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The primary objective of this pilot study is to evaluate the safety and efficacy of direct instillations of Botulinum-A toxin/DMSO into the bladder via a catheter system as a means of treating women with symptoms of overactive bladder and secondary urinary incontinence. In doing so, we will focus on estimating the percentage of women who experience an improvement in their urinary incontinence symptoms at one month and three months following this novel instillation technique.
Rationale:
To date, the standard treatment for overactive bladder (including detrusor hyperreflexia and detrusor overactivity) consists of oral anticholinergic medications that can have troublesome side effects and variable efficacy. What's more, patients failing pharmacological therapy must either live with their malady or undergo open surgery that is irreversible and carries a prolonged convalescence. The fact remains however that treatment for overactive bladder is necessary to help maintain quality of life and prevent upper urinary tract deterioration. In recent years, cystoscopic-guided injection of Botulinum-A toxin has been used as a novel method of addressing detrusor hyperreflexia and overactivity by blocking acetylcholine transmission at the bladder. The obvious benefits of a more targeted therapy notwithstanding, this method requires the use of a cystoscope, needle delivery of the agent through approximately 30 separate injection sites and either regional or topical intravesical anesthesia for peri-operative pain control. Clearly, the identification of less invasive and more cost effective means of delivering the beneficial effects of Botulinum-A toxin to the bladder muscle has the potential to enhance the overall appeal of this treatment method.
Objectives:
The primary objective of this pilot study is to evaluate the safety and efficacy of direct instillations of Botulinum-A toxin/DMSO into the bladder via a catheter system as a means of treating women with symptoms of overactive bladder and secondary urinary incontinence. In doing so, we will focus on estimating the percentage of women who experience an improvement in their urinary incontinence symptoms at one month and three months following this novel instillation technique.
Study Design:
We are proposing a single center, Phase II pilot study for this investigation. In this proposal, 25 sterile women between 18-90 years of age with urodynamic evidence of detrusor overactivity, hyperreflexia or symptoms of overactive bladder syndrome who lack evidence of infection and stress incontinence will be offered bladder instillation of Botulinum-A toxin with DMSO as a carrier agent if they have failed anticholinergic medications or cannot tolerate the pharmacological side effects. We will use two validated measurement tools for determining urinary incontinence severity. These measurement tools will be administered to each women at baseline and then again at one month and three-month follow-up time points. Our analysis will also focus on identifying and describing adverse events among these women and estimating the percentage of women that experience a successful improvement in their urinary incontinence symptoms.
Study Duration:
Patients will sign an informed consent and be screened for eligibility. Once determined eligible for the study, each patient will be scheduled for baseline evaluation and instillation of Botox/DMSO. Patients will be then followed up at one month and three months. Patients will be removed from the study if they withdraw consent, experience one of the study stopping criteria (in which case the entire study will stop) or when they complete the final follow-up evaluation at three-months.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Botox/DMSO Solution | Experimental | Subjects received Botulinum-A toxin and Dimethyl sulfoxide solution. The first 3 subjects in Phase 1 underwent bladder instillation of 50 cc of the solution utilizing 200 units of botulinum-A toxin and 50cc DMSO. The next 6 subjects in the Phase 1 trial received 300 units of botulinum-A toxin and 50cc DMSO. All subjects in the Phase 2 trial received 300 units of botulinum-A toxin and 50cc DMSO. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Botulinum-A toxin | Drug | A simple bladder catheterization in the office with a standard urinary catheter and instill the Botulinum-A toxin/DMSO solution. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Median Number of Incontinent Episodes During 24 Hours | The study coordinator instructed the subject to keep record of any incontinence episodes during the 24-hour period prior to their baseline and follow-up visits. | baseline, 1 month, 3 months |
| Measure | Description | Time Frame |
|---|---|---|
| Median 24 Hour Pad Weight | Prior to baseline and follow-up visits, the study coordinator weighed standard pads provided to the subject for the study time period. The study coordinator instructed the subject to bring in any pads used during the 24-hour period prior to baseline and follow up visits. The study coordinator recorded the 24-hour pad weights into the study dataset. | baseline, 1 month, 3 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Steven Petrou, MD | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic Jacksonville | Jacksonville | Florida | 32224 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19648387 | Result | Petrou SP, Parker AS, Crook JE, Rogers A, Metz-Kudashick D, Thiel DD. Botulinum a toxin/dimethyl sulfoxide bladder instillations for women with refractory idiopathic detrusor overactivity: a phase 1/2 study. Mayo Clin Proc. 2009 Aug;84(8):702-6. doi: 10.4065/84.8.702. |
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Subjects were recruited from November 2006 to March 2009 at Mayo Clinic in Jacksonville, Florida.
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| ID | Title | Description |
|---|---|---|
| FG000 | Botox/DMSO Solution | Subjects received Botulinum-A toxin and Dimethyl sulfoxide solution. The first 3 subjects in Phase 1 underwent bladder instillation of 50 cc of the solution utilizing 200 units of botulinum-A toxin and 50cc DMSO. The next 6 subjects in the Phase 1 trial received 300 units of botulinum-A toxin and 50cc DMSO. All subjects in the Phase 2 trial received 300 units of botulinum-A toxin and 50cc DMSO. Botulinum-A toxin: A simple bladder catheterization in the office with a standard urinary catheter and instill the Botulinum-A toxin/DMSO solution. Dimethyl sulfoxide (DMSO): Subjects received 50 cc of DMSO in an aqueous solution for intravesical instillation with botulinum-A toxin. Each cc contained 0.54 gm DMSO. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 |
| |||||||||||||
| Phase 2 |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Botox/DMSO Solution | Subjects received Botulinum-A toxin and Dimethyl sulfoxide solution. The first 3 subjects in Phase 1 underwent bladder instillation of 50 cc of the solution utilizing 200 units of botulinum-A toxin and 50cc DMSO. The next 6 subjects in the Phase 1 trial received 300 units of botulinum-A toxin and 50cc DMSO. The 6 subjects in the Phase 1 trial who received 300 units of botulinum-A toxin and 50cc DMSO also continued in the Phase 2 trial. All subjects in the Phase 2 trial received 300 units of botulinum-A toxin and 50cc DMSO. Botulinum-A toxin: A simple bladder catheterization in the office with a standard urinary catheter and instill the Botulinum-A toxin/DMSO solution. Dimethyl sulfoxide (DMSO): Subjects received 50 cc of DMSO in an aqueous solution for intravesical instillation with botulinum-A toxin. Each cc contained 0.54 gm DMSO. |
| 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 | Median Number of Incontinent Episodes During 24 Hours | The study coordinator instructed the subject to keep record of any incontinence episodes during the 24-hour period prior to their baseline and follow-up visits. | Posted | Median | Inter-Quartile Range | number of incontinent episodes | baseline, 1 month, 3 months |
|
Phase 1 patients (9) were assess immediately, 4 hours 24 hours, and 7 days after instillation. Phase 2 patients were assessed immediately, 2 hours, and 4 hours after instillation. All patients were assessed at 1 month and 3 month follow-up intervals.
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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 | Botox/DMSO Solution | Subjects received Botulinum-A toxin and Dimethyl sulfoxide solution. The first 3 subjects in Phase 1 underwent bladder instillation of 50 cc of the solution utilizing 200 units of botulinum-A toxin and 50cc DMSO. The next 6 subjects in the Phase 1 trial received 300 units of botulinum-A toxin and 50cc DMSO. All subjects in the Phase 2 trial received 300 units of botulinum-A toxin and 50cc DMSO. Botulinum-A toxin: A simple bladder catheterization in the office with a standard urinary catheter and instill the Botulinum-A toxin/DMSO solution. Dimethyl sulfoxide (DMSO): Subjects received 50 cc of DMSO in an aqueous solution for intravesical instillation with botulinum-A toxin. Each cc contained 0.54 gm DMSO. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pelvic soreness in first 24 hours | Renal and urinary disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Steven P. Petrou | Mayo Clinic | 904-953-7330 | petrou.steven@mayo.edu |
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| ID | Term |
|---|---|
| D053201 | Urinary Bladder, Overactive |
| ID | Term |
|---|---|
| D001745 | Urinary Bladder Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D019274 | Botulinum Toxins, Type A |
| C542869 | abobotulinumtoxinA |
| C545476 | incobotulinumtoxinA |
| D004121 | Dimethyl Sulfoxide |
| ID | Term |
|---|---|
| D001905 | Botulinum Toxins |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
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|
| Dimethyl sulfoxide (DMSO) | Drug | Subjects received 50 cc of DMSO in an aqueous solution for intravesical instillation with botulinum-A toxin. Each cc contained 0.54 gm DMSO. |
|
| Blaivas-Groutz Anti-Incontinence Score at Baseline | The Blaivas-Groutz Anti-incontinence scale was used as a measure of urinary incontinence. This scale combines information on the number of incontinent episodes in a 24-hour period, 24-hour pad weights, and a qualitative rating by the patient into a single score ranging from 0 to 6. This score is then used to categorize incontinence as none (0), mild (1-2), moderate (3-4), or severe (5-6). | baseline |
| Blaivas-Groutz Anti-Incontinence Score at 1 Month | The Blaivas-Groutz Anti-incontinence scale was used as a measure of urinary incontinence. This scale combines information on the number of incontinent episodes in a 24-hour period, 24-hour pad weights, and a qualitative rating by the patient into a single score ranging from 0 to 6. This score is then used to categorize incontinence as none (0), mild (1-2), moderate (3-4), or severe (5-6). | 1 month after treatment |
| Blaivas-Groutz Anti-Incontinence Score at 3 Months | The Blaivas-Groutz Anti-incontinence scale was used as a measure of urinary incontinence. This scale combines information on the number of incontinent episodes in a 24-hour period, 24-hour pad weights, and a qualitative rating by the patient into a single score ranging from 0 to 6. This score is then used to categorize incontinence as none (0), mild (1-2), moderate (3-4), or severe (5-6). | 3 months after treatment |
| Mean Number of Pads Per Day | baseline, 1 month, 3 months |
| Postvoid Residual | baseline, 1 month, 3 months |
| Urine Culture | baseline, 1 month, 3 months |
| Urinary Urgency at Baseline | Urinary urgency was measured by the Indevus Urgency Severity Scale (IUSS). The IUSS asks patients to assess the severity of 'urgency' at each void. The scale employs the following wording: "Degree of urgency is meant to describe your urge to urinate. Sometimes you may feel a very strong urge to urinate and at other times, you may feel a milder urge prior to the onset of a toilet void. Rate this feeling by circling 0, 1, 2, or 3, defined as: 0: NONE - no urgency, 1: MILD - awareness of urgency, but it is easily tolerated and you can continue with your usual activity or tasks, 2: MODERATE - enough urgency discomfort that it interferes with or shortens your usual activity or tasks, 3: SEVERE - extreme urgency discomfort that abruptly stops all activity or tasks." | baseline |
| Urinary Urgency at 1 Month | Urinary urgency was measured by the Indevus Urgency Severity Scale (IUSS). The IUSS asks patients to assess the severity of 'urgency' at each void. The scale employs the following wording: "Degree of urgency is meant to describe your urge to urinate. Sometimes you may feel a very strong urge to urinate and at other times, you may feel a milder urge prior to the onset of a toilet void. Rate this feeling by circling 0, 1, 2, or 3, defined as: 0: NONE - no urgency, 1: MILD - awareness of urgency, but it is easily tolerated and you can continue with your usual activity or tasks, 2: MODERATE - enough urgency discomfort that it interferes with or shortens your usual activity or tasks, 3: SEVERE - extreme urgency discomfort that abruptly stops all activity or tasks." | 1 month after treatment |
| Urinary Urgency at 3 Months | Urinary urgency was measured by the Indevus Urgency Severity Scale (IUSS). The IUSS asks patients to assess the severity of 'urgency' at each void. The scale employs the following wording: "Degree of urgency is meant to describe your urge to urinate. Sometimes you may feel a very strong urge to urinate and at other times, you may feel a milder urge prior to the onset of a toilet void. Rate this feeling by circling 0, 1, 2, or 3, defined as: 0: NONE - no urgency, 1: MILD - awareness of urgency, but it is easily tolerated and you can continue with your usual activity or tasks, 2: MODERATE - enough urgency discomfort that it interferes with or shortens your usual activity or tasks, 3: SEVERE - extreme urgency discomfort that abruptly stops all activity or tasks." | 3 months after treatment |
| Median Urogenital Distress Inventory (UDI-6) Scores | The UDI-6 was one measure of urinary-associated quality of life. The UDI-6 questionnaire has 6 items, scored from 0 (not at all) to 3 (greatly), with total scores ranging from 0 to 18, a higher score indicating greater distress. | baseline, 1 month, 3 months |
| Bothersomeness | The bothersomeness refers to the question: On a scale of 1-10 (0 is not at all; 10 is intolerable), how badly does loss of urinary control bother you? | baseline, 1 month, 3 months |
| Incontinence Impact Questionnaire-short Form (IIQ-7) Scores | The IIQ-7 was one measure of urinary-associated quality of life. The IIQ-7 questionnaire has 7 items, scored from 0 (not at all) to 3 (greatly), with total scores ranging from 0 to 21, a higher score indicating greater distress. | baseline, 1 month, 3 months |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index | Median | Full Range | kg/m^2 |
|
|
|
|
| Secondary | Median 24 Hour Pad Weight | Prior to baseline and follow-up visits, the study coordinator weighed standard pads provided to the subject for the study time period. The study coordinator instructed the subject to bring in any pads used during the 24-hour period prior to baseline and follow up visits. The study coordinator recorded the 24-hour pad weights into the study dataset. | Posted | Median | Inter-Quartile Range | g | baseline, 1 month, 3 months |
|
|
|
|
| Secondary | Blaivas-Groutz Anti-Incontinence Score at Baseline | The Blaivas-Groutz Anti-incontinence scale was used as a measure of urinary incontinence. This scale combines information on the number of incontinent episodes in a 24-hour period, 24-hour pad weights, and a qualitative rating by the patient into a single score ranging from 0 to 6. This score is then used to categorize incontinence as none (0), mild (1-2), moderate (3-4), or severe (5-6). | Posted | Number | participants (per category) | baseline |
|
|
|
| Secondary | Blaivas-Groutz Anti-Incontinence Score at 1 Month | The Blaivas-Groutz Anti-incontinence scale was used as a measure of urinary incontinence. This scale combines information on the number of incontinent episodes in a 24-hour period, 24-hour pad weights, and a qualitative rating by the patient into a single score ranging from 0 to 6. This score is then used to categorize incontinence as none (0), mild (1-2), moderate (3-4), or severe (5-6). | Posted | Number | participants (per category) | 1 month after treatment |
|
|
|
|
| Secondary | Blaivas-Groutz Anti-Incontinence Score at 3 Months | The Blaivas-Groutz Anti-incontinence scale was used as a measure of urinary incontinence. This scale combines information on the number of incontinent episodes in a 24-hour period, 24-hour pad weights, and a qualitative rating by the patient into a single score ranging from 0 to 6. This score is then used to categorize incontinence as none (0), mild (1-2), moderate (3-4), or severe (5-6). | Posted | Number | participants (per category) | 3 months after treatment |
|
|
|
|
| Secondary | Mean Number of Pads Per Day | Posted | Mean | Inter-Quartile Range | pads per day | baseline, 1 month, 3 months |
|
|
|
|
| Secondary | Postvoid Residual | Posted | Median | Inter-Quartile Range | mL | baseline, 1 month, 3 months |
|
|
|
|
| Secondary | Urine Culture | Posted | Number | participants | baseline, 1 month, 3 months |
|
|
|
|
| Secondary | Urinary Urgency at Baseline | Urinary urgency was measured by the Indevus Urgency Severity Scale (IUSS). The IUSS asks patients to assess the severity of 'urgency' at each void. The scale employs the following wording: "Degree of urgency is meant to describe your urge to urinate. Sometimes you may feel a very strong urge to urinate and at other times, you may feel a milder urge prior to the onset of a toilet void. Rate this feeling by circling 0, 1, 2, or 3, defined as: 0: NONE - no urgency, 1: MILD - awareness of urgency, but it is easily tolerated and you can continue with your usual activity or tasks, 2: MODERATE - enough urgency discomfort that it interferes with or shortens your usual activity or tasks, 3: SEVERE - extreme urgency discomfort that abruptly stops all activity or tasks." | Posted | Number | participants (per category) | baseline |
|
|
|
| Secondary | Urinary Urgency at 1 Month | Urinary urgency was measured by the Indevus Urgency Severity Scale (IUSS). The IUSS asks patients to assess the severity of 'urgency' at each void. The scale employs the following wording: "Degree of urgency is meant to describe your urge to urinate. Sometimes you may feel a very strong urge to urinate and at other times, you may feel a milder urge prior to the onset of a toilet void. Rate this feeling by circling 0, 1, 2, or 3, defined as: 0: NONE - no urgency, 1: MILD - awareness of urgency, but it is easily tolerated and you can continue with your usual activity or tasks, 2: MODERATE - enough urgency discomfort that it interferes with or shortens your usual activity or tasks, 3: SEVERE - extreme urgency discomfort that abruptly stops all activity or tasks." | Posted | Number | participants (per category) | 1 month after treatment |
|
|
|
|
| Secondary | Urinary Urgency at 3 Months | Urinary urgency was measured by the Indevus Urgency Severity Scale (IUSS). The IUSS asks patients to assess the severity of 'urgency' at each void. The scale employs the following wording: "Degree of urgency is meant to describe your urge to urinate. Sometimes you may feel a very strong urge to urinate and at other times, you may feel a milder urge prior to the onset of a toilet void. Rate this feeling by circling 0, 1, 2, or 3, defined as: 0: NONE - no urgency, 1: MILD - awareness of urgency, but it is easily tolerated and you can continue with your usual activity or tasks, 2: MODERATE - enough urgency discomfort that it interferes with or shortens your usual activity or tasks, 3: SEVERE - extreme urgency discomfort that abruptly stops all activity or tasks." | Posted | Number | participants (per category) | 3 months after treatment |
|
|
|
|
| Secondary | Median Urogenital Distress Inventory (UDI-6) Scores | The UDI-6 was one measure of urinary-associated quality of life. The UDI-6 questionnaire has 6 items, scored from 0 (not at all) to 3 (greatly), with total scores ranging from 0 to 18, a higher score indicating greater distress. | Posted | Median | Inter-Quartile Range | units on a scale | baseline, 1 month, 3 months |
|
|
|
|
| Secondary | Bothersomeness | The bothersomeness refers to the question: On a scale of 1-10 (0 is not at all; 10 is intolerable), how badly does loss of urinary control bother you? | Posted | Median | Inter-Quartile Range | units on a scale | baseline, 1 month, 3 months |
|
|
|
|
| Secondary | Incontinence Impact Questionnaire-short Form (IIQ-7) Scores | The IIQ-7 was one measure of urinary-associated quality of life. The IIQ-7 questionnaire has 7 items, scored from 0 (not at all) to 3 (greatly), with total scores ranging from 0 to 21, a higher score indicating greater distress. | Posted | Median | Inter-Quartile Range | units on a scale | baseline, 1 month, 3 months |
|
|
|
|
| 0 |
| 25 |
| 18 |
| 25 |
| Positional light-headedness in first 24 hours | General disorders | Systematic Assessment |
|
| Anxiety in first 24 hours | Psychiatric disorders | Systematic Assessment |
|
| Bladder spasms in first 24 hours | Renal and urinary disorders | Systematic Assessment |
|
| Urethral discomfort in first 24 hours | Renal and urinary disorders | Systematic Assessment |
|
| Dysuria in first 24 hours | Renal and urinary disorders | Systematic Assessment |
|
| Urinary tract infection after 24 hours | Renal and urinary disorders | Systematic Assessment |
|
| Perineal rash 7 days after injection | Reproductive system and breast disorders | Systematic Assessment |
|
| Throbbing with urination 7 days after injection | Renal and urinary disorders | Systematic Assessment |
|
| Dysuria after 24 hours | Renal and urinary disorders | Systematic Assessment |
|
| Bladder spasms after 24 hours | Renal and urinary disorders | Systematic Assessment |
|
| Urethral discomfort after 24 hours | Renal and urinary disorders | Systematic Assessment |
|
| Pelvic tenderness after 24 hours | Renal and urinary disorders | Systematic Assessment |
|
Not provided
Not provided
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D059411 | Lower Urinary Tract Symptoms |
| D020924 | Urological Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006867 |
| Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D045726 | Metalloproteases |
| D001426 | Bacterial Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001427 | Bacterial Toxins |
| D014118 | Toxins, Biological |
| D001685 | Biological Factors |
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| Title | Measurements |
|---|---|
|
| 0.43 |
| No |
| Superiority or Other |
| Title | Measurements |
|---|
|
| Severe |
|
| Title | Measurements |
|---|
|
| Severe |
|
| Title | Measurements |
|---|
|
| Severe |
|
| Title | Measurements |
|---|---|
|
| 0.14 |
| No |
| Superiority or Other |
| Title | Measurements |
|---|---|
|
| 0.033 |
| No |
| Superiority or Other |
| Title | Measurements |
|---|---|
|
| 1 month positive |
|
| 3 months negative |
|
| 3 months positive |
|
| 0.25 |
| No |
| Superiority or Other |
| Title | Measurements |
|---|
|
| Severe |
|
| Title | Measurements |
|---|
|
| Severe |
|
| Title | Measurements |
|---|
|
| Severe |
|
| Title | Measurements |
|---|---|
|
| 0.001 |
| No |
| Superiority or Other |
| Title | Measurements |
|---|---|
|
| <0.001 |
| No |
| Superiority or Other |
| Title | Measurements |
|---|---|
|
| 0.002 |
| No |
| Superiority or Other |