Study of Efficacy of ARA 290 on Corneal Nerve Fiber Density and Neuropathic Symptoms of Subjects With Sarcoidosis

The purpose of this study is to determine whether ARA 290, a new class of compound, is effective in the treatment of the neuropathic symptoms of sarcoidosis. Brief interaction of ARA 290 with the innate repair receptor results in anti-apoptotic and anti-inflammatory activities in myriad of cells, tissues and organs throughout the body to activate repair mechanisms and accelerate healing, including the nerve damage that can be associated with sarcoidosis. In this study, subjects with sarcoidosis and symptoms of small fiber neuropathy will administered ARA 290 or placebo by subcutaneous injection daily for 28 days. In addition to monitoring the safety of the treatment, the symptoms of the subjects will be assessed with several questionnaires, function tests, and measurement of nerve fibers in their cornea and skin (via a non-invasive test and a biopsy, respectively). The total participation time for each patient will be 16 weeks.

This was a double-blind, randomized, placebo-controlled study to assess the effects of daily SC administration of ARA 290 at a dose of 1 mg, 4 mg, or 8 mg or placebo on corneal nerve fiber density of subjects with sarcoidosis and neuropathic symptoms consistent with small fiber neuropathy. The safety of these doses was also assessed.

Up to 64 subjects with sarcoidosis and symptoms of small fiber neuropathy were planned to be enrolled in the study. Subjects determined to be eligible at the screening visit were asked to return to the study site for the start of the treatment period (Visit 1, study day 1) within 28 days of screening. Subjects who were not able to return for Visit 1 within 28 days of the screening visit could be rescreened. At Visit 1, the subjects were randomized to one of 4 treatment groups (approximately 16 subjects per group): 1 mg, 4 mg, or 8 mg of ARA 290 or placebo. The study drug (ARA 290 or placebo) was to be administered daily for 28 days via SC injection. The first injection of study drug was administered at the study site at Visit 1. After the first injection, the subjects were required to stay at the research site for 1 hour post dose for safety observation and recording of any adverse events (AEs). The subjects were trained for self-injection of the study drug and asked to self-administer the study medication daily at home before breakfast for the remaining treatment period using the supplied individual vials and disposable insulin needles and syringes.

The subjects were asked to visit the study site after 14 ± 2 days of dosing (Visit 2) and at the end of the treatment period Day 28 ± 2 (Visit 3). Additionally, the study personnel contacted the subjects by telephone at study days 7 and 21. Following the treatment period the subjects were followed-up for a further 12 weeks (until study day 112). During this period the subjects visited the study site at Day 56 ± 2 days (Visit 4) and study personnel contacted the subjects by telephone at study days 35 and 42 and biweekly from study days 70 to 112. The duration of study participation for each subject was 16 weeks. Throughout the study the subjects were asked to complete several questionnaires regarding general health and well-being, pain, fatigue and neuropathic symptoms. Further assessments included the 6MWT, and determination of nerve fiber density. If feasible at the site, quantitative sensory and cardiac autonomic reflex testing were to be performed.

The protocol was later amended to administer the Columbia-Suicide Severity Rating Scale (C-SSRS). Any positive results for active suicidal ideation and behavior, based on evaluation of the C-SSRS questionnaire, were reported as AEs. During the treatment period the subjects were also asked to complete a diary card to document compliance. Safety assessments included the documentation of AEs, vital signs and electrocardiogram (ECG), safety laboratory, physical examination and a test for ARA 290 antibodies.

Eligibility Criteria:
Inclusion Criteria:

• Established diagnosis of sarcoidosis with both of the following two criteria:

1. Score of 4 or greater on Brief Pain Inventory "pain now" or "average pain" questions (BPI; 0 (least discomfort)-10 (worst discomfort))
2. Discomfort defined as distal pain/discomfort plus one of the following: 1) dysesthesia, 2) burning/painful feet worsening at night, or 3) intolerance of sheets or clothes touching the legs or feet

AND either of the following two criteria

1. Corneal nerve fiber density reduced compared to normal (i.e., greater than 1 standard deviation less than the mean of a normative population)
2. A previous skin biopsy (obtained within the prior 2 years) showing a reduced intraepidermal nerve fiber density ((i.e., greater than 1 standard deviation less than the mean of a normal age and gender relevant population)

In addition, subjects must:

* Be able to read and understand the written consent form, complete study-related procedures, and communicate with the study staff
* Be willing to comply with study restrictions
* Be willing to check in with the study center via the telephone
* Between 18 and 70 years of age (inclusive)
* Body Mass Index (BMI) \< 40 kg/m2 (inclusive)
* If female of childbearing potential, a negative urine pregnancy test at screening and acceptable contraception will be maintained during the screening and dosing period and 1 month beyond. Acceptable contraception consists of hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 full cycle (based on the subject's usual menstrual cycle period) before study entry, intrauterine device (IUD), or double barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream).
* Able to complete self-administered questionnaires (RAND-36, SFNSL, BPI, FAS, NPSI)
* Refrigerator and freezer at home for storage of study medication.

Exclusion Criteria:

* Clinically relevant abnormal history of physical and mental health other than conditions related to sarcoidosis, as determined by medical history taking (as judged by the investigator)
* Clinically relevant abnormal laboratory results, vital signs, or physical findings other than conditions related to sarcoidosis or could interfere with conduct of 6-minute walk assessment (as judged by the investigator)
* Other medical conditions known to be associated with small nerve fiber loss, except for diabetes in good control (as judged by the investigator)
* Known clinically relevant abnormalities in ECG (as judged by the investigator)
* Illicit drug abuse or excessive alcohol consumption (as judged by the investigator)
* History of serious malignancy within the last 5 years other than a basal cell or squamous cell carcinoma of the skin that has been removed
* History of severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food (as judged by the investigator)
* Anti-TNF therapy, other biological anti-inflammatory agents, or immunoglobulins administered within the 3 months prior to screening.
* Use of erythropoiesis stimulating agents within the two months prior to screening or during the trial
* Participation in an investigational drug trial in the 3 months prior to administration of the initial dose of study drug or more than 4 times in the calendar year preceding study enrollment
* Inadequate venous accessibility as judged by clinicians (physician or nurse)
* Inability or unwillingness to self-administer ARA 290 via subcutaneous injections (or not have access to home health care for assistance in administration)
* If female, pregnant or breast-feeding
* Any other condition that in the opinion of the investigator would complicate or compromise the study, or the well-being of the subject