap is maintained on MSK-owned servers that are kept in a 
locked server room with appropriate environmental modifications (e.g. proper ventilation, 
power redundancy and fault tolerance arrangement) and backed up nightly with some back-
up tapes stored off-site. The MSK Information Systems group is responsible for applying all 
operating system patches and security updates to the REDCap servers. All connections to 
REDCap utilize encrypted (SSL-based) connections. Nationally, the REDCap software is 
developed, enhanced, and supported through a multi-institutional consortium led by 
Vanderbilt University. 
Source documentation will be available to support the computerized patient data. The 
confidentiality of patient information will be carefully protected. Following data entry by 
Integrative Medicine Service research staff, data will be maintained in a secure location in 
the Integrative Medicine offices.  All data will be stored in a fashion consistent with FDA 
guidelines (21CFR11 compliant) and HIPAA security rules. 
Final data sets for publication will be locked and stored centrally for potential future access 
requests from outside entities.  
16.3 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random-sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
per year, more frequently if indicated. 
16.4 
Data and Safety Monitoring 
The Data and Safety Monitoring Plan utilized for this study must align with the MSK DSM 
Plan, where applicable.  
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New York, New York 10065 
 
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The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were approved by 
the National Cancer Institute in August 2018. The plans address the new policies set forth by 
the NCI in the document entitled “Policy of the National Cancer Institute for Data and Safety 
Monitoring of Clinical Trials.”  
There are several different mechanisms by which clinical studies are monitored for data, 
safety and quality. At a departmental/PI level there exists procedures for quality control by 
the research team(s). Institutional processes in place for quality assurance include protocol 
monitoring, compliance and data verification audits, staff education on clinical research QA 
and two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Deputy Physician-in-Chief, Clinical Research. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required.  
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials.  The 
DSMB/C have oversight over the following trials: 
 
MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
 
External studies where MSK is the data coordinating center 
 
Low risk studies identified as requiring DSMB/C review 
The DSMC will initiate review following the enrollment of the first participant/or by the end of 
the year one if no accruals and will continue for the study lifecycle until there are no 
participants under active therapy and the protocol has closed to accrual. The DSMB will 
initiate review once the protocol is open to accrual. 
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18.0    APPENDICES 
Appendix 1. Acupuncture Intervention Protocol 
Appendix 2. Procedures to Determine Outpatient Opioid Use and Dose Consumed 
Appendix 3. MCT External Site SAE Report Form Template 
 
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IRB Number: 20-264 A(9)
Approval date: 21-Dec-2022