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Endocrine therapy is an established treatment for hormone receptor-positive breast cancer, but can cause significant side effects with deterioration in quality of life. The side effects of all forms of endocrine therapy are well recognized and can lead to treatment non-persistence or non-compliance. Chronotherapy, also called chronotherapeutics, is defined as the administration of a medication in coordination with circadian rhythm in order to minimize side effects and yield a greater efficacy. The investigators propose to perform a pragmatic, multi-centre, 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.
Endocrine therapy is an established treatment for hormone receptor-positive breast cancer, but can cause significant side effects with deterioration in quality of life. The side effects of all forms of endocrine therapy are well recognized and can lead to treatment non-persistence 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 duration. 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 mortality. Chronotherapy, also called chronotherapeutics, is defined as the administration of a medication in coordination with circadian rhythm in order to minimize side effects and yield a greater efficacy. The investigators propose to perform a pragmatic, multi-centre, 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Morning administration of endocrine therapy | Active Comparator | Administration of endocrine therapy defined as, within one hour of the patient wake up time |
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| Evening administration of endocrine therapy | Active Comparator | Administration of endocrine therapy defined as, within one hour of the patient bed time |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Morning administration of endocrine therapy | Other | Endocrine therapy administered within one hour of patient wake up time |
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| Measure | Description | Time Frame |
|---|---|---|
| Change in Endocrine Toxicity and Tolerability at 12 Weeks | Measured by the change in total Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaire from baseline to 12 weeks following the beginning of endocrine therapy. FACT-ES is a validated sub scale of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system. FACT-ES consists of 46 items on a 5 point Likert type scale ranging from 0 (not at all) to 4 (very much), with a total range of 0 to 184. Higher FACT-ES scores indicate better outcomes. The current outcome is a change in FACT-ES scores. | Baseline to 12 weeks after treatment initiation |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Endocrine Toxicity and Tolerability | Measured by the change in total score and individual Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaires from baseline to 4, 8, 12 and 52 weeks following the beginning of endocrine therapy. FACT-ES consists of 46 items on a 5 point Likert type scale ranging from 0 (not at all) to 4 (very much), with a total score range of 0 to 184. Higher scores indicate better quality of life. The current outcome is a change in FACT-ES scores over time. |
| Measure | Description | Time Frame |
|---|---|---|
| Rates of Non-compliance to Endocrine Therapy | Comparing rates of non-compliance and non-persistence to endocrine therapy with patient age, turmour stage, chemotherapy use and type of endocrine therapy. The rates of non-compliance and rates of non-persistence will be tracked throughout the duration of the study and then compared to patient age, tumour stage, chemotherapy use and the type of endocrine therapy used. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Marie-France Savard, MD | Ottawa Hospital Research Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Ottawa Hospital Cancer Centre | Ottawa | Ontario | Canada | |||
| Thunder Bay Regional Health Sciences Centre |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34287262 | Background | Beltran-Bless AA, Vandermeer L, Ibrahim MFK, Hutton B, Shorr R, Savard MF, Clemons M. Does the Time of Day at Which Endocrine Therapy Is Taken Affect Breast Cancer Patient Outcomes? Curr Oncol. 2021 Jul 6;28(4):2523-2528. doi: 10.3390/curroncol28040229. | |
| 40442096 | Result | Savard MF, Ibrahim M, Saunders D, Pond GR, Ng TL, Awan AA, Sehdev S, Alqahtani N, Vandermeer L, MacDonald F, Beltran-Bless AA, Fallowfield L, Clemons M. A pragmatic, multicenter, randomized trial comparing morning versus evening dosing of adjuvant endocrine therapy (REaCT-CHRONO Study). NPJ Breast Cancer. 2025 May 29;11(1):49. doi: 10.1038/s41523-025-00762-7. |
| Label | URL |
|---|---|
| The Rethinking Clinical Trials (REaCT) website | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Morning Administration of Endocrine Therapy | Administration of endocrine therapy defined as, within one hour of the patient wake up time Morning administration of endocrine therapy: Endocrine therapy administered within one hour of patient wake up time |
| FG001 | Evening Administration of Endocrine Therapy |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 12, 2021 |
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| Evening administration of endocrine therapy | Other | Endocrine therapy administered within one hour of the patient bed time |
|
| Baseline, 4, 8, 12 and 52 weeks after treatment initiation |
| Change in Health Related Quality of Life Scores | Measured by the change in the total score and individual sub scales of the validated Functional Assessment of Cancer Therapy for patients with Breast cancer (FACT-B) questionnaire from baseline to 4, 8, 12 and 52 weeks following the beginning of endocrine therapy. The FACT-B consists of 37 items on a 5 point Likert type scale ranging from 0 (not at all) to 4 (very much), with a total score range of 0 to 148. Higher FACT-B scores indicate better quality of life. The current outcome is a change in FACT-B scores over time. | Baseline, 4, 8, 12 and 52 weeks after treatment initiation |
| Number of Participants Who Were Compliant With ET | Rates of non-persistence or non-compliance with initially prescribed endocrine therapy (ET) | 52 weeks after treatment initiation |
| Cost-effectiveness | Incremental cost-effectiveness rations (cost per one quality-adjusted life year (QALY) gained). | 52 weeks after treatment initiation |
| 52 weeks after treatment initiation |
| Thunder Bay |
| Ontario |
| P7B 6V4 |
| Canada |
Administration of endocrine therapy defined as, within one hour of the patient bed time Evening administration of endocrine therapy: Endocrine therapy administered within one hour of the patient bed time |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Morning Administration of Endocrine Therapy | Administration of endocrine therapy defined as, within one hour of the patient wake up time Morning administration of endocrine therapy: Endocrine therapy administered within one hour of patient wake up time |
| BG001 | Evening Administration of Endocrine Therapy | Administration of endocrine therapy defined as, within one hour of the patient bed time Evening administration of endocrine therapy: Endocrine therapy administered within one hour of the patient bed time |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Sex (male/female) was not collected. | Count of Participants | Participants |
| |||||||||||||||
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
| |||||||||||||||
| Region of Enrollment | Number | participants |
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| Type of endocrine therapy | Participants can be counted in more than one category | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Endocrine Toxicity and Tolerability at 12 Weeks | Measured by the change in total Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaire from baseline to 12 weeks following the beginning of endocrine therapy. FACT-ES is a validated sub scale of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system. FACT-ES consists of 46 items on a 5 point Likert type scale ranging from 0 (not at all) to 4 (very much), with a total range of 0 to 184. Higher FACT-ES scores indicate better outcomes. The current outcome is a change in FACT-ES scores. | The participants who answered the FACT-ES at baseline and 12 weeks. | Posted | Mean | Standard Deviation | units on a scale | Baseline to 12 weeks after treatment initiation |
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| Secondary | Change in Endocrine Toxicity and Tolerability | Measured by the change in total score and individual Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaires from baseline to 4, 8, 12 and 52 weeks following the beginning of endocrine therapy. FACT-ES consists of 46 items on a 5 point Likert type scale ranging from 0 (not at all) to 4 (very much), with a total score range of 0 to 184. Higher scores indicate better quality of life. The current outcome is a change in FACT-ES scores over time. | The number analyzed differs from overall number analyzed because not all participants completed the questionnaires at all timepoints. | Posted | Mean | Standard Deviation | units on a scale | Baseline, 4, 8, 12 and 52 weeks after treatment initiation |
| ||||||||||||||||||||||||||||||
| Secondary | Change in Health Related Quality of Life Scores | Measured by the change in the total score and individual sub scales of the validated Functional Assessment of Cancer Therapy for patients with Breast cancer (FACT-B) questionnaire from baseline to 4, 8, 12 and 52 weeks following the beginning of endocrine therapy. The FACT-B consists of 37 items on a 5 point Likert type scale ranging from 0 (not at all) to 4 (very much), with a total score range of 0 to 148. Higher FACT-B scores indicate better quality of life. The current outcome is a change in FACT-B scores over time. | The number analyzed differs from the overall number of participants analyzed because not all participants completed all questionnaires at all timepoints. | Posted | Mean | Standard Deviation | units on a scale | Baseline, 4, 8, 12 and 52 weeks after treatment initiation |
| ||||||||||||||||||||||||||||||
| Secondary | Number of Participants Who Were Compliant With ET | Rates of non-persistence or non-compliance with initially prescribed endocrine therapy (ET) | This is the modified intention-to-treat population. | Posted | Count of Participants | Participants | 52 weeks after treatment initiation |
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| Secondary | Cost-effectiveness | Incremental cost-effectiveness rations (cost per one quality-adjusted life year (QALY) gained). | Not Posted | Dec 2026 | 52 weeks after treatment initiation | Participants | |||||||||||||||||||||||||||||||||
| Other Pre-specified | Rates of Non-compliance to Endocrine Therapy | Comparing rates of non-compliance and non-persistence to endocrine therapy with patient age, turmour stage, chemotherapy use and type of endocrine therapy. The rates of non-compliance and rates of non-persistence will be tracked throughout the duration of the study and then compared to patient age, tumour stage, chemotherapy use and the type of endocrine therapy used. | This was an exploratory analysis and it was not performed. | Posted | 52 weeks after treatment initiation |
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52 weeks
Adverse events not collected. This was a pragmatic clinical trial with two standard of care arms. The protocol did not include adverse event reporting.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Morning Administration of Endocrine Therapy | Administration of endocrine therapy defined as, within one hour of the patient wake up time Morning administration of endocrine therapy: Endocrine therapy administered within one hour of patient wake up time | 0 | 122 | 0 | 0 | 0 | 0 |
| EG001 | Evening Administration of Endocrine Therapy | Administration of endocrine therapy defined as, within one hour of the patient bed time Evening administration of endocrine therapy: Endocrine therapy administered within one hour of the patient bed time | 0 | 123 | 0 | 0 | 0 | 0 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Marie-France Savard, MD | The Ottawa Hospital Cancer Centre | 613-737-7700 | 70170 | msavard@toh.ca |
| Aug 26, 2025 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
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