Anxiety Disorder, Depression, Recurrent Breast Cancer, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer
Conditions
Keywords
Breast Cancer
Brief summary
This randomized clinical trial studies how well minocycline hydrochloride works in reducing chemotherapy induced depression and anxiety in patients with stage I-III breast cancer. Minocycline hydrochloride may prevent changes in memory and thinking and improve the quality of life of breast cancer patients receiving chemotherapy.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate anxiety and depression in women with stages I-III breast cancer during the first 8 weeks of doxorubicin-based adjuvant therapy randomized to receive either minocycline (minocycline hydrochloride) or placebo. II. To evaluate markers of neuro-inflammation as assessed by blood based inflammatory cytokines and C11-choline positron emission tomography (PET) in women with stages I-III breast cancer during the first 8 weeks of doxorubicin-based adjuvant therapy randomized to receive either minocycline or placebo. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Beginning 1 week prior to chemotherapy, patients receive minocycline hydrochloride orally (PO) twice daily (BID) for 9 weeks. ARM II: Beginning 1 week prior to chemotherapy, patients receive placebo PO BID for 9 weeks. After completion of study treatment, patients are followed up for 6 months.
Interventions
100 mg bid given by mouth for 9 weeks
OTHERplacebo
Placebo given by mouth for 9 weeks
OTHERlaboratory biomarker analysis
Correlative blood levels for cortisol, high sensitivity c-reactive protein (hs-CRP) and inflammatory factors including but not limited to IL-6, TNF-α, IL-1β, and MCP-1 will also be obtained weekly on protocol.
OTHERQuestionnaire administration
The CES-D and STAI will be administrated weekly.
Sponsors
Ohio State University Comprehensive Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women diagnosed with breast cancer stages I-III initiating first line adjuvant or neoadjuvant doxorubicin hydrochloride (DOX) chemotherapy * Postmenopausal defined as amenorrhea \> 12 months or follicle stimulating hormone (FSH) and estradiol in institutional postmenopausal range * Ability to understand English and read and write at the 8th grade level and give a written informed consent document * For additional cohort, women with breast cancer stages I-III who currently on or within 18 months of completing first line adjuvant or neoadjuvant DOX chemotherapy or other chemotherapy for breast cancer.
Exclusion criteria
* Rheumatoid arthritis and other types of autoimmune and inflammatory joint disease, with the exception of osteoarthritis and fibromyalgia * Concurrent other malignancy or metastatic malignancy of any kind * Reported diagnosis of major depression or anxiety disorder prior to breast cancer (BC) diagnosis * Currently prescribed psychotropic medications including anti-depressants * Known bleeding disorders * History of diabetes mellitus, heart disease or stroke * Current use of warfarin or other anticoagulants * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, hypertension, or psychiatric illness/social situation that would limit compliance with study requirements * Pregnant or nursing women * Concurrent use of daily full dose aspirin (\>= 325 mg/day), nonsteroidal anti-inflammatory drugs (NSAIDs) or NSAID-containing products or steroids; one month washout period is required prior to randomization * Unable to give informed consent * Tetracycline allergy * Any contraindication to magnetic resonance imaging (MRI)/PET examination including but not limited to ferromagnetic metal in the body, pacemaker, or severe claustrophobia; (however, this portion is optional and if patient is otherwise eligible, can enroll in study without participating in imaging study)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Center for Epidemiological Studies Depression Scale (CES-D) Scores | Baseline to 9 weeks | CES-D scale a short self-reported scaled designed to measure depressive symptomology in the general population. At baseline, depressive symptom severity will be assessed using the CES-D instrument. Evaluation of the patients assessment if suicidal ideation is reported at baseline. A value of 0, 1, 2, or 3 is assigned to a response depending upon positively or negatively. The subject will be withdrawn from the administrated serially every cycle starts on protocol during clinic visits (Patients will self-administer forms given out by research coordinator).The internal consistency for the STAI is .95; higher scores indicate greater anxiety.41 The internal consistency for the CES-D is approximately .85 among BC patients,42 and an important benefit of using this scale in medical studies is that it is relatively unaffected by physical symptoms. Total scores range from 0-60 with higher scores reflecting greater depressive symptoms. The 95% confidence intervals of the depression change from b |
| Changes in the State Trait Anxiety Index (STAI) Scores | Baseline to 9 weeks | The mean changes over time in State Trait Anxiety Index (STAI) scores from baseline to the end of study for the two study groups. The influences of covariate, such as disease stage and depression drug usage, will be considered in the mixed models as exploratory analyses. The range of possible scores for form Y of the STAI varies from a minimum score of 20 to a maximum score of 80. STAI scores are commonly classified as no or low anxiety (20-37), moderate anxiety (38-44), and high anxiety (45-80).The 95% confidence intervals of the change in the primary outcome measures from baseline to the end of study and the differences between the treatment and placebo groups will be estimated based on the models. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Hamilton Anxiety Rating Scale Scores | Baseline to 9 weeks | The 95% confidence intervals of the anxiety change from baseline to the end of study and the difference between the treatment and placebo groups. The influences of covariate, such as disease stage and depression drug usage, will be considered in the mixed models as exploratory analyses. In addition, change overtime of all outcomes for each individual will be plotted to visually explore any patterns and to generate hypothesis to be tested in future studies. |
| Changes in Hamilton Rating Scale for Depression Scores | Baseline to 9 weeks | The 95% confidence intervals of the depression change from baseline to the end of study and the difference between the treatment and placebo groups. The influences of covariate, such as disease stage and depression drug usage, will be considered in the mixed models as exploratory analyses. In addition, change overtime of all outcomes for each individual will be plotted to visually explore any patterns and to generate hypothesis to be tested in future studies. |
| Changes in Inflammatory Blood Markers | Baseline to 6 months | Scatter plots will be used to explore the pair-wise correlation among the changes of CES-D and STAI scores, blood biomarkers changes, and PET/MRI measures. A statistical model will be used to explore whether the blood based biomarkers and PET/MRI measures can be used to predict the changes in CES-D and STAI scores, which then could be used as potential surrogate markers in future studies. |
| Changes in the PET/MRI Measures | Baseline to 6 months | Scatter plots will be used to explore the pair-wise correlation among the changes of CES-D and STAI scores, blood biomarkers changes, and PET/MRI measures. A statistical model will be used to explore whether the blood based biomarkers and PET/MRI measures can be used to predict the changes in CES-D and STAI scores, which then could be used as potential surrogate markers in future studies. |
Countries
United States
Participant flow
Recruitment details
Recruitment was from June 2015 until June 2020
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Minocycline Hydrochloride) Beginning 1 week prior to chemotherapy, patients receive minocycline hydrochloride orally PO BID for 9 weeks. Laboratory biomarker analysis will also be obtained weekly on protocol. Questionnaire administration weekly.
minocycline hydrochloride: 100 mg bid given by mouth for 9 weeks
laboratory biomarker analysis: Correlative blood levels for cortisol, high sensitivity c-reactive protein (hs-CRP) and inflammatory factors including but not limited to IL-6, TNF-α, IL-1β, and MCP-1 will also be obtained weekly on protocol.
Questionnaire administration: The CES-D and STAI will be administrated weekly. | 28 |
| Arm II (Placebo) Beginning 1 week prior to chemotherapy, patients receive placebo PO BID for 9 weeks. Laboratory biomarker analysis will also be obtained weekly on protocol. Questionnaire administration weekly.
placebo: Placebo given by mouth for 9 weeks
laboratory biomarker analysis: Correlative blood levels for cortisol, high sensitivity c-reactive protein (hs-CRP) and inflammatory factors including but not limited to IL-6, TNF-α, IL-1β, and MCP-1 will also be obtained weekly on protocol.
Questionnaire administration: The CES-D and STAI will be administrated weekly. | 28 |
| Total | 56 |
Baseline characteristics
| Characteristic | Arm I (Minocycline Hydrochloride) | Total | Arm II (Placebo) |
|---|---|---|---|
| Age, Continuous | 50.9 years STANDARD_DEVIATION 11 | 51.8 years STANDARD_DEVIATION 11.3 | 52.7 years STANDARD_DEVIATION 11.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 55 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 51 Participants | 25 Participants |
| Region of Enrollment United States | 28 participants | 56 participants | 28 participants |
| Sex: Female, Male Female | 28 Participants | 56 Participants | 28 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 28 / 28 | 28 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 |
Outcome results
Primary
Changes in Center for Epidemiological Studies Depression Scale (CES-D) Scores
CES-D scale a short self-reported scaled designed to measure depressive symptomology in the general population. At baseline, depressive symptom severity will be assessed using the CES-D instrument. Evaluation of the patients assessment if suicidal ideation is reported at baseline. A value of 0, 1, 2, or 3 is assigned to a response depending upon positively or negatively. The subject will be withdrawn from the administrated serially every cycle starts on protocol during clinic visits (Patients will self-administer forms given out by research coordinator).The internal consistency for the STAI is .95; higher scores indicate greater anxiety.41 The internal consistency for the CES-D is approximately .85 among BC patients,42 and an important benefit of using this scale in medical studies is that it is relatively unaffected by physical symptoms. Total scores range from 0-60 with higher scores reflecting greater depressive symptoms. The 95% confidence intervals of the depression change from b
Time frame: Baseline to 9 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I (Minocycline Hydrochloride) | Changes in Center for Epidemiological Studies Depression Scale (CES-D) Scores | 0.57 score on a scale |
| Arm II (Placebo) | Changes in Center for Epidemiological Studies Depression Scale (CES-D) Scores | -3.18 score on a scale |
Primary
Changes in the State Trait Anxiety Index (STAI) Scores
The mean changes over time in State Trait Anxiety Index (STAI) scores from baseline to the end of study for the two study groups. The influences of covariate, such as disease stage and depression drug usage, will be considered in the mixed models as exploratory analyses. The range of possible scores for form Y of the STAI varies from a minimum score of 20 to a maximum score of 80. STAI scores are commonly classified as no or low anxiety (20-37), moderate anxiety (38-44), and high anxiety (45-80).The 95% confidence intervals of the change in the primary outcome measures from baseline to the end of study and the differences between the treatment and placebo groups will be estimated based on the models.
Time frame: Baseline to 9 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I (Minocycline Hydrochloride) | Changes in the State Trait Anxiety Index (STAI) Scores | -5.86 scores on a scale |
| Arm II (Placebo) | Changes in the State Trait Anxiety Index (STAI) Scores | -9.41 scores on a scale |
Secondary
Changes in Hamilton Anxiety Rating Scale Scores
The 95% confidence intervals of the anxiety change from baseline to the end of study and the difference between the treatment and placebo groups. The influences of covariate, such as disease stage and depression drug usage, will be considered in the mixed models as exploratory analyses. In addition, change overtime of all outcomes for each individual will be plotted to visually explore any patterns and to generate hypothesis to be tested in future studies.
Time frame: Baseline to 9 weeks
Population: Data was not collected and analyzed
Secondary
Changes in Hamilton Rating Scale for Depression Scores
The 95% confidence intervals of the depression change from baseline to the end of study and the difference between the treatment and placebo groups. The influences of covariate, such as disease stage and depression drug usage, will be considered in the mixed models as exploratory analyses. In addition, change overtime of all outcomes for each individual will be plotted to visually explore any patterns and to generate hypothesis to be tested in future studies.
Time frame: Baseline to 9 weeks
Population: Data not collected or analyzed
Secondary
Changes in Inflammatory Blood Markers
Scatter plots will be used to explore the pair-wise correlation among the changes of CES-D and STAI scores, blood biomarkers changes, and PET/MRI measures. A statistical model will be used to explore whether the blood based biomarkers and PET/MRI measures can be used to predict the changes in CES-D and STAI scores, which then could be used as potential surrogate markers in future studies.
Time frame: Baseline to 6 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Arm I (Minocycline Hydrochloride) | Changes in Inflammatory Blood Markers | IL-6 | 0.17 pg/ml |
| Arm I (Minocycline Hydrochloride) | Changes in Inflammatory Blood Markers | TNF-a | 0.18 pg/ml |
| Arm I (Minocycline Hydrochloride) | Changes in Inflammatory Blood Markers | IL-8 | 0.07 pg/ml |
| Arm I (Minocycline Hydrochloride) | Changes in Inflammatory Blood Markers | TNF-RII | 0.11 pg/ml |
| Arm I (Minocycline Hydrochloride) | Changes in Inflammatory Blood Markers | IL-1b | 0.04 pg/ml |
| Arm II (Placebo) | Changes in Inflammatory Blood Markers | TNF-RII | 0.06 pg/ml |
| Arm II (Placebo) | Changes in Inflammatory Blood Markers | IL-1b | 0 pg/ml |
| Arm II (Placebo) | Changes in Inflammatory Blood Markers | IL-6 | 0.26 pg/ml |
| Arm II (Placebo) | Changes in Inflammatory Blood Markers | IL-8 | 0.14 pg/ml |
| Arm II (Placebo) | Changes in Inflammatory Blood Markers | TNF-a | 0.11 pg/ml |
Secondary
Changes in the PET/MRI Measures
Scatter plots will be used to explore the pair-wise correlation among the changes of CES-D and STAI scores, blood biomarkers changes, and PET/MRI measures. A statistical model will be used to explore whether the blood based biomarkers and PET/MRI measures can be used to predict the changes in CES-D and STAI scores, which then could be used as potential surrogate markers in future studies.
Time frame: Baseline to 6 months
Population: Data not collected and analyzed