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

This study has been terminated.
(Study drug expiration and supply shortage)
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Harvey Jay Cohen, Duke University Medical Center Identifier:
First received: January 6, 2012
Last updated: October 26, 2015
Last verified: October 2015
The purpose of this study is to determine whether treatment of unexplained anemia in older adults and elevated inflammatory markers with oral salsalate can improve hemoglobin levels and improve physical activity and quality of life.

Condition Intervention Phase
Drug: Salsalate
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo Controlled Pilot Trial of Oral Salsalate in the Treatment of the Subset of Unexplained Anemia in Elderly Patients With Elevated Interleukin-6

Resource links provided by NLM:

Further study details as provided by Duke University:

Primary Outcome Measures:
  • Change in Hemoglobin Level From Baseline to 6 Month Visit [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To test whether the administration of oral salsalate to a subset of elderly subjects with unexplained anemia (UAE) and high interleukin (IL-6) levels will improve hemoglobin level

Secondary Outcome Measures:
  • Assessment in Inflammatory Proteins [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To assess whether oral salsalate reduces markers of inflammation including IL-6, Tumor Necrosis Factor Receptor1 (TNF-R1), and C-reactive protein (CRP) in UAE subjects

  • Assessment of Serum Biomarkers of Erthropoiesis [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To assess whether oral salsalate improves serum biomarkers of erythropoiesis by increasing erythropoietin (Epo) and decreasing growth differentiation factor-15 (GDF-15) in UAE subjects

  • Reduction in Serum Hepcidin Levels [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To assess whether salsalate will reduce serum hepcidin levels and whether such a change is proportional to the decline in IL-6 levels

  • Change in Cognitive Outcome Measures [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To quantify the impact salsalate treatment on the following functional and self-report outcome measures as assessed by the geriatric evaluation panel (GEP) consisting of the following:Trail-Making Test and CogState cognitive tests; Short-Form 36 and physical component score (PCS) subscale; Functional Assessment in Chronic Illness Therapy-Anemia (FACIT-An).

  • Change in Self Reported Outcomes Measures [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To quantify the impact of anemia treatment with oral salsalate on self-reported outcomes measures by change in Short Form 36 (SF-36) 8 scale scores and the physical component score and FACIT-AN 5 subscale scores, a trial outcome index and a total score

  • Change in Frailty Index [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To quantify the impact of anemia treatment with oral salsalate on change in the frailty index as measured by change in self-reported exhaustion score, self-reported activity level score, Grip-strength (kgs) and 4 meter walk speed (meters/sec)

Other Outcome Measures:
  • To Assess Whether Oral Salsalate Improves Performance in the 6 Minute Walk Test (6MWT) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To assess the impact of treatment of anemia with oral salsalate will improve 6 minute walk test (6MWT) distance from baseline to 6 months as measured in meters and centimeters.

  • Change in Markers of Inflammation [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To assess whether treatment of anemia with oral salsalate reduces markers of inflammation from baseline to 6 months. Inflammatory markers to be measured are iL-6, Tumor Necrosis Factor alpha Receptor1 (TNF-R1), and C-reactive protein (CRP) in anemia subjects

Enrollment: 11
Study Start Date: March 2012
Study Completion Date: November 2014
Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Active drug - oral salsalate
Subjects randomized to active drug arm will receive 750mg of salsalate (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 (if the 750mg dose was tolerated) for a further 5 months. Total treatment time is 6 months.
Drug: Salsalate
Salsalate 750mg tablet 1 pill bid for one month followed by Salsalate 750mg tablets 2 pills (1500mg) twice a day for a further 5 months (total duration of treatment will be 6 months)
Other Names:
  • salicylate
  • salicylate acid
Placebo Comparator: Placebo Arm
Subjects randomized to the placebo arm will receive a matching placebo pill (one pill) twice a day (am and pm) for one month. After one month the dose will be increased to 2 matching placebo pills twice a day (if the one pill dose was tolerated) for a further 5 months. Total treatment time is 6 months.
Drug: Placebo
Placebo tablet - one pill twice daily for one month, followed by 2 pills twice daily for a further 5 months. Total duration of treatment is 6 months
Other Name: Placebo tablet

Detailed Description:

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.


Ages Eligible for Study:   65 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01506726

United States, Florida
Lakeview Medical Research
Summerfield, Florida, United States, 34491
United States, Georgia
St Joseph's/Candler Health System
Savannah, Georgia, United States, 31405
United States, Illinois
University of Illinois, Chicago
Chicago, Illinois, United States, 60612
University of Chicago Medical Center
Chicago, Illinois, United States, 60637
United States, Kentucky
Central Kentucky Research Associates
Lexington, Kentucky, United States, 40509
United States, Maryland
Johns Hopkins University Geriatrics Center
Baltimore, Maryland, United States, 21224
United States, Ohio
Case Western Reserve University Medical Center
Cleveland, Ohio, United States, 44106
United States, Tennessee
Clinical Research Solutions
Columbia, Tennessee, United States, 38401
Clinical Research Solutions
Franklin, Tennessee, United States, 37064
Clinical Research Solutions
Smyrna, Tennessee, United States, 37167
United States, Utah
University of Utah School of Medicine
Salt Lake City, Utah, United States, 84132
United States, Virginia
Institute for Advanced Studies in Aging (IASIA)
Falls Church, Virginia, United States, 22042
Sponsors and Collaborators
Harvey Jay Cohen
National Institute on Aging (NIA)
Principal Investigator: William Ershler, MD Institute for Advanced Studies in Aging (IASIA)
Study Chair: Stanley Schrier, MD Stanford University
Principal Investigator: Jeremy Walston, MD Johns Hopkins University
  More Information

Additional Information:
Responsible Party: Harvey Jay Cohen, Director, Professor and Chair, Duke University Medical Center Identifier: NCT01506726     History of Changes
Other Study ID Numbers: Pro00033852  U01AG034661 
Study First Received: January 6, 2012
Results First Received: October 26, 2015
Last Updated: October 26, 2015
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
unexplained anemia
older adults
over 65

Additional relevant MeSH terms:
Hematologic Diseases
Salicylsalicylic acid
Sodium Salicylate
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action processed this record on July 28, 2016