Evaluating Patient-Reported Outcomes Monitoring in Routine Care of Patients With Chronic Myeloid Leukemia for Increasing Adherence and Clinical Response to THerapY: The EMPATHY Pilot Study
Phase: NA
Conditions: Leukemia, Chronic Myeloid, Cancer
Sponsor: Northwestern University

 
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STUDY TITLE: 
Evaluating Patient-Reported Outcomes Monitoring in Routine Care of Patients 
with Chronic Myeloid Leukemia for Increasing Adherence and Clinical Response 
to THerapY: The EMPATHY Pilot Study 
 
PRINCIPAL INVESTIGATOR: 
Name: David Cella, Ph.D. 
Department: Medical Social Sciences, Northwestern University Feinberg School 
of Medicine 
 
Name: Fabio Efficace, Ph.D.  
Department: Outcomes Research Unit, GIMEMA Foundation (Italian Group for 
Adult Hematologic Diseases), Rome, Italy;  
Medical Social Sciences, Northwestern University Feinberg School of Medicine 
 
 
 
CO-INVESTIGATORS: 
Name: Betina Yanez, Ph.D. 
Department: Medical Social Sciences, Northwestern University Feinberg School 
of Medicine 
Name: Vamsi Kota, MD 
Department: Hematology and Oncology, Augusta University 
 
 
  
FUNDING SOURCE:  National Cancer Institute (Grant Number: 1R21CA230367-
01A1) 
 
 
 
VERSION DATE: 
2/7/2020 
 
NCT NUMBER: NCT04384848 
 
 
 
 

 
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Check any applicable boxes in the table below – you will be asked for 
further detail on these topics later in the protocol form: 
 
Indicate Vulnerable 
Population(s) to be Enrolled 
☐ Children  
☐ Cognitively Impaired Adults   
☐ Pregnant Women (IF the research activities will affect   
the pregnancy or the fetus) 
☐ Prisoners (or other detained/paroled individuals)  
 
International Research 
(check this box if you will 
collect data from 
individuals located outside 
the United States) 
 
 
☒ 
Research involving external 
collaborators (some 
research activities will be 
carried out by individuals 
not employed by 
Northwestern or NU 
affiliates) 
 
 
 
☒ 
 
Research has U.S. Federal 
government funding (e.g., 
NIH, NSF, other federal 
agencies/departments) 
 
☒ 
 
 
 
 

 
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1.0 
Purpose of the study: 
 
In less than two decades, clinical outcomes of patients with chronic myeloid leukemia 
(CML) treated with oral tyrosine kinase inhibitors (TKIs) have dramatically improved 
compared to previous standard chemotherapies. Life expectancy of these patients now 
approaches that of the general population. However, therapy is now lifelong and patients 
are required to take medication daily and typically experience multiple and diverse 
adverse effects (AEs) which persist over time and negatively affect adherence to therapy, 
healthcare utilization, cost, and health related quality of life (HRQoL). 
Several studies have documented the problem of non-adherence to oral TKI therapies in 
CML, clearly documenting that symptomatic AEs are the most frequent cause of 
treatment non-adherence. This has major clinical implications, as empirical evidence 
demonstrates that full exposure to TKI treatment schedule, is necessary to maximize 
response to therapy. Systematic collection of Patient-Reported Outcomes (PRO) in 
routine practice in other cancer conditions has shown several advantages, including the 
enhancing of treatment tolerability and resulting adherence. A key question that remains 
unanswered is whether systematic collection of relevant PRO information in routine 
CML care will result in improved adherence to TKI therapy and associated treatment 
effectiveness, including improved HRQoL. 
 
We propose to assemble a network of treatment sites across the US (Northwestern 
University and Augusta University) and Italy (Italian Group for Adult Hematologic 
Disease, “GIMEMA”), with the goal of developing and piloting a tailored monitoring 
intervention targeting symptomatic, patient-reported AEs in CML patients undergoing 
first-line TKI therapy. The tailored monitoring intervention will draw primarily from the 
PRO-CTCAE Item Library, with additional items drawn from the FACIT and EORTC 
Item libraries as necessary. In all cases, items will be selected based on two criteria: 1) a 
side effect observed (any grade) in >10% of patients based on clinical trial reports of 
monotherapy administration; and 2) available in approved and certified English and 
Italian versions. After identifying the full set of AEs to be monitored, we will load the 
patient assessment and report program into tablets for electronic administration in the 
busy clinic setting. We will then pilot a six-month intervention aimed to monitor and 
manage emerging AEs, coupled with assessment of intervention feasibility, patient 
acceptability and satisfaction, provider acceptability and clinical management utility, 
adherence to TKI therapy, and HRQoL. 
 
We expect that adherence to therapy, clinical response, and HRQoL will be enhanced by 
such an intervention. However, before testing this in a large international randomized 
controlled trial (RCT), we propose to demonstrate the intervention’s feasibility and 
acceptability across three treatment organizations spanning the US and Italy. We 
anticipate that systematic monitoring of PRO in CML routine care is broadly acceptable 
to patients and physicians, practically feasible and capable to facilitate clinical 
management. Our proposed plan will investigate preliminary evidence of the efficacy of 
systematic monitoring of patient-reported symptomatic AEs in CML practice, in terms of 
self-reported adherence and pill count, HRQoL (including fatigue), and clinical response 
to therapy. Most importantly, this proposed study will demonstrate the ability of this 

 
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network to work together on a common project in order to best inform the development 
of a large international RCT. 
 
Our specific aims for this intervention development and feasibility pilot study are: 
 
1) To develop an online platform for systematic monitoring of patient-reported AE 
assessment that is tailored to the unique demands of TKI therapy for CML.  
 
2) To assess patient and physician acceptability and satisfaction with use of this platform 
in CML routine practice and evaluate its value in improving symptom management, 
HRQoL, adherence to therapy as well as preliminary efficacy.  
 
We hypothesize that systematic collection of PROs in routine practice of CML patients 
will enhance patient-physician communication, enabling physicians to more promptly 
adopt strategies to reduce dose, address side effects, or switch to another TKI, before 
treatment becomes ‘too burdensome’. Ultimately, we expect this approach will positively 
influence treatment outcomes. In this pilot study, we will also explore clinical responses 
as secondary outcomes according to predefined international criteria. 
 
 
2.0 
Background / Literature Review / Rationale for the study: 
 
CML is a hematopoietic disorder characterized by the malignant expansion of bone 
marrow stem cells, with the presence of a reciprocal translocation between chromosomes 
9 and 22 resulting in the fusion gene, BCR-ABL a constitutively activated tyrosine 
kinase, which is present in virtually all patients with CML1. This knowledge led the 
development of a number of orally active small molecule TKIs that inhibits BCR-ABL 
kinase activity2-4. Since the introduction of TKIs, clinical outcomes of patients with CML 
have dramatically improved compared to previous interferon (IFN)-based standard 
chemotherapies2. Indeed, life expectancy of these patients now approaches that of the 
general population5.  
 
Although TKIs have revolutionized CML therapy, patients are required to take 
medication daily since therapy is lifelong, and TKIs produce unpleasant, often chronic 
side effects that must be managed in routine care. Considering the chronic nature of TKI 
administration and the fact that patients are to be on treatment indefinitely and assume the 
drug on a daily basis, even low grade AEs have been found to significantly interfere with 
daily functioning and negatively affect HRQoL6-8.  
 
Remarkably, empirical data in CML research indicates that AEs are the most frequent 
cause for non-adherence to TKI therapy9. There is convincing evidence that full 
adherence to TKIs therapy is a critical factor to obtain and maintain an optimal response 
to therapy10,11. Importantly, it has also been found that early response to therapy (i.e., at 
3-month assessment from start of therapy) is the most important factor in predicting long-
term outcomes10. Therefore, there is urgent need to develop effective strategies that may 

 
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facilitate medication-taking behaviors (possibly from the very beginning of therapy), to 
boost drug effectiveness and maximize chance to obtain optimal long-term outcomes.  
Despite compelling evidence of the need to improve adherence to TKI therapy in order to 
improve clinical outcomes in CML10-12, intervention studies aimed at this goal are 
lacking13. Our proposed study is innovative in the following ways: 1) it will assemble a 
comprehensive list of symptomatic AEs relevant for the CML population under TKI 
therapy; 2) it will develop an online platform specifically devised to monitor patient-
reported AEs in CML; 3) it may establish a new model for routine CML care that could 
increase treatment-free remissions (TFRs). Finally, a major innovation of this proposal is 
its international element, across Italy and the Unites States, allowing us a window to 
explore cultural variation in response to the intervention. 
 
In this regard, another major point of innovation of our proposed research is the potential 
to establish a new model of routine CML care that could maximize clinical response (by 
increasing adherence to therapy) and eventually offer the possibility to stop lifelong TKI 
treatment to a greater proportion of CML patients. Also, considering, the high costs of 
TKI therapies, which currently impose a substantial financial burden to many CML 
patients and healthcare systems14, any research effort aimed at maximizing chances to 
TFR, such as the one proposed in this application, may have major implications in 
reducing healthcare costs. 
 
Ultimately, according to previous findings showing that an ‘integrated’ patient-centered 
approach of PRO evaluation in clinical practice is feasible and associated with a number 
of benefits15-17, we plan to conduct a large international RCT to investigate whether 
prospective and systematic electronic PROs collection in newly diagnosed CML patients 
improves clinical response to therapy and long-term patient outcomes.  
The intervention that will be piloted is the real-time collection of patient-reported AEs 
during clinical visits, with real-time feedback to treating physicians who will then have 
this data available, already at the time of consultation. 
 
3.0 
Inclusion and Exclusion Criteria: 
 
Patient inclusion criteria will include:  
 
1) Diagnosis of Philadelphia chromosome positive and/or BCR-ABL positive CML 
confirmed by cytogenetic and/or molecular analysis; 
 2) Newly diagnosed chronic phase (CP)-CML patients planned to receive one of the 
three TKI approved as first line treatment (i.e., imatinib, dasatinib or nilotinib);  
3) Adult patients (≥18 years) at the time of study entry; Children under the age of 18 will 
be excluded from the study. The exclusion of children is justified by the following 
circumstances: a) The condition is relatively rare in children, as compared to adults; b) 
Issues of study preclude direct applicability of hypotheses and/or interventions to both 
adults and children. 
4) Written informed consent.  
5) Written informed consent from patient’s physician as a participant. 

 
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5) Newly diagnosed chronic phase (CP)-CML patients who are within 4 weeks of first 
line TKI therapy (any of the three TKI approved in the USA and Europe, that is: imatinib, 
dasatinib or nilotinib). 
6) Ability to read/converse in English (Northwestern University and Augusta University 
sites). Ability to read/converse in Italian (GIMEMA site). 
 
Patient exclusion criteria will include:  
1) Major cognitive deficits or psychiatric problems hampering a self-reported evaluation; 
2) Having received any CML treatment prior to therapy with imatinib, dasatinib or 
nilotinib for more than three months. 
 
This project will focus on CML, which affect both men and women. Therefore, there are 
no exclusion/inclusion criteria based on sex/gender. In addition, there are no 
exclusion/inclusion criteria based on race and ethnicity. 
 
Physician inclusion criteria will include:  
1) Provider of clinical care for patient who meets inclusion criteria for the study 
 
Please note that physician consent is requisite for the patient to be enrolled as a 
participant in the study. 
 
4.0 
Sample Size: 
 
Sample size is based on the available resources for conducting this study. We define the 
adherence rate (AR) as the overall proportion of pills taken out of those prescribed, from 
baseline to six months, averaged over the number of pill-count assessments. Based on 
adherence rates reported by previous works10,18, we defined 72% as a minimum threshold 
of AR (H0). In order to detect at least 85% of AR (H1), with power of 80% and 2.5% 
type I error probability (one sided exact test for binomial proportions), we will need 84 
patients. However, considering overall 11% of attrition rate, 94 patients are actually 
required. 
 
 
5.0 
Recruitment and Screening Methods: 
 
Each study site will follow the same recruitment and screening methods.  
 
Study staff at each site will have IRB/HIPAA compliant approval to access electronic 
medical records (EMR) systems and will be able to pre-screen patient medical records 
prior to the patient visits. Once a patient is identified as potentially eligible based on the 
EMR pre-screen, research staff will discuss the case with the attending physician and 
medical staff and obtain approval prior to making contact with the patient. Data extracted 
from the medical records during the pre-screen will be destroyed at the earliest 
opportunity for patients that do not consent to participate in the research study. To ensure 
HIPAA compliancy, each potential participant will first be approached or contacted by 
his or her physician or a member of the treatment team who will explain the study. 

 
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Potentially eligible newly diagnosed patients will be consecutively invited to in the 
designed research location at the earliest convenience. Once the patient provides written 
informed consent, they will be asked in the waiting room (just before each scheduled 
clinical visit), to complete the newly developed touch-screen PRO-CML Survey. At the 
time of enrollment, the local clinical research staff member will register the participant in 
the CHES platform, which will generate a login ID and password enabling the participant 
to log in to CHES. The clinical research staff member will instruct each patient to 
complete self- reported questions via tablet computers. The appointed clinical research 
staff member will provide technical assistance to patients, if necessary, but will not be 
allowed to provide assistance in symptom rating. At each clinical visit, a tablet computer 
will be brought to participants, possibly in a private area of clinic waiting rooms to 
complete the survey. The clinical research staff member will bring the participant’s 
CHES log-in information up on the tablet, enabling the participant to log in and complete 
the survey. 
 
For physician participants, once a patient is identified as potentially eligible based on the 
EMR pre-screen, research staff will discuss the case with the attending physician and 
medical staff and obtain approval prior to making contact with the patient. Each potential 
physician participant will be approached by a member of the research team who will 
explain the study and obtain written informed consent. Potentially eligible newly 
physician participants will be consecutively invited to participate at the earliest 
convenience.  
 
Inclusion of women 
 This project will focus on Chronic Myeloid Leukemia, which affects both men 
and women. There are no exclusion/inclusion criteria based on sex/gender. 
Therefore, 50% of the sample will be women and 50% of the sample will be 
men approximately. In the event that we have over-representation of either men 
or women, we will over-recruit to have a roughly equal distribution of men and 
women. 
 
Inclusion of minorities 
Subject recruitment will be performed by the Northwestern Medical Group, the 
GIMEMA Research Network and Augusta University. There are no 
exclusion/inclusion criteria based on race and ethnicity. Patient population will 
reflect the diversity of the general population of the recruiting centers. 
Concerning the U.S. population, we will enroll a sample that is representative of 
the U.S. population. Approximately 17% of the US population identifies as 
Hispanic/Latino, 13% identifies as Black or African American, and 5% 
identifies as Asian. Therefore, we will enroll a minimum of 15% of participants 
who identify as Hispanic/Latina (8% women, 7% men) and another 15% (8% 
women, 7% men) who identify as Black/African American and another 4% will 
identify as Asian. We will monitor recruitment on a weekly basis to ensure that 
our sample is representative of the US population. In the event that our sample is 
not representative, we will work with the Northwestern Medicine enterprise data 

 
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warehouse to identify racial/ethnic minority patients and over-recruit minorities 
to ensure their representation in our sample. 
 
 
6.0 
Research Locations: 
 
1. Northwestern University 
 
Robert H. Lurie Comprehensive Cancer Center Comprehensive Cancer Center 
(RHLCCC)  
The Robert H. Lurie Comprehensive Cancer Center of Northwestern University provides 
state-of-the art therapies and comprehensive cancer care to patients in two modern 
outpatient clinical cancer center locations. The outpatient Clinical Cancer Center in 
Northwestern's Galter Pavilion offers leading-edge medical, surgical and radiation 
oncology treatment options, as well as access to specialized research, clinical trials and 
diagnostic services. Both locations are supported by on-site pharmacy and lab services, as 
well as a comprehensive nutrition and Supportive Oncology Program. All Lurie Cancer 
Center physicians are full-time faculty of Northwestern University's Feinberg School of 
Medicine, applying the knowledge and experience gained from clinical research and 
education to their practices at Northwestern Memorial Hospital. 9 We also have several 
connections with clinical, research, and administrative staff at the Robert H. Lurie 
Comprehensive Cancer Center. All these medical facilities have well integrated 
electronic medical record systems that will facilitate identification and recruitment of 
potential participants consistent with IRB and HIPAA guidelines. Drs. Cella, Yanez and 
Penedo will work close with the oncology clinics following similar procedures for current 
studies to facilitate access and recruitment of participants meeting study criteria. 
 
Clinical Research Resources Available to the Study Team: Access to study 
population. We have several connections with clinical, research, and administrative staff 
at the Robert H. Lurie Comprehensive Cancer Center. All these medical facilities have 
well integrated electronic medical record systems that will facilitate identification and 
recruitment of potential participants consistent with IRB and HIPAA guidelines.  
 
 
2. The GIMEMA Foundation (Italian Group for Adult Hematologic Diseases)  
The GIMEMA (Italian Group for Adult Hematologic Diseases) is a non-profit research 
Cooperative Group, with a long-standing history of clinical research in haematology. It 
consists of a well established network of about 150 haematology centers throughout Italy 
(including both Community and University-based Hospitals) plus a Data Centre (located 
in Rome). The GIMEMA Data Center is in charge of centralizing data collection of any 
GIMEMA sponsored study and is also responsible, for quality assurance, management 
and statistical analysis in accordance with the highest methodological and regulatory 
standards. The GIMEMA Data Center operates according to the highest quality and 
transparent international standards of clinical research, so as certified by quality 
procedures of the European Clinical Research Infrastructure Network (ECRIN) 
(http://www.ecrin.org/en/). The scientific leadership of the GIMEMA is composed by 

 
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nine GIMEMA Research Working Parties (WPs), each of which is focused on a specific 
hematologic disease area. In addition there is also the GIMEMA Quality of Life (QoL) 
Working Party whose mission is to foster Patient-Reported Outcomes (PRO) studies in 
hematologic disease and provide assistance in the design and the conduct of any 
GIMEMA trial including a PRO component. The large and well established research 
network of centers affiliated to the GIMEMA is an asset for the successful conduct 
clinical research in patients with hematologic disease by ensuring rapid enrolment of 
patients into clinical trials. GIMEMA has been conducting clinical trials at an 
international level in collaboration with major clinical trial Groups including a long-
standing collaboration with the European Organization for Research and Treatment on 
Cancer (EORTC). 
 
GIMEMA Quality of Life (QoL) Working Party  
The GIMEMA Working Party Quality of Life (WPQoL) was set up in 2010. The mission 
of the WPQoL is to coordinate all GIMEMA studies including a PRO component. The 
GIMEMA WPQoL consists of the Advisory Board composed by five international QoL 
specialists, plus a number of persons with various professional backgrounds, including 
physicians, statisticians and administrative staff members. The GIMEMA WPQoL data 
centre has specific expertise in the design, collection and analysis of patient-reported 
outcomes (PROs) and QoL data.  
 
 
GIMEMA Research Network. The GIMEMA Medical Group is currently involved in 
about 30 clinical trials, and include about 150 hematology centers throughout Italy. 
Hospital staff is composed by highly professional medical doctors and healthcare 
providers, who guarantee a collaborative network operating across the country to assist 
the patient during the disease path. 
 
 
3. Augusta University 
The Division of Hematology/Medical Oncology at the Medical College of Georgia at 
Augusta University strives to excel in the care of patients with cancer and blood 
disorders with a focus on treatment, education, and research advancement. The division 
has witnessed continued growth, both in the inpatient and outpatient settings. The 
Hematology/Medical Oncology division provides services to the CSRA community 
through several comprehensive programs.  
 
All required permissions and/or approvals are already obtained or will be obtained at 
each research location prior to project implementation.   
 
Procedures for coordination of study activities 
Both PIs will provide scientific and administrative oversight for all proposed activities 
and scientific aims in this application including program development, procedures for 
participant recruitment and assessment, data coordination and data flow to NU. They will 
also oversee and direct integrated scientific activities across the three performance sites 
(e.g., standardization of study protocol, coordination of multi-site staff training and 

 
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research meetings). They will also be responsible for ensuring that systems are in place to 
guarantee institutional compliance with US laws, EU laws, DHHS and NIH policies and 
regulations including protection of human subjects, data concerns and facilities. 
  
Dr. Cella will serve as contact PI and in that role, serve as the primary contact person in 
correspondence with NCI. He will assume responsibility for maintaining communication 
with the NIH and submission of annual reports, after obtaining input of Dr. Efficace. Dr. 
Efficace will serve as scientific project director surrounding the development of the 
intervention and its associated clinical report. He will also be responsible for training 
implementation and supervision of psychosocial assessment and intervention procedures, 
assuring standardization across sites and coordination of data transfer to NU. Cella and 
Efficace together will be responsible for recruitment and will finalize outcome measures 
and ensure quality data collection, as complete as possible. Both PIs will collaboratively 
share responsibility for local standardization of intervention procedures (Cella in US and 
Efficace in Italy), and coordination/standardization of all other scientific activities across 
sites. PIs Cella and Efficace will work together to discuss any changes in the direction of 
the proposed research and the redirection of funds, if necessary. A publication policy will 
be established based on the relative scientific contributions of the PIs and other key 
personnel.  
 
 
Procedures for data collection and safeguard 
The sources of research material obtained from participants will be the participants 
themselves in the form of medical history and patient-reported data. Participants will 
furnish demographic and psychosocial information and patient-reported outcomes. We 
will also collect medical treatment and disease characteristics (e.g., type of treatment, 
time since diagnosis, etc.). Medical treatment and disease characteristic information will 
be collected via chart review by our research team under procedures established in prior 
work. All material will be obtained exclusively for research purposes and in full IRB and 
HIPAA compliance. All sources of information will be coded using a special participant 
number, which precludes it being matched with identifying information. Because all our 
participants will be individuals treated for CML, the issues surrounding confidentiality 
are of supreme importance. The participants will sign a statement attesting to their 
understanding that the information they provide will be held as personal and confidential 
to the extent permitted by law. Access to the computer data files will be by password 
codes. The list matching participant number to identifying information will be maintained 
in a locked drawer in the office of the PI. Additionally, in order to be able to track 
participants across the longitudinal period of the project, we will keep a separate record 
of each participant’s address, telephone number and contact person information. This 
record will indicate whether or not a participant has completed an assessment but will not 
include information concerning their assessment or intervention performance. 
Participants will be made explicitly aware at the time of the informed consent of the 
nature of the two separate records that will be kept.  
 
Patient assessment and report program will be loaded into tablets for electronic 
administration in the clinic setting. The CHES platform enables this administration with 
an already existing web-based software. Therefore, the CHES web-based platform, will 

 
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be used by all participating sites in order to ensure standardization of PRO assessment 
and outcomes interpretation. At each site, a clinical research staff (CRS) member will be 
appointed to undergo a standardized 20/30 minute, web-enabled teleconference before 
initiation of enrollment to learn how to use the secure online platform system. Treating 
physicians also will be trained to use the web-based platform and interpret graphical 
display of outcomes. Participating sites will be assessed for wireless internet connectivity 
in clinic waiting areas and also wireless tablet computers will be provided to sites if 
needed. 
 
Northwestern Memorial Hospital has an electronic medical records (EMR) management 
system that will be accessed by our staff consistent with IRB/HIPAA guidelines as we 
have in our prior studies. Procedures across all recruitment sites follow similar 
approaches and our approach encompasses a highly integrated recruitment relationship 
between the medical professionals at each location and our research staff. All medical 
facilities have well integrated electronic medical record systems that will facilitate 
identification and recruitment of potential participants consistent with IRB and HIPAA 
guidelines. All psychosocial data, participant tracking and flow, and intervention data 
will be collected via CHES ( for further details: Provisions to Protect the Privacy and 
Confidentiality of Participants and the Research Data).  
 
GIMEMA Data Center has well integrated electronic medical record systems that will 
facilitate identification and recruitment of potential participants consistent with IRB and 
HIPAA guidelines. In addition, the GIMEMA WPQoL has a specific server (QoL 
server), located at the WPQoL’s office. The server provide web services, database 
services, file storage, and print services. Server management is allowed only to specific 
IT personnel, while network access is limited to the GIMEMA WPQoL data center staff, 
and each authorized person has his unique ID and password. GIMEMA WPQoL has its 
own internal Information Technology group that manages all hardware, software, and 
support needs also for the GIMEMA WPQoL. Computers use either Windows or MacOS 
operating system and run individual firewalls and antivirus.  
All sites involved in this study by GIMEMA have well integrated electronic medical 
record systems that will facilitate identification and recruitment of potential participants 
consistent with IRB and HIPAA guidelines.  
 
Drs. Efficace, Cella, Yanez, Penedo and Kota will work close with the oncology clinics 
following similar procedures for current studies to facilitate access and recruitment of 
patients meeting study criteria. 
 
We confirm that all non-compliance with the study protocol or applicable requirements 
will be reported in accordance with local policy. 
 
 
7.0 
Multi-site Research (research that involves external collaborating 
institutions and individuals): 
 

 
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Drs. Cella and Efficace are the two Study PIs. In addition to their role as Study PIs, they 
each serve as the Site PI at Northwetsern University and GIMEMA, respectively. Dr. 
Kota is not a Study PI, but serves as the Site PI at Augusta University. He will not be 
involved in overall study oversight beyond recruitment and data collection at Augusta 
University.  
 
1) Northwestern University (Site PI: Cella) 
 Role: recruitment, consent, study-related procedures (described in greater detail 
in section 9.0), patient-reported outcome data collection via CHES, medical 
record (identifiable) data collection, de-identified data analysis and interpretation 
 
2)  GIMEMA foundation research network (Site PI: Efficace) 
Role: recruitment, consent, study-related procedures (described in greater detail in 
section 9.0), patient-reported outcome data collection via CHES, medical record 
data (identifiable) collection, de-identified data analysis and interpretation 
 
3) Augusta University (Site PI: Kota) 
Role: recruitment, consent, study-related procedures (described in greater detail in 
section 9.0), patient-reported outcome data collection via CHES, medical record 
data (identifiable) collection 
 
Reliance Agreement: We propose that Northwestern University will serve as the IRB of 
record for the Augusta University site. An IRB Authorization Agreement will be 
completed and uploaded to the application prior to the implementation of any study 
activities at Augusta University. The fully completed and signed IAA will be uploaded as 
a modification to this submission upon its arrival and following the initial approval of the 
submission.  
 
A reliance agreement is not needed for the GIMEMA site because they will be obtaining 
IRB approval externally at their site. Upon approval from GIMEMA’s IRB, the approval 
letter will be uploaded to this submission as a separate modification.   
 
8.0 
International Research (where data collection will occur outside 
the United States and U.S. territories) 
 
The study includes one international site, GIMEMA Foundation, located in Italy.  
Although Dr. Efficace has an adjunct appointment at Northwestern University, for the 
purpose of this study, he will be serving as the site PI at GIMEMA (his primary 
affiliation), not in his capacity as adjunct faculty at NU.  
 
The GIMEMA site will be obtaining IRB approval externally at their site. Upon approval 
from GIMEMA’s IRB, the approval letter will be uploaded to this submission as a 
separate modification.   
 

 
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Dr. Efficace has a strong track record in conducting patient-reported outcome data in 
Italy. We do not anticipate any cultural or literacy barriers to eligible participants at the 
GIMEMA site.  
 
All study procedures will comply with the European Union General Data Protection 
Regulations.  
 
 
9.0 
Procedures Involved: 
 
Aim 1. To develop an online platform for systematic monitoring of patient-reported AE 
assessment that is tailored to the unique demands of TKI therapy for CML.  
 
We propose to assemble a network of treatment sites across the US (Northwestern 
University and Augusta University) and Italy (Italian Group for Adult Hematologic 
Disease, “GIMEMA”), with the goal of developing and piloting a tailored monitoring 
intervention targeting side effects (i.e., patient-reported AEs) in CML patients 
undergoing first-line TKI therapy. The tailored monitoring intervention will draw 
primarily from the well-established PRO-CTCAE Item Library19, with additional CML-
specific items drawn from the FACIT20 and EORTC item21 libraries as necessary. While 
we expect that the majority of selected symptoms will be drawn from the PRO-CTCAE 
Item Library, we anticipate this might not include specific TKI side-effects. Therefore, a 
comprehensive list of items for CML patients has to be also drawn from other available 
sources (FACIT and EORTC). Items to be implemented will be selected based on two 
criteria: 1) a side effect observed (any grade) in >10% of patients based on clinical trial 
reports of monotherapy administration; and 2) available in approved and certified 
English, and Italian versions. At this stage, the main goal will be that of identifying a 
parsimonious set of items so as to reduce patient burden as much as possible. We will 
aim for a list not including more than 20 items so as to make this assessment feasible in a 
busy clinical practice. After having identified this set of relevant AEs items to be 
monitored (i.e., PRO-CML Survey), we will load the patient assessment and report 
program into tablets for electronic administration in the clinic setting. CHES enables this 
administration with an already existing web-based software. Therefore, a common web-
based platform, housed at NU, will be used by all participating sites in order to ensure 
standardization of PRO assessment and outcomes interpretation. At each site, a clinical 
research staff (CRS) member will be appointed to undergo a standardized 20/30 minute, 
web-enabled teleconference before initiation of enrollment to learn how to use the secure 
online platform system. Treating physicians also will be trained to use the web-based 
platform and interpret graphical display of outcomes. Participating sites will be assessed 
for wireless internet connectivity in clinic waiting areas and also wireless tablet 
computers will be provided to sites if needed. Aim 1 does not involve any participant 
procedures. 
 
 

 
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Aim 2. To assess patient and physician acceptability and satisfaction with use of this 
platform in CML routine practice and evaluate its value in improving symptom 
management, HRQoL, adherence to therapy as well as preliminary efficacy. 
 
If a patient is eligible and would like to participate, the consent procedures will be 
conducted and patients will be asked in the waiting room (just before the scheduled 
clinical visit), to complete the newly developed touch-screen PRO-CML Survey. Reasons 
for refusal to participate will be systematically tracked. At the time of enrollment, the 
local clinical research staff member will register the participant in CHES platform, which 
will generate a login ID and password enabling the participant to log in to CHES. The 
clinical research staff member will instruct each patient to complete self- reported 
questions via tablet computers. The appointed clinical research staff member will provide 
technical assistance to patients, if necessary, but will not be allowed to provide assistance 
in symptom rating. At each clinical visit, a tablet computer will be brought to 
participants, possibly in a private area of clinic waiting rooms to complete the survey. 
The clinical research staff member will bring the participant’s CHES log-in information 
up on the tablet, enabling the participant to log in and complete the survey.  PRO—CML 
Survey results will be feed-backed in real time to physicians who will have this data 
available (in a graphical format to ease interpretation) at the time of consultation on their 
computers. (No results related to adherence will be communicated to physicians). 
Similarly, to previous studies22, symptoms will be graded on a five-point scale from 0 
(not present) to 4 (severe). At subsequent clinic visits, patients will be reminded by a staff 
member of the opportunity to log in the system, but such logins will not be mandatory. 
Similarly, to previous studies22 whether to and how to incorporate a discussion of PRO-
CML Survey results into routine visits will be left to patient and their treating physician 
discretion. In addition, patients will be given a remote access option, enabling completion 
of the Survey at their convenience, between scheduled clinic visits at home. A clinical 
research staff member will provide participants with an envelope containing a piece of 
paper that includes the link to the study on CHES, as well as their log-in information. For 
home log-in session between visits, there will be no automatic reminders to patients. 
However, the web-system will be programmed to trigger e-mail alerts to a designated 
member of the clinical staff, whenever a patient-reported symptom will worsen by >1 
point; or will reach an absolute grade of 3. A report tracking participants’ PRO-CML 
Survey symptoms will be printed at each clinic visit for the treating physician. No 
specific guidance will be provided to physicians about what actions to take in response to 
alerts or printed symptom profiles22. We intend to provide this intervention for the first 
six months of treatment, typically covering 8-10 clinical encounters. We anticipate that 
participants will complete 8-10 surveys, which will take approximately 5-10 minutes to 
complete. The time to complete the surveys may vary since certain surveys will only be 
administered at certain time points. These surveys will be administered via tablet devices 
using CHES web-based platform. 
 
Our proposed plan will investigate preliminary evidence of the efficacy of systematic 
monitoring of patient-reported symptomatic AEs in CML practice, in terms of self-
reported adherence and pill count, HRQoL (including fatigue), and clinical response to 
therapy. Most importantly, this proposed study will demonstrate the ability of this 

 
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network to work together on a common project in order to best inform the development 
of a large international RCT. 
 
Primary Outcome Measures 
Adherence to therapy will be evaluated in two ways. These two measures are based on 
previously published recommendations23, and on empirical evidence in CML indicating 
that pill count is associated with clinical response to TKI therapy11. 
 
Pill Count Adherence to therapy (PCA): Pill count will be based on data from the 
pharmacy database and computed, for each patient and scheduled treatment period, as the 
following proportion: (number of pills delivered at Tj – number of pills returned at 
Tj+1)x100, divided by number of pills delivered at Tj  24. We will assess pill count from 
baseline to six months, averaged for each patient over the number of pill-count 
assessments. This data will be obtained from specialty oncology pharmacies in the 
treating clinics of the participating sites. We do not anticipate the need to obtain pill 
count data from entities other than the participating sites; however, should this need arise, 
we will obtain HIPAA authorization from these entities prior to any data collection 
outside of the three participating sites. 
 
Self-reported adherence to therapy: The Adherence to Refills and Medications Scale 
(ARMS) will be used to evaluate self-reported adherence25. ARMS will be assessed via 
CHES -10 at 3 and 6 months, with reassurance that treating physicians will not have 
access to results.  
 
Secondary Outcome measures 
 
Health Related Quality of life (HRQoL): The Functional Assessment of Cancer Therapy-
General (FACT-G) (version 4)26 will assess HRQoL. The FACT-G has four subscales: 
physical well-being, social / family well-being, emotional well-being, and functional 
well-being, with higher scores indicating better outcomes. Score range is 0-108). 
Selection of this questionnaire is based on its extensive use in clinical trials, and evidence 
indicating its sensitivity to improvement when using PRO in clinical practice16. This 
outcome will be evaluated at: baseline and at 3 and 6 months. 
 
Fatigue: Fatigue, a component of HRQoL, has been chosen as one of the key patient 
outcome measure in this study, given previous data indicating this is a main concern for 
CML patients receiving TKIs6,27. Fatigue will be evaluated with the PROMIS Fatigue 
SF13a28. This outcome will be evaluated at: baseline and at 3 and 6 months. 
 
Feasibility: Based on similar feasibility studies29 feasibility is considered to be 
demonstrated if 80% of participants complete online questionnaires on more than 60% of 
follow-up visits (i.e., after initial visit up to six months) including the total number of 
visits across the six months of follow up (typically 8-10 visits). Reasons for missing PRO 
collection at follow-up visits will be recorded. This outcome will be evaluated at: 3 and 6 
months. 
 

 
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Patient acceptability and satisfaction: An intervention-tailored questionnaire will be 
developed and administered using items adapted from available sources, with guidance 
provided by those that have been used successfully in similar research to assess patient 
acceptability and satisfaction29. This outcome will be evaluated at: 3 and 6 months. 
 
Physician acceptability and clinical management: After seeing each patient, physicians 
will be asked to take note (by completing a brief paper checklist) the clinical usefulness 
of the collected PRO information for the individual encounter. They will then be asked to 
summarize this information in a more structured ad hoc paper questionnaire reporting 
whether they found the PRO data valuable towards accuracy of AEs documentation, 
clinical decisions, or discussions with patients. This outcome will be evaluated at: 3 and 6 
months. 
 
Clinical response to therapy: During the first year, both European30 and US NCCN 
Guidelines31, recommend evaluation-time benchmarks (i.e., at baseline, and at 3, 6 and 12 
months) for establishing treatment efficacy. On this basis, we plan to assess TKI 
responses at 3 and 6 months in accordance with follow-up planned for this study. 
Specifically, this will be examined in two ways: 1) by inspecting the proportion of 
patients achieving treatment milestones, as defined by international guidelines30,31; 2) by 
examining time to achieve treatment response.   
 
 
Data analysis plan 
 
Primary analysis 
 
Based on H0 and H1, power and Type I error (α=0.025) as specified in the section 
“Sample size”, we define the intervention achieving an optimal adherence rate if at least 
82% of patients (n=69/84) will take at least 90% of prescribed drug (Marin D, Bazeos A, 
Mahon FX, et al. J Clin Oncol. May 10 2010). We define adherence as acceptable if at 
least 72% of patients (n=61/84) take at least 90% of prescribed drug. Thus, we will 
consider 82% and 72% as thresholds defining respectively optimal and acceptable 
adherence rates based on the actual number of enrolled patients. Proportions of TKI 
responses at three and at six months and time to achieve treatment milestones will be 
reported. We will estimate HRQoL and fatigue outcomes trajectories over time by a 
repeated measure linear mixed model, assessing possible changes from baseline by an 
overall F-test testing the null hypothesis of no difference. Reasons for missing PRO 
collection at follow-up visits will be collected as well. Based on similar studies (Basch E, 
Iasonos A, Barz A, et al. J Clin Oncol. Dec 01 2007; 25(34):5374-5380) the intervention 
will be  considered feasible if at least 80% of participants complete online questionnaires 
at more than 60% of follow-up visits (i.e., after initial visit up to six months). We will 
describe all outcomes regarding feasibility, patient and physician acceptability by 
absolute frequencies and proportions. In addition, we will use the generalized linear 
mixed model (GLMM) to investigate about possible determinants of single relevant 
aspects (items) of acceptability, both for patients and physicians. Using the same GLMM 
approach, we will estimate the impact of the initial TKI on the adherence rate, accounting 

 
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for the different subject-specific number of pill count assessments over time and for the 
within-subject correlation of measurements.  Successful management of emergent 
adverse events caused by the initial TKI does include the option of switching to a 
different TKI and we will not consider this as adherence failure. That is, we will measure 
adherence primarily as the composite use of all TKI agents. However, we will investigate 
the impact of these changes on the outcomes of interest via sensitivity analyses. We will 
assess the potential impact of initial TKI on different outcomes including this information 
as a covariate in all corresponding analyses. Unless not differently specified above, all 
the statistical tests will be two-sided with statistical significance set as p<0.05. 
 
 
10.0 Research with Vulnerable Populations 
 
Not applicable.  
 
 
11.0 Incomplete Disclosure or Deception: 
 
Not applicable.  
 
12.0 Consent Process:  
 
Potentially eligible newly diagnosed patients will be consecutively invited to participate 
in the study by a member of the medical team (e.g., physician, advanced providers, 
patient navigators) at the earliest convenience (in any case, after local ethics approval). 
The member of the medical team will inform patients about the study, handing or mailing 
a recruitment study brochure and query whether the patient would like to learn more 
about participating. When a patient expresses interest, before compilation of informed 
consent, all the information about the study will be explained in a non- technical fashion 
to patients, and they will have ample time to ask any questions to the investigator or to 
the study staff. Furthermore, patients will be asked if they have any specific questions or 
concerns about the study and they will be informed about every precaution that must to 
be taken in order to protect the privacy of patients and the confidentiality of their 
personal information. Patients younger than eighteen years old and/or having major 
cognitive deficits or psychiatric problems hampering a self-reported evaluation and the 
compilation of informed consent will be not enrolled in the study. At the time of 
recruitment, the study research assistant (RA) will obtain participants’ informed consent 
and HIPAA authorization according to IRB approved procedures. Potential subjects 
wishing to participate will be asked to read the consent and HIPAA forms in their entirety 
and will be given time to discuss the study and ask questions prior to signing. Patients 
wanting additional time may take consents home to review.  
 
Because all our participants will be individuals treated for CML, the issues surrounding 
confidentiality are of supreme importance. The participants will sign a statement attesting 
to their understanding that the information they provide will be held as personal and 
confidential to the extent permitted by law. 

 
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For patients recruited at the GIMEMA site, all consent procedures and forms will be in 
Italian. 
 
Process to Document Consent:  
The study RA will obtain participants’ informed consent and HIPAA authorization in 
writing. The informed consent document will be stored by the study RC in locked 
enclosures. It is accessible only by staff on the study team. 
 
13.0 Research with Children – Parental Permission, Child Assent, and 
Other Considerations: 
 
Not applicable. 
 
 
14.0 Waiver of Participant Signature on Consent Form: 
 
Not applicable. 
 
 
15.0 Waivers and Alterations of Consent Information: 
 
Not applicable. 
 
16.0 Financial Compensation: 
 
This study involves minimal risk to study participants, thus financial compensation for 
research related injury is not applicable. 
 
 
17.0 Audio/Video Recording/Photography 
 
Not applicable. 
 
 
18.0 Potential Benefits of this Research:  
 
The specific objectives of the proposal aim to monitor intentional and non-intentional 
reasons for not be adherent to therapy in CML patients during standard care, in order to 
more promptly adopt strategies aiming to enhance patient-medication-taking behavior 
and so improving response to therapy. This study will contribute to establishing the 
feasibility of an intervention program to improve the management of adverse events 
(AEs) among individuals diagnosed with CML. Constant physician monitoring of AEs, 
should enhance communication with patients and induce a more promptly adopt 
strategies to lessen side effects, or to switch to another tyrosine kinase inhibitors (TKIs), 

 
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before treatment becomes ‘too burdensome’. Therefore, participants could have direct 
benefits from the study intervention. Once clinical efficacy is established in a future 
RCT, findings will increase the likelihood that web-based interventions can be used to 
improve the clinical management of CML patients taking TKIs. As risks are relatively 
low and easily managed, and because benefits for participants are potentially substantial, 
the balance of risks-to-benefits are reasonable.   
 
19.0 Risks to Participants: 
Participants will incur no appreciable physical risks through participation in this study, 
though they may undergo psychological discomfort at some time points. During 
participation in our study, participants will be given CML-related information, as well as 
be asked to complete assessments of sensitive topics that may lead some to experience 
transient and mild anxiety. In addition, some participants are likely to manifest signs of 
severe symptom burden and in some rare cases, disease progression, throughout the 
follow-up component of the study. These participants are likely to experience affective 
distress. There is a slight risk of loss of confidentiality. While communications being sent 
to and from the Website are protected, there is some possibility that others may see the 
participant’s open the website. The main intervention risk is that patients occasionally try 
to access the website or participate in assessments while walking or driving using a tablet 
or Smartphone. 
 
Participants will be informed during the consenting process and throughout the study that 
they can stop at any time, that they do not have to answer any questions that may make 
them uncomfortable, and that they can withdraw their participation at any time if they so 
choose. They will be instructed to promptly contact David Cella (at Northwestern 
University), Vamsi Kota (at Augusta University), Fabio Efficace (for GIMEMA 
foundation research network ) and study staff of each site (staff will be determined later) 
with their questions and concerns. Every measure will be taken to ensure the safety of 
research participants throughout the duration of their study participation.  
 
Participants will be informed during the consenting process and throughout the study that 
they can abstain from any question that is too uncomfortable or too difficult for them, and 
that they can withdraw their participation at any time if they so choose. Participants will 
be informed during the consenting process of what they can do if they should have 
questions or concerns during study participation. They will be instructed to promptly 
contact David Cella (at Northwestern University), Vamsi Kota (at Augusta University), 
Fabio Efficace (for GIMEMA foundation research network ) and study staff of each site 
(staff will be determined later) with their questions and concerns, or if they have any 
illness or injury during their time on this study. Since some of the questions in the 
assessment packet deal with anxiety, depression, and well being, and could be answered 
in ways that signal distress, the research team will promptly report signs of distress to the 
study investigators.  
 
Participants may be withdrawn from the study without their consent under the following 
circumstances: (1) no longer meet inclusion and exclusion criteria (e.g., become 

 
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bedridden, or physical debilitation, such that study participation would not be feasible or 
would create undue hardship; leaves active surveillance protocol to receive definitive 
therapy); (2) unsuitable as group participant (e.g., verbal or physical aggression toward 
study team or other research participants); early termination of study by study P.I.  
Participants who complete the study will be sent a Thank You and Debriefing message 
via email or postal mail, explaining the details of the study and thanking them for their 
participation in the research study. They will be also given the option of receiving 
information on study results and publications that result from the study upon study 
termination.  
 
Participants may choose to withdraw from the study at any time. The withdrawal reasons 
data that participants provide will be collected for study purposes. 
 
20.0 Provisions to Protect Participant Privacy and Data 
Confidentiality: 
 
All psychosocial data, participant tracking and flow, and intervention data will be 
collected via CHES. Medical record data will also be entered in the AC platform. AC is 
securely stored at the Northwestern University (NU) Research Data Center and available 
via the web. The data management environment meets the security requirements 
identified in the Agency Automated Information Systems Security Program (AISSP) 
Handbook. AC requires use of current passwords and log-on codes to protect sensitive 
AIS (Automated Information System) data from unauthorized access: All system access 
requires a user name and password. All users who require anything more than “internet 
user” security to the NU campus network must have a unique ID assigned. The NU ID is 
used to control access to data files and applications that reside on the network. Every NU 
ID is required to have a complex password assigned. Access to AC is restricted to 
participants by means of a username and password incorporated within the participant 
registration process. Restriction to AC involves maintaining an encrypted list of current 
users and authorizations based on permissions and roles assigned to each user. NU 
provides AC administrators with secure Virtual Private Network (VPN) access. 
Operating system and database based permissions are set by the AC administrators. User 
accounts have limited system resource access. The availability and flow of data is limited 
to the security access identified and signed off by management, and is controlled by the 
database administrator who pre-defines security access levels. This ensures that only data 
necessary for that individual’s work function are viewable. All requests are validated 
before attempting to submit data to the database. Any internal or stored reference to a 
participant is accomplished through a unique identifier key. Data is stored and accessed 
in full compliance with institutional IRB and governmental regulations regarding privacy 
and security. NU has a secure data center that houses all servers. This center is limited to 
authorized employees via the use of a card swiping system and biometric reader on the 
entrance doors. 
 
21.0 Data Monitoring Plan to Ensure the Safety of Participants: 

 
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This study involves minimal risk to study participants. Risks associated with website use 
and walking or driving will be managed by informing the participants that they are not 
permitted to use the phones while driving and very minimal use while walking or driving. 
The data safety and monitoring board (DSMB) will be chaired by Dr. Laurie Wakschlag 
(who is otherwise not associated with the project), and will include Drs. Sofia Garcia. 
Judith Moskowitz, and Susan Yount (also not associated with the project). The DSMB 
will meet annually. Occurrence of serious adverse events (e.g., hospitalization, injury, or 
death of a study participant) will be discussed at weekly project meetings at each site. 
Adverse events will be documented, logged and submitted to the NU-IRB in writing 
within 10 working days as mandated. The PI will review data safety quarterly, and a 
cumulative report will be submitted to the IRB on an annual basis as required for 
continuing review and/or final report. Interim study analyses for the purpose of 
discontinuing the study will only be conducted if during a review of adverse events it 
seems that risks or complications appear to be greater than those originally stated. If the 
PI suspects that an unusual number of adverse events is occurring, our Statistician in 
collaboration with Ms. Beaumont, Manager of the Quantitative Methods Core, 
Department of Medical Social Sciences at NU (not associated with the study), will break 
the condition assignment and participant identifier code and determine if the adverse 
events occur significantly more frequently in any one condition. The DSMB will be 
convened at this point (in addition to biannual meetings) to address unexpected 
complications. As the potential source of adverse events is likely to come from 
psychosocial assessment, our statistician will attempt to assess any relationship between 
these factors and adverse events. In the unlikely event of such analyses, the IRB will be 
kept informed of the results in a timely manner. Moreover, all the IRB will be notified 
within one working day of any temporary or permanent suspension of the study protocol.  
 
22.0 Long-term Data and Specimen Storage and Sharing:  
 
All data is kept in encrypted and password protected files on a locked Northwestern 
University network. Participant names and all other identifying information are kept in a 
separate, locked and protected location Data will be stored for a period of five years after 
the study results have been published. At this point any paper-based data will be shredded 
and electronic data will be deleted. Data may be released to a third party if required by 
law (e.g., court order). All data will be kept in encrypted and password protected files on 
a locked Northwestern University network. Participant names and all other identifying 
information are kept in separate, locked and protected locations to ensure participant 
identity cannot be linked to their study data.  
 
The subcontract Institutions agree to transfer to NU Research Data Center the study 
database in the existing format (SAS, ASCII) and according to the applicable national 
law and regulations. 
 
23.0 Qualifications of Research Team to Conduct the Research: 

 
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HRP-583 / v05062019 
 
Key investigators on this project are Prof. David Cella (mPI) and Prof. Fabio Efficace 
(mPI), who have been collaborating on common projects32,33. Also, Prof. Efficace has a 
primary appointment in a National Cooperative Group in Italy (GIMEMA) which has a 
long-standing experience of clinical research in CML and will actively be involved in this 
study. Prof. Efficace also holds an appointment as, Adjunct Professor, in the Department 
of Medical Social Sciences (MSS) at Northwestern University (NU) lead by Prof. Cella. 
Other investigators from the Department of MSS with expertise in health outcomes 
research, include Prof. Betina Yanez and Prof. Frank J. Penedo. Other key clinical 
(hematologists) investigators include: Prof. Vamsi Kota, from Augusta University (USA) 
and Prof. Michele Baccarani, an internationally renowned CML expert (Chair of the 
GIMEMA CML Working Party, Italy), whom will provide invaluable clinical expertise 
for the successful conduct of the project.  
 
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