Thalidomide for Decreasing Collagen Biosynthesis in People With Progressive Systemic Sclerosis

Progressive systemic sclerosis (SSc), also known as scleroderma, is a disease of the body's
connective tissue. It is characterized by fibrosis of the skin, or formation of scar-like
tissue, resulting in progressively increased restriction of joint range of motion. Fibrosis
of internal organs also occurs, leading to irregular heart rhythms, acid reflux, and
respiratory problems. Unfortunately, no therapies have been developed to effectively treat
SSc.

The disease is believed to be an immunological disorder that affects T-helper type 2 (Th2)
cells, which stimulate the production of antibodies and interleukin-4 (IL-4), a protein with
profibrotic properties. T-helper type 1 (Th1) cells produce interferon-γ (IFN-γ), a protein
that prevents fibroblast production of collagen, a primary component of the body's
connective tissue. It is possible that shifting the disease's target from the Th2 cells to
the Th1 cells may decrease collagen production, and thereby reduce fibrosis. Thalidomide is
an immune modulatory drug that has been shown to stimulate production of Th1 cells. This
study will evaluate the effectiveness of thalidomide in treating adults with SSc.

Following screening procedures, participants in this 48-week, double-blind study will be
randomly assigned to receive placebo or thalidomide at a dose of 50 mg/day. The thalidomide
dose will be increased to 100 mg/day at Week 2, then to 200 mg/day at Week 4, and finally to
300 mg/day at Week 6. Participants who experience dose intolerance will immediately switch
to the previously tolerated dose. Inpatient hospital visits lasting 2 days will occur at the
beginning of the study before starting thalidomide treatment and at Weeks 16 and 48.
Assessments and procedures at these visits will include blood and urine collection, a
physical exam, a chest X-ray, an electrocardiogram, a skin biopsy, and various
questionnaires. Outpatient study visits will occur at Weeks 2, 4, 6, 8, 12, 18, 20 and then
every 4 weeks until Week 44. Assessments will include measures of immune function, clinical
disease, hypothalamic-pituitary-adrenal axis, and safety. Following the Week 48 inpatient
visit, thalidomide will be tapered off over a 2-week period for all participants.

Inclusion Criteria:

- Diagnosis of scleroderma

- Agrees to use an effective form of contraception for 1 month prior to study entry,
throughout the study, and for 60 days after completing the study

- Positive serum anti-nuclear antibody titer

Exclusion Criteria:

- Systemic sclerosis-like illnesses associated with environmental, ingested, or
injected agents or with other connective tissue diseases

- Significant existing damage to any of the following internal organs:

- Kidneys, defined as a serum creatinine level greater than 2 mg/dl or renal
crisis

- Lungs, defined as needing supplemental oxygen

- Heart, defined as left ventricular ejection fraction less than or equal to 40%

- Gut, defined as pseudo-obstruction or malabsorption requiring total parental
nutrition

- Concurrent interventional therapy that might independently influence the outcome of
this trial (e.g., D-penicillamine, cyclosporine, interferon-γ, methotrexate, or
photophorosis)

- Clinically significant and inadequately medically treated concurrent endocrine,
blood, liver, lung, or kidney diseases

- Pregnant

- Recent drug or alcohol abuse

- Documented noncompliance

- Significant psychiatric history

- Therapy with another investigational drug within 4 weeks prior to study entry

- Screening laboratory results exceeding the following limits: hemoglobin level less
than 7 gm/dl; white blood cell level less than 3,000/nl; platelet count less than
50/nl; alanine aminotransferase (ALT) level greater than 65 U/L; creatinine level
greater than 2 mg/dl