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Metformin is a medication that is commonly used in the treatment of diabetes. Recently small studies in cancer patients without diabetes suggest that metformin may benefit in lowering insulin levels. In those studies of patients with cancer but not diabetes, glucose (or sugar) levels in the blood are generally no lowered. Insulin and insulin-like growth factors affect the growth of cancer cells.
This randomized study will compare different interventions; exercise, exercise and metformin, metformin alone, or a control arm. The investigators are not directly testing how either exercise or metformin affects your disease. The investigators are testing how they affect insulin levels in your body as well as other blood markers. The investigators believe that these blood tests may either be related to cancer recurrences or be an early sign of cancer recurrences and they are testing how both exercise and metformin may change those markers.
Subjects will be randomized into one of four groups: exercise training, exercise training and metformin, metformin alone, or control arm. All subjects will have lifestyle measurements, interviews regarding activity level, diet questionnaires, and blood tests.
Subjects randomized to exercise training will participate in two supervised exercise sessions per week with an exercise physiologist for 3 months. They will also be asked to exercise on their own for up to an additional 120 minutes each week.
Subjects randomized to exercise training and metformin will participate in two supervised exercise sessions per week and will take metformin. Metformin will be taken once daily for the first two weeks and then twice daily for 3 months.
Subjects randomized to metformin will take metformin once daily for the first two weeks and then twice daily.
Subjects on the control arm will receive a packet of educational information on nutrition and physical activity developed by the National Cancer Institute and American Cancer Society. In addition to education information, they will be offered two supervised sessions with an exercise physiologist as well as a pedometer 3 months after enrollment in the study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Exercise training | Active Comparator | Exercise training with exercise physiologist |
|
| Exercise training with metformin | Active Comparator | Exercise training with exercise physiologist with oral metformin |
|
| Metformin | Active Comparator | Metformin |
|
| Control | Active Comparator | Educational information |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Exercise training | Behavioral | Two supervised exercise sessions per week |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Fasting Insulin Level | Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting insulin level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting insulin levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. | 0 and 3 months (change between 0 and 3 months) |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Other Insulin-Related Biomarkers | Markers related to insulin and insulin-like growth factors (including insulin-like growth factor 1 [IGF-1], IGF binding protein-1 [IGFBP-1], IGF binding protein-3 [IGFBP-3], leptin) will be measured by a blood draw at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. | 0 and 3 months (change between 0 and 3 months) |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Body Composition by Treatment Arm - Weight | Negative least square means indicate a decrease at 3 month comparing to baseline value. | 0 and 3 months (change between 0 and 3 months) |
| Changes in Body Composition by Treatment Arm - BMI |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey Meyerhardt, MD, MPH | Dana-Farber Cancer Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Yale School of Medicine | New Haven | Connecticut | 06520 | United States | ||
| Dana-Farber Cancer Institute |
Stratification factors: BMI (< 30 v > 30), gender, tumor site (CRC v BC)
In a phase 2 RCT, stage I-III CRC & BC survivors at least 2 months from completing standard therapy were randomized. Major eligibility included absence of recurrence, absence of diabetes (glucose < 160 (random) or < 126 (fasting) mg/dl), and exercising < 120 min/wk. 1,426 patients screened, and 139 enrolled from September 2011 to December 2015.
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| ID | Title | Description |
|---|---|---|
| FG000 | Exercise Training With Metformin | Exercise training with exercise physiologist with oral metformin Exercise training plus metformin: Two supervised exercise sessions per week. Oral metformin QD for 2 weeks, then BID |
| FG001 | Exercise Training | Exercise training with exercise physiologist Exercise training: Two supervised exercise sessions per week |
| FG002 | Metformin | Metformin Metformin: Oral metformin QD for two weeks, then BID |
| FG003 | Control | Educational information Educational information: educational information |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Exercise Training With Metformin | Exercise training with exercise physiologist with oral metformin Exercise training plus metformin: Two supervised exercise sessions per week. Oral metformin QD for 2 weeks, then BID |
| BG001 | Exercise Training |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 Fasting Insulin Level | Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting insulin level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting insulin levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. | 11 patients are excluded for missing baseline blood samples. | Posted | Least Squares Mean | Standard Error | mU/L | 0 and 3 months (change between 0 and 3 months) |
|
3 months
Mortality was recorded for all patients. Non serious adverse events were collected for patients treated with Metformin (two arms: Exercise Training With Metformin, and Metformin only).
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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 | Exercise Training With Metformin | Exercise training with exercise physiologist with oral metformin Exercise training plus metformin: Two supervised exercise sessions per week. Oral metformin QD for 2 weeks, then BID |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
Limited sample size, higher than anticipated dropout, short duration of therapy
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Meyerhardt, Jeffrey,M.D.,M.P.H. | Dana-Farber Cancer Institute | 617-632-6855 | Jeffrey_Meyerhardt@dfci.harvard.edu |
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| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D001943 | Breast Neoplasms |
| D007333 | Insulin Resistance |
| D009043 | Motor Activity |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
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| ID | Term |
|---|---|
| D015444 | Exercise |
| D008687 | Metformin |
| ID | Term |
|---|---|
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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| Metformin | Drug | Oral metformin QD for two weeks, then BID |
|
|
| Educational information | Other | educational information |
|
| Change in Fasting Glucose Level | Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting Glucose level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting Glucose levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. | 0 and 3 months (change between 0 and 3 months) |
Negative least square means indicate a decrease at 3 month comparing to baseline value.
| 0 and 3 months (change between 0 and 3 months) |
| Changes in Body Composition by Treatment Arm - Waist to Hip Ratio | Negative least square means indicate a decrease at 3 month comparing to baseline value. | 0 and 3 months (change between 0 and 3 months) |
| Boston |
| Massachusetts |
| 02215 |
| United States |
| Withdrawal by Subject |
|
| Adverse Event |
|
| Physician Decision |
|
| Unrelated sickness |
|
Exercise training with exercise physiologist Exercise training: Two supervised exercise sessions per week |
| BG002 | Metformin | Metformin Metformin: Oral metformin QD for two weeks, then BID |
| BG003 | Control | Educational information Educational information: educational information |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Study Site | Count of Participants | Participants |
|
| BMI | Median | Inter-Quartile Range | kg/m^2 |
|
| Tumor Location | Count of Participants | Participants |
|
| Cancer Stage | Cancer is present. The higher the number, the larger the cancer tumor and the more it has spread into nearby tissues. | Count of Participants | Participants |
|
| Prior Chemotherapy | Count of Participants | Participants |
|
| Prior Radiation Therapy | Count of Participants | Participants |
|
| OG001 | Exercise Training | Exercise training with exercise physiologist Exercise training: Two supervised exercise sessions per week |
| OG002 | Metformin | Metformin Metformin: Oral metformin QD for two weeks, then BID |
| OG003 | Control | Educational information Educational information: educational information |
|
|
|
| Secondary | Changes in Other Insulin-Related Biomarkers | Markers related to insulin and insulin-like growth factors (including insulin-like growth factor 1 [IGF-1], IGF binding protein-1 [IGFBP-1], IGF binding protein-3 [IGFBP-3], leptin) will be measured by a blood draw at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. | 11 patients are excluded for missing baseline blood samples. | Posted | Least Squares Mean | Standard Error | ng/mL | 0 and 3 months (change between 0 and 3 months) |
|
|
|
|
| Secondary | Change in Fasting Glucose Level | Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting Glucose level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting Glucose levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. | 11 patients are excluded for missing baseline blood samples. | Posted | Least Squares Mean | Standard Error | mg/dL | 0 and 3 months (change between 0 and 3 months) |
|
|
|
|
| Other Pre-specified | Changes in Body Composition by Treatment Arm - Weight | Negative least square means indicate a decrease at 3 month comparing to baseline value. | 2 patients are excluded for missing baseline measurements. | Posted | Least Squares Mean | Standard Error | kg | 0 and 3 months (change between 0 and 3 months) |
|
|
|
|
| Other Pre-specified | Changes in Body Composition by Treatment Arm - BMI | Negative least square means indicate a decrease at 3 month comparing to baseline value. | 2 patients are excluded for missing baseline measurements. | Posted | Least Squares Mean | Standard Error | kg/m^2 | 0 and 3 months (change between 0 and 3 months) |
|
|
|
|
| Other Pre-specified | Changes in Body Composition by Treatment Arm - Waist to Hip Ratio | Negative least square means indicate a decrease at 3 month comparing to baseline value. | 2 patients are excluded for missing baseline measurements. | Posted | Least Squares Mean | Standard Error | ratio | 0 and 3 months (change between 0 and 3 months) |
|
|
|
|
| 0 |
| 35 |
| 0 |
| 35 |
| 21 |
| 35 |
| EG001 | Exercise Training | Exercise training with exercise physiologist Exercise training: Two supervised exercise sessions per week | 0 | 35 | 0 | 35 | 0 | 0 |
| EG002 | Metformin | Metformin Metformin: Oral metformin QD for two weeks, then BID | 0 | 35 | 0 | 35 | 23 | 35 |
| EG003 | Control | Educational information Educational information: educational information | 0 | 34 | 0 | 34 | 0 | 0 |
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Abdomen Pain | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Bloating | Gastrointestinal disorders | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Headache | General disorders | Systematic Assessment |
|
| Anorexia | Gastrointestinal disorders | Systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Blood bilirubin increased | Blood and lymphatic system disorders | Systematic Assessment |
|
| Cardiac disorders | Cardiac disorders | Systematic Assessment |
|
| Dehydration | General disorders | Systematic Assessment |
|
| Dry mouth | General disorders | Systematic Assessment |
|
| Flu like symptoms | General disorders | Systematic Assessment |
|
| Hypertension | Blood and lymphatic system disorders | Systematic Assessment |
|
| Hypoglycemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Hypotension | Blood and lymphatic system disorders | Systematic Assessment |
|
| Pain in extremity | General disorders | Systematic Assessment |
|
| Palpitations | Cardiac disorders | Systematic Assessment |
|
| Pharyngeal necrosis | Gastrointestinal disorders | Systematic Assessment |
|
| Tinnitus | Ear and labyrinth disorders | Systematic Assessment |
|
Not provided
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Not provided
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D001519 | Behavior |
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| IGF-I |
|
| IGFBP-1 |
|
| IGFBP-3 |
|
| Null hypothesis: decrease of IGFBP_1 in treatment arm is greater than the control arm. | Mixed Models Analysis | An intention-to-treat analysis, with a mixed model that was adjusted for baseline outcome value, BMI (< 30 or > 30), gender, cancer, and study site. | 0.002 | One-sided un-adjusted p-values to test if the decrease in treatment arm is greater than the control arm. Holm's method was performed for multiple comparisons to provide an overall significance level of 5%. Only significant p-values were reported. | Superiority |
| Null hypothesis: decrease of IGFBP_1 in treatment arm is greater than the control arm. | Mixed Models Analysis | An intention-to-treat analysis, with a mixed model that was adjusted for baseline outcome value, BMI (< 30 or > 30), gender, cancer, and study site. | 0.02 | One-sided un-adjusted p-values to test if the decrease in treatment arm is greater than the control arm. Holm's method was performed for multiple comparisons to provide an overall significance level of 5%. Only significant p-values were reported. | Superiority |
| Null hypothesis: decrease of Leptin in combined arm is greater than the exercise-only or metformin-only arm. | Mixed Models Analysis | An intention-to-treat analysis, with a mixed model that was adjusted for baseline outcome value, BMI (< 30 or > 30), gender, cancer, and study site. | 0.0002 | One-sided un-adjusted p-values to test if the decrease in treatment arm is greater than the control arm. Holm's method was performed for multiple comparisons to provide an overall significance level of 5%. Only significant p-values were reported. | Superiority |
| Null hypothesis: decrease of Leptin in combined arm is greater than the exercise-only or metformin-only arm. | Mixed Models Analysis | An intention-to-treat analysis, with a mixed model that was adjusted for baseline outcome value, BMI (< 30 or > 30), gender, cancer, and study site. | 0.02 | One-sided un-adjusted p-values to test if the decrease in treatment arm is greater than the control arm. Holm's method was performed for multiple comparisons to provide an overall significance level of 5%. Only significant p-values were reported. | Superiority |
| Null hypothesis: decrease of Glucose in treatment arm is greater than the control arm. | Mixed Models Analysis | An intention-to-treat analysis, with a mixed model that was adjusted for baseline outcome value, BMI (< 30 or > 30), gender, cancer, and study site. | 0.007 | One-sided un-adjusted p-values to test if the decrease in treatment arm is greater than the control arm. Holm's method was performed for multiple comparisons to provide an overall significance level of 5%. Only significant p-values were reported. | Superiority |
| Null hypothesis: decrease of Weight in treatment arm is greater than the control arm. | Mixed Models Analysis | An intention-to-treat analysis, with a mixed model that was adjusted for baseline outcome value, BMI (< 30 or > 30), gender, cancer, and study site. | <0.0001 | One-sided un-adjusted p-values to test if the decrease in treatment arm is greater than the control arm. Holm's method was performed for multiple comparisons to provide an overall significance level of 5%. Only significant p-values were reported. | Superiority |
| Null hypothesis: decrease of Weight in treatment arm is greater than the control arm. | Mixed Models Analysis | An intention-to-treat analysis, with a mixed model that was adjusted for baseline outcome value, BMI (< 30 or > 30), gender, cancer, and study site. | 0.01 | One-sided un-adjusted p-values to test if the decrease in treatment arm is greater than the control arm. Holm's method was performed for multiple comparisons to provide an overall significance level of 5%. Only significant p-values were reported. | Superiority |
| Null hypothesis: decrease of BMI in treatment arm is greater than the control arm. | Mixed Models Analysis | An intention-to-treat analysis, with a mixed model that was adjusted for baseline outcome value, BMI (< 30 or > 30), gender, cancer, and study site. | <0.0001 | One-sided un-adjusted p-values to test if the decrease in treatment arm is greater than the control arm. Holm's method was performed for multiple comparisons to provide an overall significance level of 5%. Only significant p-values were reported. | Superiority |
| Null hypothesis: decrease of BMI in treatment arm is greater than the control arm. | Mixed Models Analysis | An intention-to-treat analysis, with a mixed model that was adjusted for baseline outcome value, BMI (< 30 or > 30), gender, cancer, and study site. | 0.02 | One-sided un-adjusted p-values to test if the decrease in treatment arm is greater than the control arm. Holm's method was performed for multiple comparisons to provide an overall significance level of 5%. Only significant p-values were reported. | Superiority |