A Two-Part Study of BOTOX® Therapy for Ischemic Digits

A 28-Day Randomized, Double-Blind, Placebo-Controlled Clinical Trial and 5-Year Prospective Outcomes Study: A Two-Part Study of BOTOX® Therapy for Ischemic Digits

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.

Study Overview

• Status: Completed
• Conditions: Raynaud's Disease
• Intervention / Treatment: Drug: onabotulinum toxin type-A

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• aged 18-75 years
• diagnosed with Raynaud's disease/phenomenon
• ischemia not due to peripheral artery disease or other vascular disease
• otherwise healthy individual
• up-to-date tetanus immunization
• ability to return/be available for follow-up evaluations
• ability/willingness to give informed consent

Exclusion Criteria:

• HIV/AIDS positive or otherwise immunocompromised
• history of neuromuscular disease
• reported allergy to BOTOX®; reported allergy to lidocaine or other local anesthetic agent
• ever received botulinum toxin vaccine
• ultrasound or angiogram showing digital ischemia due to blocked vessel and not Raynaud's disease
• history or symptoms of any significant medical problem in the last year (i.e., bradycardia, impaired cardiovascular function, liver disease)
• symptoms of infection or illness during initial enrollment
• pregnant or lactating women
• unable or unwilling to maintain abstinence or use contraception for 28 days following all injections
• cognitive impairment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: placebo; no intervention
Active Comparator: 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	Drug: 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; Other Names: BOTOX®; botulinum toxin type A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Southern Illinois University
• Investigators: Principal Investigator: Michael W Neumeister, MD, Southern Illinois University School of Medicine

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Allergan product website
• U.S. Food and Drug Administration
• Drugs@FDA; U.S. Food and Drug Administration

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): May 19, 2016
• Study Completion (Actual): July 13, 2016

Study Registration Dates

• First Submitted: March 4, 2011
• First Submitted That Met QC Criteria: March 4, 2011
• First Posted (Estimate): March 7, 2011

Study Record Updates

• Last Update Posted (Actual): January 8, 2019
• Last Update Submitted That Met QC Criteria: January 7, 2019
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: ischemia; botulinum toxin A; botulinum toxin; botox; botox treatment; onabotulinum; onabotulinum toxin; onabotulinum toxin type A; raynaud's; raynaud's disease; raynaud's syndrome; raynaud's phenomenon; ischemic digits
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Peripheral Vascular Diseases; Raynaud Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
• Other Study ID Numbers: NEU-SIUSOM-11-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: We will not be sharing data.