A Study of Adalimumab to Treat Sarcoidosis of the Skin

The cutaneous lesions of sarcoidosis are often disfiguring and can produce functional impairment. They tend to be hard to treat with most topical therapies and often require systemic medications which carry the risk of significant side effects. Often such treatments are withheld unless there is a need to use them for visceral involvement. There is thus an unmet need for safe and effective treatments for these patients. In addition there is essentially no controlled trial data for any treatments for cutaneous sarcoidosis. This study is intended to determine if adalimumab might offer a viable therapeutic option for this condition by comparing the response of cutaneous sarcoid lesions to this drug as compared to placebo.

Inclusion criteria

• Subject is > 18 years of age.
• Subject must have moderate to severe cutaneous sarcoidosis with chronic indurated lesions (papules, nodules, and/or plaques), which histopathologically show non-caseating granulomas with negative special stains for microorganisms (AFB and PAS or GMS). Accepted clinical variants include, but are not necessarily limited to the following:

• lupus pernio
• nodular
• subcutaneous
• annular
• angiolupoid
• plaque
• papular
• lichenoid
• psoriasiform
• For purposes of this study "moderate to severe cutaneous sarcoidosis" is defined as the presence of sarcoidal skin lesions with any of the following features:

• At least 5 easily visible facial lesions, or
• Disease which involves > 3% BSA, or
• Disease which confers functional impairment (e.g. nasal or visual field obstruction), or
• Disease which confers significant symptoms of itching and/or pain.
• If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or is using one of the following methods of birth control for the duration of the study and 90 days after study completion:

• condoms, sponge, foams, jellies, diaphragm, or intrauterine device
• contraceptives (oral or parenteral) for three months prior to study drug administration
• a vasectomized sole partner
• Females of childbearing potential must have a negative serum pregnancy test at screening visit.
• Subject must have no history of nor evidence of tuberculosis, either active or previously treated. This determination will be based on a negative PPD skin test and negative chest radiograph at screening, negative history of previous tuberculosis, and negative history of previous exposure to tuberculosis.
• Subject must be willing and able to give informed consent and to comply with the requirements of the protocol.
• Subject must be willing and able to self-administer SC injections or to have a qualified person available to administer SC injections.
• The following criteria for concomitant treatments of sarcoidosis must be met:

• Topical therapies (corticosteroids) must be discontinued at least 2 weeks prior to baseline visit.
• Intralesional therapies (corticosteroids) must be discontinued at least 4 weeks prior to baseline visit.
• Systemic therapies (MTX, antimalarials, prednisone, immunosuppressants, thalidomide, tetracycline derivatives) must be discontinued at least 4 weeks prior to baseline visit.

OR if a subject is on such topical or oral medications, the dose has been stable for these same time intervals and is likely to remain stable for the duration of the study. Patients whose non-cutaneous disease is being managed by other physicians will continue to have their care directed by these physicians. The managing physicians will be kept informed of the patients' status, consistent with study blinding. If the patient's dose of a concomitant systemic therapy for non-cutaneous sarcoidosis must change by more than 20% of the dose at study entry due to a change in medical condition during the double-blind phase, the subject will be discontinued from the study. During the open-label phase the need for a greater than 20% increase in dose of concomitant treatment for non-cutaneous sarcoidosis will be viewed as treatment failure and the patient will be discontinued from the study. Reduction of the dose of such treatment of any magnitude will not result in discontinuance. Continued use of intralesional therapies is not permitted. Inhaled corticosteroids for a stable medical condition are allowed.

Exclusion criteria

• Evidence of other active skin diseases or skin infections during screening that may interfere with evaluation of sarcoidosis.
• Subject has a known sensitivity to any component of the study medication. (See Table 4.)
• Subject has an active infection requiring systemic antibiotics at time of screening.
• Subject has a history of malignancy or lymphoproliferative disease within the past 5 years, excluding successfully treated non-melanoma epithelial skin cancer and/or localized carcinoma in situ of the cervix.
• Subject has a history of congestive heart failure.
• Subject has a poorly controlled medical condition including, but not limited to, unstable cardiovascular disease, poorly controlled diabetes, recent stroke, history of recurrent infections, or any other condition for which, in the opinion of the investigator, participation in the study would place the subject at risk.
• Subject has a history of demyelinating CNS disease.
• Subject has a history of listeriosis, treated or untreated tuberculosis, exposure to individuals with tuberculosis, persistent or active infections requiring hospitalization or treatment with IV antibiotics, IV antiretrovirals, or IV antifungals within 30 days of baseline, OR oral antibiotics, antivirals, or antifungals for purpose of treating infection, within 14 days of baseline.
• Subject is currently using or plans to use antiretroviral therapy at any time prior to or during study.
• Previous use of anti-TNF agent(s).
• Receipt of any other investigational product within 30 days prior to the first dose of investigational product.
• Subject is known to have immune deficiency or is immunocompromised.
• Female subjects who are pregnant, breast feeding, or are considering becoming pregnant during the study or within 150 days of the last dose of study medication.
• Subject has a history of clinically significant drug or alcohol abuse in the last year.
• Subject is considered by the investigator, for any reason, to be an unsuitable candidate for study participation.
• Clinically significant ECG abnormalities at screening visit.
• Hgb < 8.5 g/dL in females and < 9.0 in males.
• WBC count < 3000/mm2
• AST or ALT > 2.0 times the upper limit of normal for the age range, confirmed by a repeat measure.
• Bilirubin > 3mg/dL
• Creatinine > 1.6 mg/dL in women, and > 1.8 mg/dL in men.
• Subject plans to receive any live vaccines during the study.
• Subject has a variant of sarcoidosis that is not amenable to study evaluation, in the absence of chronic indurated lesions, such as:

• Acute, "benign" sarcoid associated with erythema nodosum
• Acute iritis
• Ichthyosiform sarcoidosis
• Hypo- or hyperpigmented macular sarcoidosis
• Ulcerative sarcoidosis
• Erythroderma
• Alopecia