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Temozolomide (TMZ) is the chemotherapy drug approved by the FDA to increase survival in glioblastoma (GBM) patients beyond surgical resection and radiation therapy alone. Give its activity in astrocytomas, TMZ is commonly used in grade III anaplastic astrocytoma (AA) as well. Both grade III AA and grade IV GBM are high grade gliomas (HGG). The short half-life of this drug and known oscillations in DNA damage repair make it an ideal candidate for chronotherapy.
Chronotherapy is the improvement of treatment outcomes by minimizing treatment toxicity and maximizing efficacy through delivery of a medication according to the timing of biological rhythms within a patient. Chronotherapy has improved outcomes through the reduction of side effects and increase in anti-tumor activity for a variety of cancers, but has never been applied to the treatment of gliomas.
Based on the preliminary preclinical data for chronotherapeutic TMZ treatment of intracranial glioma xenografts and the success of chronotherapy in the treatment of other cancers, the investigators hypothesize that the timing of TMZ treatment will alter its efficacy and toxicity.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1: Temozolomide morning | Experimental |
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| Arm 2: Temozolomide evening | Experimental |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Temozolomide | Drug | -Given standard of care |
|
| Measure | Description | Time Frame |
|---|---|---|
| Feasibility of Patient Treatment Compliance as Measured by Number of Participants Who Were at Least 80% Compliance With Assigned Administration Time | Compliance is defined as no more than one of five doses of temozolomide per cycle taken outside of the assigned administration time. | Through completion of treatment (median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles) |
| Duration of Response |
| Through completion of follow-up (estimated to be 30 months) |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients Experiencing Grade 3 or 4 Lymphopenia, Thrombocytopenia, Neutropenia, Leukopenia, and Anemia in Each Group as Measured by Standard Blood Draws |
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Inclusion Criteria:
Exclusion Criteria:.
-Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
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| Name | Affiliation | Role |
|---|---|---|
| Milan Chheda, M.D. | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35601970 | Derived | Damato AR, Katumba RGN, Luo J, Atluri H, Talcott GR, Govindan A, Slat EA, Weilbaecher KN, Tao Y, Huang J, Butt OH, Ansstas G, Johanns TM, Chheda MG, Herzog ED, Rubin JB, Campian JL. A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma. Neurooncol Pract. 2022 Jan 31;9(3):193-200. doi: 10.1093/nop/npac003. eCollection 2022 May. |
| Label | URL |
|---|---|
| Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm 1: Temozolomide Morning | -Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m^2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the morning (before 10:00). |
| FG001 | Arm 2: Temozolomide Evening | -Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the evening (after 20:00). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Arm 1: Temozolomide Morning | -Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m^2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the morning (before 10:00). |
| BG001 | Arm 2: Temozolomide Evening |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Feasibility of Patient Treatment Compliance as Measured by Number of Participants Who Were at Least 80% Compliance With Assigned Administration Time | Compliance is defined as no more than one of five doses of temozolomide per cycle taken outside of the assigned administration time. | Patients who received one full cycle of TMZ are evaluable for this outcome measure. | Posted | Count of Participants | Participants | Through completion of treatment (median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles) |
|
All-cause mortality was collected from start of treatment through completion of follow-up (median length of follow-up 568.5 days, full range 1-1134 days) Adverse events were collected from start of treatment through end of treatment visit (median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles).
Only grade 3 or higher hematologic adverse events were collected along with all serious adverse events.
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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 | Arm 1: Temozolomide Morning | -Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m^2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the morning (before 10:00). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Aspartate aminotransferase increased | Investigations | CTCAE (4.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Milan Chheda | Washington University School of Medicine | 314-747-2712 | mchheda@wustl.edu |
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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 20, 2022 | Feb 14, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D005910 | Glioma |
| D005909 | Glioblastoma |
| ID | Term |
|---|---|
| D018302 | Neoplasms, Neuroepithelial |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D000077204 | Temozolomide |
| ID | Term |
|---|---|
| D003606 | Dacarbazine |
| D014226 | Triazenes |
| D009930 | Organic Chemicals |
| D007093 | Imidazoles |
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| Functional Assessment of Cancer Therapy - Brain | Other |
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| ActTrust Condor Instrument Watch | Other | -Will be required to wear 24 hours per day and will only be removed at specified data collection time points |
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| Through completion of treatment (median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles) |
| Change in Quality of Life as Measured by FACT-Br Score - Physical Well-being Score | 7-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range is 0-28. A higher score indicates a lower physical well-being quality of life. | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
| Change in Quality of Life as Measured by FACT-Br Score - Social/Family Well-being Score | 7-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range 0-28. A higher score indicates a higher social/family well-being quality of life. | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
| Change in Quality of Life as Measured by FACT-Br Score - Emotional Well-being Score | 6-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range 0-24. A higher score indicates a lower emotional well-being quality of life. | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
| Change in Quality of Life as Measured by FACT-Br Score - Functional Well-being Score | 7-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range 0-28. A higher score indicates a higher emotional well-being quality of life. | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
| Median Progression-free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. | Through completion of follow-up (median length of follow-up 568.5 days, full range 1-1134 days) |
| Median Overall Survival | Through completion of follow-up (median length of follow-up 568.5 days, full range 1-1134 days) |
| Comparison of Sleep Questionnaire in Participants Receiving Temozolomide in the Morning Versus Participants Receiving Temozolomide in the Evening | Sleep Questionnaire - 1 yes/no question of "do you have problems getting to sleep or staying asleep?" | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
| Comparison of Sleep Questionnaire in Participants Receiving Temozolomide in the Morning Versus Participants Receiving Temozolomide in the Evening | - Sleep Questionnaire:
| Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
| Mean Circadian Amplitude |
| From start of treatment through 2 months after end of treatment (median length 100 days, full range 78-240 days) |
| Mean Sleep Regularity Index (SRI) |
| From start of treatment through 2 months after end of treatment (median length 100 days, full range 78-240 days) |
| Lack of Efficacy |
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| Hospice |
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-Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the evening (after 20:00). |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| OG001 |
| Arm 2: Temozolomide Evening |
-Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the evening (after 20:00). |
|
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| Primary | Duration of Response |
| Data was not collected for this outcome measure. Duration of response was never listed as an objective in the protocol; however it was erroneously mentioned in the statistical analysis section of the protocol and therefore was listed as a primary outcome measure in error as well. | Posted | Through completion of follow-up (estimated to be 30 months) |
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| Secondary | Number of Patients Experiencing Grade 3 or 4 Lymphopenia, Thrombocytopenia, Neutropenia, Leukopenia, and Anemia in Each Group as Measured by Standard Blood Draws |
| Posted | Count of Participants | Participants | Through completion of treatment (median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles) |
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| Secondary | Change in Quality of Life as Measured by FACT-Br Score - Physical Well-being Score | 7-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range is 0-28. A higher score indicates a lower physical well-being quality of life. | The number analyzed for each timepoint may be different from the overall number of participants analyzed if any participant did not complete the questionnaire at that time point. | Posted | Mean | Standard Deviation | score on a scale | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
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| Secondary | Change in Quality of Life as Measured by FACT-Br Score - Social/Family Well-being Score | 7-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range 0-28. A higher score indicates a higher social/family well-being quality of life. | The number analyzed for each timepoint may be different from the overall number of participants analyzed if any participant did not complete the questionnaire at that time point. | Posted | Mean | Standard Deviation | score on a scale | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
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| Secondary | Change in Quality of Life as Measured by FACT-Br Score - Emotional Well-being Score | 6-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range 0-24. A higher score indicates a lower emotional well-being quality of life. | The number analyzed for each timepoint may be different from the overall number of participants analyzed if any participant did not complete the questionnaire at that time point. | Posted | Mean | Standard Deviation | score on a scale | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
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| Secondary | Change in Quality of Life as Measured by FACT-Br Score - Functional Well-being Score | 7-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range 0-28. A higher score indicates a higher emotional well-being quality of life. | The number analyzed for each timepoint may be different from the overall number of participants analyzed if any participant did not complete the questionnaire at that time point. | Posted | Mean | Standard Deviation | score on a scale | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
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| Secondary | Median Progression-free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. | Posted | Median | 95% Confidence Interval | months | Through completion of follow-up (median length of follow-up 568.5 days, full range 1-1134 days) |
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| Secondary | Median Overall Survival | Posted | Median | 95% Confidence Interval | months | Through completion of follow-up (median length of follow-up 568.5 days, full range 1-1134 days) |
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| Secondary | Comparison of Sleep Questionnaire in Participants Receiving Temozolomide in the Morning Versus Participants Receiving Temozolomide in the Evening | Sleep Questionnaire - 1 yes/no question of "do you have problems getting to sleep or staying asleep?" | Sleep questionnaires were only collected on 6 patients in each arm. If one of the 12 patients didn't complete a sleep questionnaire then they are not included in that timepoint. | Posted | Count of Participants | Participants | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
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| Secondary | Comparison of Sleep Questionnaire in Participants Receiving Temozolomide in the Morning Versus Participants Receiving Temozolomide in the Evening | - Sleep Questionnaire:
| Sleep questionnaires were only collected on 6 patients in each arm. If one of the 12 patients didn't complete a sleep questionnaire then they are not included in that timepoint. | Posted | Count of Participants | Participants | Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)) |
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| Secondary | Mean Circadian Amplitude |
| Actimetry data was only collected on 6 participants. | Posted | Mean | Standard Deviation | counts/minute | From start of treatment through 2 months after end of treatment (median length 100 days, full range 78-240 days) |
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| Secondary | Mean Sleep Regularity Index (SRI) |
| Actimetry data was only collected on 6 participants. | Posted | Mean | Standard Deviation | units on a scale | From start of treatment through 2 months after end of treatment (median length 100 days, full range 78-240 days) |
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| 7 |
| 22 |
| 6 |
| 22 |
| 4 |
| 22 |
| EG001 | Arm 2: Temozolomide Evening | -Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the evening (after 20:00). | 6 | 20 | 5 | 20 | 1 | 20 |
| Alanine aminotransferase increased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Death due to disease progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE (4.0) | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | CTCAE (4.0) | Systematic Assessment |
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| Vascular access complication | Injury, poisoning and procedural complications | CTCAE (4.0) | Systematic Assessment |
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| Pneumonia | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Seizure | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Lung infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Headache | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Sepsis | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Hydrocephalus | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Platelet count decreased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| White blood cell count decreased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Lymphocyte count decreased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| Neutrophil count decreased | Investigations | CTCAE (4.0) | Systematic Assessment |
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| D009369 | Neoplasms |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009380 | Neoplasms, Nerve Tissue |
| D001254 | Astrocytoma |
| D001393 |
| Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Neutropenia |
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| Anemia |
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| Leukopenia |
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| End of treatment |
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| End of treatment |
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| End of treatment |
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| End of treatment |
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| No |
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| End of Treatment |
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| Difficulty staying asleep |
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| Problem waking up too early |
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| How satisfied or dissatisfied are you with your current sleeping pattern? |
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| To what extent do you consider your sleep problem to interfere with your daily functioning? |
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| How noticeable to others is your sleep problem is in terms of impairing the quality of your life |
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| How worried or distressed are you about your current sleep problem? |
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| AM Patient #2 |
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| PM Patient #1 |
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