Trial To Evaluate the Efficacy of Oral Salsalate in the Treatment of Older Adults With Unexplained Anemia

There is well-defined morbidity and mortality associated with anemia in the elderly and the
increasing proportion of elderly adults underscores the population's attributable risk of
anemia. As a potentially modifiable factor, an urgent need exists to delineate the impact of
anemia correction in the elderly. The Partnership for Anemia: Clinical and Translational
Trials in the Elderly (PACTTE) consortium has been created to focus on treatment strategies
for anemia in elderly patients. The data presented in this protocol provides a compelling
rationale to evaluate the impact of an anti-inflammatory (Salsalate) in older anemic adults
with elevated serum iL-6 levels.

Subjects will be 65 years or older adults with unexplained anemia and a elevated serum iL-6
≥ 1.0 pg/mL.

Subjects will receive 750mg of salsalate or matching placebo (one pill) twice a day (am and
pm) for one month. After one month the dose will be increased to 1500mg (2 pills) twice a
day (am and pm) if the 750mg dose was tolerated for a further 5 months (for a total of 6
months)

The primary endpoint is to assess whether salsalate improves hemoglobin levels from baseline
to 6 month visit.

Inclusion Criteria:

- Understand and voluntarily sign an informed consent form

- Age 65 years and older, residing in the community or in an assisted-living facility

- Able to adhere to the study visit schedule and other protocol requirements

- Hemoglobin concentration ≥ 9.0 g/dL and < 11.5 g/dL for women and ≥ 9.0 to < 12.7
g/dL for men

- Unexplained anemia (See Appendix 2 for definitions of anemia diagnosis to determine
anemia is unexplained)

- Serum IL-6 level ≥ 1.0 pg/mL obtained during screening period (performed at central
laboratory).

- Must be able to understand and speak in English; or Spanish speaking subjects who do
not speak English may be enrolled per local IRB process and approval, provided the
site has appropriate bilingual study staff.

Exclusion Criteria:

- Red blood cell transfusions within the past 3 months

- Estimated glomerular filtration rate (eGFR) of < 30 ml/min (by abbreviated MDRD)

- Use of erythropoiesis stimulating agents (ESA) in the past 3 months

- Active infection defined as symptomatic, requiring active treatment (prophylaxis
allowed) or hospitalized for > 24 hours primarily for infection within the past month

- Uncontrolled hypertension defined as diastolic blood pressure > 95 mm Hg or systolic
blood pressure > 160 mm Hg on 2 separate occasions during screening period

- Distance on 6MWT above the median for age and sex adjusted population medians (see
Table 4)

- Other primary uncorrected cause for anemia including:

- Known active inflammatory disease including auto-immune diseases (e.g., systemic
lupus erythematosis, rheumatoid arthritis, mixed connective tissue disease,
sarcoidosis, bronchiolitis obliterans, vasculitis, polymyalgia rheumatica,
temporal arteritis, inflammatory bowel disease or related diseases);

- Chronic active infection (e.g., HIV, viral hepatitis, tuberculosis,
osteomyelitis) or receiving therapy within the past 3 months for chronic
infection

- Acute infection within past 3 months (pneumonia, sepsis, bacteremia,
prostatitis, urosepsis, pyelonephritis, cholecystitis)

- Receipt of immunosuppressive therapy in the past 2 years including prednisone
except for topical therapy

- Any cancer (aside from non-melanoma skin cancer) in the past 2 years or on
therapy for cancer. In addition, prostate cancer will be excluded if patients
have metastatic disease, have had prostatectomy within the prior 6 months, have
ever received external beam radiation therapy or brachytherapy, or have received
androgen deprivation therapy in the prior 24 months. Subjects with a history of
any other form of cancer will likewise be excluded if they have received any
radiation or chemotherapy in the prior 24 months.

- Fecal Occult Blood Test positivity in the past 3 years, Gastrointestinal
bleeding in past 3 years and history of peptic ulcer w/ evidence of bleeding

- Elevated AST or ALT ≥ 2x upper limit of normal

- Use of any other experimental drug or therapy within 28 days of initial screening
visit

- History of moderate tinnitus affecting instrumental activities of daily activities in
the past 3 months

- Current use of acetylsalicylic acid (aspirin) in doses greater than 82 mg/day in the
past 3 months. Subjects will also be ineligible if they consume or are expected to
consume non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids,
methotrexate, furosemide or anticoagulants during the course of this study.

- Elevated thyroid stimulating hormone (TSH), or other signs of hypothyroid condition.
Patients on a stable dose of thyroid replacement are eligible, providing TSH is not
elevated.

- Seizure disorder for which phenytoin is used for treatment.

- Hypersensitivity to salsalate, salicylic acid, or acetylsalicylic acid

- History of transient ischemic attacks (TIA), cerebral vascular accident, a clinical
diagnosis of angina or myocardial infarction, any coronary interventions (PCI,
Bypass, Stent placement) within the prior 12 months to reduce the risk of subject
requiring aspirin therapy during the trial

- Dementia defined as the inability to independently provide informed consent and a
Montreal Cognitive Assessment (MoCA) score < 22