Study To Assess The Clinical Benefit Of Droxidopa In Subjects With Chronic Fatigue Syndrome

This is a phase II, single-center, open-label study to evaluate the efficacy and safety of
droxidopa in subjects with chronic fatigue syndrome. The study will enroll enough subjects
to allow 20 to be placed in the 12 week open label treatment period.

The study will consist of an initial screening period (up to 7 days) to confirm eligibility
followed by an up to 2 week dose titration period, a 12 week treatment period and a 30 day
follow up period to account for any new or on-going AEs. During the screening visit the
following assessments will be recorded:

- Demography;

- Medical history;

- Physical examination;

- ECG;

- Vital signs (BP, HR, weight)

- Stand Test (measurement of BP and heart rate in the supine position (head and torso
elevated at approximately 30° from horizontal) 10, 5, immediately before and 1, 5 and
10 minutes after standing);

- Tilt Table Test

- Blood samples for hematology and biochemistry;

- Urine sample for urinalysis

- Pregnancy test for females of child bearing potential.

- Concomitant medication review o Subjects taking ephedrine or midodrine will stop taking
these drugs for at least 7 days before the baseline assessments.

Within 7 days of successful screening, the following baseline assessments will be recorded:

- Inclusion/Exclusion review;

- Standing test (measurement of BP and heart rate 10, 5, immediately before and 1, 5 and
10 minutes after standing);

- Vital signs (BP, HR, and weight);

- Urine/serum pregnancy test for WOCP;

- Concomitant medications;

- Adverse events

- Multidimensional Fatigue Inventory (MFI);

- Brief Pain Inventory (BPI);

- Clinical Global Impression of Severity (CGI-S);

- Hospital Anxiety and Depression Scale (HADS);

- Patient Global Impression of Improvement (PGI-I).

Following successful completion of screening and baseline procedures, subjects will enter
the dose titration period. Subjects will be titrated upwards by 100 mg TID, preferably on
consecutive days but definitely within 14 days of entry, until one of the following 3
criteria for ceasing dose escalation is met:

1. The subject has a sustained SBP of greater than 140 mmHg or DBP of greater than 90 mmHg
after 1, 5 or 10 minutes of standing, OR a sustained SBP greater than 150 mmHg or DBP
greater than 100 mmHg measured in the supine position (head and torso elevated at
approximately 30° from horizontal).

2. The subject is unable to tolerate side effects believed to be related to the study
medication;

3. The subject reaches the maximum dose of 600 mg TID droxidopa. If a subject meets
criteria 1 they will proceed directly to the treatment period at the previous lower
dose. Subjects meeting criteria 2 will also proceed directly to the treatment period
at the previous lower dose. Subjects meeting criteria 3 will enter immediately into
the treatment period at 600 mg TID.

Subjects that meet criteria 1 or 2 at the initial 100 mg TID dose will be considered
baseline failures.

During treatment, the investigator can determine whether to modify the subject's dose. This
determination will be based on the subject's tolerability of droxidopa.

Upon successful completion of the dose titration, subjects will begin a 12 week treatment
period. Subjects will return to the clinic every 4 weeks (+/- 3 days) for efficacy, safety
and compliance check. A follow-up call will occur 30 days after completion or removal of
the trial to record any new or on-going AEs.

droxidopa

droxidopa [also, known as L-threo-3,4-dihydroxyphenylserine, L-threo-DOPS, or L-DOPS] is the
International non-proprietary name (INN) for a synthetic amino acid precursor of
norepinephrine (NE), which was originally developed by Sumitomo Pharmaceuticals Co.,
Limited, Japan. It has been approved for use in Japan since 1989.

Droxidopa has been shown to improve symptoms of orthostatic hypotension that result from a
variety of conditions including Shy Drager syndrome (Multiple System Atrophy), Pure
Autonomic Failure, and Parkinson's disease. There are four stereoisomers of DOPS; however,
only the L-threo-enantiomer (droxidopa) is biologically active.

The exact mechanism of action of droxidopa in the treatment of symptomatic NOH has not been
precisely defined; however, its NE replenishing properties with concomitant recovery of
decreased noradrenergic activity are considered to be of major importance.

Droxidopa has been marketed in Japan since 1989. Data from clinical studies and
post-marketing surveillance programs conducted in Japan show that the most commonly reported
adverse drug reactions with droxidopa are increased blood pressure, nausea, and headache. In
clinical studies, the prevalence and severity of droxidopa adverse effects appear to be
similar to those reported by the placebo control arm.