Trial To Evaluate the Efficacy of Intravenous Iron in 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 with a short course of weekly intravenous iron infusions can improve physical activity and therefore quality of life.

Detailed Description
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There is a tremendous 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 a well-tolerated IV iron preparation in community dwelling older anemic adults with intermediate serum ferritin values. Subjects will be 65 years or older adults with unexplained anemia and a serum ferritin between 20 and 200 ng/mL. Subjects will be randomized on a 1:1 basis to either receive a 5 week course of treatment with intravenous iron immediately or to a waitlist control group who will receive treatment with intravenous iron following a 12 week observation period. Both groups will ultimately receive 200mg of intravenous iron sucrose weekly for 5 weeks to determine if this can lead to improvement in 6 Minute Walk Test results. The primary endpoint is change in 6 Minute Walk Test distances from baseline to 12 weeks. The procedures in this protocol will include the use of outcomes tools that have been selected for their ability to show improvement in quality of life in this patient population. Blood samples will also be collected for analysis both at the local lab (safety tests - eg hemoglobin or Hb) or at a central lab for research purposes.

Official Title
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A Randomized, Open-Label, Wait-list Control Trial To Evaluate the Efficacy of Intravenous Iron in Older Adults With Unexplained Anemia and a Serum Ferritin Between 20 and 200 ng/mL

Conditions
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Anemia, Unexplained Anemia (UAE)

Intervention / Treatment
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* Drug: iron sucrose
* Drug: iron sucrose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 65 years old Hemoglobin concentration ≥ 9.0 g/dL and < 11.5 g/dL (women) or < 12.7 g/dL (men) Unexplained anemia Serum ferritin level ≥ 20 and ≤ 200 ng/mL Able to walk without the use of a walker, motorized device or the assistance of another person. Able to understand and willing to provide written informed consent in the absence of dementia Must be able to understand and speak in English Exclusion Criteria: Red blood cell transfusions within the past 3 months Use of erythropoiesis stimulating agents (ESA) in the past 3 months Intravenous Iron Infusions within the past 3 months Distance on baseline 6MWT (6 minute walk test) above the median for age and sex History of unstable angina or myocardial infarction in the past 3 months History of stroke or TIA (transient ischemic attack) the past 3 months Uncontrolled hypertension (diastolic blood pressure > 100 mm Hg or systolic blood pressure > 160 mm Hg on 2 separate occasions) Positive fecal occult blood test within the screening period Elevated AST (aspartate aminotransferase) or ALT (alanine aminotransferase) ≥ 2x upper limit of normal Documented anaphylactic reaction to iron sucrose infusion in the past Subjects initiated on oral iron supplementation within the last 6 weeks, or those initiated on oral iron within the last 3 months who have had at least a one gram/dL improvement in Hb since starting oral iron supplementation

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immediate Intervention Group<br>Subjects randomized to the immediate treatment group will be scheduled to begin treatment with IV iron infusion immediately (or within 2 business days). They will receive 200mg IV iron sucrose a week for 5 weeks followed by 19 weeks of follow up. | Drug: iron sucrose<br>* Patients will receive intravenous iron sucrose preparation at a dose of 200 mg per week through a peripheral intravenous catheter.<br>* Other names: Venofer®;|
| Experimental: Wait List Control<br>Subjects randomized to the wait list control group will have an observation visit at week 6 and week 12. After that they will begin treatment with IV iron infusion. They will receive 200mg IV iron sucrose a week for 5 weeks followed by 7 weeks of follow up | Drug: iron sucrose<br>* Following 12 weeks of observation patients will receive intravenous iron sucrose preparation at a dose of 200 mg per week through a peripheral intravenous catheter.<br>* Other names: Venofer®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6 Minute Walk Test Results | Subjects were asked to walk for 6 minutes, unassisted. The distance walked was recorded in meters at baseline (time of randomization) and 12 weeks after baseline (time of randomization). The change from baseline to 12 weeks, related to distance, is compared and documented. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had a Hemoglobin Increase >= 1g/dL | To assess the efficacy of IV iron sucrose in improving Hemoglobin by at least 1 g/dL; an increase from baseline to week 12. | baseline, 12 weeks | 
| Change in Cognitive Outcome Measures as Determined by Trail Making Test Part B | To quantify the impact of anemia treatment by IV iron sucrose 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 week 12. | Baseline, 12 weeks | 
| 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 IV iron sucrose 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 week 12. 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, 12 weeks | 
| Correlation Between Baseline Serum Ferritin, Serum Iron, and Transferrin Saturation and the Change in Hemoglobin (HB) | Correlation between baseline serum ferritin, serum iron, and transferrin saturation and the change in HB from baseline to 12 weeks. | baseline, 12 weeks | 
| 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 week 12 as reported by the subject. | baseline, 12 weeks | 
| Change in Cognitive Outcome Measures as Determined by Speed of Processing | To quantify the impact of anemia treatment by IV iron sucrose 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. | Baseline, 12 Week | 
| Change in Cognitive Outcome Measures as Determined by Composite Complex Attention/Executive Processing | To quantify the impact of anemia treatment by IV iron sucrose 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. | Baseline, 12 week | 
| Change in Cognitive Outcome Measures as Determined by Composite Learning and Memory | To quantify the impact of anemia treatment by IV iron sucrose 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. Higher numbers indicated a better response.There is no scale, as the results are normalized variables. | Baseline, 12 week | 
| Change in Self Reported Outcomes Measures as Reported by FACIT-AN Total Score | To quantify the impact of anemia treatment by IV iron sucrose 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 12 weeks. Scores range from 0-188 with higher scores indicating better function. | Baseline, 12 weeks | 
| Change in the Frailty Component as Determined by Self-reported Activity Level | To quantify the impact of anemia treatment by IV iron sucrose 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 week 12. | Baseline, 12 week | 
| Change in Frailty Component as Determined by Grip Strength | To quantify the impact of anemia treatment by IV iron sucrose 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 week 12). 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 week 12. | Baseline, 12 weeks | 
| Change in Frailty Component as Determined by the 4 Meter Walk Speed | To quantify the impact of anemia treatment by IV iron sucrose 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 week 12). 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 week 12. | Baseline, 12 weeks | 
| Correlation Between Baseline Soluble Transferrin Receptor and the Change in HB From Baseline to 12 Weeks | Correlation between baseline soluble transferrin receptor and the change in hemoglobin from the baseline to 12 weeks. | baseline, 12 weeks | 
| Correlation Between Baseline Soluble Transferrin Receptor Index (Soluble Receptor/Log Ferritin) and the Change in Hemoglobin | Correlation between baseline soluble transferrin receptor index (soluble receptor/log ferritin) and the change in hemoglobin from baseline to 12 weeks. | baseline, 12 weeks | 
| Correlation Between Baseline Serum Ferritin, Serum Iron, and Transferrin Saturation and the Change in 6 Minute Walk Test Distance | Correlation between baseline serum ferritin, serum iron, and transferrin saturation and the change in 6 Minute Walk Test distance from baseline to 12 weeks. | baseline, 12 weeks | 
| Correlation Between Baseline Soluble Transferrin Receptor and the Change in the 6 Meter Walk Test Distance | Correlation between baseline soluble transferrin receptor and the change in the 6 Meter Walk Test distance from baseline to 12 weeks | baseline, 12 weeks | 
| Correlation Between Baseline Soluble Transferrin Receptor Index (Soluble Receptor/Log Ferritin) and the Change in the 6 Minute Walk Test Distance | Correlation between baseline soluble transferrin receptor index (soluble receptor/log ferritin) and the change in the 6 Minute Walk Test Distance from baseline to 12 weeks | baseline, 12 weeks | 

 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, iron, pactte, pactee, aging, aged, old, older