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

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.

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