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

• Sponsor: Harvey Jay Cohen (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01506726
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 11
• Locations: 12
• Arms: 2
• Duration (Months): 32
• Patients Per Site: 0.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Anemia	Drug: Salsalate; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, 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
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Placebo tablet

Outcome Measures

Primary Outcome Measures

1. Change in Hemoglobin Level From Baseline to 6 Month Visit [baseline; 6 months]

   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

1. Change in Markers of Inflammation [prior to study drug; 6 months]

   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.

2. Assessment of Serum Biomarkers of Erthropoiesis [prior to study drug; 6 months]

   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.

3. Change in Serum Hepcidin Levels [prior to study drug; 6 months]

   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.

4. Change in Cognitive Outcome Measures-Trail Making Test Part B [baseline; 6 months]

   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.

5. Change in Frailty Component Related to Fatigue/ Exhaustion [baseline; 6 months]

   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.

6. Change in Cognitive Outcome Measures as Determined by Speed of Processing [baseline; 6 months]

   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.

7. Change in Cognitive Outcome Measures as Determined by Composite Complex Attention/Executive Processing [baseline; 6 months]

   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.

8. Change in Cognitive Outcome Measures as Determined by Composite Learning and Memory [baseline; 6 months]

   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.

9. Change in Self Reported Outcomes Measures as Reported by Short Form-36 (SF-36) Physical Component Score (PCS) [baseline; 6 months]

   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.

10. Change in Self Reported Outcomes Measures as Reported by FACIT-AN Total Score [baseline; 6 months]

    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.

11. Change in the Frailty Component as Determined by Self-reported Activity Level [baseline; 6 months]

    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.

12. Change in Frailty Component as Determined by Grip Strength [baseline; 6 months]

    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.

13. Change in Frailty Component as Determined by the 4 Meter Walk Speed [baseline; 6 months]

    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.

14. Change in Markers of Inflammation [prior to study drug; 6 months]

    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.

15. Assessment of Serum Biomarkers of Erthropoiesis [prior to study drug; 6 months]

    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.

Other Outcome Measures

1. Change in the 6 Minute Walk Test (6MWT) Distance. [baseline; 6 months]

   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.

2. Association Between Change in Hemoglobin and Change in Markers of Inflammation. [prior to study drug; 6 months]

   To examine whether there is an association between change in hemoglobin and changes in markers of inflammation from prior to study drug 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.Correlation between change in the inflammatory markers and the change in HB from prior to study drug to 6 months.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• 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

Locations

	Site	City	State	Country	Postal Code
1	Lakeview Medical Research	Summerfield	Florida	United States	34491
2	St Joseph's/Candler Health System	Savannah	Georgia	United States	31405
3	University of Illinois, Chicago	Chicago	Illinois	United States	60612
4	University of Chicago Medical Center	Chicago	Illinois	United States	60637
5	Central Kentucky Research Associates	Lexington	Kentucky	United States	40509
6	Johns Hopkins University Geriatrics Center	Baltimore	Maryland	United States	21224
7	Case Western Reserve University Medical Center	Cleveland	Ohio	United States	44106
8	Clinical Research Solutions	Columbia	Tennessee	United States	38401
9	Clinical Research Solutions	Franklin	Tennessee	United States	37064
10	Clinical Research Solutions	Smyrna	Tennessee	United States	37167
11	University of Utah School of Medicine	Salt Lake City	Utah	United States	84132
12	Institute for Advanced Studies in Aging (IASIA)	Falls Church	Virginia	United States	22042

Sponsors and Collaborators

• Harvey Jay Cohen
• National Institute on Aging (NIA)

Investigators

• 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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• PACTTE Consortium Website

Publications

None provided.

• Responsible Party: Harvey Jay Cohen, Director, Professor and Chair, Duke University
• ClinicalTrials.gov Identifier: NCT01506726
• Other Study ID Numbers: Pro00033852; U01AG034661
• First Posted: Jan 10, 2012
• Last Update Posted: Oct 18, 2016
• Last Verified: Aug 1, 2016

• Keywords provided by Harvey Jay Cohen, Director, Professor and Chair, Duke University: anemia; unexplained anemia; elderly; geriatric; older adults; UAE; over 65; salsalate; PACTTE; pactee; aging; aged; old; older
• Additional relevant MeSH terms: Anemia; Salicylic Acid; Salicylsalicylic acid; Salicylates

Study Results

Participant Flow

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Period Title: Overall Study
STARTED	6	5
COMPLETED	5	3
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm	Total
Arm/Group Description	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. 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)	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. 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	Total of all reporting groups
Overall Participants	6	5	11
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	82.2 (3.4)	74.2 (4.7)	78.5 (5.6)
Sex: Female, Male (Count of Participants)
Female	3 50%	4 80%	7 63.6%
Male	3 50%	1 20%	4 36.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	6 100%	5 100%	11 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	6 100%	3 60%	9 81.8%
Black or African American	0 0%	1 20%	1 9.1%
Asian	0 0%	1 20%	1 9.1%
Hemoglobin (g/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/dL]	11.12 (0.55)	11.28 (0.34)	11.19 (0.45)

Outcome Measures

1. Primary Outcome

Title	Change in Hemoglobin Level From Baseline to 6 Month Visit
Description	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
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	6	5
Mean (Standard Deviation) [g/dL]	0.06 (0.76)	1.00 (0.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.230
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon two sample test
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.94
	Confidence Interval	(2-Sided) 95%; -2.08 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Other Pre-specified Outcome

Title	Change in the 6 Minute Walk Test (6MWT) Distance.
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

Two subjects were missing outcome measure in both the active drug and the placebo arm.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	4	3
Mean (Standard Deviation) [meters]	-20.77 (38.28)	29.24 (87.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.347
	Comments
	Method	t-test, 2 sided
	Comments

3. Other Pre-specified Outcome

Title	Association Between Change in Hemoglobin and Change in Markers of Inflammation.
Description	To examine whether there is an association between change in hemoglobin and changes in markers of inflammation from prior to study drug 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.Correlation between change in the inflammatory markers and the change in HB from prior to study drug to 6 months.
Time Frame	prior to study drug; 6 months

Outcome Measure Data

Analysis Population Description

One subject from the active drug oral salsalate group and 2 subjects from the placebo arm group are missing outcomes.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
IL6 correlation	-0.113	-0.446
TNF correlation	0.948	-0.977
CRP correlation	0.156	-0.166

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.857
	Comments	Correlation between change in IL-6 and change in hemoglobin in the salsalate group. Testing the correlation equal to 0.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.706
	Comments	Correlation between change in IL-6 and change in hemoglobin in the placebo group. Testing the correlation equal to 0.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	Correlation between change in TNF and change in hemoglobin in the salsalate group. Testing the correlation equal to 0.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.136
	Comments	Correlation between change in TNF and change in hemoglobin in the placebo group. Testing the correlation equal to 0.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.803
	Comments	Correlation between change in CRP and change in hemoglobin in the salsalate group. Testing the correlation equal to 0.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.894
	Comments	Correlation between change in CRP and change in hemoglobin in the placebo group. Testing the correlation equal to 0.
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Change in Markers of Inflammation
Description	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.
Time Frame	prior to study drug; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and two subjects in the placebo arm group were missing outcome measures.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
IL6	-1.096 (1.210)	0.703 (1.871)
Tumor Necrosis Factor Receptor1 (TNF-R1),	133.48 (390.99)	-189.40 (260.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.143
	Comments	P value comparing change in IL6 between treatment groups.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.257
	Comments	P value comparing the change in TNF between treatment groups.
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Assessment of Serum Biomarkers of Erthropoiesis
Description	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.
Time Frame	prior to study drug; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate arm and two subjects in the placebo arm are missing outcome measures.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
Mean (Standard Deviation) [mIU/ml]	-0.014 (3.237)	-1.540 (2.982)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.535
	Comments	P-value comparing the change in EPO between treatment groups.
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Change in Serum Hepcidin Levels
Description	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.
Time Frame	prior to study drug; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate arm and 3 subjects in the placebo arm are missing outcome measures.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	2
Mean (Standard Deviation) [ng/ml]	0.879 (13.378)	15.462 (10.329)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.232
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Change in Cognitive Outcome Measures-Trail Making Test Part B
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

Two subjects in the active drug oral salsalate group and 3 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	4	2
Mean (Standard Deviation) [second per completed circle]	-0.18 (0.68)	1.23 (0.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.076
	Comments
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Change in Frailty Component Related to Fatigue/ Exhaustion
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and 2 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
Number [participants]	1 16.7%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Chi-squared
	Comments

9. Secondary Outcome

Title	Change in Cognitive Outcome Measures as Determined by Speed of Processing
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and 3 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	2
Mean (Standard Deviation) [change in Z-Score]	0.29 (0.53)	1.42 (1.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.187
	Comments
	Method	t-test, 2 sided
	Comments

10. Secondary Outcome

Title	Change in Cognitive Outcome Measures as Determined by Composite Complex Attention/Executive Processing
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and 3 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	2
Mean (Standard Deviation) [change in Z-Score]	0.71 (0.67)	-0.07 (0.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.193
	Comments
	Method	t-test, 2 sided
	Comments

11. Secondary Outcome

Title	Change in Cognitive Outcome Measures as Determined by Composite Learning and Memory
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and 3 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	2
Mean (Standard Deviation) [change in Z-Score]	0.15 (1.18)	-0.34 (0.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.619
	Comments
	Method	t-test, 2 sided
	Comments

12. Secondary Outcome

Title	Change in Self Reported Outcomes Measures as Reported by Short Form-36 (SF-36) Physical Component Score (PCS)
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and 2 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
Mean (Standard Deviation) [t score]	1.63 (7.30)	3.77 (1.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.642
	Comments
	Method	t-test, 2 sided
	Comments

13. Secondary Outcome

Title	Change in Self Reported Outcomes Measures as Reported by FACIT-AN Total Score
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and 2 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
Mean (Standard Deviation) [scores on a scale]	18.9 (19.8)	7.7 (12.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	t-test, 2 sided
	Comments

14. Secondary Outcome

Title	Change in the Frailty Component as Determined by Self-reported Activity Level
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and 2 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
Number [participants]	1 16.7%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments
	Method	Chi-squared
	Comments

15. Secondary Outcome

Title	Change in Frailty Component as Determined by Grip Strength
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and 2 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
Number [participants]	0 0%	1 20%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.375
	Comments
	Method	Chi-squared
	Comments

16. Secondary Outcome

Title	Change in Frailty Component as Determined by the 4 Meter Walk Speed
Description	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.
Time Frame	baseline; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and 2 in the placebo arm group were missing outcome measure.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
Number [participants]	0 0%	0 0%

17. Secondary Outcome

Title	Change in Markers of Inflammation
Description	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.
Time Frame	prior to study drug; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate group and two subjects in the placebo arm group were missing outcome measures.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
Mean (Standard Deviation) [ug/ml]	-1.976 (1.676)	1.890 (6.267)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.398
	Comments
	Method	t-test, 2 sided
	Comments

18. Secondary Outcome

Title	Assessment of Serum Biomarkers of Erthropoiesis
Description	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.
Time Frame	prior to study drug; 6 months

Outcome Measure Data

Analysis Population Description

One subject in the active drug oral salsalate arm and two subjects in the placebo arm are missing outcome measures.

Arm/Group Title	Active Drug - Oral Salsalate	Placebo Arm
Arm/Group Description	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. 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)	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. 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
Measure Participants	5	3
Mean (Standard Deviation) [pg/ml]	16.688 (308.863)	187.240 (139.226)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Drug - Oral Salsalate, Placebo Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.412
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	All non-serious adverse events and serious adverse events will be collected from the time of randomization through the subject's final study visit up to 6 months.
Adverse Event Reporting Description	Adverse events and serious adverse events will be collected for subjects who terminate early from the study until the time of their withdrawal.
Arm/Group Title	Active Drug - Oral Salsalate		Placebo Arm
Arm/Group Description	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. 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)		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. 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
All Cause Mortality
	Active Drug - Oral Salsalate		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Active Drug - Oral Salsalate		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		2/5 (40%)
Ear and labyrinth disorders
hypoascusis	1/6 (16.7%)	1	0/5 (0%)	0
Gastrointestinal disorders
Diarrheoea	1/6 (16.7%)	2	0/5 (0%)	0
Immune system disorders
sarcoidosis	0/6 (0%)	0	1/5 (20%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cell carcinoma	0/6 (0%)	0	1/5 (20%)	1
Renal and urinary disorders
renal failure acute	1/6 (16.7%)	1	1/5 (20%)	1
Other (Not Including Serious) Adverse Events
	Active Drug - Oral Salsalate		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		5/5 (100%)
Gastrointestinal disorders
diarrhoea	2/6 (33.3%)	2	1/5 (20%)	1
nausea	1/6 (16.7%)	1	2/5 (40%)	2
abdominal upper pain	1/6 (16.7%)	1	1/5 (20%)	1
constipation	1/6 (16.7%)	1	0/5 (0%)	0
diarrhoea haemorrhagic	1/6 (16.7%)	1	0/5 (0%)	0
retching	1/6 (16.7%)	1	0/5 (0%)	0
vomiting	1/6 (16.7%)	1	0/5 (0%)	0
General disorders
malaise	0/6 (0%)	0	2/5 (40%)	2
crepitations	1/6 (16.7%)	1	0/5 (0%)	0
fatigue	1/6 (16.7%)	1	0/5 (0%)	0
oedema peripheral	1/6 (16.7%)	1	0/5 (0%)	0
Infections and infestations
sinusitis	0/6 (0%)	0	1/5 (20%)	1
Investigations
weight decreased	0/6 (0%)	0	2/5 (40%)	2
Metabolism and nutrition disorders
dehydration	1/6 (16.7%)	1	0/5 (0%)	0
hypoglycemia	1/6 (16.7%)	1	0/5 (0%)	0
Musculoskeletal and connective tissue disorders
arthralgia	2/6 (33.3%)	2	1/5 (20%)	1
muscle spasms	0/6 (0%)	0	1/5 (20%)	1
musculoskeletal stiffness	1/6 (16.7%)	1	0/5 (0%)	0
Nervous system disorders
dizziness	2/6 (33.3%)	2	0/5 (0%)	0
headache	0/6 (0%)	0	1/5 (20%)	1
syncope	1/6 (16.7%)	1	0/5 (0%)	0
Renal and urinary disorders
chromaturia	0/6 (0%)	0	1/5 (20%)	1
dysuria	1/6 (16.7%)	1	0/5 (0%)	0
renal impairment	1/6 (16.7%)	1	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
dyspnoea	0/6 (0%)	0	1/5 (20%)	1
Skin and subcutaneous tissue disorders
night sweats	0/6 (0%)	0	1/5 (20%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.