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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Anemia

Intervention / Treatment
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* Drug: Salsalate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active drug - oral salsalate<br>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<br>* 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)<br>* Other names: salicylate acid;|
| Placebo Comparator: Placebo Arm<br>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<br>* 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<br>* Other names: Placebo tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hemoglobin Level From Baseline to 6 Month Visit | 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 | baseline; 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Markers of Inflammation | To assess whether oral salsalate reduces markers of inflammation including IL-6 and Tumor Necrosis Factor Receptor1 (TNF-R1) in UAE subjects. Change in the marker from prior to study drug to 6 months. | prior to study drug; 6 months | 
| Assessment of Serum Biomarkers of Erthropoiesis | To assess whether oral salsalate improves serum biomarkers of erythropoiesis by increasing erythropoietin (Epo) in UAE subjects. Change in the Epo from prior to study drug to 6 months. | prior to study drug; 6 months | 
| Change in Serum Hepcidin Levels | To compare the change in serum hepcidin levels between treatment groups and whether such a change is proportional to the decline in IL-6 levels. Change in the hepcidin from prior to study drug to 6 months. Positive changes represent increases in hepcidin levels and negative changes represent decreases. | prior to study drug; 6 months | 
| Change in Cognitive Outcome Measures-Trail Making Test Part B | To quantify the impact of anemia treatment by salsalate on cognitive outcomes based on the Trail Making Test (TMT) Part B as measured by subjects drawing a line from 25 circled numbers to letters in 300 seconds. The change in seconds per completed circle from baseline to month 6. | baseline; 6 months | 
| Change in Frailty Component Related to Fatigue/ Exhaustion | Subjective fatigue/exhaustion: If any of the following three criteria are met, the patient will be classified as frail for fatigue/exhaustion: In the past month, on average, have you been feeling unusually tired during the day? is answered yes and indicated as all of the time or most of the time. In the past month, on average, have you felt unusually weak? is answered yes and indicated as all of the time or most of the time. Energy level on a scale of 0 (no energy) to 10 (most energy) reported as ≤ 3. If the subject answers YES to any of the above noted 3 questions, then they are classified as FRAIL. The change in frailty for fatigue/ exhaustion is defined as changing from frail at baseline to not frail at month 6 as reported by the subject. | baseline; 6 months | 
| Assessment of Serum Biomarkers of Erthropoiesis | To assess whether oral salsalate improves serum biomarkers of erythropoiesis by decreasing growth differentiation factor-15 (GDF-15) in UAE subjects. Change in the GDF-15 from prior to study drug to 6 months. | prior to study drug; 6 months | 
| Change in Cognitive Outcome Measures as Determined by Speed of Processing | To quantify the impact of anemia treatment by salsalate on cognitive outcomes based on speed of processing was derived using the z-scores of the following three tests: (1) TMT Part A seconds per completed circle, (2) simple reaction time from the CogState Detection Task, and (3) choice reaction time from the CogState Identification Task. The composite score for a subject at each time point was defined as the mean of the Z-scores for the three tests at the time point. For each subject, the Z-score for each test at time point was derived by subtracting the subject's score at the time point from the overall baseline mean of the test and then dividing by the overall baseline standard deviation of the test. Positive z-scores indicate a better performance compared to the baseline average.The change in the Z-score from baseline to month 6. | baseline; 6 months | 
| Change in Cognitive Outcome Measures as Determined by Composite Complex Attention/Executive Processing | To quantify the impact of anemia treatment by salsalate on cognitive outcomes based on Complex attention/executive processing was derived using the z-scores of the following three tests: (1) TMT Part B seconds per completed circle, (2) time score from the CogState One Back Task, and (3) accuracy score from the CogState One Back Task. The composite score for a subject at each time point was defined as the mean of the Z-scores for the three tests at the time point. For each subject, the Z-score for each test at time point was derived by subtracting the overall baseline mean of the test from the subject's score at the time point (accuracy score) or by subtracting the subject's score at the time point from the overall baseline mean of the test (TMT and time score) and then dividing by the overall baseline standard deviation of the test. Positive z-scores indicate a better performance compared to the baseline average. The change in the Z-score from baseline to month 6. | baseline; 6 months | 
| Change in Cognitive Outcome Measures as Determined by Composite Learning and Memory | To quantify the impact of anemia treatment by salsalate on cognitive outcomes based on Learning and memory was derived using the z-scores of the following three tests: (1) CogState ISL immediate recall score (total score from three learning trials), (2) CogState ISL immediate recall score from the first learning trial, and (3) CogState ISL delayed recall scores. The composite score for a subject at each time point was defined as the mean of the Z-scores for the three tests at the time point. For each subject, the Z-score for each test at time point was derived by subtracting the overall baseline mean of the test from the subject's score at the time point and then dividing by the overall baseline standard deviation of the test. Positive z-scores indicate a better performance compared to the baseline average. The change in the Z-score from baseline to month 6. | baseline; 6 months | 
| Change in Self Reported Outcomes Measures as Reported by Short Form-36 (SF-36) Physical Component Score (PCS) | To quantify the impact of anemia treatment by salsalate on self-reported outcomes measures by change in SF36 physical component score. The SF-36 form identifies self-report physical function and global measure of quality of life and is a multi-purpose, short-form health survey consisting of 36 questions. The Physical Component Summary (PCS) is a subscale of the SF-36 that correlates with physical health domains of the SF-36 ( Physical Function, Role-Physical, and Bodily Pain). The change is calculated and compared from baseline to 6 months. The SF-36 PCS score is a norm based sore with a mean of 50 and standard deviation of 10 where results above and below 50 are above and below the average, respectively, in the 2009 general US population. | baseline; 6 months | 
| Change in Self Reported Outcomes Measures as Reported by FACIT-AN Total Score | To quantify the impact of anemia treatment by salsalate on self -reported outcomes measures by subjects answering 47 questions for patients with anemia and or fatigue. This test detects self-report functional changes and QoL. Change from baseline to 6 months. Scores range from 0-188 with higher scores indicating better function. | baseline; 6 months | 
| Change in the Frailty Component as Determined by Self-reported Activity Level | To quantify the impact of anemia treatment by salsalate on change in the frailty as measured by change in self-reported activity level. Frailty for activity level is classified by subjects responses to 6physical activity questions on the short version of the Minnesota Leisure Time Activity Questionnaire , were related to walking for exercise, moderately strenuous outdoor chores, dancing, bowling, and regular exercise. The Women's Health And Aging Study (WHAS) scoring algorithm was used to define frailty for self-reported activity level. The answers to these questions were used to calculate kilocalories (Kcals) per week, using the WHAS algorithm, which is further satisfied by by gender. For men, Kcals < 128 per week is frail. For women, Kcals < 90 per week is frail. This is a categorical measurement of yes or no. The outcome is the number of participants who were classified as frail at baseline and changed to not frail at 6 months. | baseline; 6 months | 
| Change in Frailty Component as Determined by Grip Strength | To quantify the impact of anemia treatment by salsalate on change in the frailty as measured by change in grip strength. Subjects squeeze the grip strength machine 3 times with each hand. For the frailty outcome the maximum grip strength from the dominant hand is used. (change from frail at baseline to not frail at 6 months). Grip strength is stratified by gender and BMI. For men with (BMI <= 24 and a grip strength (GS) <= 29) or (BMI 24.1-28 and grip strength <= 30) or (BMI >28 and a grip strength <= 32) were classified as frail. For women with (BMI <= 23 and a grip strength of <= 17) or (BMI 23.1-26 and a GS <= 17.3) or (BMI 26.1-29 and a GS <= 18) or (BMI > 29 and a GS <= 21) were classified as frail.The outcome is the number of participants who were classified as frail at baseline and changed to not frail at 6 months. | baseline; 6 months | 
| Change in Frailty Component as Determined by the 4 Meter Walk Speed | To quantify the impact of anemia treatment by salsalate on change in the speed of the 4 meter walk speed. Subjects are asked to walk as fast as they can for 4 meters. Frailty was determined by the subject's speed. (change from frail at baseline to not frail at 6 months). 4 m walking speed is stratified by gender and height. For men, (height of <= 173 cm and a walking speed of <= 0.65 meter/sec) or a (height > 173, <= .76 meter/sec) were classified as frail. For women, (height of <= 159 cm and a walking speed of <=.65 meter/sec) or (height >159 cm <= 0.76 meter/sec) were classified as frail.The outcome is the number of participants who were classified as frail at baseline and changed to not frail at 6 months. | baseline; 6 months | 
| Change in Markers of Inflammation | To assess whether oral salsalate reduces C-reactive protein (CRP) in UAE subjects. Change in the CRP from prior to study drug to 6 months. | prior to study drug; 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anemia, unexplained anemia, elderly, geriatric, older adults, UAE, over 65, salsalate, PACTTE, pactee, aging, aged, old, older