Diosmiplex (Vasculera®) in Primary and Secondary Raynaud's Phenomenon

Raynaud's phenomenon is a disorder characterized by spasm of digital arteries leading to
blanching, coldness and discomfort of the affected digit, affecting up to 3-5% of the
population at some time in their lives. Raynaud's is roughly classified into primary and
secondary forms. The primary form may occur without apparent cause or following such things
as acute trauma, repetitive vibrating trauma or frostbite. Secondary Raynaud's occurs in
association with a variety of systemic immunological diseases such as rheumatoid arthritis
(RA), systemic lupus erythematosus (SLE), systemic sclerosis (SS) and Sjogren's syndrome.
Perhaps the most severe forms are associated with systemic sclerosis, less often in SLE
where severe microvascular changes can lead to digital ulcerations which are difficult to
heal and produce considerable functional impairment Treatment of Raynaud's has been a
significant clinical challenge. The primary modality is to avoid cold exposure. Many drug
classes have been shown to have some, but highly variable and potential toxicities.

Diosmiplex is a prescription medical food product composed of the botanical based flavonoid
molecule, diosmin, and a proprietary systemic blood alkalinizing agent, Alka4-complex.
Diosmin has been used successfully in Europe as a drug for chronic venous insufficiency and
its complications, including venous ulcers for more than 35 years. There is a large body of
published literature regarding the molecular activity, clinical efficacy and safety of the
active molecule in diosmin as well as its effects on the microvasculature where it has been
shown to reduce inflammation, improve structural integrity, reduce capillary damage and
improve capillary flow but no prospective clinical studies have been published regarding its
effect in Raynaud's phenomenon. This will be the first prospective study to examine the
efficacy and safety of diosmin, as diosmiplex, in both primary and secondary Raynaud's. The
study will intentionally seek to enroll a subset of subjects with scleroderma with Raynaud's
complicated by digital ulcers.

This will be a two (2) month randomized, double blind, placebo controlled study. Patients
with either primary or secondary Raynaud's phenomenon present for at least 12 months and
either untreated or inadequately controlled on therapy, defined as having at least four (4)
vasospastic episodes/week, will be eligible for enrollment

Inclusion Criteria:

- either gender, ages 18-80

- established diagnosis of primary or secondary Raynaud's phenomenon

- minimum of 4 vasospastic episodes/week

- medication specifically for Raynaud's must be stable for 30 days prior to the
screening visit and must be maintained unchanged for the duration of the study
medication specifically for digital ulceration must be stable for 60 days prior to
the screening visit and must be maintained unchanged for the duration of the study

- not pregnant or breast feeding

- using approved method of birth control if capable of becoming pregnant (Appendix II)

- capable of reading and understanding the informed consent document

Exclusion Criteria:

- pregnant or nursing women

- any change in dose of oral medication specifically for Raynaud's or digital ulcers
including, but not limited to, vasodilators, adrenergic blockers, antihypertensives,
calcium channel blockers, ACE inhibitors, phosphodiesterase inhibitors (e.g.,
sildenofil,) endothelin receptor antagonists (e.g., bosentan), prostanoids (e.g.,
iloprost) within the 30 days prior to the screening visit for Raynaud's and /or 60
days for digital ulcers and during the duration of the study.

- any intravenous or intra-arterial Raynaud's therapy within 1 month prior to the
screening visit

- Raynaud's secondary to mechanical (non-thermal) trauma

- concomitant use of diclofenac or metronidazole

- history of unstable coronary artery disease, chronic hepatic disease with ALT, AST,
or alkaline phosphatase >1.3 time upper limit of normal for reference laboratory,
renal disease with serum creatinine >2.5 or any gastrointestinal disease that could
potentially interfere with absorption of the study product.

- history of substance abuse including "recreational drugs" and/or alcohol intake in
excess of one unit daily. For the purposes of this study a unit of alcohol is defined
as 12 ox. of beer, 6 oz. of wine or 1.5 oz. of hard liquor.

- history of any significant medical condition that, in the opinion of the investigator
might put the subject at risk in this trial

- participation in another clinical trial within 30 days of the screening visit or 7
half lives of the study product, whichever is longer