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Treating patients with Raynaud's phenomenon who have chronic pain and ulcerations is extremely challenging. Published reports and our previous work support our hypothesis that symptomatic patients experience relief of pain and healing of ulcerations with minimal adverse effects when treated with botulinum toxin type A (Btx-A) injections for Raynaud's phenomenon. The proposed study is the first clinical trial and prospective study designed to document whether or not 1) Btx-A injection relieves pain in a patient's hand affected with Raynaud's disease better than a placebo within 28 days of injection, and 2) Btx-A injection relieves pain associated with Raynaud's disease for longer than 28 days, improving patients' quality of life. Through this study we intend to further determine the effect of injected Btx-A on relieving chronic pain and ulcerations to the ischemic hand while characterizing the patients for whom this treatment is most effective.
PROJECT SUMMARY OVERVIEW: Treating patients with Raynaud's phenomenon who have chronic pain and ulcerations is extremely challenging. Pharmacologic vasodilators and surgical sympathectomies offer variable benefits. Case reports, small retrospective outcomes studies, and our previous work documenting symptomatic patients treated with botulinum toxin type A (Btx-A) injections for Raynaud's phenomenon have demonstrated relief of pain and healing of ulcerations with minimal adverse effects. We propose to conduct the first clinical trial and prospective study documenting the efficacy of this novel treatment modality.
STUDY AIMS: The aims of this proposal are to 1) examine the short-term efficacy of Btx-A injection compared to placebo in treating pain associated with digit ischemia due to Raynaud's disease, and 2) describe the long-term efficacy of Btx-A injection in treating pain associated with digit ischemia due to Raynaud's disease by measuring patient satisfaction and quality of life changes over time.
APPROACH: Two groups of patients will be enrolled: Group 1 will consist of patients with primary Raynaud's disease (n=20) and Group 2 of patients with secondary Raynaud's (n=20). Comparisons between treatment (Btx) and placebo (saline) will occur during the first 28 days to determine Btx-A's short-term efficacy. Follow-up visits will occur at Days 7 and 28. Post-assessment on Day 28 marks the beginning of the longitudinal observational study of patient outcomes. Placebo will no longer be used and patients still suffering from pain will be eligible for additional Btx-A injections. Patients may receive up to 4 injections of Btx-A during the 1-year study period if pain or ulcerations recur. During the study period participants will be followed to collect data on pain-free intervals, ulcer healing, subsequent treatment choices, patient satisfaction, and changes in quality of life and hand function. Group comparisons will be made to analyze results. Further stratifications for data analysis will be made as enrollment numbers allow to control for additional demographic and disease variables. Quality-adjusted life-years will be calculated to help determine the societal and individual cost of this treatment.
HYPOTHESIS: We hypothesize that 1) Btx-A injection relieves ischemic pain associated with Raynaud's disease better than a placebo within 28 days of injection, and 2) Btx-A injection relieves ischemic pain associated with Raynaud's disease for longer than 28 days, improving patients' quality of life. Through this study we intend to further elucidate the efficacy of injected Btx-A on relieving chronic pain and ulcerations to the ischemic hand while characterizing the patients for whom this treatment is most effective. This data will help us to apply for national funding to become the coordinating center for a multi-center clinical trial. The results of this research have enormous potential to impact millions of patients who suffer with Raynaud's phenomenon.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| placebo | No Intervention | no intervention | |
| onabotulinum toxin type-A | Active Comparator | up to 4 injections per hand dosage per injection: 100 units diluted in 2.0 mL normal saline; dosing will not exceed 360 units in a 3 month interval frequency: no less than 28 days between injections duration: during Study Year 1 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| onabotulinum toxin type-A | Drug | up to 4 injections per hand dosage per injection: 100 units diluted in 2.0 mL normal saline; dosing will not exceed 360 units in a 3 month interval frequency: no less than 28 days between injections duration: during Study Year 1 |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Patient Reported Pain-free Days | Subjective pain scales [visual analogue scale (VAS) and faces pain assessment]. Subjects reporting total number of pain free days within the time period of 0-28 days. | baseline to 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| Pain Related Quality of Life | SF-12v2® Health Survey - Pain Enhanced | change from baseline to 28 days |
| Hand Function | Quick-DASH (Disabilities of the Arm, Shoulder, and Hand) Outcome Measure |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael W Neumeister, MD | Southern Illinois University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Southern Illinois University School of Medicine | Springfield | Illinois | 62702 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21134617 | Background | Neumeister MW. Botulinum toxin type A in the treatment of Raynaud's phenomenon. J Hand Surg Am. 2010 Dec;35(12):2085-92. doi: 10.1016/j.jhsa.2010.09.019. | |
| 19568080 | Background | Neumeister MW, Chambers CB, Herron MS, Webb K, Wietfeldt J, Gillespie JN, Bueno RA Jr, Cooney CM. Botox therapy for ischemic digits. Plast Reconstr Surg. 2009 Jul;124(1):191-201. doi: 10.1097/PRS.0b013e3181a80576. |
| Label | URL |
|---|---|
| U.S. Food and Drug Administration | View source |
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We will not be sharing data.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | no intervention |
| FG001 | Onabotulinum Toxin Type-A | up to 4 injections per hand dosage per injection: 100 units diluted in 2.0 mL normal saline; dosing will not exceed 360 units in a 3 month interval frequency: no less than 28 days between injections duration: during Study Year 1 onabotulinum toxin type-A: up to 4 injections per hand dosage per injection: 100 units diluted in 2.0 mL normal saline; dosing will not exceed 360 units in a 3 month interval frequency: no less than 28 days between injections duration: during Study Year 1 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Race and Ethnicity were not collected for this protocol.
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | no intervention |
| BG001 | Onabotulinum Toxin Type-A | up to 4 injections per hand dosage per injection: 100 units diluted in 2.0 mL normal saline; dosing will not exceed 360 units in a 3 month interval frequency: no less than 28 days between injections duration: during Study Year 1 onabotulinum toxin type-A: up to 4 injections per hand dosage per injection: 100 units diluted in 2.0 mL normal saline; dosing will not exceed 360 units in a 3 month interval frequency: no less than 28 days between injections duration: during Study Year 1 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Percentage of Patient Reported Pain-free Days | Subjective pain scales [visual analogue scale (VAS) and faces pain assessment]. Subjects reporting total number of pain free days within the time period of 0-28 days. | Posted | Number | percentage of pain free days | baseline to 28 days |
|
For adverse events were followed to resolution.
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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 | Placebo | no intervention | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Broken bone | Injury, poisoning and procedural complications | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pain, Redness, Bleeding | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Research Administrator | Southern Illinois University School of Medicine | 217-545-2531 | surgeryresearch@siumed.edu |
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| ID | Term |
|---|---|
| D011928 | Raynaud Disease |
| D007511 | Ischemia |
| ID | Term |
|---|---|
| D000090122 | Livedoid Vasculopathy |
| D013927 | Thrombosis |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D019274 | Botulinum Toxins, Type A |
| ID | Term |
|---|---|
| D001905 | Botulinum Toxins |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
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|
| baseline to 28 days |
| Patient Satisfaction | The Optum SF-12v2® Health Survey - A Short Patient Reported Survey Measuring Health Using Excellent, Very Good, Good, Fair and Poor Indicators. On a scale from Excellent to Poor, Excellent being the maximum outcome. Good is scored as average. Patient satisfaction assessed as the percentage of participants who responded; Excellent, Very Good and Good on the health survey on average feeling between baseline and 28 days. | baseline to 28 days |
| Tissue Perfusion | Doppler perfusion imager and Periscan image analysis software | baseline to 28 days |
| EQ-5D A Standardised Patient Reported Measure of Health Status for Clinical and Economic Appraisal | A combined reported score measuring 5 dimensions; mobility, self care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels; no problems, some problems, extreme problems | baseline to 28 days |
| 15086364 | Background | Sycha T, Graninger M, Auff E, Schnider P. Botulinum toxin in the treatment of Raynaud's phenomenon: a pilot study. Eur J Clin Invest. 2004 Apr;34(4):312-3. doi: 10.1111/j.1365-2362.2004.01324.x. No abstract available. |
| 17255677 | Background | Van Beek AL, Lim PK, Gear AJL, Pritzker MR. Management of vasospastic disorders with botulinum toxin A. Plast Reconstr Surg. 2007 Jan;119(1):217-226. doi: 10.1097/01.prs.0000244860.00674.57. |
| 19258141 | Background | Fregene A, Ditmars D, Siddiqui A. Botulinum toxin type A: a treatment option for digital ischemia in patients with Raynaud's phenomenon. J Hand Surg Am. 2009 Mar;34(3):446-52. doi: 10.1016/j.jhsa.2008.11.026. |
| Drugs@FDA; U.S. Food and Drug Administration | View source |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Secondary | Pain Related Quality of Life | SF-12v2® Health Survey - Pain Enhanced | Data were not collected, | Posted | change from baseline to 28 days |
|
|
| Secondary | Hand Function | Quick-DASH (Disabilities of the Arm, Shoulder, and Hand) Outcome Measure | Data were not collected | Posted | baseline to 28 days |
|
|
| Secondary | Patient Satisfaction | The Optum SF-12v2® Health Survey - A Short Patient Reported Survey Measuring Health Using Excellent, Very Good, Good, Fair and Poor Indicators. On a scale from Excellent to Poor, Excellent being the maximum outcome. Good is scored as average. Patient satisfaction assessed as the percentage of participants who responded; Excellent, Very Good and Good on the health survey on average feeling between baseline and 28 days. | Posted | Number | percentage of participants | baseline to 28 days |
|
|
|
| Secondary | Tissue Perfusion | Doppler perfusion imager and Periscan image analysis software | Data were not collected | Posted | baseline to 28 days |
|
|
| Secondary | EQ-5D A Standardised Patient Reported Measure of Health Status for Clinical and Economic Appraisal | A combined reported score measuring 5 dimensions; mobility, self care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels; no problems, some problems, extreme problems | not were not collected | Posted | baseline to 28 days |
|
|
| 25 |
| 5 |
| 25 |
| 25 |
| 25 |
| EG001 | Onabotulinum Toxin Type-A | up to 4 injections per hand dosage per injection: 100 units diluted in 2.0 mL normal saline; dosing will not exceed 360 units in a 3 month interval frequency: no less than 28 days between injections duration: during Study Year 1 onabotulinum toxin type-A: up to 4 injections per hand dosage per injection: 100 units diluted in 2.0 mL normal saline; dosing will not exceed 360 units in a 3 month interval frequency: no less than 28 days between injections duration: during Study Year 1 | 0 | 23 | 2 | 23 | 22 | 23 |
| Infection | Infections and infestations | Non-systematic Assessment |
|
| Collapsed Lung | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Dizziness | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Throat Swelling | General disorders | Non-systematic Assessment |
|
| Swelling, Tenderness, Bruising | General disorders | Non-systematic Assessment |
|
| Temporary Weakness or numbness of muscle | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Dizziness, Drowsiness | General disorders | Non-systematic Assessment |
|
| Dry Eyes, Dry Mouth | General disorders | Non-systematic Assessment |
|
| Vision Changes | Eye disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Increased Cough, Runny nose | General disorders | Non-systematic Assessment |
|
| Allergic Reaction or Itching | General disorders | Non-systematic Assessment |
|
| Tingling | General disorders | Non-systematic Assessment |
|
| Shortness of breath | General disorders | Non-systematic Assessment |
|
| Difficulty Swallowing | General disorders | Non-systematic Assessment |
|
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| D002318 |
| Cardiovascular Diseases |
| D016491 | Peripheral Vascular Diseases |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D010335 | Pathologic Processes |
| 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 |