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| Name | Class |
|---|---|
| Veloxis Pharmaceuticals | INDUSTRY |
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The purpose of this study is to compare once-daily tacrolimus extended-release (Envarsus XR®) to twice-daily immediate release tacrolimus to find out if people taking tacrolimus extended release (Envarsus XR®) report fewer side effects, increased medication compliance and higher scores on quality of life assessments compared to people taking twice daily tacrolimus immediate release.
Despite improvement in short-term graft outcomes in organ transplant, transplant patients still have to take on complex medication regimens to achieve current results. Adherence to these complex medications is an important problem in light of the potential risk of acute and chronic rejection and the associated burden of increased hospitalization, cost, and diminished quality of life that results from missed doses and poor overall drug taking. Part of the diminished quality of life is also tied to the bothersome symptoms patient feel after transplant. Most patients experience symptoms that relate to either the overall transplant immunosuppression or medication specific side effects. In the BENEFIT and BENEFIT-EXT trials, >60% of patients reported tiredness and lack of energy as an issue. Sleep problems, mood swings, restlessness, anxiety, depression, and concentration and memory difficulties appeared in approximately 50-60% of patients. In addition to these symptoms, >38% patients also reported numerous others side effects that have been strongly associated with calcineurin-inhibitors such as tacrolimus that include dizziness, muscle cramps, trembling hands, tingling in hands and feet, and headache.
The investigators hypothesize that the use of once-daily Envarsus XR® could decrease some transplant- and tacrolimus-related adverse symptoms and potentially lead to improvement in quality of life and medication adherence when compared to twice-daily tacrolimus. In order to assess this hypothesis, a prospective, multi-center, randomized, open-label, pilot study to investigate medication adherence and patient reported symptom occurrence and interference with daily life comparing once-daily Envarsus XR® and twice-daily immediate release tacrolimus in adult renal transplant recipients (SIMPLE) is being proposed.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tacrolimus twice-daily | Active Comparator | Subjects assigned to this arm will take tacrolimus two times daily by mouth, at the clinically prescribed dose. |
|
| Envarsus XR | Active Comparator | Subjects assigned to this arm will take Envarsus XR one time daily by mouth, at the clinically prescribed dose. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Envarsus XR | Drug | Once daily Envarsus XR |
| |
| Tacrolimus twice daily |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Change in Calcineurin Inhibitor-related Symptoms Severity Score | The CIRS is a questionnaire that assesses five symptoms (from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]) that have been shown to be associated with calcineurin inhibitors. These symptoms include trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. Each symptom is based on symptom severity in the last 7 days scaled from 0 (none) - 4 (very severe). The cumulative score ranges from 0-20, with higher scores indicating a worse outcome. | Baseline; 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the Severity Score in Each of the Five Individual CIRS Items | The change in the severity score in each of the five individual CIRS items: trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. The CIRS is a questionnaire that assesses five symptoms (from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]) that have been shown to be associated with calcineurin inhibitors. These symptoms include trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. Each symptom is based on symptom severity in the last 7 days scaled from 0 (none) - 4 (very severe), with higher scores indicating a worse outcome. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mark Stegall, M.D. | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic Arizona | Phoenix | Arizona | 85054 | United States | ||
| Mayo Clinic Florida |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36094829 | Derived | Mellon L, Doyle F, Hickey A, Ward KD, de Freitas DG, McCormick PA, O'Connell O, Conlon P. Interventions for increasing immunosuppressant medication adherence in solid organ transplant recipients. Cochrane Database Syst Rev. 2022 Sep 12;9(9):CD012854. doi: 10.1002/14651858.CD012854.pub2. |
| Label | URL |
|---|---|
| Mayo Clinic Clinical Trials | View source |
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28 subjects withdrew prior to randomization.
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| ID | Title | Description |
|---|---|---|
| FG000 | Tacrolimus Twice-daily | Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus |
| FG001 | Envarsus XR | Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Tacrolimus Twice-daily | Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus |
| BG001 | Envarsus XR |
| 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 | Mean Change in Calcineurin Inhibitor-related Symptoms Severity Score | The CIRS is a questionnaire that assesses five symptoms (from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]) that have been shown to be associated with calcineurin inhibitors. These symptoms include trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. Each symptom is based on symptom severity in the last 7 days scaled from 0 (none) - 4 (very severe). The cumulative score ranges from 0-20, with higher scores indicating a worse outcome. | 20 subjects in the Tacrolimus arm and 45 subjects in the Envarsus arm did not complete the CIRS questionnaire at the 12-month mark, therefore no data exists for those 65 subjects. | Posted | Mean | Standard Deviation | score on a scale | Baseline; 12 months |
|
Adverse events were collected from the time of informed consent through study completion, approximately 12 months.
Adverse events were collected through monthly blood labs and safety assessments.
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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 | Tacrolimus Twice-daily | Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose. Tacrolimus twice daily: Twice daily tacrolimus |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mark Stegall, M.D. | Mayo Clinic | 507-266-4505 | stegall.mark@mayo.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 | Apr 8, 2021 | Oct 13, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D016559 | Tacrolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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| Drug |
Twice daily tacrolimus |
|
| Baseline; 12 months |
| Number of Subjects With a Moderately Severe, Severe or Very Severe Score on Any CIRS Item | Number of subjects in each treatment group with a moderately severe, severe or very severe score (2, 3 or 4) on any CIRS item. The CIRS is a questionnaire that assesses five symptoms (from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]) that have been shown to be associated with calcineurin inhibitors. These symptoms include trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. Each symptom is based on symptom severity in the last 7 days scaled from 0 (none) - 4 (very severe). The cumulative score ranges from 0-20, with higher scores indicating a worse outcome. | 12 months |
| Change in the Number of Subjects Who Had a Reduction in Severity of Calcineurin Inhibitor-related Symptoms | The change in the number of subjects with a reduction in a CIRS item score from a severe or very severe score (3 to 4) to a mild to moderate (1 or 2) score from 4 months to 12 months. | 4 months; 12 months |
| Change in the Number of Subjects Who Had at Least One Calcineurin Inhibitor-related Symptom Reduced by 1 Point or Greater | The change in the number of subjects with a reduction in any single CIRS item by 1 point or greater from 4 months to 12 months. | 4 months; 12 months. |
| Transplant-related Symptoms as Measured by the Difference in Mean Transplant-related Symptoms (TRS) Score. | The TRS is a 30-item questionnaire capturing 15 symptoms (from PRO-CTCAE) that have been shown to be associated with transplant and general health-related quality of life improvement. These symptoms include change in taste, constipation, diarrhea, swelling in arms or legs, palpitations, dry skin, darkening of skin, blurry vision, headache, insomnia, anxiety, sadness, discouraged, increase in appetite, and fatigue. Each symptom is based on symptom severity in the last 7 days and scaled from 0 (none) - 4 (very severe). Total scores range from 0 to 120, with higher scores indicating a worse outcome. | Baseline; 12 months |
| Change in Health-related Quality of Life (HRQoL), as Measured by the Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) Health Profile. | The PROMIS-29 questionnaire measures physical and mental health outcomes for patients. Patients responded to 29 questions in seven categories: physical function, pain interference, depressive symptoms, anxiety, ability to participate in social activities, and sleep disturbance. Scores were scaled so that an average healthy person would score 50 points. A higher score represents a worse outcome. Patient questionnaire responses are scored using the PROMIS-29 scoring algorithm. Scores were scaled to a mean of 50 for a healthy reference population with a standard deviation of 10. | Baseline; 12 months |
| Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom | The change in the transplant related symptoms score in each of the fifteen individual TRS items: change in taste, constipation, diarrhea, swelling in arms or legs, palpitations, dry skin, darkening of skin, blurry vision, headache, insomnia, anxiety, sadness, depression, increase in appetite, and fatigue. The TRS is a multi-item questionnaire capturing 15 symptoms (from PRO-CTCAE) that have been shown to be associated with transplant and general health-related quality of life improvement. These symptoms include change in taste, constipation, diarrhea, swelling in arms or legs, palpitations, dry skin, darkening of skin, blurry vision, headache, insomnia, anxiety, sadness, depression, increase in appetite, and fatigue. Each symptom is based on symptom severity in the last 7 days and scaled from 0 (none) - 4 (very severe), with higher scores indicating a worse outcome. | Baseline; 12 months |
| Change in Overall Tolerability or Patient Bother Due to Side Effects | Measured by item GP5 ("I am bothered by side effects of treatment") from the FACT-G Questionnaire. FACT-G GP5 is a single-item measure from the Functional Assessment of Cancer Therapy (FACT) scale, specifically designed to assess patient-reported tolerability to cancer treatments. Subjects are asked to rate their level of tolerability on a scale of 0 (not at all bothered) to 4 (very much bothered), with a higher score indicating a worse outcome. | Baseline; 12 months |
| Change in Medication Adherence | Defined as the percentage of prescribed doses taken each day | 12 months |
| Change in Patient Medication Satisfaction as Assessed by Question 14 of the Treatment Satisfaction Questionnaire for Medication. | Question 14 of the Treatment Satisfaction Questionnaire for Medication measures medication satisfaction on a 7-item scale ranging from 0 (Extremely Dissatisfied) to 7 (Extremely Satisfied), with higher scores indicating better satisfaction. | Baseline; 12 months |
| Correlation Between de Novo DSA and Degree of Taking and Timing Adherence | Proportion of patients at different adherence thresholds of taking and timing adherences between 4 months and 12 months post transplant will be correlated with the presence or absence of dnDSA by 12 months post-transplant | 4 months; 12 months |
| Adverse Events | Number of adverse events reported | 12 months |
| Jacksonville |
| Florida |
| 32224 |
| United States |
| Mayo Clinic Rochester | Rochester | Minnesota | 55905 | United States |
| Drug Conversion |
|
Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose.
Envarsus XR: Once daily Envarsus XR
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex/Gender, Customized | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Subjects assigned to this arm took tacrolimus two times daily by mouth, at the clinically prescribed dose.
Tacrolimus twice daily: Twice daily tacrolimus
| OG001 | Envarsus XR | Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR |
|
|
|
| Secondary | Change in the Severity Score in Each of the Five Individual CIRS Items | The change in the severity score in each of the five individual CIRS items: trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. The CIRS is a questionnaire that assesses five symptoms (from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]) that have been shown to be associated with calcineurin inhibitors. These symptoms include trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. Each symptom is based on symptom severity in the last 7 days scaled from 0 (none) - 4 (very severe), with higher scores indicating a worse outcome. | 20 subjects in the Tac arm and 45 subjects in the Envarsus arm didn't complete the CIRS questionnaire at the 12-month mark, therefore no data exists for those 65 subjects. 1 subject in the Tac arm and 1 in the Envarsus arm didn't complete the muscle weakness section of the questionnaire. 1 subject in the Tac arm didn't complete the swollen gums section of the questionnaire. 2 subjects in the Tac arm and 1 in the Envarsus arm didn't complete the hair growth section of the questionnaire. | Posted | Median | Full Range | score on a scale | Baseline; 12 months |
|
|
|
|
| Secondary | Number of Subjects With a Moderately Severe, Severe or Very Severe Score on Any CIRS Item | Number of subjects in each treatment group with a moderately severe, severe or very severe score (2, 3 or 4) on any CIRS item. The CIRS is a questionnaire that assesses five symptoms (from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]) that have been shown to be associated with calcineurin inhibitors. These symptoms include trembling hands, muscle cramps, muscle weakness, swollen gums, and increased hair growth. Each symptom is based on symptom severity in the last 7 days scaled from 0 (none) - 4 (very severe). The cumulative score ranges from 0-20, with higher scores indicating a worse outcome. | 20 subjects in the Tacrolimus arm and 45 subjects in the Envarsus arm did not complete the CIRS questionnaire at the 12-month mark, therefore no data exists for those 65 subjects. | Posted | Count of Participants | Participants | 12 months |
|
|
|
|
| Secondary | Change in the Number of Subjects Who Had a Reduction in Severity of Calcineurin Inhibitor-related Symptoms | The change in the number of subjects with a reduction in a CIRS item score from a severe or very severe score (3 to 4) to a mild to moderate (1 or 2) score from 4 months to 12 months. | 29 subjects in the Tacrolimus arm and 54 subjects in the Envarsus arm did not complete the CIRS questionnaire at the 4-month mark, therefore no data exists for those 83 subjects. 2 subjects in the Tacrolimus arm only filled out a portion of the survey at the 4-month mark, due to this those two subjects were not included in the analysis for this outcome as a change in reduction of symptoms from very severe/severe to mild/moderate could not be calculated. | Posted | Count of Participants | Participants | 4 months; 12 months |
|
|
|
| Secondary | Change in the Number of Subjects Who Had at Least One Calcineurin Inhibitor-related Symptom Reduced by 1 Point or Greater | The change in the number of subjects with a reduction in any single CIRS item by 1 point or greater from 4 months to 12 months. | 29 subjects in the Tacrolimus arm and 54 subjects in the Envarsus arm did not complete the CIRS questionnaire at the 4-month mark, therefore no data exists for those 83 subjects. | Posted | Count of Participants | Participants | 4 months; 12 months. |
|
|
|
| Secondary | Transplant-related Symptoms as Measured by the Difference in Mean Transplant-related Symptoms (TRS) Score. | The TRS is a 30-item questionnaire capturing 15 symptoms (from PRO-CTCAE) that have been shown to be associated with transplant and general health-related quality of life improvement. These symptoms include change in taste, constipation, diarrhea, swelling in arms or legs, palpitations, dry skin, darkening of skin, blurry vision, headache, insomnia, anxiety, sadness, discouraged, increase in appetite, and fatigue. Each symptom is based on symptom severity in the last 7 days and scaled from 0 (none) - 4 (very severe). Total scores range from 0 to 120, with higher scores indicating a worse outcome. | 20 subjects in the Tacrolimus arm and 45 subjects in the Envarsus arm did not complete the TRS questionnaire at the 12-month mark, therefore no data exists for those 65 subjects. | Posted | Mean | Standard Deviation | score on a scale | Baseline; 12 months |
|
|
|
|
| Secondary | Change in Health-related Quality of Life (HRQoL), as Measured by the Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) Health Profile. | The PROMIS-29 questionnaire measures physical and mental health outcomes for patients. Patients responded to 29 questions in seven categories: physical function, pain interference, depressive symptoms, anxiety, ability to participate in social activities, and sleep disturbance. Scores were scaled so that an average healthy person would score 50 points. A higher score represents a worse outcome. Patient questionnaire responses are scored using the PROMIS-29 scoring algorithm. Scores were scaled to a mean of 50 for a healthy reference population with a standard deviation of 10. | 36 subjects in the Tacrolimus arm and 56 subjects in the Envarsus arm did not complete the PROMIS-29 questionnaire at the 12-month mark, therefore no data exists for those 92 subjects. | Posted | Median | Full Range | score on a scale | Baseline; 12 months |
|
|
|
|
| Secondary | Change in Transplant-related Symptoms as Measured by the Difference in Transplant-related Symptoms (TRS) Score in for Each Individual Symptom | The change in the transplant related symptoms score in each of the fifteen individual TRS items: change in taste, constipation, diarrhea, swelling in arms or legs, palpitations, dry skin, darkening of skin, blurry vision, headache, insomnia, anxiety, sadness, depression, increase in appetite, and fatigue. The TRS is a multi-item questionnaire capturing 15 symptoms (from PRO-CTCAE) that have been shown to be associated with transplant and general health-related quality of life improvement. These symptoms include change in taste, constipation, diarrhea, swelling in arms or legs, palpitations, dry skin, darkening of skin, blurry vision, headache, insomnia, anxiety, sadness, depression, increase in appetite, and fatigue. Each symptom is based on symptom severity in the last 7 days and scaled from 0 (none) - 4 (very severe), with higher scores indicating a worse outcome. | 20 in Tac arm,45 in XR arm didn't complete TRS at 12months,therefore no data exists for the 65 subjects.1 in XR arm didn't complete taste/palpitation/headache/insomnia/fatigue sections.1 in Tac arm didn't complete appetite/swelling/palpitation/fatigue/anxiety/depression section.3 in XR arm didn't complete diarrhea/depression/sadness sections.2 in Tac arm didn't complete vision/sadness sections.3 in Tac arm didn't complete headache section.8 in Tac arm,7 in XR arm didn't complete darkskin section | Posted | Median | Full Range | score on a scale | Baseline; 12 months |
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|
|
| Secondary | Change in Overall Tolerability or Patient Bother Due to Side Effects | Measured by item GP5 ("I am bothered by side effects of treatment") from the FACT-G Questionnaire. FACT-G GP5 is a single-item measure from the Functional Assessment of Cancer Therapy (FACT) scale, specifically designed to assess patient-reported tolerability to cancer treatments. Subjects are asked to rate their level of tolerability on a scale of 0 (not at all bothered) to 4 (very much bothered), with a higher score indicating a worse outcome. | 21 subjects in the Tacrolimus arm and 45 subjects in the Envarsus arm did not complete the FACT-G questionnaire at the 12-month mark, therefore no data exists for those 66 subjects. | Posted | Median | Full Range | score on a scale | Baseline; 12 months |
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|
|
| Secondary | Change in Medication Adherence | Defined as the percentage of prescribed doses taken each day | Data for this outcome measure were not collected in either treatment arm. The electronic data capture system was configured incorrectly and did not include the fields required to record medication adherence. As a result, the study team was unable to collect adherence data for any participants. | Posted | 12 months |
|
|
| Secondary | Change in Patient Medication Satisfaction as Assessed by Question 14 of the Treatment Satisfaction Questionnaire for Medication. | Question 14 of the Treatment Satisfaction Questionnaire for Medication measures medication satisfaction on a 7-item scale ranging from 0 (Extremely Dissatisfied) to 7 (Extremely Satisfied), with higher scores indicating better satisfaction. | 99 subjects in the Tacrolimus arm and 116 subjects in the Envarsus arm did not complete the Treatment Satisfaction questionnaire at the 12-month mark, therefore no data exists for those 215 subjects. | Posted | Median | Full Range | score on a scale | Baseline; 12 months |
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| Secondary | Correlation Between de Novo DSA and Degree of Taking and Timing Adherence | Proportion of patients at different adherence thresholds of taking and timing adherences between 4 months and 12 months post transplant will be correlated with the presence or absence of dnDSA by 12 months post-transplant | Data for this outcome measure were not collected in either treatment arm. The electronic data capture system was configured incorrectly and did not include the fields required to record correlation between de novo DSA and degree of taking and timing adherence. As a result, the study team was unable to collect correlation between de novo DSA and degree of taking and timing adherence data on any participant. | Posted | 4 months; 12 months |
|
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| Secondary | Adverse Events | Number of adverse events reported | Posted | Number | events | 12 months |
|
|
|
| 1 |
| 109 |
| 0 |
| 109 |
| 0 |
| 109 |
| EG001 | Envarsus XR | Subjects assigned to this arm took Envarsus XR one time daily by mouth, at the clinically prescribed dose. Envarsus XR: Once daily Envarsus XR | 3 | 124 | 0 | 124 | 0 | 124 |
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| Muscle Cramps |
|
|
| Muscle Weakness |
|
|
| Swollen Gums |
|
|
| Increased Hair Growth |
|
|
| 0.451 |
| Superiority |
| Muscle Weakness | Kruskal-Wallis | 0.953 | Superiority |
| Swollen Gums | Kruskal-Wallis | 0.579 | Superiority |
| Increased Hair Growth | Kruskal-Wallis | 0.513 | Superiority |
| Appetite |
|
|
| Constipation |
|
|
| Diarrhea |
|
|
| Swelling |
|
|
| Palpitations |
|
|
| Dry Skin |
|
|
| Darker Skin |
|
|
| Blurry Vision |
|
|
| Headache |
|
|
| Insomnia |
|
|
| Fatigue |
|
|
| Anxiety |
|
|
| Depression |
|
|
| Sadness |
|
|
| 0.486 |
| Superiority |
| Constipation | Kruskal-Wallis | 0.452 | Superiority |
| Diarrhea | Kruskal-Wallis | 0.750 | Superiority |
| Swelling | Kruskal-Wallis | 0.764 | Superiority |
| Palpitations | Kruskal-Wallis | 0.726 | Superiority |
| Dry Skin | Kruskal-Wallis | 0.421 | Superiority |
| Darker Skin | Kruskal-Wallis | 0.679 | Superiority |
| Blurry Vision | Kruskal-Wallis | 0.779 | Superiority |
| Headache | Kruskal-Wallis | 0.533 | Superiority |
| Insomnia | Kruskal-Wallis | 0.668 | Superiority |
| Fatigue | Kruskal-Wallis | 1.00 | Superiority |
| Anxiety | Kruskal-Wallis | 0.232 | Superiority |
| Depression | Kruskal-Wallis | 0.566 | Superiority |
| Sadness | Kruskal-Wallis | 0.038 | Superiority |