A Pragmatic Randomised, Multicentre Trial Evaluating the Dose Timing (Morning vs Evening) of Endocrine Therapy and Its Effects on Tolerability and Compliance (REaCT-CHRONO)
Phase: PHASE4
Conditions: Breast Cancer
Sponsor: Ottawa Hospital Research Institute

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A pragmatic randomised, multicentre trial evaluating the dose timing 
(morning vs evening) of endocrine therapy and its effects on tolerability 
and compliance (REaCT-CHRONO Study). 
Coordinating Centre: 
Principal Investigator: 
Support Centre: 
Principal Investigator : 
Thunder Bay Regional Health Sciences Centre 
Mohammed Ibrahim, MD 
Thunder Bay Regional Health Sciences Centre 
Ottawa Hospital Research Institute and the 
Ottawa Hospital Cancer Centre 
Marie-France Savard, MD, FRCPC 
The Ottawa Hospital Cancer Centre 
Co-Investigators:   
Mark Clemons 
Lesley Fallowfield  
Gregory Pond 
Kednapa Thavorn 
Ana-Alicia Beltran-Bless 
Funding provided by: NOAMA Innovation Grant (2021) 
Clinical Trial Registration: NCT04864405 
Protocol Date: 12 Sept 2021 
Amendments: 2 

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PROTOCOL SIGNATURE PAGE 
 
My signature below confirms that I have reviewed and approved this protocol and agree 
that it contains all necessary details for carrying out the study as described. I will conduct 
this protocol as outlined therein, and according to Good Clinical Practice and all 
applicable local regulations 
 
 
 
 
 
 
 
 
 
 
 
 
Qualified Investigator (Please Print) 
 
 
 
 
 
 
 
 
 
 
 
Qualified Investigator Signature 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 

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Table of Contents 
1 
BACKGROUND...................................................................................................................4 
1.1 
Pragmatic trials ............................................................................................................. 8 
1.2 
Central Hypothesis or Research Question .................................................................... 9 
2 
OUTCOMES .....................................................................................................................10 
2.1 
Primary Outcome ........................................................................................................ 10 
2.2 
Secondary Outcomes ................................................................................................. 10 
2.3 
Exploratory analyses ................................................................................................... 10 
2.4 
Interim analysis / feasibility ......................................................................................... 11 
3 
STUDY DESIGN ...............................................................................................................11 
3.1 
Consent Process......................................................................................................... 12 
4 
ELIGIBILITY ......................................................................................................................13 
4.1 
Inclusion Criteria ......................................................................................................... 13 
4.2 
Exclusion Criteria ........................................................................................................ 13 
5 
STATISTICAL ANALYSIS AND SAMPLE SIZE CALCULATION .......................................13 
5.1 
Sample size ................................................................................................................ 13 
5.2 
Analysis Methods ........................................................................................................ 14 
5.3 
Randomization and Stratification ................................................................................. 16 
5.4 
Blinding ....................................................................................................................... 17 
6. TIMELINE AND FOLLOW-UP ...............................................................................................17 
7.  DATA COLLECTION ............................................................................................................17 
8. RISKS ...................................................................................................................................19 
9. PREMATURE WITHDRAWAL ..............................................................................................19 
10. MONITORING .....................................................................................................................20 
11.  FIGURES ...........................................................................................................................21 
Table 1: Study Calendar ........................................................................................................ 22 
12.  REFERENCES ...................................................................................................................23 
 
 
 

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1 
BACKGROUND 
 
Endocrine therapy in breast cancer 
Endocrine therapy is an established treatment for hormone receptor-positive breast 
cancer 1–3. Endocrine therapy can cause significant side effects with deterioration in 
quality of life4. Tamoxifen and aromatase inhibitors (e.g. letrozole, anastrozole and 
exemestane) share common side effects such as hot flashes, arthralgia/joint stiffness, 
insomnia, weight gain, mood changes, gastrointestinal symptoms, and skin and vaginal 
dryness. In addition, while tamoxifen carries a higher risk of vaginal bleeding or discharge, 
thromboembolic events and uterine cancer, the aromatase inhibitors are associated with 
an increased risk of cardiovascular events, osteoporosis and bone fractures5–7. 
 
Non-persistance or non-compliance to endocrine therapy 
The side effects of all forms of endocrine therapy are well recognised and can lead to 
treatment non-persistance or non-compliance. Compliance is defined as the degree or 
extent of conformity to the recommended administration by the provider, whereas 
persistence refers to the act of continuing treatment for a certain prescribed duration8. A 
systematic review of adjuvant endocrine treatment found that 41 to 72% of patients did 
not take the correct dosage at the prescribed frequency and 31 to 73% discontinue 
endocrine therapy9. Treatment adherence is especially important in breast cancer, as 
early cessation or reduced compliance to hormonal therapy are associated with reduced 
disease-free survival and increased mortality10,11. In order to maximize adherence, 
strategies have been used to mitigate these side effects. Regarding the hot flashes, 

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patients may benefit from lifestyle changes such as exercising and avoiding caffeine, 
alcohol as well as smoking12,13. Many nonhormonal pharmacotherapies have been used 
to try controlling vasomotor symptoms including selective serotonin reuptake 
inhibitors/serotonin-norepinephrine reuptake inhibitors antidepressants, gabapentin and 
oxybutynin13. Most recently the Oncology Nursing Society published guidelines for cancer 
related hot flashes suggesting the use of sertraline, fluoxetine, escitalopram, duloxetine 
or clonidine. However, these pharmacologic strategies to control endocrine therapy side 
effects present their own array of potential side effects and often not well tolerated 
themselves14. 
Chronotherapy 
Chronotherapy, also called chronotherapeutics, is defined as the administration of a 
medication in coordination with the circadian rhythm in order to minimize side effects and 
yield a greater efficacy15. While this concept is based on a strong mechanistic foundation 
involving xenobiotic metabolism and detoxification of drugs, only a few clinical trials, 
mainly for neurologic, behavioral and psychiatric conditions, factored in circadian timing15. 
Recently, a study demonstrated that the time of day at which antihypertensives are taken 
can impact their effectiveness16. In breast cancer, one randomized trial evaluating the 
optimal time for administering vinorelbine showed a non-statistical benefit for the 
incidence of grade 3-4 neutropenia when administered at 21:00 and grade 3-4 
gastrointestinal toxicity when administered at 10:3017. Furthermore, there is some 
evidence suggesting that the adherence to drugs might be greater in the morning as 
compared to the evening18. Many online forums exist with breast cancer patients seeking 
insight on the time of day (i.e. morning vs evening) to take their endocrine therapy19. In 

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our practice, we often see doctors and nurses using a trial and error method to help 
patients determine the best time of day at which to take their endocrine therapy to try 
reducing these side effects, with anecdotal success. Even though this clinical practice is 
not evidence-based, there is increasing molecular evidence suggesting an interplay 
between circulating estradiol and expression of circadian clock genes that may support 
this practice20. 
 
Evidence from a recent systematic review 
Our team recently conducted a systematic review to assess the evidence currently 
available regarding the circadian administration of endocrine therapy in terms of side 
effects, quality of life and disease-free survival in breast cancer patients. Ovid Medline, 
EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 
1947 to August 2020 for relevant randomized control trials or prospective cohort studies 
and off 361 unique citations identified, 0 studies met eligibility criteria.  
 
Ongoing clinical trials 
A search of the ClinicalTrials.gov database to identify all active registered trials looking at 
the best “time-of-day” administration of endocrine therapy was done on December 18, 
2020. No registered studies on this specific question were found. 
 
Clinical trial rationale 

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Although optimal time-finding trials have been conducted in other medical fields, none 
have been undertaken for hormonal therapy in breast cancer15,20. Patients and clinicians 
are relying on a trial and error approach to determine the best time of treatment with the 
goal of reducing side effects and improving QoL and adherence. However, this practice 
is neither evidence-based nor standard of care. Therefore, conducting the world’s first 
prospective randomized clinical trial to evaluate the dose timing (morning versus 
evening) of endocrine therapy and its effects on tolerability and adherence is warranted 
and needed.  
 
Clinical trial significance  
Nonadherence and discontinuation of endocrine therapy has been an important clinical 
issue given its high prevalence and its negative impact on breast cancer mortality11,21. 
New non-pharmacological interventions to improve adherence and side effect profile of 
endocrine therapy are critically needed11. Changing the time of the day at which a 
medication is taken is a new, simple, easy intervention that does not generate additional 
costs.  
 
From a patient perspective, finding a new strategy to reduce side effects associated with 
endocrine therapy will improve the quality of life of thousands of Canadian women with 
breast cancer and will help increase their compliance to endocrine therapy. Optimizing 
adherence to endocrine therapy by changing the time of the day at which it is taken will 
have a positive impact on breast cancer outcomes. Furthermore, this will reduce indirect 

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cost related to breast cancer recurrence and the use of pharmacological interventions to 
reduce side effects. 
 
1.1 Pragmatic trials 
Since 2014 the Rethinking Clinical Trials (REaCT) has been operating across Canada 
with the specific aim of performing pragmatic trials when physicians do not know what the 
“best” treatment for patients is, and genuine uncertainty (“clinical equipoise”) exists. 
Currently the choice between taking endocrine therapy in the morning or evening 
depends more on choosing between different “standards” in their personal practice, using 
idiosyncratic decision-making processes, without the physician or the patient relying on 
an evidence-based option. Determining the optimal treatment timing remains an important 
medical issue for both patients and physicians. 
 
This study will use robust methodology to allow comparisons of established standard of 
care treatment using the “integrated consent model” as part of a pragmatic clinical trial22. 
By integrating medical and clinical practices, physicians will be able to inform their 
patients about the RCT, through a typical conversation between the physician and patient, 
with oral informed consent. This clinical interaction would then be documented in the 
consult note, as ordinarily done in practice.  
 
Pragmatic clinical trials are being given increased importance, as they commonly consist 
of comparative effectiveness research, thus comparing the safety and effectiveness of 

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diagnostic, therapeutic or delivery systems. Additionally, these studies have not only the 
ability to leverage patient data from electronic health records to increase sample size of 
trials at much lower costs, but also enabling major national and international initiatives to 
generate the data needed to improve care22. As such, the Integrated Consent Model is 
being increasingly used internationally to improve patient care22,23. In fact, The Ottawa 
Hospital Cancer Centre is leading this program with over 3000 patients already enrolled 
on REACT trials at 15 Canadian Cancer Centres. These studies have shown excellent 
patient feedback with 97% of patients rating being ‘completely satisfied’ with the REaCT 
process.  
 
Thus, we propose to perform a pragmatic, multicentre, open-label, randomized clinical 
trial to establish the optimal timing (morning vs evening) of administering endocrine 
therapy based on side effects and benefits in early stage breast cancer patients.  
 
1.2  Central Hypothesis or Research Question  
Hypothesis: We hypothesize that the dose timing (morning vs evening) of endocrine 
therapy will impact side effects and benefits as assessed using the validated Functional 
Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES)24,25. 

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2 
OUTCOMES 
2.1 Primary Outcome 
• Endocrine toxicity and tolerability measured by the change in total FACT-ES score 
(a validated subscale of the FACIT measurement system) from baseline to 12 
weeks following the beginning of endocrine therapy 
2.2  Secondary Outcomes  
• Endocrine toxicity and tolerability measured by the change in total score and 
individual items of FACT-ES from baseline to 4, 8, 12 and 52 weeks following the 
beginning of endocrine therapy 
• Quality of life measured by the change in the total score and individual subscales 
of the validated Functional Assessment of Cancer Therapy for patients with a 
Breast cancer (FACT-B) questionnaire from baseline to 4, 8, 12 and 52 weeks 
following the beginning of endocrine therapy  
• Rates of discontinuation, interruption  and non-compliance (defined as patient 
taking less than 80% of the prescribed endocrine therapy)  with initially prescribed 
endocrine therapy 
• Cost-effectiveness: incremental cost-effectiveness ratios (cost per one quality-
adjusted life year (QALY) gained  
2.3 Exploratory analyses 
• Comparing rates of non-persistance or non-compliance with patient age, tumour 
stage, chemotherapy use, type of endocrine therapy 

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2.4 Interim analysis / feasibility 
An interim analysis will be performed after the first year of study initiation, focusing on 
recruitment and safety aspects only. The study will be stopped if recruitment is <80 
patients (~40% of total target) after one year or if considerable unanticipated safety issues 
arise. 
3 
STUDY DESIGN 
The study schema is shown in Figure 1. Eligible patients with hormone receptor positive 
breast cancer who will receive adjuvant endocrine therapy will be eligible for this study. 
Patients will be consented either by their treating medical oncologist or a member of their 
circle of care. Consenting patients will be randomized to one of two arms: 
 
Arm A: Morning administration of endocrine therapy defined as, within one hour 
of the patient wake up time. 
or 
Arm B: Evening administration of endocrine therapy defined as, within one hour 
of the patient bed time. 
There will be no study mandated change in either the type of endocrine therapy. 
Endocrine therapy can be started either before, prior or after radiation therapy prescribed, 
as per patients’ choice. 
Patients will be approached by their medical oncologists during routine clinic visits. In 
order to ensure trial findings are applicable to the broadest population possible, eligibility 

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criteria will be pragmatic. Patients will be assessed either as per their usual clinic visits, 
or as the study does not involve additional clinic visits, study questionnaires will be 
completed via electronic link sent via email.   The questionnaires will be built into the 
electronic database developed by the Ottawa Methods Centre and patients will receive a 
secure electronic link to complete the questionnaires at the required study timepoints. If 
patients do not have access to a computer/internet, they can request to receive paper 
copies in the clinic or by mail.   
Outcomes will be measured at:   
• Baseline (prior to start endocrine therapy) 
• 4 weeks (± 1 week) after the start of endocrine therapy 
• 8 weeks (± 1 week) after the start of endocrine therapy  
• 12 weeks (± 2 week) after the start of endocrine therapy 
• 52 weeks (± 2 week) after the start of endocrine therapy 
 
The study calendar is shown in Table 1. 
3.1 Consent Process 
 
Potential study participants will be approached by their medical oncologist at the time of 
their routine clinic visit during the aforementioned timeline. The physician will give the 
patient an Information Sheet that briefly outlines the study and answer any questions.   
Patients will be asked to provide oral consent to be randomized to one of the two pre-
specified treatment arms. This integrated consent model is akin to a typical conversation 
between the physician and patient and the interaction is documented in the patient’s 

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medical record. Written informed consent will not be sought as the integrated consent 
model is ethically acceptable as the only prominent change to the standard of care 
treatment is the randomization process and there is no evidence-based standard of care 
for dose timing of endocrine therapy. 
4 
ELIGIBILITY 
4.1 Inclusion Criteria 
 
• Patients with an early stage or locally advanced hormonal receptor positive breast 
cancer 
• Plan to receive endocrine therapy 
• Age 18 years 
• Able to provide oral consent  
• 
Willing and able to complete questionnaires as per study protocol 
4.2 Exclusion Criteria 
• Metastatic cancer  
• Previous endocrine therapy for breast cancer 
• Plan to receive adjuvant abemaciclib 
5 
STATISTICAL ANALYSIS AND SAMPLE SIZE CALCULATION 
5.1  Sample size 
Our primary outcome is the change in total FACT-ES score from baseline to 12 weeks 
following the beginning of endocrine therapy. 

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Based on Fallowfield et al., a clinically meaningful effect would be observed if the change 
exceeded 0.5 of the standard deviation at baseline and the standard deviation at baseline 
is approximately 8.525. Therefore a ‘clinically meaningful change’ from baseline to 12 
weeks would be a change of 4.25 or greater. It is also assumed that 40% of patients will 
experience a clinically meaningful change, and prescribing the time of day for 
administration of treatment would be important if there was an actual difference in 
clinically meaningful change rates of 20% or more (i.e. 40% with a clinically meaningful 
change in one arm and 60% in the other). Therefore, based on these assumptions and 
using a two-sided, alpha=0.05 Fisher’s exact test, we would need 214 total patients to 
achieve 80% statistical power. To account for potential loss to follow-up, and to account 
for stratification factors, the target sample size will be inflated by 10% to a total of 235. 
5.2 Analysis Methods 
Descriptive analysis: Baseline characteristics will be presented with means (continuous 
measures) or proportions (categorical or ordinal data) with 95% confidence intervals. 
Intention-to-treat analysis: The primary analysis will be based on the intent-to-treat 
principle, thus, all participants who are randomized will be included in the final study 
analysis. The last observation carried forward method will be used to impute results for 
any patient who is lost to follow-up, or who does not have a FACT-ES score measured at 
the 12 week time point. This is a conservative approach to imputation, as it will likely result 
in smaller differences between groups than would actually be present (if there is an actual 
difference), under the assumption that increased effects will occur over time up to week 
12. In addition, a per protocol analysis of the primary outcome measure will be conducted, 

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which will include only those patients who follow the intervention as prescribed in the 
protocol, and who complete both the baseline and 12 week FACT-ES score. 
Analysis of primary and secondary outcomes:  Dichotomous outcomes will be 
summarized according to proportions and 95% confidence intervals. Continuous 
outcomes will be summarized according to means and standard deviations or medians 
and interquartile ranges as appropriate. The primary analysis will be based on a logistic 
regression analysis with adjustment for stratification factors. Additional logistic and linear 
regression analyses will be performed with adjustment for stratum. Univariable 
comparisons between the intervention and control groups will be examined using a Chi-
Squared test for dichotomous events, and a student’s t-test for continuous measures. 
Non-parametric methods may be used in lieu of these tests as appropriate. All analyses 
will be supplemented with 95% confidence intervals where relevant. 
Health economic evaluation: We will perform a cost utility analysis alongside this 
pragmatic randomized controlled trial. Resource use and health utility values will be 
measured from the trial at the baseline and follow up interviews. We will derive health 
utility values from the European Quality of Life-5 Dimensions 5-level (EQ-5D-5L) 
questionnaire. We will develop a Markov model that represents lifetime experience of a 
patient cohort following her treatment option to predict the long-term prognosis of patients. 
The model will consist of multiple distinct states, representing breast cancer progression 
and relevant adverse events. It will also have the capacity to capture medication 
adherence. We will derive input parameters required for the model from the concurrent 
trial and the published literature. The results will be presented as incremental cost per 
quality-adjusted life year (QALY) gained and incremental cost per one endocrine toxicity 

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case averted. Both costs and outcome will be discounted at 1.5% annually. A series of 
sensitivity analysis will be undertaken to examine the effect of conducting a complete 
case only analysis and of varying input parameters. Parameter uncertainty will be 
assessed using Monte Carlo simulations with 10,000 simulations. The results of the 
simulations will be shown as effectiveness acceptability curves (CEACs), which represent 
the probability of a treatment being cost-effective to a range of potential threshold values 
that the health system may be willing to pay for an additional unit of effect.   All analysis 
will be conducted using Microsoft Excel. 
Compliance and loss to follow-up:  Supportive analyses will be performed to better 
understand the impact of non-compliance, loss to follow-up and protocol violations.  The 
primary analysis is clearly defined, and other analyses will be performed understanding 
the supportive and secondary nature of these results. Interpretation of results will be 
performed, clearly acknowledging the a priori defined primary analysis.  
 
5.3 Randomization and Stratification  
Eligible and consented patients will be randomized using a permuted block design 
developed by the Ottawa Methods Centre to receive either one of the two study arms 
(1:1). The variable block sizes will be randomly selected between sizes of 4 and 6.  
Subjects will be stratified based on: study site, tamoxifen (yes/no), and chemotherapy 
(yes/no). The patient will be randomized through a secure web-based randomization 
system on the physician’s clinic desktop or mobile device or through the designated study 
CRA. The randomization system also confirms the study eligibility criteria prior to 
randomization. The study does not involve changing the standard of care patients receive. 

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The study co-investigators (i.e. study qualified physicians) will ensure verbal consent and 
eligibility review has taken place prior to randomization. For all patients, the primary 
oncologist will dictate in the patient’s electronic medical record that the consent process 
has taken place. 
5.4 Blinding 
Patients and investigators will not be blinded to treatment allocation as the study is 
randomizing treatment schedule only. This is in keeping with a pragmatic trial design 
6. TIMELINE AND FOLLOW-UP 
We would anticipate that the study will take two years for accrual and 1 year for 
completion of follow-up on the quality of life primary study endpoint. Therefore, we would 
anticipate that the study runs for 2.5 years.  
7.  DATA COLLECTION 
Once the patient has been randomized, the study CRA will collect participant information 
on patient demographics (e.g. age), tumour characteristics (e.g. stage), surgery type, 
chemotherapy use, radiotherapy use and endocrine therapy type. From a study 
standpoint only the CRA will access this information. Data not available at the time of visit 
will be collected from the dictated physician note. CRAs will enter data into the electronic 
database developed by the Ottawa Methods Centre within the timeframes agreed in the 
site agreement.   
The physician will document any study related events either in his dictated physician note 
and will complete a Health Care Provider Questionnaire at the 12 week clinic visit and at 
52 weeks (end of study).  This questionnaire will collect study related events including: 

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compliance to dose timing (date at which patient decided to change dose time and 
reasons), discontinuation of endocrine therapy (date and reasons), switch from an 
endocrine therapy type to another one (date and type and reasons). To reflect real-world 
practice, no additional clinic visit will be required, but participants will be contacted by a 
CRA or a health care provider at 12 weeks and 52 weeks to collect compliance 
information. In addition, treating physicians are encouraged to email the CRA if at any 
time a significant event (i.e. hospitalization, recurrence or death) occurs. 
Participant data to be collected over the treatment period: 
• Treatment assignment 
• Treatment received 
• FACT-ES questionnaire for assessing endocrine therapy symptoms and FACT-B 
questionnaire for assessing quality of life. Because the first portion of the FACT-
ES and FACT-B questionnaires are the same, we will only have study participants 
complete the duplicate sections once at each time point (combined into FACT-B 
and ES questionnaire) 
• Follow up questions about compliance to endocrine therapy, compliance to dose 
timing, dose interruptions, discontinuation and reasons for discontinuation, switch 
from an endocrine therapy type to another one 
• EQ-5D-5L questionnaire for assessing health utility values to facilitate a cost-utility 
analysis 
• Timing preference questionnaire will be collected from the participant at the 
beginning and end of the study 

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If the patient is randomized and either the patient or physician refuses the randomization 
selection, reasons for this will be recorded. If physicians choose to break the protocol, 
they must inform the patient as to why the allocated selection should not be used from 
the randomization process. We will monitor the charts to ensure that this reason has been 
recorded. 
 
Participating sites will be responsible for maintaining a master list of eligible, enrolled 
patients, including first name, last name, date of birth (month and year only).  This list will 
be generated, password-protected and maintained by the research coordinator, and 
stored on the secure hospital network at each site. 
8. RISKS 
There are no incremental risks associated with this study as both arms are standard of 
care treatments. 
9. PREMATURE WITHDRAWAL 
Participants have the right to withdraw from the study treatment at any time for any 
reason. 
Investigator has the right and obligation to withdraw subjects from the study treatment in 
the event of: 
• 
Intercurrent illnesses which would, in the judgment of the investigator, affect 
assessment of clinical status to a significant degree, and require discontinuation of 
protocol therapy 

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• 
Any toxicity that would produce further harm if subject continued on the protocol 
• 
Request by the participant or of their legally authorized representative (consent 
withdrawal) 
• 
Non-compliance to the study protocol or logistic consideration 
• 
Participant is lost to follow-up 
The reason for withdrawal will be collected on the End of Study case report form so that 
it can be presented in the CONSORT diagram. 
10. MONITORING 
This study will be conducted according to the International Conference on Harmonisation 
Good Clinical Practice Guidelines.  Routine quality assurance and monitoring will be 
completed by the REaCT study team to ensure that the study is being run according to 
the protocol at each participating site. This monitoring will include: 
- 
random spot checks on inclusion and exclusion criteria to confirm that only eligible 
patients are participating in the trial 
- 
routine evaluation of source data to ensure accuracy 
- 
evaluation of the data from the first participant and corresponding source 
documents from each site (de-identified and uploaded to the REaCT SharePoint 
site) to ensure that they are being completed according to the protocol. 
The investigator(s)/institutions(s) will permit trial-related monitoring, audits, REB review 
and regulatory inspection(s), providing direct access to source data/documents as 
required. 
 
 
 

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11.  FIGURES 
 
Figure 1 Study schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligible, newly diagnosed breast cancer patients who 
will receive adjuvant endocrine therapy  
Consent template discussed with patient 
and oral consent obtained 
  Randomization in clinic 
Patient completes study questionnaires 
Physician completed Follow Up questionnaire on 
clinic visits  
(see study calendar for timing) 
Exclusion Criteria: 
• 
Metastatic cancer  
• 
Previous endocrine 
therapy for breast 
cancer 
Stratification factors: 
• 
Study site 
• 
Chemotherapy use 
• 
Endocrine therapy 
type 
Arm B: Evening dose of 
endocrine therapy 
Arm A: Morning dose of 
endocrine therapy 

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Table 1: Study Calendar  
1. To reflect real-world practice, no additional clinic visit will be required, but participants will be contacted by a CRA or a health 
care provider at 12 weeks and 52 weeks to collect compliance information.  
Event 
Screening 
 Baseline 
4 weeks  
(± 1 week) 
 
8 weeks 
(±1weeks) 
12 weeks  
(± 2 week) 
52 weeks 
(± 2 week) 
Initial assessment 
X 
 
 
 
 
 
Confirmation of Eligibility 
X 
 
 
 
 
 
Integrated Oral Consent 
X 
 
 
 
 
 
Randomized to either morning or evening dose of 
endocrine therapy 
 
X 
 
 
 
 
Questionnaires 
- 
EuroQoL-5D-5L 
- 
FACT-B and ES 
 
 
X 
X 
X 
X 
X 
Participant Follow up and compliance 
 
 
 
 
X 
X 
Timing Preference Questionnaire 
 
X 
 
 
 
X 
Health Care Provider Follow up Questionnaire1 
 
 
 
 
X 
X 

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12.  REFERENCES 
 
1. 
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 
Oncology: Breast Cancer, Version 3.2020. (2020). Available at: 
https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.  
2. 
Burstein, H. J. et al. Adjuvant Endocrine Therapy for Women With Hormone 
Receptor–Positive Breast Cancer: ASCO Clinical Practice Guideline Focused 
Update. J. Clin. Oncol. 37, 423–438 (2019). 
3. 
Cardoso, F. et al. Early breast cancer: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann. Oncol. 30, 1194–1220 (2019). 
4. 
Ferreira, A. R. et al. Differential impact of endocrine therapy and chemotherapy 
on quality of life of breast cancer survivors: a prospective patient-reported 
outcomes analysis. Ann. Oncol. 30, 1784–1795 (2019). 
5. 
Garreau, J. R., DeLaMelena, T., Walts, D., Karamlou, K. & Johnson, N. Side 
effects of aromatase inhibitors versus tamoxifen: the patients’ perspective. Am. J. 
Surg. 192, 496–498 (2006). 
6. 
Amir, E., Seruga, B., Niraula, S., Carlsson, L. & Ocaña, A. Toxicity of Adjuvant 
Endocrine Therapy in Postmenopausal Breast Cancer Patients: A Systematic 
Review and Meta-analysis. JNCI J. Natl. Cancer Inst. 103, 1299–1309 (2011). 
7. 
Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-
analysis of the randomised trials. Lancet 386, 1341–1352 (2015). 
8. 
Cramer, J. A. et al. Medication Compliance and Persistence: Terminology and 
Definitions. Value Heal. 11, 44–47 (2008). 
9. 
Murphy, C. C., Bartholomew, L. K., Carpentier, M. Y., Bluethmann, S. M. & 
Vernon, S. W. Adherence to adjuvant hormonal therapy among breast cancer 
survivors in clinical practice: a systematic review. Breast Cancer Res. Treat. 134, 
459–478 (2012). 
10. 
Chirgwin, J. H. et al. Treatment Adherence and Its Impact on Disease-Free 
Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, 
Alone and in Sequence. J. Clin. Oncol. 34, 2452–2459 (2016). 
11. 
Hershman, D. L. et al. Early discontinuation and non-adherence to adjuvant 
hormonal therapy are associated with increased mortality in women with breast 
cancer. Breast Cancer Res. Treat. 126, 529–537 (2011). 
12. 
Santen, R. J. et al. Managing Menopausal Symptoms and Associated Clinical 
Issues in Breast Cancer Survivors. J. Clin. Endocrinol. Metab. 102, 3647–3661 
(2017). 
13. 
Gupta, A. Hormone Therapy–Related Hot Flashes and Their Management. JAMA 
Oncol. 4, 595 (2018). 

12 Sept 2021 
 
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14. 
Kaplan, M. et al. ONS GuidelinesTM for Cancer Treatment–Related Hot Flashes in 
Women With Breast Cancer and Men With Prostate Cancer. Oncol. Nurs. Forum 
47, 374–399 (2020). 
15. 
Selfridge, J. M. et al. Chronotherapy: Intuitive, Sound, Founded…But Not Broadly 
Applied. Drugs 76, 1507–1521 (2016). 
16. 
Hermida, R. C. et al. Bedtime hypertension treatment improves cardiovascular 
risk reduction: the Hygia Chronotherapy Trial. Eur. Heart J. (2019). 
doi:10.1093/eurheartj/ehz754 
17. 
Coudert, B. et al. A Randomized Multicenter Study of Optimal Circadian Time of 
Vinorelbine Combined with Chronomodulated 5‐Fluorouracil in Pretreated 
Metastatic Breast Cancer Patients: EORTC Trial 05971. Chronobiol. Int. 25, 680–
696 (2008). 
18. 
Phillips, L. A., Burns, E. & Leventhal, H. Time-of-Day Differences in Treatment-
Related Habit Strength and Adherence. Ann. Behav. Med. (2020). 
doi:10.1093/abm/kaaa042 
19. 
BREAST CANCER NOW. TAMOXIFEN. Available at: 
https://breastcancernow.org/information-support/facing-breast-cancer/going-
through-treatment-breast-cancer/hormone-therapy/tamoxifen. (Accessed: 4th 
August 2020) 
20. 
Hatcher, K. M., Royston, S. E. & Mahoney, M. M. Modulation of circadian rhythms 
through estrogen receptor signaling. Eur. J. Neurosci. 51, 217–228 (2020). 
21. 
Canadian Cancer Society. Breast Cancer Statistics. Available at: 
http://www.cancer.ca/en/cancer-information/cancer-
type/breast/statistics/?region=on.  
22. 
Kim, S. Y. H. & Miller, F. G. Informed Consent for Pragmatic Trials — The 
Integrated Consent Model. N. Engl. J. Med. 370, 769–772 (2014). 
23. 
Sugarman, J. & Califf, R. M. Ethics and Regulatory Complexities for Pragmatic 
Clinical Trials. JAMA 311, 2381 (2014). 
24. 
Cella, D. et al. Quality of Life of Postmenopausal Women in the ATAC 
(“Arimidex”, Tamoxifen, Alone or in Combination) Trial after Completion of 5 
years’ Adjuvant Treatment for Early Breast Cancer. Breast Cancer Res. Treat. 
100, 273–284 (2006). 
25. 
Fallowfield, L. J., Leaity, S. K., Howell, A., Benson, S. & Cella, D. Assessment of 
quality of life in women undergoing hormonal therapy for breast cancer: validation 
of an endocrine symptom subscale for the FACT‐B. Breast Cancer Res. Treat. 55, 
187–197 (1999).