Understanding Adolescent and Young Adult 6-Mercaptopurine Adherence and mHealth Engagement During Cancer Treatment: Protocol for Ecological Momentary Assessment

Background Adolescents and young adults (AYAs) with cancer demonstrate suboptimal oral chemotherapy adherence, increasing their risk of cancer relapse. It is unclear how everyday time-varying contextual factors (eg, mood) affect their adherence, stalling the development of personalized mobile health (mHealth) interventions. Poor engagement is also a challenge across mHealth trials; an effective adherence intervention must be engaging to promote uptake. Objective This protocol aims to determine the temporal associations between daily contextual factors and 6-mercaptopurine (6-MP) adherence and explore the proximal impact of various engagement strategies on ecological momentary assessment survey completion. Methods At the Children’s Hospital of Philadelphia, AYAs with acute lymphoblastic leukemia or lymphoma who are prescribed prolonged maintenance chemotherapy that includes daily oral 6-MP are eligible, along with their matched caregivers. Participants will use an ecological momentary assessment app called ADAPTS (Adherence Assessments and Personalized Timely Support)—a version of an open-source app that was modified for AYAs with cancer through a user-centered process—and complete surveys in bursts over 6 months. Theory-informed engagement strategies will be microrandomized to estimate the causal effects on proximal survey completion. Results With funding from the National Cancer Institute and institutional review board approval, of the proposed 30 AYA-caregiver dyads, 60% (18/30) have been enrolled; of the 18 enrolled, 15 (83%) have completed the study so far. Conclusions This protocol represents an important first step toward prescreening tailoring variables and engagement components for a just-in-time adaptive intervention designed to promote both 6-MP adherence and mHealth engagement. International Registered Report Identifier (IRRID) DERR1-10.2196/32789

1 K08 CA241335-01 3 NCI-J PSIHOGIOS, A ecological momentary assessment with AYA patients and their caregivers (n=30 pairs). In Aim 2, the investigative team will begin to develop a just-in-time adaptive mobile intervention, designed to promote 6-mercaptopurine adherence in this population, by developing contextually-tailored mobile messages and decision rules about the conditions under which to deliver the messages. Just-in-time mobile interventions are well-suited to address limitations of previous interventions by providing personalized adherence support, at the right time, only when it is needed. The creation of messages and decision rules will follow a rigorous mobile health development approach by iteratively incorporating selfmanagement theory, empirical evidence, expert input, and stakeholder feedback. Focus groups with 15 AYA from Aim 1 will be conducted to user-test and refine the messages. In Aim 3, the just-in-time adaptive mobile intervention called AYA ADAPTS (Adherence Assessments and Personalized Timely Support) will be pilot tested in a micro-randomized trial with 30 newly recruited patients. AYA ADAPTS will integrate the tailored mobile messages and decision rules developed and refined in Aim 2. The research team will determine the feasibility and acceptability of this intervention in preparation for the PI's larger-scale optimization trial (R01 proposal). This proposal has methodological, theoretical, clinical, and technological innovations. The research and career development plan, supported by a multi-disciplinary team of experts in a rich academic environment, will support the PI's transition to an independent clinician-scientist who possesses the skills and expertise to use cutting-edge mobile health methods to design the most potent adherence-promotion interventions for pediatric cancer patients. This K08 will provide opportunities to acquire skills and knowledge in: (1) ecological momentary assessment and multi-level statistics, (2) behavior change intervention development applied to mobile health, and (3) the conduct of clinical trials and intervention dissemination and implementation.

PUBLIC HEALTH RELEVANCE:
Stagnant survival and relapse rates for adolescents and young adults with cancer are partially attributed to a modifiable behavior-nonadherence to cancer treatments. To address multiple calls from the NCI and other federal agencies for research targeting disparities in cancer treatment outcomes for this population, this K08 research will use novel real time mobile health methodologies to examine and intervene on the time-varying, contextual factors that influence daily oral chemotherapy adherence in adolescents and young adults with acute lymphoblastic leukemia. The proposed research and career development plan will yield critical multi-level data and a just-in-time adaptive intervention for nonadherence, with the potential for the investigator to advance adherence intervention science and improve clinical outcomes in adolescents and young adults with cancer. ! CRITIQUE: The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that critiques and criteria scores, prepared prior to the review meeting, may not have been revised following discussions at the meeting. The "Resume and Summary of Discussion" section summarizes the final opinions of the review committee.

Weaknesses
• Dr. Psihogios is very early in her career; however, this concern is mitigated by her accomplishments to date.

Career Development Plan/Career Goals & Objectives: Strengths
• Dr. Psihogios's long term goal is to become an independent clinician-scientist who improves cancer treatment outcomes in adolescents and young adults (AYA) by targeting nonadherence. • The short-term goals including gaining skills and knowledge in (1) EMA and multi-level statistics applied to AYA with acute lymphoblastic leukemia (ALL), (2) behavior change intervention development incorporating mHealth to establish methodological competencies for developing effective and engaging adherence-promotion interventions, (3) clinical trials and intervention dissemination and implementation. • The rationale, mentorship, coursework and seminars/workshops for each career goal are well delineated.

Research Plan: Strengths
• Use of a JITAI adaptive design is innovative and an appropriate method to evaluate adherence among AYA with ALL. • The proposed work is guided by the Pediatric Self-Management Model and the mobile health tool development will be guided by the BUS Framework. • Examples of the potential tailoring variables and mobile messages are provided.

Weaknesses
• The plans appear to be a bit ambitious in terms of developing the tailored messages, adapting the app to incorporate these messages and recruiting for the Aim 3 JITAI trial.

Environment and Institutional Commitment to the Candidate: Strengths
• The environment is appropriate for the proposed work. Weaknesses • None noted.

Study Timeline Strengths
• The timeline for the proposed research (and training activities) are well described.
Protections for Human Subjects: Acceptable Risks and Adequate Protections.
• Risks, protections and benefits are well described by each aim.

Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):
Acceptable.

Inclusion of Women, Minorities and Children:
• Sex/Gender: Distribution justified scientifically.
• For NIH-Defined Phase III trials, Plans for valid design and analysis: Scientifically acceptable.
• Inclusion/Exclusion of Children under 18: Including ages < 18; justified scientifically. • Appropriate and well described. Overall Impact: Dr. Alexandra Psihogios is a clinical-psychologist and a Postdoctoral Research Fellow in the Division of Oncology, CHOP, Philadelphia (2017-). The candidate's long-term goal is to become an independent clinician-scientist who improves cancer treatment outcomes in adolescents and young adults (AYA) by targeting non-adherence. To reach her research and career goal, she proposes a 5-yr K08 application. Dr. Psihogios is a stellar candidate with a strong commitment to cancer control particularly in the field of adherence intervention. The mentoring and advisory team are outstanding. The statements from the mentors clearly show their strong commitment to the candidate's success, describe the candidate's strengths and the areas needed improvements and also very clear description of the mentor's role in providing guidance and advice to achieve the candidate's career goal. The candidate also has strong institutional support and excellent research/ and training environment at CHOP-UPenn. The proposed study is innovative and well designed and has strong scientific premise.
Overall impact is high.

Candidate: Strengths
• The candidate has extensive training in pediatric psychology and an excellent track record of publications focused on children, adolescents, and young adults with a variety of chronic medical conditions (13 papers; 8 as first author and 2 book chapters). She also received numerous academic awards. • The candidate has a high potential for becoming an independent investigator. She is a PI of several pilot grants. Strong reference letters indicating this as well. • Strong motivation and commitment to meeting the program objectives to become an independent investigator in research.

Weaknesses
• No major weaknesses noted.

Career Development Plan/Career Goals & Objectives: Strengths
• The candidate's prior training and research experience are appropriate for this award.
• Very clear description of the plans for monitoring and evaluating the candidate's progress toward independence. • Nice integration of research activities, training activities with candidate's research and career goals.

Research Plan: Strengths
• The proposed study is innovative and supported with a strong scientific premise.
• Study is well-designed with alternative strategies provided for potential pitfalls.
• The proposed research is appropriate to the candidate's stage of research development and can provide her the research skills necessary as described in the CDP.

Weaknesses
• The research plan is somewhat ambitious, however, this is not a major concern because of the promising candidate and strong mentorship.

Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s): Strengths
• Mentoring committee and advisory committee have relevant and complementary research experience. • The primary mentor Dr. Lamia Barakat is a well-known researcher in psycho-oncology, and co-mentors Dr. Susan Murphy is an expert on mobile health and Dr. Lisa Schwartz is an AYA oncology researcher. • Dr. Barakat has an excellent mentoring experience and is suitable to provide mentorship in behavior intervention development and the conduct of clinical trials in the context of pediatric oncology (in addition to the mentoring and advisory committee). This is an area that was not provided in the candidate's postdoctoral training. • Very clear description of the quality and extent of the mentors' proposed role in providing guidance and advice to the candidate and also for plans for monitoring and evaluating the candidate's progress toward independence. Weaknesses • None noted.

Environment and Institutional Commitment to the Candidate: Strengths
• The Division of Oncology is fully committed to protecting 75% of the candidate's time for CDP activities. 25% will be dedicated to clinical practice in the cancer center. • Committed to promote the candidate to an Instructor in Pediatrics in June 2019, not contingent on receiving K08 award. • CHOP-UPENN environment are ideal for the candidate's proposed training and research.

Weaknesses
• No major weaknesses noted.

Study Timeline Strengths
• Study timeline for study aims is described in detail including the feasibility of research activities.

Inclusion of Women, Minorities and Children:
• Sex/Gender: Distribution justified scientifically. Overall Impact: Dr. Psihogios is a clinical psychologist completing her post-doctoral training at Children's Hospital of Pennsylvania. She seeks to leverage effective interventions that improve cancer treatment adherence in real-time among adolescent and young adult cancer patients diagnosed with acute lymphoblastic leukemia (ALL). Dr. Psihogios seeks to employ ecological momentary assessment (EMA) methodologies to obtain contextual, mood/affect and social (peer/family), physical symptoms and motivation level data from brief smartphone-based surveys combined with adherence data collected from MEMS caps. Dr. Psihogios has established a well-rounded team of mentors to provide overview and support for the proposed training and research activities. However, the training plan could be strengthened with the addition of more formal coursework over the entire CDA period. Finally, there are data collection, transfer and management and safety considerations that need to be acknowledged in the application of EMA in the proposed work.

Candidate: Strengths
• Dr. Psihogios is a licensed clinical psychologist and a post-doctoral fellow at the Children's Hospital of Pennsylvania. She has completed a MA and PhD in Clinical Psychology at Loyola University and a pre-doctoral clinical internship in pediatric psychology at Children's Hospital of Philadelphia. • Dr. Psihogios has received 2 grants to fund pilot studies on medication adherence among AYA cancer patients and a text messaging service to assess oral chemotherapy adherence. • A solid publication record that includes 13 peer-reviewed articles (8 as first author).
• Two of these publications deal with childhood/AYA cancer.

Weaknesses
• No major weakness noted.

Career Development Plan/Career Goals & Objectives: Strengths
• Dr. Psihogios seeks to gain further training in novel and timely intervention mechanisms that are relevant to AYA cancer patients by pursuing the following training goals (1) Ecological momentary assessment (EMA) and multi-level statistics applied to AYA with acute lymphoblastic leukemia (ALL) who are at-risk for nonadherence, (2) behavior change intervention development incorporating mHealth in effective adherence-promotion interventions, (3) clinical trials and intervention dissemination and implementation.

Weaknesses
• Training with Dr. Schwartz is in recruitment/retention with AYA oncology patients, but formal course work in Cancer and Health Disparities (even beyond seminars in pediatric oncology) is recommended.
1 K08 CA241335-01 9 NCI-J PSIHOGIOS, A • Dr. Psihogios proposes 1 course per year for years 1-3 and none in years 4-5; would suggest more formal, didactic coursework rather than weekly meetings/tutorials in advanced survey, study design and statistical methods to take advantage of this 5-year training period. Also consider training programs offered by NIH, such as OBSSR's Clinical Trials summer institute and other relevant trainings.

Research Plan: Strengths
• Dr. Psihogios seeks to evaluate a potentially novel and timely adherence intervention for AYA cancer patients diagnosed with acute lymphoblastic leukemia. She seeks to undertake the following research activities: (1) to conduct a 6-month EMA study with 30 AYA with ALL in the maintenance phase of treatment and their caregivers to determine the temporal associations between intrapersonal and interpersonal contextual variables and electronically-monitored 6MP adherence; (2) develop contextually-tailored mobile messages and potential decision rules for a JITAI; and (3) pilot test the JITAI in a 28-day micro-randomized trial. • This theoretically grounded and highly innovative intervention has the potential to meet the needs of AYA cancer patients and enhance medication adherence outcomes.

Weaknesses
• Will RAs review how to enter EMA data to both AYA and their caregivers? Will the app be available for both Apple and android (to name just two, but there are other devises) iOS (as well as other operating systems)? How and when will data be transferred to CHOP? • EMA data will first be collected on smartphones; will they be stored there as well? How and when will data be transferred to CHOP? Is there a secure server that data can be transferred to? Will patients be assigned unique IDs to ensure that data transfers are confidential? Please provide information on data back-up plans and also a contingency plan for storing data on smartphones in case transfers are not possible. Information on maintaining data security is required. Can patient delay their responses? What if they turn off their phones?

Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s): Strengths
• Dr. Psihogios has identified a primary mentor (Dr. Lamia Barakat), two co-mentors, (Drs. Susan Murphy and Lisa Schwartz) and four content advisors (Drs. Jean-Phillipe Laurenceau, Ahna Pai, Linda Fleisher, and Stephen Hunger). • Dr. Barakat provides expertise in psycho-oncology and behavior change interventions in pediatric populations. Dr. Murphy provides expertise in mHealth interventions and JITAI. Dr. Schwartz provides mentorship in AYA cancer. The advisory team provides collective expertise in EMA and statistical analysis of EMA data (Laurenceau), adherence and pediatric oncology (Pai), health communications (Fleisher) and pediatric ALL (Fleisher).

Environment and Institutional Commitment to the Candidate: Strengths
• Children's Hospital of Philadelphia (CHOP) is an excellent environment to conduct the proposed activities.
• The applicant has a commitment from the Division of Oncology for 75% protected time for scholarly activity. • Dr. Hunger, Division Chief of Pediatric Oncology, indicates that they have initiated the process of appointing Dr. Psihogios as an Instructor in Pediatrics, to begin in June 2019 after she completes her fellowship. Weaknesses • None noted.

Study Timeline Strengths
• Study timeline for each study aim is included and appropriately describes feasibility of study activities.
Protections for Human Subjects: Acceptable Risks and Adequate Protections.
• Description of risks and adequate protection against risks is appropriately described.

Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):
Acceptable.

Inclusion of Women, Minorities and Children:
• Sex/Gender: Distribution justified scientifically.
• For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable.
• All sex/gender, race/ethnicity, and age-based inclusion/exclusion criteria are scientifically. justified.
Vertebrate Animals: Not Applicable (No Vertebrate Animals).

Biohazards: Not Applicable (No Biohazards).
Training in the Responsible Conduct of Research: Acceptable.

Select Agents: Not Applicable (No Select Agents).
Resource Sharing Plans: Acceptable.

Authentication of Key Biological and/or Chemical Resources: Not Applicable (No Relevant Resources).
Budget and Period of Support: Recommend as Requested.