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Study PI and Chair: Heather Jim, PhD Moffitt Cancer Center, Tampa, FL

Randomized Placebo-Controlled Trial of Bupropion for Cancer-Related Fatigue (a.k.a . The PEP Study). Study PI and Chair: Heather Jim, PhD Moffitt Cancer Center, Tampa, FL Study Co-Chair: Luke Peppone , PhD, MPH University of Rochester Cancer Center, Rochester, NY. Study Aims.

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Study PI and Chair: Heather Jim, PhD Moffitt Cancer Center, Tampa, FL

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  1. Randomized Placebo-Controlled Trial of Bupropion for Cancer-Related Fatigue(a.k.a. The PEP Study) Study PI and Chair: Heather Jim, PhD Moffitt Cancer Center, Tampa, FL Study Co-Chair: Luke Peppone, PhD, MPH University of Rochester Cancer Center, Rochester, NY

  2. Study Aims • Determine efficacy of bupropion compared to placebo in improving fatigue • Examine effects of bupropion on depression, quality of life • Assess tolerability of bupropion • Explore effects of bupropion on symptomatology, cognition • Explore effects on putative mechanisms (cytokines, cortisol slope) • Explore association of CYP2B6 genotype on bupropion metabolism and changes in fatigue

  3. Eligibility Criteria • At least 18 years of age • Female • Diagnosis of Stage I-III breast cancer • Currently breast cancer free • Report moderate to severe cancer-related fatigue in the past week (i.e., score of 4 or greater on 0-10 scale) • Attribute fatigue to cancer or its treatment (Screening Measures, question 2) • Completed surgery, radiation, standard-dose chemotherapy, and/or targeted therapy 12-60 months previously (eligible if on current hormonal therapy) • Read and speak English • If childbearing age, must agree to use adequate contraception* *barrier method, hormonal contraception, or abstinence • Capable of providing written informed consent

  4. Exclusion Criteria • Another medical condition in which fatigue is a prominent symptom (e.g., anemia, autoimmune disease, sleep apnea) • Currently taking Zyban, anti-depressant, anti-psychotic, systemic anti-TNF agent, systemic corticosteroid • Participants who completed treated with these agents at least one week prior are eligible (two weeks for MAOI inhibitor) • History of renal impairment (i.e., glomerular filtration rate <45) • History of cirrhosis (i.e., Child-Pugh score >5) • History of seizures • History of bulimia or anorexia nervosa • Report sensitivity to bupropion • Report a lactose allergy • Documented psychiatric or neurological disorder that would interfere with participation • Current pregnancy or breastfeeding or planned within next four months

  5. Study Schema Screening, Consent, Baseline Questionnaires, Blood Draw, Randomization N=422 participants Randomization: 50/50, block of 4 or 8, stratified by study site, previous receipt of chemotherapy, current hormonal therapy Arm 1: Bupropion XL (150 mg/capsule) n=211 Week 1: 1 capsule Weeks 2-12: 2 capsules Week 13: 1 capsule Week 14: 0 capsules Arm 2: Placebo (lactose supplement) n=211 Week 1: 1 capsule Weeks 2-12: 2 capsules Week 13: 1 capsule Week 14: 0 capsules Week 12: End of study assessment

  6. Screening and Approach • Participants identified through appointment schedule • Initial eligibility assessed through medical chart review and consultation with treating physician • Final eligibility determined by participant report • Fatigue score of >4 on 0-10 scale • Participant attributes fatigue to cancer

  7. Enrollment • Sign consent • Complete blood draw • Complete baseline questionnaire packet • Provide saliva collection supplies, instructions, diary, and prepaid mailer • Randomize participant • Provide study drug if possible • Participants can pick up their study drug at a later date (ie. When dropping off saliva collections & diary)

  8. Baseline Questionnaires • Participant Information • Participant Contact Form • On study form (sociodemographics) • FACIT-F (Fatigue) • MDASI (Symptomatology) • ISI (Insomnia) • IPAQ (Physical activity) • PROMIS (Cognition and Depression) • Symptom Interference • Saliva Diary/Health Behavior Questionnaire *All questionnaires must be completed at the Baseline visit*

  9. Blood Collection • For serum cytokines, leukocyte gene expression, CYP2B6 genotype (baseline only), bupropion metabolites (final only) • Kits will be provided • Collection: preferably done in AM • One 10 ml red top, one 10 ml purple top, one 2.5 ml PaxGene Blood RNA tube • Complete blood requisition form • Blood draw does not have to be fasting

  10. Blood Requisition Form: Baseline

  11. Blood Processing: Baseline • Red-top: processed for serum, aliquotted • Purple-top: rocked 10 times, frozen for batch shipping • PaxGene RNA: rocked 10 times, room temperature for 2-24 hours, frozen for batch shipping

  12. Blood Processing Guide: Baseline

  13. Saliva Collection • Baseline: Three times a day for three days after randomization • Week 12: Three times a day for the three days leading up to Week 12 visit • Upon waking before getting out of bed • 4:00-6:30 pm • Bedtime • Salimetrics passive drool and diary – kits will be provided • Reminders: texting preferred, also email and phone call

  14. Text Reminders: Mosio • Texting will be scheduled using Mosio: a two-way mobile messaging platform enabling research staff to deploy automated alerts and engage in two-way text messaging communications. Texts will not contain protected health information (PHI) • Participants can opt for text reminders for saliva collection • The night before saliva collection at 7:00 pm • Twice each day of collection: at 4:00 pm and 7:00 pm • After the collection period ends: once every three days (at 7:00 pm) to mail their saliva samples and diary until they notify the research associate that they have been mailed, up to seven mailing reminders (e.g., on day 1, day 4, day 7, up to day 20). • Required information for texting will be collected through the Participant Contact Form on REDCap

  15. Phone Call Reminders • Phone call reminders will be made the day before saliva collection begins • Also on 1st and 3rd day of saliva collection • After completion of saliva collection period, phone call reminders will be made every 3 days • Up to 7 total reminder calls • Or after participant confirms saliva samples have been mailed

  16. Emailed Reminders • Emailed reminders will be sent the day before saliva collection begins and every day during saliva collection period • After completion of saliva collection period, emailed reminders will be sent every 3 days • Up to 7 total reminder emails • Or after participant confirms saliva samples have been mailed

  17. Saliva Collection Instructions

  18. Saliva Diary • Participants should fill out 1 Diary (3 pages) per day • Need 3 Diaries (9 pages total) at each time point

  19. Saliva Sample Collection and Storage Each row should hold samples from the same participant and collection period. Do not mix participants and time points within rows. • Participants will be given a postage-paid mailer to mail back Baseline samples • Participants will need their Week 12 kits mailed 1 week prior to visit

  20. Bupropion Administration • Study drug is started after saliva collection is completed (4 days after Baseline visit) • Participants will be instructed to take: • 1 capsule every morning during week 1 • 2 capsules every morning weeks 2-12 • NO capsules taken morning of Week 12 Visit • Will take 2 capsules (regular dose) after their visit is completed • After Week 12 visit is complete, participants will taper to 1 capsule every morning for 1 week after visit (week 13) • Study drug discontinued by week 14

  21. Week 12 Study Visit • Attempted from all randomized participants • Mail saliva collection supplies at least one week prior to Week 12 study visit • Saliva supplies and diaries returned at visit • Phone call, email, or text reminder • IMPORTANT: participant should not take study capsule on morning of study visit – will take regular doseafter visit has been completed • Complete questionnaires • Complete blood draw: AM preferred • Pill count

  22. Week 12 Questionnaires • FACIT-F (Fatigue) • MDASI (Symptomatology) • ISI (Insomnia) • IPAQ (Physical activity) • PROMIS (Cognition and Depression) • Symptom Interference • Adherence Questionnaire • Saliva Diary/Health Behavior Questionnaire *All questionnaires must be completed at Week 12 visit*

  23. Blood Requisition Form: Week 12

  24. Blood Processing: Week 12 • Red-top: processed for serum aliquots • Purple-top: processed for plasma aliquots • PaxGene RNA: rocked 10 times, room temperature for 2-24 hours, frozen for batch shipping

  25. Blood Processing Guide: Week 12 CLEAR TOP (PAXGENE) RED TOP (SERUM) PURPLE TOP EDTA (PLASMA) Gently rock 10x to mix Gently rock 10x to mix Allow to coagulate 30 minutes at room temperature in upright position Place in upright container at room temperature for a minimum of 2 hours and a maximum of 24 hours Spin for 15 minutes at 1600 g (at 0-4 C if possible) Place in upright container at -20 C for a minimum of 72 hours Aliquot using provided pipette Red top tube gets aliquoted into pre-labeled pink 2.0 mL microfuge tubes Purple top tube gets aliquoted into pre-labeled purple 2.0 mL microfuge tubes Put in a blue URCC18007 Study Freezer Box on side and store at -20 C or -80 C if available (-80 C is preferred) Store in a blue URCC18007 Study Freezer Box at -20 C or -80 C if available (-80 C is preferred)

  26. Adverse Event Reporting • Assessed by phone at weeks 4, 8, and 14 • Assessed at Week 12 study visit • All adverse events should be documented by coordinator and kept onsite • Described and graded using CTCAE version 5.0 • Grade 1/2 AE that were Unrelated/Unlikely not reported to URCC • All other AE reported to URCC NCORP Research Base via REDCap

  27. Adverse Event Reporting • Any mania, hypomania, psychosis or seizure must be immediately reported to treating oncologist and URCC NCORP Research Base – they will contact medical monitor team to determine whether dose reduction or study drug discontinuation is warranted • Suicidality must be reported immediately to the participant’s treating oncologist and URCC NCORP Research Base, who will contact the medical monitor team to determine if immediate hospitalization is warranted • If immediate hospitalization is not warranted: participant will be provided suicide hotline information, a family member will be notified and a direct referral will be made to a local psychiatrist. • Actions taken in response to suicidality will be documented by the site research associate • Other expedited reporting:

  28. Off-Agent • Participants may stop study agent due to: • Completing intervention • Adverse or serious adverse event • Inadequate supply of study agent • Noncompliance • Participants who elect to stop the intervention should taper study drug • Participants will continue to be followed, if possible, for safety reasons and to collect endpoint data according to the schedule of events

  29. Reimbursement • Participants will receive • $35 per completed assessment • $5 per saliva sample (9 potential samples per time point) • Bonus $20 per assessment if blood and saliva samples are collected accurately • Checks will be mailed to participants from Moffitt • Participant addresses will be collected through Participant Information form in REDCap • URCC NCORP Research Base: keeps track of completed assessments and samples as submitted • Moffitt: will be reimbursing participants directly through mail - based on research base information

  30. Questions?

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