Clinical trial NCT02420223
Conditions: Multiple Myeloma
Keywords: Recipients
Sponsor: Medical College of Wisconsin
Start date: 2015-07-17; Completion date: 2020-02-01
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized controlled pilot study designed to evaluate whether the beta-adrenergic antagonist propranolol is effective in decreasing gene expression of stress-mediated beta-adrenergic pathways among a cohort of individuals receiving an autologous hematopoietic stem cell transplant (HCT) for multiple myeloma.

Detailed description:
This is a randomized controlled pilot study designed to evaluate whether a drug designed to block the physiologic effects of stress is effective at blocking stress-related gene expression in people receiving autologous stem cell transplants (their own cells) for multiple myeloma. Such stress-related gene expression is one way that the body is programmed to make specific proteins under conditions of stress. These proteins are believed to contribute to worse health outcomes. By using the drug propranolol, we aim to see whether we might block these negative health effects of stress as occur in the cancer setting and during the transplant process. We hypothesize that individuals taking propranolol will have more favorable gene expression.

We will enroll 40 individuals, randomizing half to receive propranolol and half to serve as the control group not on the study drug. Study participants will start propranolol three weeks prior to their transplant and continue it until 30 days after the transplant. We will explore the effect of socioeconomic status, depression, and anxiety on individuals' gene expression response to propranolol with the idea that the more impoverished, anxious, or depressed individuals will display an even greater change in their gene expression. Part of the purpose of this study is also be to assess whether it is feasible to give this drug to individuals with cancer. Results of this study may inform larger trials assessing the effects of propranolol on cancer progression.

Arms: arm 1: Patient's randomized to the Propranolol arm will be starting 7 days prior to transplant and continuing through 28 days post-transplant. Propranolol will start at 20mg twice daily and will be titrated to 40mg twice daily as tolerated. Both groups will come back to the hospital weekly in order to assess items such as patient's level of anxiety, depression, your adherence, and also to monitor for side effects. The patient's will complete questionnaires during your visit. These will take approximately 15 minutes to complete. This will continue for up to 7 total weeks for patient's on the Propranolol arm. arm 2: Both groups will come back to the hospital weekly in order to assess items such as patient's level of anxiety, depression, your adherence, and also to monitor for side effects. The patient's will complete questionnaires during your visit. These will take approximately 15 minutes to complete. This will continue for 6 total weeks for patient's on the control arm.
Interventions: intervention 1: Propranolol
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
1 
RANDOMIZED CONTROLLED PILOT STUDY USING PROPRANOLOL TO 
DECREASE GENE EXPRESSION OF STRESS-MEDIATED BETA-
ADRENERGIC PATHWAYS IN HEMATOPOIETIC STEM CELL 
TRANSPLANT RECIPIENTS 
 
 
Version 3.0 
 
Principal Investigator: 
Jennifer M. Knight, MD 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Telephone: 414-955-8908 
Fax: 414-955-6285 
Email: jmknight@mcw.edu 
 
Co-Investigator: 
 
J. Douglas Rizzo, MD, MS 
CIBMTR 
 
Froedtert and the Medical College of Wisconsin 
Clinical Cancer Center 
9200 W. Wisconsin Avenue Suite C5500 
Milwaukee, WI 53226 
Telephone: 414-805-0700 
Fax: 414-805-0714 
Email: drizzo@mcw.edu 
 
Co-Investigator: 
 
Parameswaran Hari, MD, MS 
Froedtert and the Medical College of Wisconsin 
Clinical Cancer Center 
9200 W. Wisconsin Avenue Suite C5500 
Milwaukee, WI 53226 
Telephone: 414-805-4600 
Fax: 414-805-4606 
 
 
 
 
Email: phari@mcw.edu 
 
Consultant 
 
 
Steve W. Cole, PhD 
and Statistician: 
 
UCLA-David Geffen School of Medicine 
 
 
 
 
10833 LeConte Ave 
 
 
 
 
11-934 Factor Bldg 
 
 
 
 
Los Angeles, CA 90095-1678 
 
 
 
 
Telephone: 310-267-4243 
 
 
 
 
Email: coles@ucla.edu 
 
 
 
 


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Sponsor: 
 
 
Medical College of Wisconsin 
 
Funding Sponsor: 
 
This project has an offer of sponsorship from  
 
 
 
 
 
the National Cancer Institute, National Institutes of Health,  
 
 
 
 
under Contract No. HHSN261200800001E.  
 
 
 
 
 
 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
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PROTOCOL SYNOPSIS 
 
Randomized Controlled Pilot Study Using Propranolol to Decrease Gene Expression 
of Stress-Mediated Beta-Adrenergic Pathways in Hematopoietic Stem Cell 
Transplant Recipients 
 
Principal Investigator: 
 
Jennifer M. Knight, MD 
 
Study Design: 
This is a randomized controlled pilot study designed 
to evaluate whether the beta-adrenergic antagonist 
propranolol 
is 
effective 
in 
decreasing 
gene 
expression 
of 
stress-mediated 
beta-adrenergic 
pathways among a cohort of individuals receiving 
an autologous hematopoietic stem cell transplant 
(HCT) for multiple myeloma. 
 
Primary Objective: 
The primary objective of this study is to assess 
whether beta-blocker administration to individuals 
undergoing HCT alters genome-wide transcriptional 
pathways involved in beta-adrenergic signaling. 
 
Secondary Objectives:  
Explore the impact of socioeconomic status, 
depression, and anxiety on gene expression as well 
as on the relationship between beta-blocker and 
gene expression; assess clinical feasibility and 
efficacy.  
 
Eligibility:  
Eligible patients are between 18 and 75 years 
undergoing autologous HCT for treatment of 
multiple myeloma who are ≤ 1 year since initiation 
of systemic anti-myeloma therapy and who have 
had no prior progression or relapse of myeloma 
prior to HCT. They must have an ECOG 
performance status of 0 or 1, and have a stem cell 
graft with >2.0 x 106 CD34+ cells/kg available for 
transplant. Patients are excluded if they have had a 
prior autologous HCT, are on a beta-blocker at the 
time of study entry, have a previous intolerance to 
beta-blockers, have any medical contraindications 
to beta-blockers therapy, or have active depression. 
  
Treatment Description: 
Patients enrolled in this study will be randomized to 
either receive propranolol or not starting 7 (± 2) 
days prior to transplant and continuing through 28 
days post-transplant. Propranolol will start at 20mg 


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twice daily and will be titrated to 40mg twice daily 
as tolerated.  
. 
Accrual Objective: 
 
40 patients will be enrolled to the clinical trial. 
 
Accrual Period: 
 
The estimated accrual period is 9 months. 
 
Study Duration: 
It is estimated that the entire duration of the study 
will not exceed one year as follow-up is 30-45 days. 


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Glossary of Study Abbreviations 
AE:  
 
adverse events 
ANC:   
absolute neutrophil count 
CC:  
 
Cancer Center 
CR:  
 
complete response 
CRC:  
clinical research coordinator 
CTCAE:  
Common Terminology Criteria for Adverse Events  
CTRA: 
conserved transcriptional response to adversity 
DSM:  
Data and Safety Monitoring 
DSMC:  
Data and Safety Monitoring Committee 
ECOG: 
Eastern Cooperative Oncology Group 
FCBP:  
Female of Child Bearing Potential 
G-CSF:  
granulocyte-colony stimulating factor 
HADS:  
Hospital Anxiety and Depression Scale 
HCT:   
hematopoietic stem cell transplantation  
HED:   
human equivalent dose 
ICSR:  
Individual Case Safety Reports 
IMWG:  
International Myeloma Working Group 
IRB: 
 
Institutional Review Board 
MCW:  
Medical College of Wisconsin 
MM:   
multiple myeloma 
nCR:   
near complete response 
OS:  
 
overall survival 
PFS:   
progression-free survival 
PI: 
 
Principal Investigator 
SES:   
socioeconomic status 
sCR:   
stringent complete response 
SNS:   
sympathetic nervous system 
TRM:   
treatment-related mortality 
UCLA: 
University of California Los Angeles 
VGPR:  
very good partial response 


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Table of Contents 
 
1.0 BACKGROUND AND RATIONALE  .................................................7 
     1.1 Beta-adrenergic signaling in the tumor microenvironment  .............7 
     1.2 Beta-blockade and cancer  ................................................................7 
     1.3 Propranolol dosing for cancer control ..............................................8 
     1.4 Socioenvironmental impact on gene expression  ..............................8 
     1.5 Rationale  ..........................................................................................9 
2.0 STUDY DESIGN ..................................................................................9 
     2.1 Primary objective  .............................................................................9 
     2.2 Secondary objectives  .......................................................................9  
     2.3 Patient eligibility  ............................................................................10  
     2.4 Treatment plan  ...............................................................................10 
     2.5 Study drug information  ..................................................................12 
     2.6 Participant risks  ..............................................................................13 
3.0 STUDY ENDPOINTS  ........................................................................13 
     3.1 Primary endpoint  ............................................................................13 
     3.2 Secondary endpoints  ......................................................................13 
4.0 ENROLLMENT PROCEDURES  ......................................................16 
     4.1 Patient enrollment  ..........................................................................16 
     4.2 Baseline demographic-, disease-, and treatment-related variables  17 
     4.3 Data and safety monitoring plan  ....................................................17 
     4.4 Specimen collection  .......................................................................19 
     4.5 Gene expression profiling  ..............................................................19 
     4.6 Psychosocial assessments  ..............................................................20 
     4.7 Study monitoring  ...........................................................................20  
5.0 STATISTICAL ANALYSIS  ..............................................................23 
     5.1 Study design  ...................................................................................23 
     5.2 Sample size and power calculation  ................................................23 
     5.3 Analysis of primary endpoints  .......................................................23 
     5.4 Analysis of secondary endpoints  ...................................................24 
 
 
LIST OF APPENDICES 
 
APPENDIX A  ..................................................... DRUG INTERACTIONS  
 
APPENDIX B ....................................... ADVERSE EVENT REPORTING 


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1.0 BACKGROUND AND RATIONALE: 
 
1.1 Beta-adrenergic signaling in the tumor microenvironment 
 
Research suggests beta-adrenergic signaling regulates multiple cellular processes that 
contribute to the initiation and progression of cancer, including inflammation, 
angiogenesis, apoptosis/anoikis, cell motility and trafficking, activation of tumor-
associated viruses, DNA damage repair, cellular immune response, and epithelial–
mesenchymal transition.1 Within the tumor microenvironment, beta-adrenergic receptors 
on tumor and stromal cells are activated by catecholamines from local sympathetic nerve 
fibers (norepinephrine) and circulating blood (epinephrine). Studies of beta-adrenergic 
influence on tumor biology were motivated by epidemiologic observations in humans 
associating stressful life circumstances with accelerated progression of incident cancers.2, 
3 In several experimental cancer models, activation of the sympathetic nervous system 
(SNS) has been shown to promote the metastasis of solid epithelial tumors and the 
dissemination of hematopoietic malignancies via beta-adrenoreceptor–mediated 
pathways.4 SNS regulation of cancer cell biology and the tumor microenvironment is 
helping to clarify the molecular basis for long-suspected relationships between stress and 
cancer progression, and now suggests a highly leveraged target for therapeutic 
intervention.1  
 
1.2 Beta-blockade and cancer 
 
Retrospective epidemiologic studies have linked the use of beta-blockers to reduced rates 
of progression for several solid tumors.5-9 Recently, a retrospective case-control study of 
MM patients identified that concurrent use of any beta-blocker is associated with more 
favorable 5-year overall and disease-specific survival.10 Preclinical pharmacologic and 
biomarker studies in animals are now laying the groundwork for translation of beta-
blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology, 
linking the use of beta-adrenergic antagonists (beta-blockers) with reduced disease 
progression in humans.4-9, 11-17 Further, propranolol, a non-selective beta-adrenergic 
receptor blocker, has apoptotic and anti-proliferative effects on multiple myeloma (MM) 
cells.18 Propranolol is the most studied nonselective beta-blocker;19 this, along with its 
safe side effect profile, cost-effectiveness, and efficacy in vitro in preventing tumor 
progression as compared to selective beta-antagonists1, 16, 20 make it our preferred beta-
blocker for use in the current proposal. Propranolol does not have any significant drug 
interactions with the more common antineoplastic (melphalan) and infection-related 
drugs utilized to treat MM. 
 
The first 30 days following autologous hematopoietic stem cell transplantation (HCT) 
generally constitute the time period around transplantation of greatest psychological and 
physiological stress and inflammatory processes.21, 22 Psychosocial stress gradually 
improves over time with a return to pre-transplant psychosocial functioning by about one 
year post-transplant.23, 24 Therefore, it follows that the first 30 days may also be the time 
period of highest beta-adrenergic signaling due to increased stress response. Further, data 


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from mouse models have demonstrated that beta-blockade with propranolol 8 days prior 
to exogenous stress exposure is effective in blocking beta-adrenergic signaling at the 
tumor level.4 Tumor metastasis in mouse models is increased 30-fold as compared to the 
control group after 20 days of exposure to chronic stress.25 
 
1.3 Propranolol dosing for cancer control 
 
Murine models have demonstrated propranolol serum concentrations of 20 ng/ml (range 
0.16-0.26 ng/ml) (Sloan, personal communication) with sustained-release propranolol 
0.5mg over 21 days to be effective in beta-blockade mediated mitigation of stress-
induced tumor progression/metastases.25 Animal to human dosing may be converted 
using the dose translation formula based on body surface area where human equivalent 
dose (HED) (mg/kg) = animal dose (mg/kg) multiplied by Animal Km/Human Km 
(where animal Km = 3, human Km = 37).26 The HED is 122 mg/day or 142 mg/day for a 
60 kg and 70 kg human, respectively. However, the 0.5 mg dose is not a single-dose; 
therefore, with the sustained-release formulation the HED could be as low as 6 mg/day or 
7 mg/day, respectively. The actual HED is likely near the midpoint of the low and high 
values calculated, which would be 60 to 80 mg per day. Therefore, a goal dose of 40mg 
orally twice daily in humans should achieve similar serum concentrations as that 
demonstrated in mice to affect cancer progression. Both 20mg and 40mg of propranolol 
(one administration of a twice daily administration regimen) are effective for anxiolysis.27 
Given this as well as the variable pharmacokinetic profile of propranolol,28-30 it is also 
feasible that 20mg bid may affect change at the level of gene expression. 
 
1.4 Socioenvironmental impact on gene expression 
 
Stress-induced beta-adrenergic signaling within the tumor microenvironment also results 
in alterations in SNS-mediated gene expression; this was identified in an ovarian cancer 
cohort of 10 individuals with elevated biobehavioral risk factors compared to relative 
grade- and stage-matched individuals without these risk factors.31 This type of 
socioenvironmental impact on gene expression has been consistently demonstrated, with 
previous studies showing that circulating immune cells show a systematic shift in basal 
gene expression profiles during extended periods of stress, threat, or uncertainty, 
consistent with the physiology of stress-associated illness.32-36 Recently, we identified 
increased expression of genes mediated by beta-adrenergic signaling in a cohort of HCT 
recipients with acute myelogenous leukemia in first complete remission (N=78) under 
conditions of increased stress as measured by low socioeconomic status (SES) 
(unpublished data). These changes associated with low SES are reciprocally associated 
with increased relapse and leukemia-free survival (unpublished data). It is unknown, 
however, whether a nervous system-targeted intervention such as beta-blocker therapy 
would affect change at the level of gene expression. 
 
Evaluating a molecular outcome with the magnitude of data that is available as with gene 
expression studies allows us to assess biobehaviorally-mediated biological changes 
between two differing groups utilizing a small cohort, as has been done previously.31, 35 
This design provides the advantage of conducting a small, short-term, and inexpensive 


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pilot study to first assess the feasibility and tolerability of administering a beta-blocker to 
a cohort of HCT recipients while also obtaining novel information on potential 
mechanisms.  
 
1.5 Rationale 
 
There has never been a prospective human trial prophylactically administering beta-
blocker therapy with conventional cancer treatments to affect change at the level of the 
tumor microenvironment. We aim to implement the first human pilot study using a beta-
blocker to pharmacologically intervene in biobehaviorally mediated gene expression in 
cancer patients to expand our previous findings. Specifically, we aim to evaluate this 
effect among patients receiving HCT for MM, the number one indication for autologous 
transplantation at MCW as well as in the US and worldwide. Using an autologous rather 
than allogeneic HCT population will minimize the number of potentially confounding 
variables for purposes of this study. The long-term goal is to utilize findings from this 
study is to alter tumor progression.  
 
2.0 STUDY DESIGN 
 
This is a proof of concept randomized controlled pilot study assessing whether gene 
expression of beta-adrenergic signaling pathways can be altered in individuals 
undergoing autologous HCT for MM by administering a daily beta-blocker (propranolol) 
to 20 participants. Outcomes of patients on this clinical trial will be compared to 20 
participants in a control arm. Study assessment time points are detailed in Table 4.7a. 
 
2.1 Primary Objective 
 
The primary objective of this study is to assess whether beta-blocker administration to 
individuals undergoing HCT alters genome-wide transcriptional pathways involved in 
beta-adrenergic signaling. 
 
2.2 Secondary Objectives 
 
The secondary objectives of this study are: 
 
 
1) To explore additional gene expression endpoints including:  
 
 
a) the impact of SES, depression, and anxiety on gene expression as well  
 
 
as on the relationship between beta-blocker administration and gene  
 
 
expression profiles  
 
 
 
 
 
2) To assess clinical feasibility and efficacy by 
 
 
a) testing the feasibility (adherence, tolerance) of using beta-blockers  
 
 
with an intensive conventional antineoplastic treatment regimen  
 
 
 
(autologous HCT) in a cancer population 
 
 
 
b) describing meaningful clinical endpoints between the intervention vs.  
 
 
control arms including depression and anxiety, proportion of  
 


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patients developing engraftment syndrome, time to neutrophil and platelet  
 
 
engraftment, incidence of infection, myeloma response, treatment-related  
 
 
mortality, progression-free survival, and overall survival  
 
2.3 Patient Eligibility 
 
2.3.1 Inclusion Criteria 
Patients with multiple myeloma receiving an autologous HCT are eligible when the 
following criteria are met: 
 
1. 18-75 years of age 
2. ≤ 1 year since initiation of systemic anti-myeloma therapy 
3. Patient is scheduled for autologous hematopoietic stem cell transplant as the 
upfront therapy for their multiple myeloma 
4. Karnofsky Performance Status of ≥80 %; patients eligible for HCT are eligible for 
the study 
5. All men and women must agree to practice effective contraception during the 
study period if not otherwise documented to be infertile. 
 
2.3.2 Exclusion Criteria 
 
1. Prior autologous HCT 
2. Non secretory multiple myeloma 
3. Concurrent beta-blocker therapy at or within 3 weeks of study entry. Refer to 
section 2.4.4 for complete list. 
4. Previous intolerance to beta-blocker therapy 
5. Any medical contraindications to beta-blocker therapy including, but not limited 
to, symptomatic hypotension; drug hypersensitivity; sinus bradycardia, sick sinus 
syndrome, or 2nd or 3rd degree atrioventricular block without a pacemaker; 
uncompensated heart failure; or uncontrolled asthma  
6. Active, untreated depression screened for by the HCT physician (Patients who 
screen positive will be offered a referral to the MCW Psycho-Oncology program 
for further evaluation and treatment) 
7. Concurrent use of medications in section 2.4.4 throughout the study or within one 
week of study entry. 
8. Pregnant or lactating women 
 
2.4 Treatment Plan 
 
The study drug will be dispensed. Compliance will be monitored by the clinical research 
coordinator (CRC). Beta-blocker tolerability will be assessed clinically by the treating 
physician on a weekly basis and for 1 week following cessation of beta-blocker therapy; 
subjects will be questioned about specific side effects as well as assessed for blood 
pressure and heart rate during weekly appointments or by phone. 
 
 


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2.4.1 Beta-blocker dosing schedule 
 
We will take a conservative approach by initiating propranolol 20 mg orally twice 
daily for a week at the time of study commencement (Day -7 ± 2 days with respect to day 
of transplant being Day 0; nomenclature throughout protocol continues as such; see 
Figure 1) in an effort to minimize cardiac effects in this medically ill population. The 
study PI and treating HCT physician will assess drug tolerability and increase the dose to 
40 mg orally twice daily on Day 0 if there are no adverse medical or psychiatric side 
effects as described in Section 2.6. In particular, if study participants have a heart rate of 
< 50, a blood pressure of < 90/55, significant fatigue impairing their function, or signs or 
symptoms of congestive heart failure, they will be taken off propranolol. If they have any 
noticeable side effects but are less severe than described above and the patient is able to 
tolerate staying on propranolol, their dose will be held at 20mg twice daily. If participants 
are tolerating propranolol without any side effects, they will be increased to 40mg twice 
daily. The maximum dose will be 40 mg twice daily. Study participants who remain at 
20mg orally twice daily will continue on as study subjects. This informs the feasibility 
aim of the study as well as contributes to the drug-exposed population for gene 
expression analyses. As demonstrated in the above studies, there is a wide range of serum 
concentrations that can have clinical effectiveness. The target dose of 40 mg twice daily 
should possess the desired antitumor effects while minimizing hemodynamic side effects 
in most patients. This should coordinate well with Sloan’s murine model that 
demonstrated anti-tumor effects at a serum level of 20 ng/ml and should maximize the 
likelihood of effecting change at the level of gene expression.  
 
Patients taking antihypertensive medications will be monitored in the same manner as the 
other study participants with regular blood pressure and heart rate assessments. If patients 
already taking antihypertensive medication(s) develop low blood pressure on propranolol, 
their antihypertensive medication will be lowered and the propranolol dose will be 
continued as tolerated. Similarly, as the study drug is weaned, their antihypertensive 
medication(s) will be titrated as necessary. 
 
2.4.2 Study interruption 
 
Participants needing to stop beta-blocker therapy secondary to intolerance or new onset 
of a contraindication will not be considered for resumption of therapy. Outcome and 
medical data will continue to be collected and assessed for intervention arm participants 
despite an inability to remain on beta-blocker therapy for the study duration.  
 
2.4.3 Beta-blocker weaning 
 
Beta-blocker will be weaned for one of three reasons: 1) completion of drug intervention 
(28 ± 2 days post-transplant), 2) intolerance secondary to side effects, or 3) onset of new 
medical symptoms rendering beta-blocker therapy as contraindicated (see section 2.3.2). 
For patients that are at 40 mg twice daily at the time of weaning, the dose will be reduced 
to 20 mg twice daily for one week before being discontinued entirely. For patients who 
are on 20 mg twice daily at the time of weaning, their dose will be stopped altogether.  


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2.4.4 Prohibited concomitant medications and treatments  
• Beta-Blocker therapy including but not limited to: Atenolol, Carvedilol, 
Labetalol, Metoprolol, Nadolol, Propranolol, Sotalol, Timolol 
• Pgp substrates: Bosutinib, PAZOPanib, Silodosin, Topotecan, VinCRIStine 
(liposomal) 
• Ceritinib, Floctafenine, Methacholine 
• Herbal medications, including but not limited to: St. John’s Wort, ginko biloba, 
saw palmetto, and ginseng 
 
2.4.5 Concomitant medications to be used with caution: Require an investigational drug 
pharmacist consult to evaluate drug interaction  
• Full list can be found in Appendix A 
• Antihypertensives and bradycardia causing agents: 
o Alpha1 blockers, including but not limited to: Doxazosin, 
Prazosin,Tamsulosin; Terazosin 
o Alpha2 agonist, including but not limited to: 
CloNIDine,GuanFACINE,TiZANidine 
o Alpha/Beta-Agonist: Dopamine, DOPamine; EPINEPHrine; 
Isometheptene; Levonordefrin; Norepinephrine 
• Scheduled and As Needed Beta2-Agonist therapy: Albuterol; Arformoterol; 
Bambuterol; Fenoterol; Formoterol; Indacaterol; Levalbuterol; Metaproterenol; 
Olodaterol; Pirbuterol; Salmeterol; Terbutaline; Vilanterol 
• Pgp substrate: Afatinib, Colchicine, DOXOrubicin, Dabigatran, Edoxaban, 
Everolimus, Rivaroxaban, vincristine 
• Strong Cyp1A2 inducers, including but not limited to: CarBAMazepine, 
PHENobarbital, Rifampin 
• Strong Cyp1A2 inhibitors, including but not limited to: Cipro, FluvoxaMINE, 
Primaquine  
• Cyp1A2 Substrates, including but not limited to: Vemurafenib 
• Strong Cyp2D6 inhibitors, including but not limited to: BuPROPion,Cinacalcet, 
FLUoxetine,  Lopinavir, PARoxetine, Ritonavir, Terbinafine 
• Cyp2D6 Substrates, including but not limited to: Abiraterone 
 
2.5 Study Drug Information 
 
Propranolol is highly protein bound (89%) and undergoes extensive first-pass metabolism 
(hepatic extraction ratio 0.7-0.9) yielding nonrestrictive elimination where the hepatic 
extraction ratio is greater than the amount of unbound drug. This results in significant 
intra-patient variability. At higher doses used to achieve serum concentrations >30 ng/ml, 
propranolol manifests linear kinetics.30, 37 Owing to this unique pharmacokinetic profile it 
is difficult to calculate a predicted serum concentration. However, given that a mouse 
serum concentration target of 20 ng/ml has been established and that this theoretically 
correlates with target human serum concentration,25, 38 we can apply human dose-finding 
studies to determine HED need to achieve said concentration. At a dose of 120 mg/day 
mean serum trough concentrations have been reported as 54  34 ng/ml and 41.6 37.6 


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13 
ng/ml while peak serum concentrations are  >100 ng/ml.39, 40 The optimal cardiac dose 
has been established at 144 mg/day, yielding a serum trough concentration of 30  7 
ng/ml; however, some have suggested concentrations > 20 ng/ml manifest cardiac 
effects.
40 Similarly, other studies associate propranolol 80 mg/day with serum 
concentration in the 10 to 30 ng/ml range.28, 29, 41 Therefore, a goal dose of 40 mg orally 
twice daily in humans should achieve similar serum concentrations as that demonstrated 
in mice to affect cancer progression, with the possibility that the anxiolytic dose of 20 mg 
twice daily may have similar effects. Drug supply and storage will be coordinated with 
the F/MCW Clinical Trials Office. 
 
2.6 Participant Risks 
 
Rare 
  
Dizziness or passing out 
  
Hard stools (constipation) 
  
Loose stools (diarrhea) 
  
Upset stomach or throwing up 
 
Feeling sleepy 
 
Feeling tired or weak 
 
Not able to sleep 
Rare but serious adverse events that have been reported  
  
Chest pain that is new or worse 
  
Change in thinking clearly and with logic 
 
Hallucinations 
  
Memory problems or loss 
  
Mood changes 
  
A burning, numbness, or tingling feeling that is not normal 
  
Change in eyesight 
  
Shortness of breath, a big weight gain, selling in the arms or legs 
  
Any bruising or bleeding 
 
Slow heartbeat 
  
A heartbeat that does not feel normal 
 
Feeling cold 
  
Low blood sugar, signs may include dizziness, headache, feeling sleepy, feeling 
weak, shaking, a fast heartbeat, confusion, hunger, or sweating. 
  
A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) 
may happen.  It can cause very bad health problems that may not go away, and 
sometimes death.  Get medical help right away if you have signs like red, swollen, 
blistered or peeling skin (with or without fever), red or irritated eyes, or sores in your 
mouth, throat, nose, or eyes. 
  
In some cases if you stop taking propranolol all of a sudden you may develop 
chest pain that is worse and in some cases a heart attack may occur.  This risk may be 
greater if you have certain types of heart disease.  To avoid side effects, do not stop 
taking propranolol all of a sudden, you want to slowly stop this drug as ordered by your 
doctor.    Call your doctor right away if you have new or worse chest pain or if other 
heart problems occur. 


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14 
 
Allergic Reactions 
 
Allergic reaction, such as rash; hives; itching; red, swollen, blistered or peeling 
skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or 
talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue or throat 
 
In some cases if you stop taking propranolol all of a sudden you may develop chest pain 
that is worse and in some cases a heart attack may occur.  This risk may be greater if you 
have certain types of heart disease.  To avoid side effects, do not stop taking propranolol 
all of a sudden, you want to slowly stop this drug as ordered by your doctor.    Call your 
doctor right away if you have new or worse chest pain or if other heart problems occur. 
 
The FDA black box warning: 
In some cases if the patient stops taking propranolol all of a sudden the patient may 
develop chest pain that is worse and in some cases a heart attack may occur.  This risk 
may be greater if the patient has certain types of heart disease.  To avoid side effects, do 
not stop taking propranolol all of a sudden, if the patient wants to slowly stop this drug as 
ordered by their doctor.   The patient should call the doctor right away if the patient has 
new or worse chest pain or if other heart problems occur. 
 
3.0 STUDY ENDPOINTS 
 
3.1 Primary Endpoint 
 
Expression levels of beta-adrenergic mediated gene expression will be compared between 
individuals randomized to propranolol vs. control just prior to HCT as well as 28 days 
following autologous HCT for MM. Quantification of whole genome RNA production 
will be performed with specific identification of expression of beta-adrenergic signaling 
pathways.  
 
3.2 Secondary Endpoints 
 
3.2.1 Gene expression 
 
3.2.1.1 Gene expression based on psychosocial factors 
 
Expression levels of beta-adrenergic mediated gene expression will be compared between 
individuals with high vs. low levels of depression and anxiety, defined as a score of 8 or 
above on the Hospital Anxiety and Depression Scale (HADS) anxiety (HADS-A, 7 
items) and depression subscales (HADS-D, 7 items)
42 at all three blood draw timepoints. 
Expression differences will be assessed both dependently and independently of treatment 
group assignment. 
 
3.2.2 Clinical 
 
3.2.2.1 Feasibility 


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The feasibility portion of the study is the test of whether patients undergoing autologous 
HCT for MM can be placed and maintained on a beta-blocker during the immediate peri-
transplant period. Feasibility to use propranolol in autologous MM HCT recipients for the 
adjunct cancer control purposes will be determined by a 55-70% enrollment rate and 65-
70% retention rate as described below in sections 3.2.2.1a-b. The study intervention will 
be deemed feasible if both of the below parameters for enrollment and retention are met. 
 
3.2.2.1a Enrollment rate 
 
Based on similar biobehavioral cancer research efforts at other institutions, the target 
enrollment rate is 55-70%. Of all eligible patients that are approached, the goal is that 55-
70% will provide informed consent and enroll in the study. This target rate also takes into 
account the possibility that enrollment may be slightly lower due to the present study 
being a drug intervention trial with potential patient reticence to enroll.  
  
3.2.2.1b Retention rate 
 
Based on similar research and the nature of drug intervention trials (as described in 
3.2.2.1a), the target retention rate is 65-70%. Retention rate will be assessed individually 
for two time periods - prior to transplant (between Time 1 and Time 2) and from 
transplant through Day +30 (Time 2 to Time 3). This allows for assessing the impact on 
gene expression in both a run-in period preceding transplantation as well as during the 
transplant process, whereby there will be a greater number of confounding variables that 
may potentially impact gene expression and adherence. Participants will be considered to 
be retained in the study for the given time period assessment if they are 80% adherent to 
their prescribed dose of medication during the specified time period. 
 
Drug adherence will be measured as a percentage of the prescribed number of pills that 
were actually taken (either 20 mg or 40 mg twice daily). This will be determined 
outpatient via pill count on Day -2 and Day +28 and inpatient through nursing 
documentation. Patients will have one additional pill count upon return of the study 
supply of propranolol. The return will occur at the next earliest clinic appointment 
following discontinuation of the propranolol. There is no consensual standard for what 
constitutes adequate adherence. Clinical trials report average adherence rates of 43 to 78 
percent among patients taking drugs for chronic conditions; some clinical trials define 
rates above 80% as acceptable.43 A target adherence rate of 80% will be utilized in this 
study to constitute having adequately retained the patient in the study. Adherence will be 
recorded as a continuous (0-100%) variable. Adherence will be assessed separately 
during two time periods – prior to transplant (between Time 1 and Time 2) and from 
transplant through Day +28 (Time 2 to Time 3). Patients will be included in final 
analyses if and only if they have been adherent (at least 80% of the prescribed dose) to 
the study drug during the designated time period. 
 
As the retention rate (participants’ ability or inability to be maintained on the study drug) 
will necessarily be affected by side effects, we will collect side effect data to better 


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16
inform the feasibility aim of this study. Common side effects that will be screened for 
clinically at follow up time points include fatigue, dizziness, constipation, bradycardia, 
hypotension, depression, insomnia, weakness, disorientation, nausea, diarrhea, 
hypersensitivity reaction, purpura, alopecia, and impotence. Any side effects deemed 
secondary to beta-blocker usage will be documented and appropriately treated or referred 
for treatment collaboratively by the study PI and treating HCT physician, and beta-
blocker therapy will be weaned by 20 mg at each dosing time. Patients will remain at the 
weaned dose for 1 week prior to discontinuing if this dose decrease does not eliminate the 
drug entirely. Heart rate and blood pressure will be monitored and documented at 
baseline, once after initiating beta-blocker therapy but before transplant, just prior to 
transplant, and weekly thereafter; these are two of the most common and dangerous side 
effects. Given that patients aren't as acutely medically ill pre-transplant and that standard 
of care following beta-blocker initiation would involve follow-up weeks later, this 
schedule should allow for adequate study drug monitoring while minimizing patient 
study visit burden. Blood pressure less than 90/55 or heart rate less than 50 will prompt 
clinical review by the study PI and treating HCT physician for appropriateness to 
continue beta-blocker therapy. Calendar collection of adverse events (AEs) will be 
obtained through toxicity forms (Common Terminology Criteria for Adverse Events 
[CTCAE]) completed weekly until neutrophil engraftment occurs (absolute neutrophil 
count > 500/mm3 for ≥3 consecutive days) and bi-weekly thereafter until the study 
endpoint at Week 6 (See Tables 2a and 2b). Further details about AE monitoring are 
included in Section 4.3. 
 
3.2.2.2 Outcomes 
• Depression and anxiety: as assessed by the HADS, with scores of 8 or above on 
HADS-A (7 items) and HADS-D (7 items) defining significant anxiety or 
depression, respectively.42 Depression and anxiety will be described both overall 
and between treatment vs. control groups.  
• Engraftment syndrome: presence of fever, diarrhea, or rash within 48 hours before 
or after neutrophil recovery that requires steroids for treatment. This will be 
determined at the discretion of the treating physician and will be categorized as 
yes/no. 
• Neutrophil engraftment: time to absolute neutrophil count (ANC) > 0.5 x 109/L 
sustained for three consecutive assessments at least one day apart. 
• Platelet engraftment: time to achieve a platelet count of (a) >20 x 109/L 
independent of platelet transfusions for 3 consecutive assessments at least one day 
apart. 
• Infection: number of documented culture positive infections or neutropenic fever 
episodes defined as fever >100.4 degrees F. 
• Response to treatment:  The trial will assess the rates of very good partial 
response (VGPR) or better (near complete response (nCR), CR, and stringent CR 
(sCR)) according to the International Uniform Response Criteria at day 100 post-
HCT. 
• Treatment-Related Mortality (TRM): TRM is defined as death occurring in a 
patient from causes other than disease progression. TRM will be assessed at D100 


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17
for both the intervention and control arms. Patients alive and progression-free at 
100 days will be censored. 
• Progression-Free Survival (PFS): Progression (for patients not in CR) is defined 
as increase of serum paraprotein by 0.5 g/dL compared to pre-transplant levels, 
increase in 24 hour urine protein electrophoresis ≥ 200 mg compared to pre-
transplant levels, absolute increase in the difference between involved and 
uninvolved FLC levels of >10 mg/dl (only in patients without measurable 
paraprotein in the serum and urine), >25% increase in plasma cells in a bone 
marrow aspirate or on trephine biopsy (must also be an absolute increase of at 
least 10%), increase in the size of existing bone lesions or soft tissue 
plasmacytomas, development of new bone lesions or soft tissue plasmacytomas, 
development of hypercalcemia (corrected serum Ca >11.5 mg/dL or >2.8 
mmol/L) not attributable to any other cause. Development of a compression 
fracture does not exclude continued response and may not indicate progression. 
PFS will be compared between the two arms as a time to event endpoint censored 
after 100 days of follow-up on each patient. Patients are considered a failure of 
the primary endpoint if they die or suffer from disease progression. The time to 
this event is the time from randomization to progression, death, loss to follow up 
or Day 100 - whichever comes first. 
• Overall Survival (OS): The event is death from any cause. The time to this event 
is the time from randomization to death, loss to follow-up or the end of 100 days, 
whichever comes first. Patients alive at the time of last observation are considered 
censored. Estimates of OS will be described for each group at 100 days post-
transplant. 
 
 
4.0 ENROLLMENT PROCEDURES 
 
4.1 Patient Enrollment 
 
Patients will be approached for this study during the pre-transplant evaluation phase. 
Transplant physicians will evaluate the patient eligibility onto this study. Eligible patients 
willing to participate in the trial will sign an MCW IRB approved informed consent form. 
A Clinical Trials Office CRC will record the documentation of patient consent and 
proceed with registration procedures. All source documents that support eligibility 
including a signed informed consent/HIPAA and signed eligibility checklist, will be 
available, reviewed and eligibility verified. At the point of registration, a member of the 
study team will register the patient in the electronic database, including demographics, 
consent and on-study information. The patient will be assigned a unique sequence 
number for the study. The principal investigator (PI) of the study, Dr. Knight, will be 
notified prior to enrollment.  Pharmacy will be notified upon patient registration. If at any 
point in time a patient wishes to withdraw from the study, they may notify Dr. Knight 
verbally or in writing. There will be no further data collection for participants who elect 
to withdraw from the study. 
 


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Target enrollment is 40 (20 per group) and includes patients undergoing autologous HCT 
for MM at MCW. Half of the participants will be randomized via permuted block 
assignment with random block sizes to receive propranolol upon study entry. Informed 
consent will be obtained to access participants’ full medical records to ascertain relevant 
demographic and medical data as outlined in Section 4.2. The patient must have signed 
informed consent prior to registration on the study. Due to the pilot and feasibility nature 
of this study, the need to monitor response to prophylactic beta-blocker usage in a 
medically ill population, as well as the objective nature of gene expression profiling, this 
pilot study will not be blinded. Patients will be enrolled before study commencement at 
Day -7. Total study duration will be up to 7 weeks for participants assigned to the 
intervention group (1 week pre-transplant through 6 weeks post-transplant) and 5 weeks 
for those in the control arm (1 week pre-transplant through 4 weeks post-transplant). 
Additional clinical information will be collected for 100 days post-transplant as identified 
in section 3.2.2.2. 
 
4.2 Baseline Demographic-, Disease-, and Treatment-Related Variables 
 
Patient-related: 
 
- Age at transplant 
 
- Gender 
 
- Race: Caucasian vs. African American vs. Asian/Pacific Islander vs. Other 
 
- Body Mass Index: <18.5 vs. 18.5-24.9 vs. 25-29.9 vs. >=30 
 
- Smoking status in 3 months prior to HCT (Y/N) 
 
-- Household income prior to disease diagnosis: <$23,000, $23,000-$34,999, 
 
$35,000-$44,999, $45,000-$54,999, $55,000-$64,999, $65,000-$74,999, 
 
>$75,000 
 
- Number of individuals in patient’s household 
 
- Education level: < high school vs. high school graduate vs. some post high 
 
school education vs. college degree vs. professional degree     
 
Disease-related: 
 
- International Stage 
- Disease status prior to transplant: complete response, very good partial response, 
partial response, or stable disease 
- Cytogenetics: high risk vs. standard risk by International Myeloma Working 
Group (IMWG) criteria 
 
Treatment-related: 
- Number of CD34+ cells infused/kg of recipient body weight 
- Transplant setting: inpatient vs. outpatient transplant (defined as patients who 
plan to stay outpatient during entire transplant period) 
 
 
 
4.3 Data and Safety Monitoring Plan 
 


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19
4.3.1 Guideline for serious adverse event reporting 
 
Please refer to Appendix B for more details on adverse event reporting. 
 
4.3.2 Monitoring the progress of the trial and safety of participants 
 
This randomized controlled pilot study will be monitored by the PI, Dr. Knight. The PI 
will review the outcome of the data for each individual patient on an ongoing basis. The 
PI will have primary responsibility for ensuring that the protocol is conducted as 
approved by the IRB. The PI will ensure that the monitoring plan is followed and that all 
data required for oversight of monitoring are accurately reported, that all AEs are 
reported according to the protocol guidelines, and that any AEs reflecting patient safety 
concerns are appropriately reported.  
 
4.3.3 Adverse event reporting 
 
The capture of toxicities and AEs in this protocol will follow the same approach and will 
be done in two levels. First, grades 3-5 AEs will be collected at different time points 
during the study period. Any AE that fulfill this criterion will be captured and the 
frequency of each organ toxicity tabulated. The Data and Safety Monitoring Committee 
(DSMC) and IRB will receive a summary of all the AEs captured in calendar forms in a 
quarterly to biennial basis depending the schedule of protocol review meetings. 
Additionally the PIs will review the frequency of toxicities in a quarterly basis.  
 
Second, any AE that is unexpected and of grades 3 to 5 will require expedited report to 
the oversight committees (MCW IRB, MCW DSMC and FDA – if applicable for studies 
under IND). The collection grades 3-5 unexpected AEs is event driven and requires a 
more comprehensive description of the event. The report for these AEs are termed 
Individual Case Safety Reports (ICSR) and include the following components: 1) 
summary cover sheet of the event, 2) narrative of the event, 3) associated conditions, 
medications and diagnostic information, source documents with further explanation of 
the event, and an evaluation of the event by the PI. The PI will review all these events 
and will determine if they require expedited reporting. If they are considered grades 3-5 
and unexpected the report will be sent to the oversight committees within three days from 
acknowledgement of the event. If the event is not considered to fulfill criteria of grades 3-
5 unexpected AE, it will be included in the DSMC and IRB reports for scheduled 
protocol reviews and will not require expedited reporting.  
 
Reporting timelines: 
1. Fatal  (grade 5) or Life Threatening events must be reported within 24 hours 
but not later than three calendar days of the investigator’s observation or 
awareness of the event.  
2. All other events grades 3-4 unexpected events (non-fatal/non life-threatening) 
must be reported within 3 to 5 calendar days of the investigator’s observation or 
awareness of the event. 
 


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This study will be reviewed by the Medical College of Wisconsin Cancer Center Data 
Safety Monitoring Committee (MCW CC DSMC). A summary of the MCW CC DSMC 
activities are as follows: 
 
• Review the clinical trials for data integrity and safety 
• Review all adverse events requiring expedited reporting as defined per protocol 
• Review all Data and Safety Monitoring (DSM) reports 
• Submit a summary of any recommendations related to study conduct 
• Terminate the study if deemed unsafe for patients 
 
A copy of the MCW CC DSM Plan and membership roster will be maintained in the 
DSMC file and updated as membership changes. The committee will review reports from 
the study PI twice annually (or more frequently if needed) and provide recommendations 
on trial continuation, suspension or termination as necessary. Any available DSMC 
letters will be submitted to the IRB of record as required. 
 
4.4 Specimen Collection 
 
The Cancer Center Lab draw blood to be stored in PAXGene RNA tubes at three study 
time points as described in Table 4.7b. These time points include baseline (Day -7), Day -
2 (immediately prior to transplant, central line placement, or administration of any 
conditioning regimen), and Day +28. Blood will be drawn at one of two locations: in the 
hospital (if participants are immediately post-transplant and/or still or re-hospitalized) or 
in the transplant clinic during their regular visits. The PAXGene RNA tubes do not 
require any additional processing of blood samples before being frozen and sent to 
UCLA. These PAXGene RNA tubes will be stored at -80C in the Neuroscience Research 
Center, which is a locked facility, until they are batched and shipped to University of 
California Los Angeles (UCLA) for gene expression analysis. Before being stored they 
will be assigned a dummy ID that will be the sole identifier of the samples. The linked 
identifiers will be stored on a secure computer network through the CIBMTR under the 
PI’s name. Samples will be packaged with dry ice and shipped overnight to Dr. Steve 
Cole’s lab at UCLA at the time of study conclusion. This will be done on a day such that 
the UCLA lab can receive and keep the samples frozen at -80C. Our groups have 
collaborated successfully on transfer of samples in the past. All samples will be sent 
together. 
 
4.5 Gene Expression Profiling 
 
The UCLA Social Genomics Core (Directed by Dr. Steve Cole, Consultant) will conduct 
all gene expression profiling on obtained blood samples by using Illumina HT-12 human 
gene expression bead arrays.44 Total RNA will be extracted from the whole blood 
samples stored at MCW, subjected to quality assurance assays to test suitable mass (by 
spectroscopy) and integrity (by Agilent Bioanalyzer RNA Integrity Score) for analysis, 
and subjected to microarray target synthesis and hybridization in collaboration with the 
UCLA Neuroscience Genomics Core Laboratory using standard Illumina assay 
equipment and protocols. The output of these analyses is quantification of whole genome 


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21
RNA production, which will be analyzed as per the methods below (section 5.4.1). 
Patient-level genetic data from Dr. Cole’s lab will not be conveyed to the patient or the 
clinician and no clinical decision will be made on the basis of genetic findings.  
  
4.6 Psychosocial Assessments 
 
4.6.1 Socioeconomic status 
 
SES will be assessed by household income prior to diagnosis with MM. This information 
will be collected from participants at baseline/time of study enrollment. The 2012 median 
family income in Wisconsin was $51,059 (US median was $51,371) according to the US 
American Community Survey (http://www.census.gov/prod/2013pubs/acsbr12-02.pdf) 
with the poverty threshold of $23,050 for a four-person family. Thus, we categorized 
family income as <$23,000, $23,000-$34,999, $35,000-$44,999, $45,000-$54,999, 
$55,000-$64,999, $65,000-$74,999, >$75,000. Education level (< high school vs. high 
school graduate vs. some post high school education vs. college degree vs. professional 
degree) will also be collected but not used as the primary indicator of SES in analyses. 
 
4.6.2 Anxiety and depression 
 
Participants will complete a HADS for primary analysis with gene expression at three 
study time points as described in Table 4.7b. These time points include baseline (Day -
21), Day -2 (immediately prior to conditioning regimen), and Day +28. Further, HADS 
will be administered/assessed weekly in coordination with weekly beta-blocker 
assessment to ascertain further whether the beta-blocker might be affecting depression or 
anxiety. 
 
HADS  is a 14-item scale that generates ordinal data and is specifically designed to avoid 
reliance on somatic symptoms that are concomitant with medical illness. Participants can 
score between 0 and 21 for either anxiety or depression. Each item is scored on a scale of 
0-3. A cut-off point of 8 or above on HADS-A (7 items) and HADS-D (7 items) has been 
established to connote significant anxiety or depression, respectively.42 Anxiety and 
depression will be evaluated both continuously as well as categorically with a cutoff of 8 
to signify an abnormal level of anxiety or depression. Participants scoring at this level 
will be offered a referral to the MCW Psycho-Oncology program for further evaluation 
and treatment. 
 
4.7 Study Monitoring  
 
The follow-up schedule for scheduled study visits is outlined in Table 4.7a with study 
assessment time points described in Table 4.7b.  
 
 
 
 
 


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TABLE 4.7a. FOLLOW-UP SCHEDULE 
 
Study 
Assessment Time 
Point 
Target Day  
Baseline 
Up to Day -7  
Pre-Transplant 
Day -2 ± 1 day1 
Day 0 
Date of transplant 
1 week 
7 ± 2 days 
2 weeks 
14 ± 2 days 
3 weeks 
21 ± 3 days 
4 weeks² 
28 ± 3 days 
5 weeks³ 
35 ± 3 days 
6 weeks³ 
42 ± 3 days 
Next clinic 
appointment  
~8 weeks (post-transplant) 
14 weeks 
100 ± 2 weeks 
 
 
1Assessment must occur prior to any conditioning regimen 
 
 
² Research samples only can be collected ± 7 days from target day 
 
 
³Assessment time points for intervention arm only 
 
 


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23
 
 
 
TABLE 4.7b. PATIENT CLINICAL ASSESSMENTS 
 
 
Study Assessments/  
Testing 
Baseline 
Day 
-2 
 
0 
7 
14 
21 
28 
 
35 
 
42 
Next 
clinic 
appt. 
 
100 
Demographics (patient-, disease-, and treatment-related) 
X 
 
 
 
 
 
 
 
 
 
 
Additional descriptive outcomes 
 
 
 
X 
X 
X 
X 
 
 
 
X 
Socioeconomic status  
X 
 
 
 
 
 
 
 
 
 
 
Hospital Anxiety and Depression Scale (HADS) 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Blood draw for gene expression analysis 
X 
X 
 
 
 
 
X 
 
 
 
 
Pregnancy test for FCBP 
X 
 
 
 
 
 
 
 
 
 
 
Toxicity 
 
 
X 
X 
X 
X 
X 
X¹ 
X¹ 
 
 
Assessment of adherence² 
 
X 
 
 
 
 
X 
 
 
X 
 
Heart rate and blood pressure 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
Myeloma response assessment 
 
 
 
 
 
 
 
 
 
 
X 
 
Consent has to occur within 30 days prior to starting study drug 
 
Numbers indicate days relative to day of transplant, with day of transplant being 0 
 
Patients will be enrolled and randomized prior to commencement of study drug/control arm 
 
 
1 For Propranolol group only.  Patients will have toxicity assessed weekly and once more 7 days ± 3 days after discontinuing drug. 
²Adherence will be assessed weekly or monthly based on number of pills prescribed. 
 


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5.0 STATISTICAL ANALYSIS 
 
5.1 Study Design 
 
5.1.1 Accrual 
 
It is estimated that 9 months – 1 year will be necessary to enroll the targeted sample size. 
 
5.1.2 Primary Endpoint 
 
The primary endpoint is Day +28 (4 weeks) following HCT for MM, with intervention 
arm patients followed for an additional 1-2 weeks until they are weaned from beta-
blocker therapy. 
 
5.2 Sample Size and Power Calculation 
 
We will enroll 40 participants undergoing autologous HCT for MM at MCW. Accounting 
for study attrition and beta-blocker intolerance, we aim to have 30 patients with a 
complete set of gene data. A sample size of 40 will inform our feasibility aim, while a 
targeted final sample of 15 participants in the intervention group will be sufficient for 
gene expression analysis. The gene expression sample size is based on previous studies 
with similar or smaller sample sizes that have evaluated gene expression as a function of 
psychosocial factors and yielded hundreds of differentially expressed genes that generate 
statistically significant results in higher-order bioinformatics.35, 45, 46 More specific 
sample size estimates are difficult to project with any greater accuracy, as there is not 
data on the effect size for gene expression differences as a function of propranolol in 
humans. To this end, the current proposal will inform future sample size estimations. This 
study is intended mainly to generate effect size estimates and 95% confidence intervals to 
aid with planning future research projects. We will generate both simple estimates of 
effect size as well as adjusted estimates, attempting to control for any accidental 
confounding that may occur despite randomization. 
 
5.3 Analysis of Primary Endpoints 
  
5.3.1 Gene Expression Profiling 
 
The final outcome for the gene expression analysis will be expression levels of the group 
of genes comprising the conserved transcriptional response to adversity (CTRA) profile. 
The CTRA profile represents a systemic shift in basal gene expression profiles among 
circulating immune cells during extended periods of stress, threat, or uncertainty 
consistent with the physiology of stress-associated illness.32-36 This profile is 
characterized by 53-genes and includes up-regulated expression of pro-inflammatory 
genes (IL1A, IL1B, IL6, IL8, TNF, PTGS1, PTGS2, FOS, FOSB, FOSL1, FOSL2, JUN, 
JUNB, JUND, NFKB1, NFKB2, REL, RELA, and RELB) and down-regulated expression 
of genes involved in type I interferon (IFN) responses (GBP1, IFI16, IFI27, IFI27L1-2, 
IFI30, IFI35, IFI44, IFI44L, IFI6, IFIH1, IFIT1-3, IFIT5, IFIT1L, IFITM1-3, IFITM4P, 


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25
IFITM5, IFNB1, IRF2, IRF7-8, MX1-2, OAS1-3, and OASL) and antibody synthesis (IGJ, 
IGLL1, and IGLL3).33, 34, 47, 48 This CTRA profile is significantly regulated through beta-
adrenergic mediated signaling. The CTRA profile will include a composite of 
standardized scores on the 53 a priori defined genes and measured levels of each 
transcript treated as 53 repeated measurements analyzed by a mixed effect linear model 
with a residual covariance structure estimated to account for potential correlation among 
the 53 genes. 
 
Primary analyses will be performed at the time of all 3 blood draws (Baseline, Day -2, 
and Day +28) and will use general linear model analyses to quantify the association 
between expression of each of the 53 CTRA contrast genes and beta-blocker usage. To 
ensure analysis of patients with sufficient beta-blocker exposure, only gene expression 
data from study participants with an adherence rate of 80% (at either dose) will be used 
as comparators against the control group. Descriptive tables of patient-, disease-, and 
transplant-related factors will be prepared with separate columns by propranolol vs. no 
propranolol groups. Any demographic or psychosocial variables (other than those of 
primary interest) that are unevenly distributed between groups after randomization will 
be adjusted for in subsequent analyses as previously described using ANCOVA. Further, 
differences in gene expression will be compared between groups/variables that might not 
have been randomly distributed, regardless of beta-blocker treatment assignment, to 
ascertain whether these differences may be stronger than drug-attributed changes. The 
UCLA Social Genomics core will provide genetic and statistical analyses for gene 
expression data. 
 
5.4 Analysis of Secondary Endpoints 
 
5.4.1 Gene expression based on psychosocial factors 
 
Subgroup analyses will describe additional psychosocial factors (SES, depression, 
anxiety) that may result in altered gene expression or differentially affect the response to 
beta-blockers in our proposed cohort. As this study is not powered to formally assess this 
relationship, these will be exploratory analyses to determine whether there is sufficient 
signal of a response to merit further exploration in future studies. 
 
SES will be assessed by household income prior to diagnosis with MM as described in 
section 4.6.1. This information will be collected from participants at baseline/time of 
study enrollment. SES will be assessed by all 7 categorical levels collected as well as by 
lowest quartile vs. all other quartiles. Anxiety and depression will be evaluated both 
continuously as well as categorically with a cutoff of 8 or above signifying an abnormal 
level of anxiety or depression. General linear model analyses will be used to quantify the 
association between the three psychosocial variables of interest – SES, depression, and 
anxiety – with expression of the CTRA gene profile, measured continuously. Beta-
blocker usage will then be entered into this model to ascertain whether it significantly 
changes the association between SES, depression, and anxiety and gene expression as 
measured by the CTRA profile. Significance will be assessed by change in magnitude of 
the partial regression coefficient relating candidate psychosocial variables (e.g., SES) to 


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26
the composite CTRA gene expression z-score in presence vs. absence of control for beta-
blocker exposure. 
 
5.4.2 Clinical 
 
5.4.2.1 Feasibility 
 
Feasibility to use propranolol in autologous MM HCT recipients for the adjunct cancer 
control purposes will be determined by a 55-70% enrollment rate and 65-70% retention 
rate as described in section 3.2.2.1. The rates of these events will be tabulated.  
 
5.4.2.2 Outcomes 
• Depression and anxiety: HADS scores will be tabulated and evaluated 
comprehensively as well as by HADS-A and HADS-D. The trajectory of these 
scores over the course of the study will be described. Differences in scores 
between the treatment vs. control groups over the course of the study will be 
assessed. 
• Engraftment syndrome: Engraftment syndrome occurrences will be tabulated and 
the incidence described for both treatment and control arms. 
• Neutrophil engraftment: Differences in time to neutrophil engraftment will be 
determined between treatment and control arms.  
• Platelet engraftment: Differences in time to platelet engraftment will be 
determined between treatment and control arms. 
• Infection: Infection events will be tabulated and differences in events will be 
determined for treatment and control arms. 
• Response to treatment: The rates of VGPR or better (nCR, CR, and sCR) will be 
calculated at 100 days post-transplant and compared between intervention and 
control arms. 
• Treatment-Related Mortality (TRM): TRM is defined as death occurring in a 
patient from causes other than disease progression. Disease progression is a 
competing event for TRM. The time to this event is the time from randomization 
to death, disease progression, loss to follow-up or the end of 100 days post-
transplant, whichever comes first. Patients alive without disease progression at 
100 days are considered censored. The cumulative incidence of TRM at 100 days 
will be estimated separately for each treatment-group. Overall TRM through 100 
days of follow-up will be compared using Gray’s test. 
• Progression-free survival (PFS): PFS will be compared between the two arms as a 
time to event endpoint censored after 100 days of follow-up on each patient. 
Patients are considered a failure of the primary endpoint if they die or suffer from 
disease progression. The time to this event is the time from randomization to 
progression, death, loss to follow up or Day 100 - whichever comes first. The 
Kaplan-Meier estimate of survival will be estimated separately for each treatment 
group at 100 days post-transplant. 
• Overall survival (OS): The event is death from any cause. The time to this event is 
the time from randomization to death, loss to follow-up or the end of 100 days, 
whichever comes first. Patients alive at the time of last observation are considered 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
27
censored. Estimates of OS will be described for each group at 100 days post-
transplant. The Kaplan-Meier estimate of survival will be estimated separately for 
each treatment group at 100 days post-transplant. Overall survival will be 
compared using a log-rank test at a two-sided significance level of .05. 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
28
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Treatment schema diagram; day values are in reference to transplant as Day 0 
Eligibility screening: 40 
participants recruited 
β-blocker arm 
(Intervention group) 
N=20 
 No β-blocker arm 
(Control group) 
N=20 
 Assessments at 
baseline, Day 0, 
and weekly until 
Day +28 
 Assess for β-blocker 
tolerability after 7  
days (Day 0) 
 Propranolol 20mg p.o. bid x 7 days 
Not tolerating  
β-blocker 
Stop propranolol   
Tolerating β-blocker therapy, 
but contraindications(s) to 
dose increase 
Tolerating  
β-blocker 
Weekly 
assessments; wean 
if not tolerating 
Weekly assessments; increase 
propranolol to 40mg p.o. bid 
at subsequent assessments if 
no contraindications; 
discontinue if not tolerating 
Continue propranolol  
20mg p.o. bid 
Increase propranolol 
to 40mg p.o. bid 
Propranolol dose remains at 
20mg p.o. bid 
Propranolol dose at 
40mg p.o. bid 
Discontinue propranolol on 
Day +28 
Wean propranolol 
starting on Day +28 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
29
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX A 
DRUG INTERACTIONS


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
30
 
Appendix A: Full list of concomitant medications to be used with caution 
 
Abiraterone Acetate 
Lopinavir 
Afatinib  
Methotrimeprazine 
Alfuzosin 
Methoxsalen (Systemic) 
Amifostine 
Methyldopa 
Aminophylline 
Methylergonovine 
Brimonidine (Ophthalmic) 
Mexiletine 
Bromocriptine  
Norepinephrine 
Bupropion 
Norepinephrine 
Cabergoline 
Obinutuzumab 
Carbamazepine 
Ofloxacin (Systemic) 
Cinacalcet 
Paroxetine 
Ciprofloxacin (Systemic) 
Phenobarbital 
Clonidine 
Phenoxybenzamine 
Cocaine 
Phentolamine 
Colchicine 
Prazosin 
Dopamine 
Primaquine 
Doxorubicin 
Primidone 
Dabigatran Etexilate 
Rituximab 
Delavirdine 
Rifampin 
Dexmedetomidine 
Ritonavir 
Dihydroergotamine 
Rivaroxaban 
Doxazosin  
Rizatriptan 
Dronedarone 
Stiripentol 
Dyphylline 
Silodosin 
Epinephrine (Racemic, Systemic, Oral Inhalation, 
Nasal) 
Tamsulosin 
Ergoloid Mesylates 
Terazosin 
Ergonovine 
Terbinafine (Systemic) 
Ergotamine 
Theophylline 
Everolimus 
Thiabendazole 
Fluoxetine 
Thioridazine 
Fluvoxamine 
TiZANidine  
Grass Pollen Allergen Extract (5 Grass Extract) 
Tipranavir 
Guanfacine 
QuiNIDine 
Isometheptene 
Vemurafenib 
Levonordefrin 
Vincristine 
 
 
 
 
 
 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
31
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B 
ADVERSE EVENT REPORTING 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
32
Introduction 
Clinical trials that assess interventions in the setting of hematopoietic cell transplantation 
is challenging as the number of expected AEs is high. The Blood and Marrow Transplant 
Clinical Trial Network (BMT CTN) has established an AE capture approach specific for 
transplant trials. This approach has the objective of optimizing the capture of AEs by 
reducing the noise-signal ratio and identifies AEs that are not expected after transplant or 
overlaps with manifestations of common complications, such as GVHD or graft failure.  
 
Definitions 
 
Adverse Event (AE) - Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product, medical treatment or 
procedure and which does not necessarily have to have a causal relationship with this 
treatment. An AE can considered therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, medical treatment or procedure whether 
or not related to the medicinal product. AEs are expected in the HCT population. 
 
Expectedness: An adverse event can be Expected or Unexpected  
• Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event 
list, the Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk. 
• Unexpected adverse events are those that vary in nature, intensity or frequency 
from information in the current adverse event list, the Investigator’s Brochure, the 
package insert, or when it is not included in the informed consent document as a 
potential risk. 
 
  
Life-threatening Adverse Event – Any adverse event that places the patient or subject, 
in view of the investigator or treating physician, at immediate risk of death from the 
reaction. Study toxicities are graded using the adapted NCI Common Toxicity Criteria 
(where appropriate use the criteria for transplant patients.)  
  
  
• Serious Adverse Event (SAE) – Any adverse event occurring that results in any of the 
following outcomes: 
• death – regardless of cause 
• life-threatening adverse event (see above) 
• persistent or significant disability/incapacity 
• congenital anomaly 
• requires intervention to prevent permanent impairment or damage 
 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
33
AE Grading: All AEs that occur in this protocol will be graded according to the NCI 
Common Terminology Criteria for Adverse Event (CTCAE) v 4.0.  
 
AE Reporting: Depending on the type, severity and whether it is expected, each AE will 
need to be reported in an appropriate timeline to MCW IRB, Data Safety and Monitoring 
Committee and FDA (if applicable for studies under an Investigational New Drug [IND] 
protocol).   
 
 
Adverse Events Reported to the DSMB 
All adverse events that are classified as grades 3 to 5 will be reported to the DSMC. The 
differences are the timing and amount of information associated with each.  
 
The two-tier approach collects adverse events at specific time points during the trial 
(calendar-driven) and event-driven upon knowledge of an event deemed serious (grades 3 
to 5) or unexpected to be seen in a transplant setting.  
 
Grades 3-5 Adverse Events 
For the calendar-driven collection of toxicity, the protocol mandates collection of toxicity 
on a form that captures most of the most important toxicities observed post transplant. 
The forms would capture all the AEs that occur in a preceding period, for example day 28 
toxicity form, collects all the AEs that occurred from enrollment to day 28 and the grade 
of each AE. This first period includes all non-hematologic toxicity, since it is expected 
significant hematologic toxicity will occur immediately post transplant as an effect of the 
transplantation. Hematologic toxicity will be capture when it occurs beyond day 28 post 
transplant.  
 
Unexpected Grades 3-5 
The threshold for collection of adverse events outside the calendar forms is related to the 
grade (grades 3-5) and expectedness related to the transplant procedure or possibly 
related to the study drug. These events are required to be reported to the DSMC in a more 
immediate time frame and also require more information. For any adverse event that 
meets these criteria, the report would require a narrative of the event, associated 
laboratory and imaging information, associated medications and any relevant source 
documents. These reports are uploaded into Oncore and we will notify the DSMC chair 
and MCW IRB within 24 hours or 3 to 5 calendar days depending on the severity of the 
event.  Both the PI and the CTO BMT Section leader will be responsible to review and 
determine if an event meet criteria prior to uploading it in Oncore.   
 
Reporting timelines: 
1. Fatal  (grade 5) or Life Threatening events must be reported within 24 hours 
but not later than 3 calendar day of the investigator’s observation or awareness of 
the event.  
2. All other events grades 3-4 unexpected events (non-fatal/non life-threatening) 
must be reported within 3 to 5 calendar days of the investigator’s observation or 
awareness of the event. 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
34
 
 
The proposed method outlined here follows the same requirements from MCW IRB for 
prompt reporting of an event or Unanticipated Problem Involving Risks to Subjects or 
Others (UPIRSO): which is defined as any incident, experience, or outcome that meets 
all of the following criteria: 
1. Unanticipated (in terms of nature, severity, or frequency) given (a) the research 
procedures described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document, instructions for 
Use/Device Manual and or Investigator’s Brochure; and (b) the characteristics of 
the subject population being studies; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research ) or test article; and  
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
DSMC Reporting 
 
The table below summarizes the reporting practices from the study to the DSMC. For the 
ongoing review of an opened trial, the DSMC will receive a report that includes in a 
tabular form all the grades 3 to 5 that occurred in the trial, summarized according to 
reporting periods: for example 0-28d, 28-56d, 56 to 100d, 100-180d, 180-270d, 270 to 
365d and 0-365d. Additionally the report will include all the unexpected grades 3-5 that 
occurred in trial participants since activation of the trial and lastly the number of patients 
who met the graft failure stopping guidelines.  
 
For the unexpected grades 3 to 5, upon knowledge of the event, this will be discussed 
with the study PI and the CTO BMT section leader. If this fulfills criteria for expedited 
reporting to the DSMC and IRB, a narrative will be uploaded in Oncore and the DSMC 
will be notified, either through its secretary or directly to the Chair.  
 
Stopping Rules 
• 
Unexpected SAEs attributable to drug in excess of 20% would be unacceptable. 
If more than 2 out of the first (or subsequent) 10 participants enrolled in the trial 
experience a SAE resulting in life threatening complications/death, the trial will be 
stopped. 
 
 
 
 
 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
35
 
 
 
 
All Grades 3-5 
Unexpected Grades 3-5 
Type of collection 
Calendar-driven 
Event-driven 
Reporting format 
Tabular or graphical format 
Narrative with supporting 
documents 
Timing of reporting 
Biennial basis - cumulative 
Within 3 to 5 calendar days 
from knowledge of the 
event and cumulative in a 
biennial basis.  
 
 
 
 
 


Propranolol and Gene Expression in HCT                                                 Protocol v3.0, January 15, 2016 
 
36
 
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ICF_001.pdf: 
EFFECTIVE 
 
3/14/2016 
 
MCW/FH IRB
Medical College of Wisconsin & Froedtert Hospital  
  
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00024391  
IRB Approval Period: 3/14/2016 – 6/21/2016  
Page 1 of 12 
Version: 01-15-16 
Medical College of Wisconsin and Froedtert Hospital 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Name of Study Subject: ____________________________ 
 
 
RANDOMIZED CONTROLLED PILOT STUDY USING PROPRANOLOL TO 
DECREASE GENE EXPRESSION OF STRESS-MEDIATED BETA-ADRENERGIC 
PATHWAYS IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS 
 
 
Jennifer Knight, MD 
Department of Psychiatry 
414-805-6800 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee WI 53226 
 
You are invited to take part in this research study. This form tells you why this research 
study is being done, what will happen in the research study, possible risks and benefits 
to you, your choices, and other important information. If there is anything that you do not 
understand, please ask questions. Then you can decide if you want to join this study or 
not.   
 
A1. INTRODUCTION – WHY ARE WE ASKING YOU ABOUT THIS STUDY? 
You are being invited to participate in this research study of a common medication, 
propranolol, because you have multiple myeloma and are planning on receiving an 
autologous hematopoietic stem cell transplant (more commonly, a transplant of stem 
cells from your peripheral blood).  This study is looking at how a common medication, 
propranolol, might improve your body’s response to the transplant and your cancer 
outcome. 
 
A total of about 40 people are expected to participate in this study all at the Medical 
College of Wisconsin/Froedtert Hospital. 
 
The Director of the study is Jennifer Knight, MD in the Department of Psychiatry. A 
study team works with Dr. Knight. You can ask who these people are.  
 
The National Institutes of Health, a government agency, is funding this study. 
 
A2. DO I HAVE TO BE IN THIS STUDY? 
You can decide whether to take part in this study or not. You are free to say yes or no. If 
you say no, your regular medical care will not change. Even if you join this study, you do 
not have to stay in it. You may stop at any time.  


EFFECTIVE 
 
3/14/2016 
 
MCW/FH IRB
Medical College of Wisconsin & Froedtert Hospital  
  
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00024391  
IRB Approval Period: 3/14/2016 – 6/21/2016  
Page 2 of 12 
Version: 01-15-16 
 
A research study is different from routine medical care in three ways: 1) there are extra 
risks that we will tell you about in this form; 2) you may have some extra medical tests 
and visits; 3) the study procedures, tests and visits follow a set plan that must be kept. 
 
 
A3. WHY IS THIS RESEARCH STUDY BEING DONE? 
 
Patients who have multiple myeloma and undergo autologous transplants may be at risk 
for cancer relapse.  This study is looking at whether people going through a transplant 
can and will take propranolol, a common medication that may improve cancer 
outcomes. This study looks at effects of the propranolol on your genes. This study also 
looks at how propranolol affects your body’s response to the stress of transplant as well 
as cancer outcomes. Finally, you will be asked about any feelings of depression and 
anxiety that you might have during transplant, as this may contribute to the way 
propranolol affects your cancer.  
    
B1. WHAT WILL HAPPEN IF I TAKE PART IN THE STUDY?   
 
Baseline Visits 
 
You will have medical tests and procedures to help the study doctor decide if you 
can be in the study. This is called “Screening,” which will start at your first visit to 
the study site. Whether you can be in the study will depend on the results of your 
Screening tests, disease assessments, and the judgment of the study doctor. The study 
doctor and/or the study staff will discuss this with you. Screening for this study includes 
the tests and procedures below: 
 
 Informed consent form signed 
 Your demographic, socioeconomic and medical information will be collected 
 You will be asked to complete a questionnaire about anxiety, depression and 
socioeconomic status.  This will take approximately 15 minutes to complete. 
 You will have blood taken for research samples.  
 If you are able to become pregnant you will have a pregnancy test  
 A measurement of your heart rate and blood pressure will be taken 
 We will see how you are doing  
 We will look at your medical status 
 
If you meet the requirements to enter the study and agree to participate, you can 
begin the study. 
 
 
 
 


EFFECTIVE 
 
3/14/2016 
 
MCW/FH IRB
Medical College of Wisconsin & Froedtert Hospital  
  
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00024391  
IRB Approval Period: 3/14/2016 – 6/21/2016  
Page 3 of 12 
Version: 01-15-16 
Study Conduct 
 
Because no one knows if treatment with or without propranolol is best, you will be 
“randomized” into one of the two study groups. One group will receive propranolol. The 
other group (control group) will not receive propranolol. Randomization means that you 
are put into a group by chance. It is like flipping a coin.  You will have an equal chance 
of being placed in either group. Neither you nor the study doctor can choose what group 
you will be in.  
 
Propranolol group: 
 
If you are assigned to the group taking propranolol, 1 week (7 days) before your 
scheduled transplant you will begin taking propranolol.  You will take 20 mg by mouth 
two times a day for about one week.  You will be watched closely by your study doctor 
to see how you are doing.  After approximately one week if you are not having any 
serious side effects your study doctor will increase your dose of propranolol to 40 mg by 
mouth two times a day.  If you tolerate, propranolol you will continue to take it for 4 
weeks after your transplant at which time the drug will be stopped or weaned. 
 
Control group:  
 
If you are assigned to the control group you will have your transplant as scheduled per 
your clinical care.   You will have the same blood draws and questionnaires as 
described below for both groups. 
 
No matter which group you are in you will have many of the same study visits, tests and 
procedures, but only patients in the propranolol group will receive the study drug. 
 
Summary of Study Procedures: 
 
Day -2 prior to your transplant (Both Groups) 
 
No matter which group you are in, you will have a visit 2 days before your transplant.  At 
these visits you will have the following tests and procedures: 
 
 You will be asked to bring your pill bottle to these visits (Propranolol Group Only) 
 You will be asked to complete questionnaires about anxiety and depression.  
This will take approximately 15 minutes to complete. 
 You will be asked how you are doing 
 You will have mandatory blood taken for research samples on day -2 (2 days 
before your transplant) only (described below).   
 A measurement of your heart rate and blood pressure will be taken 
 
 
 


EFFECTIVE 
 
3/14/2016 
 
MCW/FH IRB
Medical College of Wisconsin & Froedtert Hospital  
  
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00024391  
IRB Approval Period: 3/14/2016 – 6/21/2016  
Page 4 of 12 
Version: 01-15-16 
Days 7, 14, 21, 28 after your transplant 
 
 You will be asked to bring your pill bottle to these visits (Propranolol Group Only) 
 You will be asked to complete a questionnaire about anxiety and depression.  
This will take approximately 15 minutes to complete. 
 The study team will collect information from your medical record about your 
transplant 
 You will be asked how you are doing 
 You will have mandatory blood taken for research samples on day 28 after your 
transplant only (described below).   
 A measurement of your heart rate and blood pressure will be taken 
 
If you are in the control group day 28 will be your last study visit. 
  
Days 35 and 42 after your transplant (Propranolol Group Only) 
 
 You will be asked how you are doing  
 
At your next clinic appointment after stopping Propranolol (Propranolol Group Only) 
 You will be asked to bring your pill bottle and return any unused study medication  
 A measurement of your heart rate and blood pressure will be taken 
  
Day 100 after your transplant 
 
 We will check your medical record to see how your disease is responding to the 
transplant 
 
Propranolol group weaning 
 
When you are done with the study treatment phase (28 days after your transplant) or if 
you have side effects that require you to stop taking your study drug, propranolol, you 
will begin weaning.  If you are currently taking the 40 mg dose twice daily, you will be 
weaned to the 20 mg dose twice daily for one week before stopping completely.  If you 
are on the 20 mg dose twice daily you will be stopped completely.  
 
Research Samples 
 
As part of this study, 3 tubes of blood (approximately 2.5 mL each) will be taken for 
research. These will occur: approximately 1-2 week prior to transplant, two days prior to 
your transplant, and 4 weeks after transplant. These samples will be used to see if the 
propranolol is causing a change in protein production.   
 
Genetic testing is done on blood and other specimens. In this study, we will do genetic 
testing on your blood. Genetic testing will be done to determine whether propranolol 


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IRB Approval Period: 3/14/2016 – 6/21/2016  
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impacts your genes and how your body responds to the stress of your hematopoietic 
stem cell transplant.  This genetic study is for research only. The purpose is not to 
discover information that could be used to change your medical care, make or change 
your diagnosis, or advise you on your risk of diseases.  
 
Only your study number will be included with your blood sample. The study team will 
have the code that links your study number to your blood sample.  The study team will 
make every effort to protect the information and keep it confidential, but it is possible 
that an unauthorized person might see it. Depending on the kind of information being 
collected, it might be used in a way that could embarrass you. It is against federal law 
(GINA) for health insurance companies to deny health insurance, or large employers to 
deny jobs, based on your genetic information. But the same law does not protect your 
ability to get disability, life, or long term care insurance. If you have questions, you can 
talk to the study doctor about whether this could apply to you. 
 
My decision about the genetic study 
Initial either 1 or 2: 
1.____I do NOT want genetic testing done on my blood in this study. This means that I 
cannot participate in the study.   
 
Stop here and speak to Dr. Knight.  Do not sign this form. 
 
2.____I agree to have genetic testing done on my blood in this study. 
 
B2. HOW LONG WILL I BE IN THE STUDY? 
 
You will be in this research study for approximately 17 weeks. 
 
B3. CAN I STOP BEING IN THE STUDY?   
You are free to withdraw from the study at any time. If you leave, your regular medical 
care will not change. If you are thinking about leaving, please tell the study doctor.  
⇒ The doctor can tell you about the effects of stopping, and you and the doctor can talk 
about what follow-up care would help you the most. 
⇒ You will be asked to come back for one more visit to check your health. 
⇒ You will be asked to return your research drug containers. 
 
The study doctor may take you out of this study at any time. This would happen if: 
• 
They think it is in your best interest. 
• 
You do not follow the study rules. 
• 
The whole study is stopped. 
If this happens, the study doctor will tell you. 
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE STUDY? 
 
There are risks to taking part in any research study. There is a risk that you may get an 
intervention that does not help your condition or may make it worse.  There also may be 


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Template A - Version: May 1, 2014 
 
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IRB Approval Period: 3/14/2016 – 6/21/2016  
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problems (side effects) we do not know about yet, from the drug itself, or how it 
combines with other drugs you are taking. If we learn about new important side effects, 
we will tell you.  
 
We watch everyone in the study for problems (side effects). You need to tell the study 
doctor or a member of the study team immediately if you experience any 
problems, side effects, or changes in your health.  If you have any problems, call 
your transplant physician. In an emergency, call 911. 
 
C2. RISKS OF PROPRANOLOL 
The research drug itself may cause problems (side effects).  Side effects may be mild or 
very serious.  Some can last a long time or never go away.  Many go away soon after 
you stop taking the drug. Drugs can affect individuals in different ways. Complications of 
some of the side effects below may lead to life-threatening events such as slow or 
irregular heart rate and allergic reactions. 
 
o Rare 
 Dizziness or passing out 
 Hard stools (constipation) 
 Loose stools (diarrhea) 
 Upset stomach or throwing up 
 Feeling sleepy 
 Feeling tired or weak 
 Not able to sleep 
 
o Rare but serious adverse events that have been reported  
 Chest pain that is new or worse 
 Change in thinking clearly and with logic 
 Hallucinations 
 Memory problems or loss 
 Mood changes 
 A burning, numbness, or tingling feeling that is not normal 
 Change in eyesight 
 Shortness of breath, a big weight gain, swelling in the arms or legs 
 Any bruising or bleeding 
 Slow heartbeat 
 A heartbeat that does not feel normal 
 Feeling cold 
 Low blood sugar, signs may include dizziness, headache, feeling 
sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, 
or sweating. 
 A very bad skin reaction (Stevens-Johnson syndrome/toxic 
epidermal necrolysis) may happen.  It can cause very bad health 
problems that may not go away, and sometimes death.  Get 
medical help right away if you have signs like red, swollen, blistered 


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Template A - Version: May 1, 2014 
 
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IRB Approval Period: 3/14/2016 – 6/21/2016  
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or peeling skin (with or without fever), red or irritated eyes, or sores 
in your mouth, throat, nose, or eyes. 
 In some cases if you stop taking propranolol all of a sudden you 
may develop chest pain that is worse and in some cases a heart 
attack may occur.  This risk may be greater if you have certain 
types of heart disease.  To avoid side effects, do not stop taking 
propranolol all of a sudden, you want to slowly stop this drug as 
ordered by your doctor.    Call your doctor right away if you have 
new or worse chest pain or if other heart problems occur. 
 
o Allergic Reactions 
 Allergic reaction, such as rash; hives; itching; red, swollen, blistered 
or peeling skin with or without fever; wheezing; tightness in the 
chest or throat; trouble breathing or talking; unusual hoarseness; or 
swelling of the mouth, face, lips, tongue or throat 
 
In some cases if you stop taking propranolol all of a sudden you may develop chest pain 
that is worse and in some cases a heart attack may occur.  This risk may be greater if 
you have certain types of heart disease.  To avoid side effects, do not stop taking 
propranolol all of a sudden, you want to slowly stop this drug as ordered by your doctor.    
Call your doctor right away if you have new or worse chest pain or if other heart 
problems occur. 
 
C3. OTHER RISKS OF THIS RESEARCH STUDY 
 
Blood Samples: 
The tests done at each visit are standard medical tests. The samples obtained for 
research purposes will be collected at the same time that you are having routine blood 
collections to monitor the status of the transplant and your disease. There are aspects 
often associated with having blood samples taken that can be viewed as unpleasant.  
These include may include fainting, pain and/or bruising. Rarely, there may be a small 
blood clot or infection at the site of the needle puncture. The blood pressure cuff may 
also cause discomfort or bruising to the upper arm. 
 
Confidentiality:  
Another risk may be loss of confidentiality. Every effort will be made to keep your study 
records confidential but we cannot guarantee it. Depending on the kind of information 
being collected, if your study information were accidentally seen, it might be used in a 
way that could make you uncomfortable or affect your ability to get insurance. If you 
have questions, you can talk to the study director about whether this could apply to you.  
 
 
 
 
 


EFFECTIVE 
 
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Medical College of Wisconsin & Froedtert Hospital  
  
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00024391  
IRB Approval Period: 3/14/2016 – 6/21/2016  
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C4. REPRODUCTIVE RISKS 
 
Risks to women who could become pregnant 
 
The drug in this study might affect a baby, before or after the baby is born. We do not 
know if the drug causes harm to a baby, so we do not want anyone who might be 
pregnant to enter the study. You should not become pregnant or nurse a baby while in 
this study. You must tell the study doctor right away if you think you are pregnant. You 
will be asked to have a pregnancy test to be sure you are not pregnant at the start of the 
study.  
 
Risks of fathering a child 
 
You should not father a baby while taking part in this study because it is unknown if the 
drug in this study could affect a baby. If your partner is able to become pregnant, one or 
both of you must use some form of effective birth control.  You must tell the study doctor 
right away if you think your partner is pregnant. 
 
Birth control methods for all subjects 
 
Check with the study doctor about the birth control methods needed for this study and 
how long to use them. Some methods might not be good enough for this study. If you 
are having sex that could lead to pregnancy, you should use birth control while you are 
in this study.   
This may include: 
 Not having vaginal sex (abstinence) 
 Taking birth control pills orally 
 Having birth control shots or patches such as Depo-Provera 
 Surgical sterilization (hysterectomy or tubal ligation) 
 Use of an intrauterine device (IUD) 
 Use of diaphragm with contraceptive jelly 
 Use of condoms with contraceptive foam 
 Use of diaphragm with condoms (“double barrier”) 
 Limiting sexual activity to a male partner who has had a vasectomy 
 
You should continue using birth control for 30 days after stopping the Propranolol. 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE STUDY? 
 
This study may or may not help you, but we hope the information from this study will 
help us develop better treatments for controlling cancer progression. 
 
 
 


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Informed Consent for Research 
Template A - Version: May 1, 2014 
 
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IRB Approval Period: 3/14/2016 – 6/21/2016  
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D1. ARE THERE ANY COSTS TO BEING IN THE STUDY? 
 
The medical care you receive in this study is considered routine care for your condition 
and would be recommended whether you join the study or not.  Costs for routine care 
will be billed to you or your insurance carrier.  Activities / costs that are part of the study 
will not be billed to you or your insurance company. These are the questionnaires, 
research only blood draws, processing and shipment of research samples and the study 
drug propranolol. Some insurers will not pay for drugs, tests or hospitalization that are 
part of research studies, so check with your insurer before you join this study. If you 
have questions regarding study costs, please contact Dr. Knight. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE STUDY? 
There is no payment for being in this study. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this study. You are free to say yes or no. If you do not join this 
study, your doctor can discuss other healthcare choices with you.  
Your other choices may include: 
• 
You may continue to transplant without participation in this study 
• 
Joining a different research study 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE STUDY? 
 
If we learn any important new information about the drug that might change your mind 
about being in the study, we will tell you about it right away.  You can then decide if you 
want to stay in the study. 
 
D5. WHAT HAPPENS IF I AM HARMED BECAUSE I TOOK PART IN THE STUDY?  
 
If you have been following directions, the injury is directly related to the research, and 
not the result of an underlying condition, then MCW will compensate you for the injury. 
 
If you think you have been injured because of this study, let the study doctors know right 
away by calling 414-805-6800. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
 
• 
If you have more questions about this study at any time, you can call Jennifer 
Knight, MD at 414-805-6800 
• 
If you have questions about your rights as a study participant, want to report any 
problems or complaints, obtain information about the study, or offer input, you can 
call the MCW/Froedtert Hospital Research Subject Advocate at 414-955-8844. 
 
 


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Informed Consent for Research 
Template A - Version: May 1, 2014 
 
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IRB Approval Period: 3/14/2016 – 6/21/2016  
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E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this study? 
To do this research study, we need your permission to collect and use some of your 
health information, or you cannot be in the study. This information may come from 
questions we ask, forms we ask you to fill out, or your medical record, as described 
below. We will only collect and use information needed for the study.  
 
The health information to be collected and used for this study is:  
• 
Hospital/ Medical Records 
• 
Biological Samples 
• 
Questionnaires 
 
E2. Who will see the health information collected for this study? 
The only MCW/Froedtert Hospital employees allowed to handle your health information 
are those on the study team, those on the Institutional Review Board (IRB) and those 
who check on the research activities to make sure the hospital’s rules are followed. 
 
The study team may share your information with people who don’t work at 
MCW/Froedtert Hospital because they planned, pay for, or work with us on this study.  
The federal Privacy Rule may no longer protect your health information once it leaves 
MCW/Froedtert Hospital.  For this study, we plan to share information with those 
doctors, researchers or government representatives working with us on this study at the 
institutions or companies listed here: 
 
      U.S. Food and Drug Administration, Rockville, MD  
Any Independent ethics committee, which approved this study 
Any Data Safety Monitoring Board appointed to review this study 
Other Regulatory Agencies and/or Their Designated Representatives 
UCLA Social Genomics Core Staff 
Those required by law 
We may record your research information, including results of tests and procedures 
done for research, in your Froedtert Hospital and/or Medical College of Wisconsin 
medical record.  As a result, this research information may be seen by people allowed 
to see your medical records for healthcare operations or treatment, by those you allow 
to see your medical records by giving written permission, and by others when required 
by law. 
 
We will not use your personal health information for a different study without your 
permission or the permission of a hospital research review board (IRB). Once all 
personal identification is removed, the information might be used or released for other 
purposes without asking you. Results of the study may be presented in public talks or 
written articles, but no information will be presented that identifies you. 
  
 
 


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Medical College of Wisconsin & Froedtert Hospital  
  
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00024391  
IRB Approval Period: 3/14/2016 – 6/21/2016  
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E3. What are the risks of sharing this health information? 
One risk of taking part in a research study is that more people will handle your personal 
health information collected for this study. The study team will make every effort to 
protect the information and keep it confidential, but it is possible that an unauthorized 
person might see it. Depending on the kind of information being collected, it might be 
used in a way that could embarrass you or affect your ability to get insurance. If you 
have questions, you can talk to the study doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this study? 
If you sign this form, we plan to keep your information without any end-date in case we 
need to check it again for this study. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health 
information, you need to send a letter to Jennifer Knight, MD at Medical College of 
Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. The letter must say that 
you have changed your mind and do not want the researcher to collect and share your 
health information. At that time, we may decide that you cannot continue to be part of 
the study. We may still use the information we have already collected.  
 
F1. FOR MORE INFORMATION ABOUT THE STUDY 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
You can look up this study by referring to the ClinicalTrials.gov number (NCT02420223) 
or by asking the study team for a printed copy.    
 
 


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Medical College of Wisconsin & Froedtert Hospital  
  
Informed Consent for Research 
Template A - Version: May 1, 2014 
 
IRB Protocol Number: PRO00024391  
IRB Approval Period: 3/14/2016 – 6/21/2016  
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CONSENT TO PARTICIPATE IN THE STUDY 
 
By signing my name below, I confirm the following: 
• 
I have read (or had read to me) this entire consent document.  All of my questions 
have been answered to my satisfaction. 
• 
The study’s purpose, procedures, risks and possible benefits have been explained to 
me.   
• 
I agree to let the study team use and share the health information and other 
information gathered for this study. 
• 
I voluntarily agree to participate in this research study.  I agree to follow the study 
procedures as directed.  I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please 
keep it where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature
Date   
 
 
 
Name of Legally Authorized 
Representative (if applicable)  
please print  
Signature of Legally Authorized 
Representative 
Date 
 
 
 
Name of Witness (if applicable) please 
print  (for short form consent process, or 
consent of blind or illiterate subject) 
Signature of Witness 
 
Date 
 
 
 
* Name of person discussing/ obtaining 
consent please print  
Signature of person 
discussing/obtaining consent 
Date 
* A member of the study team trained and authorized by the Principal Investigator to act on her/his behalf 
in obtaining informed consent according to the protocol.  In all research study protocols the Principal 
Investigator is responsible and accountable for the study.