Randomized Pilot Study for the Treatment of Cutaneous Leiomyomas With Botulinum Toxin

Study Overview
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Brief Summary
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Cutaneous leiomyomas are benign tumors of smooth muscle origin. They can be very painful, and current treatments for the tumors and for the associated pain do not produce satisfactory results. One potential treatment for localized severe muscle pain involves injections with botulinum toxin A. This study will investigate the effectiveness, side effects, and dosage of botulinum toxin A (BOTOX) as a treatment for patients with pain associated with cutaneous leiomyomas. This study will include 18 subjects, all of whom will be 18 years of age and older, who have pain associated with cutaneous leiomyomas. For the 24-week study, patients will be randomly assigned to one of two treatment groups. Neither the study team nor the patient will know to which group patients have been assigned. Before the study begins, all participants must provide a full medical history for research and evaluation purposes, fill out pain and quality-of-life questionnaires, and undergo an ice test in which researchers will apply ice to the site of the cutaneous leiomyomas and ask participants to evaluate the level of pain before and after ice application. Both groups will be required to keep a pain diary throughout the study to record their level of pain on a daily basis, and will be asked to avoid or restrict the use of specific medications or other remedies to treat the pain. At the first visit (Week 0), one group will receive a prescribed dose of botulinum toxin A, which will be administered as an injection into the leiomyoma, and the other (control) group will receive a placebo injection of a saline solution. Patients will return 4 weeks later, at which time they will undergo a medical examination, and the ice test, and complete questionnaires to assess responses and level of pain. Patients will return in Week 12, at which time the group assignment will be revealed (un-blinded) to investigators and patients. Patients who received placebo injections will be offered the opportunity to receive injection of botulinum toxin A into their leiomyomas. All patients will undergo a medical examination, the ice test, complete questionnaires, and continue completing their daily pain diaries at home. The final visit, in Week 24, will follow the same procedure as the Week 4 visit. At the end of the study, patients may be eligible to have one or more of the painful cutaneous leiomyomas surgically removed if the researchers believe that the skin lesions can be removed with a reasonable cosmetic result.

Detailed Description
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Background: Cutaneous leiomyomas are smooth muscle tumors that may arise sporadically or in association with an inherited cancer-related genodermatosis. Leiomyomas may be severely painful, and current management is generally unsatisfactory. Studies demonstrate increased nerve density within and around leiomyomas as well as increased acetylcholinesterase staining of associated nerves. Botulinum toxin-A has been used in the treatment of pain syndromes. Based on the known mechanisms of action of botulinum toxin-A, treatment with botulinum toxin-A (BOTOX; Allergan, Inc.), may ameliorate the severe paroxysmal pain of symptomatic cutaneous leiomyomas. Objectives: Primary: To assess change in worst lesional pain in the past week based on Brief Pain Inventory (BPI) from Week 0 to Week 4 in treated patients versus controls. Primary: To assess improvement in pain based on Visual Analog Scale (VAS) after application of ice at Week 4 compared to baseline in treated patients versus controls. Secondary: To assess change in magnitude and in frequency of painful episodes based on a weekly patient diary in treated patients versus controls. Secondary: To assess persistence of pain control at Weeks 12 based on the BPI and VAS. Secondary: To assess the frequency of rescue pain medication use in treated patients versus controls during the 24 week study period. Secondary: To determine the impact of leiomyoma treatment on quality of life. Secondary: To assess change in patient s condition based on the Patient Global Impression of Change. Secondary: To evaluate the immunohistochemical staining of nerve fibers and muscle in cutaneous leiomyomas in control and treated lesions following the conclusion of the study. Eligibility: Subjects greater than or equal to18 years with at least 1 symptomatic cutaneous leiomyoma. Pain symptoms must occur at least once a week and be characterized as greater than or equal to 5 out of 10. Design: A 12-week double-blind placebo controlled pilot study of 18 subjects with symptomatic leiomyomas will include initial assessment with BPI, photography, and skin biopsies, followed by treatment of subjects who initially received placebo. Cutaneous leiomyomas will undergo intralesional injection with botulinum toxin-A. Subjects will return at Weeks 4 and 12 for repeat assessment using pain and quality of life questionnaires and photography. Skin biopsies will be performed at week 12.

Official Title
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Randomized Pilot Study for the Treatment of Cutaneous Leiomyomas With Botulinum Toxin

Conditions
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Cutaneous Leiomyomas, Hereditary Leiomyomatosis and Renal Cell Cancer

Intervention / Treatment
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* Biological: Botulinum toxin type A
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Subjects must be age greater than or equal to18 years. Subjects must have a prior biopsy-proven diagnosis of cutaneous leiomyoma. Subjects must have at least 1 symptomatic leiomyomas or regions less than or equal to 60 cm^2 of leiomyomas with pain characterized as greater than 4 based on a 10-point scale, indicating pain of at least moderate severity. Pain episodes must occur at least once a week. Subjects must have the ability to participate fully and comply with the procedures of the protocol in the opinion of the investigator. Written informed consent has been obtained including consenting to have tissue samples stored, however subjects are allowed to refuse sample storage. Negative urine or serum pregnancy test in females of childbearing potential. Subjects who are clinically stable such that they can be expected to complete the 24-week study. EXCLUSION CRITERIA: Subjects with allergies to BTX-A. Females with a positive pregnancy test, or who are breast-feeding, planning a pregnancy during the study, who think that they may be pregnant at the start of the study or females of childbearing potential who are unable or unwilling to use a reliable form of contraception during the study. Subjects with neuromuscular junction disorders (ie. myasthenia gravis or Lambert-Eaton syndrome) or peripheral motor neuropathic diseases (ie. amyotrophic lateral sclerosis or motor neuropathy). Subjects with infection at the intended sites of injection. Subjects who have had prior Botulinum toxin product within the past 6 months. Subjects with pain resulting from other disease(s), specifically: pain that requires intermittent or ongoing treatment with narcotics severe, debilitating, or acute pain originating from sources other than leiomyomas Subjects taking pain medications, neuroactive agents, or other therapy directed toward treatment of cutaneous leiomyomas concurrently or within 5 days or 5 half-lives (whichever is longer) of BTX-A treatment, other than specified rescue pain medications). Patients currently on therapy directed toward OTHER mild to moderate chronic pain will be evaluated on a case-by-case basis for inclusion. Patients with well-controlled mild to moderate chronic pain such as that associated with osteoarthritis, who do not require narcotic therapy, will NOT be excluded. Aspirin for pain relief or for other indications is also acceptable. Subjects with late-stage cancers or unstable disease (such as hemodynamic instability, i.e., systolic or diastolic blood pressure fall of 20 mm Hg or greater from the stable patient s baseline measurement). A condition or situation that, in the investigator's opinion, may put the subject at significant risk or interfere significantly with the subject's participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BTX-A<br>BTX-A intralesional injection | Biological: Botulinum toxin type A<br>* Given as an intralesional injection.<br>* Other names: BTX-A;|
| Experimental: Placebo/Saline<br>Saline intralesional injection | Other: Placebo<br>* Given as an intralesional injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Worst Lesional Pain in the Past Week Based on Brief Pain Inventory | Change in worst lesional pain in the past week based on Brief Pain Inventory (BPI) from Week 0 to Week 4 in treated patients versus controls. The BPI uses an arbitrary units on a 0-10 scale. For the purposes of the statistical calculation, a difference of 1 standard deviation between groups at baseline vs. week 4 was considered significant. Any BPI value above zero (no pain) is abnormal. The mean change indicates mean change in pain score. | Between week 0 and week 4 | 
| Median Change in Average Pain Between Two Arms | Change in average pain was assessed by the Brief Pain Inventory (BPI). The BPI is a validated pain assessment tool that assesses severity of pain, location of pain, impact of pain on daily functions, pain medications, and amount of pain relief in the past 24 hours or past week (e.g. scale of 0-10 (worst pain)). | Between weeks 0 and week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 37 months | 
| Visual Analog Scale (VAS) of Patient Perceived Pain at Leiomyoma Site Prior to Ice Provocation at Week 0 vs. Week 4 | The VAS is a commonly used validated tool for assessment of pain. For this measure, a 10-cm VAS was used to assess current patient pain/discomfort before application of ice to study lesions at week 0 and week 4. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Range is 0-10; 0 is no pain and 10 is worst possible pain. | Week 0 vs. week 4 | 
| Comparison of Change in Skin Related Quality of Life by Total Dermatology Life Quality Index (DLQI) at Week 0 vs. Week 4 | The DLQI is a 10-question quality of life survey which has been extensively validated and frequently used in dermatologic disorders such as atopic dermatitis, acne, and psoriasis. Score is 0-30 based on 10 questions. The higher the score, the more quality of life is impaired. | Week 0 vs. week 4 | 
| Specific Skin Pain-Related Question on the Dermatology Life Quality Index | The DLQI is a 10-question quality of life survey which has been extensively validated and frequently used in dermatologic disorders such as atopic dermatitis, acne, and psoriasis. Participants response to the question Over the last week, how itchy, sore, painful or stinging has your skin been? was assessed by the Dermatology Life Quality Index. This outcome refers to a single specific question on the DLQI, so the range for this outcome is 0-3. Lower values in the DLQI indicate less impairment (or greater improvement) in life quality from the skin disease. | Week 0 vs. week 4 | 
| Change in Post-Ice Provocation Visual Analog Score (VAS) Between Week 12 and Week 24 | The VAS is a commonly used validated tool for assessment of pain. The 10-cm VAS was used to assess current patient pain/discomfort before and after application of ice to study lesions. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Scale is 0-10. 10 denotes worse pain than 0. | Between week 12 and 24 | 
| Immunohistochemical Staining of Cutaneous Leiomyomas for Acetylcholinesterase (AchE) Before (i.e.,Week 0) and 12 Weeks After Botulinum Toxin Administration | AchE staining was scored as 0 (none), 1 (rare), 2 (scattered), or 3 (focal or greater). | Week 0 vs. week 12 | 
| Immunohistochemical Staining of Cutaneous Leiomyomas for C-fos Before (i.e., Week 0) and 12 Weeks After Botulinum Toxin Administration | c-fos, a marker of neuronal activation after pain stimulation, was scored as 0 (none), 1 (scattered), 2 (<66% of tumor cells), or 3 (≥66% of tumor cells). | Week 0 vs. week 12 | 
| Percentage of Patients With a Change in Average Pain Score | Average pain was determined from a 0-10 scale question on the Brief Pain Inventory (BPI). 10 denotes worse pain. | Week 0 score vs. week 4 score | 
| Percentage of Patients With a Change in Pre-Ice Visual Analog Score (VAS) Between Week 0 and Week 4 | The VAS is a commonly used validated tool for assessment of pain. The 10-cm VAS was used to assess current patient pain/discomfort before and after application of ice to study lesions. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Scale of 0-10. 10 = worse pain. | Week 0 vs. week 4 | 
| Percentage of Patients With a Change in Post-Ice Visual Analog Score (VAS) Between Week 0 and Week 4 | The VAS is a commonly used validated tool for assessment of pain. The 10-cm VAS was used to assess current patient pain/discomfort before and after application of ice to study lesions. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Scale is 0-10. 10 = worse pain. | Week 0 vs. week 4 | 
| Worst Pain Severity | Pain severity was assessed by the Brief Pain Inventory (BPI). The BPI is a validated pain assessment tool that assesses severity of pain, location of pain, impact of pain on daily functions, pain medications, and amount of pain relief in the past 24 hours or past week (e.g. scale of 0-10 (worst pain)). This outcome was based on a single 0-10 question on the BPI. | Week 0 vs. week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cutaneous Leiomyomas, Skin Pain, Botox Therapy, Hereditary Leiomyomatosis, Renal Cell Cancer, Cutaneous Leiomyoma