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| ID | Type | Description | Link |
|---|---|---|---|
| P30AG021334 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Institute on Aging (NIA) | NIH |
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This research study is being done to see whether losartan can prevent the decrease in strength associated with aging.
Muscle loss is associated with aging and has multiple symptoms such as weakness, slowness, and fatigue (tiredness). Older adults with muscle weakness have a higher risk of falls and disability. In addition, the loss of independence for older adults can lead to a poorer quality of life.
Recently, it was discovered that losartan, a medication commonly used to treat high blood pressure, had slowed the strength decline seen in older mice. In addition, it allowed injured mice skeletal muscle to heal faster. Therefore, we would like to see if losartan can do the same for older adults.
Losartan is approved by the Food and Drug Administration (FDA) for the treatment of high blood pressure, heart failure, and to protect the kidneys in diabetic patients. Losartan is not FDA-approved to prevent the decrease in strength associated with aging.
In this study, participants age 70 and older will be asked to take losartan or a placebo to see if losartan can help prevent loss of muscle strength. A placebo is a substance that looks like the study drug but that contains no active ingredients.
The loss of independence in older adults is among the most costly and disturbing events in the life span. This loss is often influenced by multiple etiologies, including medical and neurological conditions, cognitive decline, non-supportive social/environmental settings and frailty. Frailty is a syndrome of multi-systemic, age-related decline characterized by weakness, weight loss, fatigue, low levels of activity, and slowness. Frail older adults have a higher risk for adverse outcomes including hospitalization, disability, and mortality.
Recently, Johns Hopkins University Older Americans Independence Center (JHU OAIC) investigators Burks and Cohn found that blocking angiotensin type 1 receptors with losartan, an angiotensin-receptor blocker (ARB) in older mice markedly accelerated injured skeletal muscle healing and decreased vulnerability to disuse atrophy and strength decline. These findings provide potent rationale for testing the hypothesis that losartan attenuates strength decline and other-frailty related measures in older adults.
To prepare to test this hypothesis, a phase 2 randomized, placebo controlled pilot clinical trial of losartan in pre-frail adults over age 70 is proposed that aims to assess safety and tolerability, estimate dosing range, and estimate treatment effects using inter- and intra-subject variability of potential outcome measures. Losartan is a medication that is commonly utilized in older adults for the treatment of hypertension and is generally well tolerated in that condition and in other cardiovascular conditions.
The study will take place over 24 weeks in the Clinical Research Unit (CRU) on the Hopkins Bayview Medical Campus, where 24 pre-frail subjects will be recruited from the OAIC frailty registry. Successful completion of this study will provide the safety, dosing, and outcome measure data necessary to design the pivotal study needed to determine if longer term treatment with losartan can significantly improve frailty and related skeletal muscle phenotypes.
Interventions, such as losartan, that can prevent the decline seen in frailty have the potential to improve function and help older adults maintain their independence. This is of the utmost importance in maintaining good quality-of-life for older adults.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Losartan | Active Comparator | For those subjects randomized to the losartan group, they will receive losartan 25mg by mouth daily for 8 weeks, then increase to 50mg by mouth daily for another 8 weeks, then increase to 100mg by mouth daily for a final 8 weeks. |
|
| Placebo | Placebo Comparator | For those subjects randomized to placebo, they will receive a placebo to take for 24 weeks total. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Losartan | Drug | Losartan will be given in increasing doses to those in the losartan arm. |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Isokinetic Strength | Isokinetic Strength was measured by knee extension exercises where bilateral knee concentric strength was measured using a Biodex System 3 dynamometer set at an angular velocity of 30deg/sec through a joint arc from 90 degrees to 30 degrees (0 degrees- full extension). The change in strength between baseline and week 8 (i.e., baseline minus week 8) was the outcome of the analysis. A negative number indicates that there was a decrease in isokinetic strength from week 0 to week 8. | Baseline to Week 8 |
| Change From Baseline in Isokinetic Strength | Isokinetic Strength was measured by knee extension exercises where bilateral knee concentric strength was measured using a Biodex System 3 dynamometer set at an angular velocity of 30deg/sec through a joint arc from 90 degrees to 30 degrees (0 degrees- full extension). The change in strength between baseline and week 16 (i.e., baseline minus week 16) was the outcome of the analysis. A negative number indicates decrease in strength from week 0 to week 16. | Baseline to Week 16 |
| Change From Baseline in Isokinetic Strength | Isokinetic Strength was measured by knee extension exercises where bilateral knee concentric strength was measured using a Biodex System 3 dynamometer set at an angular velocity of 30deg/sec through a joint arc from 90 degrees to 30 degrees (0 degrees- full extension). The change in strength between baseline and week 24 (i.e., baseline minus week 24) was the outcome of the analysis. A negative number indicates a decrease in strength from week 0 to week 24. | Baseline to Week 24 |
| Fatiguability | Fatiguability was tested using bilateral knee extension with an external load equal to 40% of the maximal voluntary contraction force. Fatiguability was defined as the ratio (expressed as a percentage) of the total work in the last 3 of the 10 repetitions to the total work in the first 3 of the 10 repetitions, where the total work for n repetitions is defined as the sum of peak torque (FT-LBS) over n repetitions (i.e., last three reps/first three reps). The maximum of the two sides was used in the analysis. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Experiencing Any Amount of Decrease in Frailty | Number of participants experiencing any amount of decrease in frailty score from baseline to Week 8 (i.e., improvement in frailty status) | from baseline to 8 weeks |
| Number of Participants Experiencing Any Amount of Decrease in Frailty |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jeremy Walston, MD | Johns Hopkins University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Johns Hopkins Bayview Clinical Research Unit | Baltimore | Maryland | 21224 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21562229 | Background | Burks TN, Andres-Mateos E, Marx R, Mejias R, Van Erp C, Simmers JL, Walston JD, Ward CW, Cohn RD. Losartan restores skeletal muscle remodeling and protects against disuse atrophy in sarcopenia. Sci Transl Med. 2011 May 11;3(82):82ra37. doi: 10.1126/scitranslmed.3002227. | |
| 21852574 | Background | Abadir PM, Foster DB, Crow M, Cooke CA, Rucker JJ, Jain A, Smith BJ, Burks TN, Cohn RD, Fedarko NS, Carey RM, O'Rourke B, Walston JD. Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14849-54. doi: 10.1073/pnas.1101507108. Epub 2011 Aug 18. |
| Label | URL |
|---|---|
| Johns Hopkins Trials listing | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Losartan | For those subjects randomized to the losartan group, they will receive losartan 25mg by mouth daily for 8 weeks, then increase to 50mg by mouth daily for another 8 weeks, then increase to 100mg by mouth daily for a final 8 weeks. Losartan: Losartan will be given in increasing doses to those in the losartan arm. |
| FG001 | Placebo | For those subjects randomized to placebo, they will receive a placebo to take for 24 weeks total. Placebo: Placebo will be given to those in placebo arm |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Losartan | For those subjects randomized to the losartan group, they will receive losartan 25mg by mouth daily for 8 weeks, then increase to 50mg by mouth daily for another 8 weeks, then increase to 100mg by mouth daily for a final 8 weeks. Losartan: Losartan will be given in increasing doses to those in the losartan arm. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in Isokinetic Strength | Isokinetic Strength was measured by knee extension exercises where bilateral knee concentric strength was measured using a Biodex System 3 dynamometer set at an angular velocity of 30deg/sec through a joint arc from 90 degrees to 30 degrees (0 degrees- full extension). The change in strength between baseline and week 8 (i.e., baseline minus week 8) was the outcome of the analysis. A negative number indicates that there was a decrease in isokinetic strength from week 0 to week 8. | Compliant Completers: Participants who discontinued treatment during study but who continued follow-up visits and completed a final visit at 24 weeks. | Posted | Mean | Standard Deviation | Newton | Baseline to Week 8 |
|
24 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Losartan | For those subjects randomized to the losartan group, they will receive losartan 25mg by mouth daily for 8 weeks, then increase to 50mg by mouth daily for another 8 weeks, then increase to 100mg by mouth daily for a final 8 weeks. Losartan: Losartan will be given in increasing doses to those in the losartan arm. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Myocardial Infarction | Cardiac disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jeremy D. Walston, M.D. , Raymond and Anna Lublin Professor of Geriatric Medicine | Johns Hopkins University | 410-550-1003 | jwalston@jhmi.edu |
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| ID | Term |
|---|---|
| D055948 | Sarcopenia |
| D000073496 | Frailty |
| ID | Term |
|---|---|
| D009133 | Muscular Atrophy |
| D020879 | Neuromuscular Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D019808 | Losartan |
| ID | Term |
|---|---|
| D001713 | Biphenyl Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
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| Placebo |
| Drug |
Placebo will be given to those in placebo arm |
|
| Week 8 |
| Fatiguability | Fatiguability was tested using bilateral knee extension with an external load equal to 40% of the maximal voluntary contraction force. Fatiguability was defined as the ratio (expressed as a percentage) of the total work in the last 3 of the 10 repetitions to that of the first 3 of the 10 repetitions, where the total work for n repetitions is defined as the sum of peak torque (FT-LBS) over n repetitions (i.e., last three reps/first three reps). The maximum of the two sides was used in the analysis. | Week 16 |
| Fatiguability | Fatiguability was tested using bilateral knee extension with an external load equal to 40% of the maximal voluntary contraction force. Fatiguability was defined as the ratio (expressed as a percentage) of the total work in the last 3 of the 10 repetitions to that of the first 3 of the 10 repetitions, where the total work for n repetitions is defined as the sum of peak torque (FT-LBS) over n repetitions (i.e., last three reps/first three reps). The maximum of the two sides was used in the analysis. | Week 24 |
Number of participants experiencing any amount of decrease in frailty score from baseline to Week 16 (i.e., improvement in frailty status) |
| from baseline to 16 weeks |
| Number of Participants Experiencing Any Amount of Decrease in Frailty | Number of participants experiencing any amount of decrease in frailty score from baseline to Week 24 (i.e., improvement in frailty status) | from baseline to 24 weeks |
| 35511890 | Derived | Lee JL, Zhang C, Westbrook R, Gabrawy MM, Nidadavolu L, Yang H, Marx R, Wu Y, Anders NM, Ma L, Bichara MD, Kwak MJ, Buta B, Khadeer M, Yenokyan G, Tian J, Xue QL, Siragy HM, Carey RM, de Cabo R, Ferrucci L, Moaddel R, Rudek MA, Le A, Walston JD, Abadir PM. Serum Concentrations of Losartan Metabolites Correlate With Improved Physical Function in a Pilot Study of Prefrail Older Adults. J Gerontol A Biol Sci Med Sci. 2022 Dec 29;77(12):2356-2366. doi: 10.1093/gerona/glac102. |
| Placebo |
For those subjects randomized to placebo, they will receive a placebo to take for 24 weeks total. Placebo: Placebo will be given to those in placebo arm |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | Placebo | For those subjects randomized to placebo, they will receive a placebo to take for 24 weeks total. Placebo: Placebo will be given to those in placebo arm |
|
|
|
| Primary | Change From Baseline in Isokinetic Strength | Isokinetic Strength was measured by knee extension exercises where bilateral knee concentric strength was measured using a Biodex System 3 dynamometer set at an angular velocity of 30deg/sec through a joint arc from 90 degrees to 30 degrees (0 degrees- full extension). The change in strength between baseline and week 16 (i.e., baseline minus week 16) was the outcome of the analysis. A negative number indicates decrease in strength from week 0 to week 16. | Compliant Completers: Participants who discontinued treatment during study but who continued follow-up visits and completed a final visit at 24 weeks. | Posted | Mean | Standard Deviation | Newton | Baseline to Week 16 |
|
|
|
|
| Primary | Change From Baseline in Isokinetic Strength | Isokinetic Strength was measured by knee extension exercises where bilateral knee concentric strength was measured using a Biodex System 3 dynamometer set at an angular velocity of 30deg/sec through a joint arc from 90 degrees to 30 degrees (0 degrees- full extension). The change in strength between baseline and week 24 (i.e., baseline minus week 24) was the outcome of the analysis. A negative number indicates a decrease in strength from week 0 to week 24. | Compliant Completers: Participants who discontinued treatment during study but who continued follow-up visits and completed a final visit at 24 weeks. | Posted | Mean | Standard Deviation | Newton | Baseline to Week 24 |
|
|
|
|
| Primary | Fatiguability | Fatiguability was tested using bilateral knee extension with an external load equal to 40% of the maximal voluntary contraction force. Fatiguability was defined as the ratio (expressed as a percentage) of the total work in the last 3 of the 10 repetitions to the total work in the first 3 of the 10 repetitions, where the total work for n repetitions is defined as the sum of peak torque (FT-LBS) over n repetitions (i.e., last three reps/first three reps). The maximum of the two sides was used in the analysis. | Compliant Completers: Participants who discontinued treatment during study but who continued follow-up visits and completed a final visit at 24 weeks. | Posted | Mean | Standard Deviation | percentage of work | Week 8 |
|
|
|
|
| Primary | Fatiguability | Fatiguability was tested using bilateral knee extension with an external load equal to 40% of the maximal voluntary contraction force. Fatiguability was defined as the ratio (expressed as a percentage) of the total work in the last 3 of the 10 repetitions to that of the first 3 of the 10 repetitions, where the total work for n repetitions is defined as the sum of peak torque (FT-LBS) over n repetitions (i.e., last three reps/first three reps). The maximum of the two sides was used in the analysis. | Compliant Completers: Participants who discontinued treatment during study but who continued follow-up visits and completed a final visit at 24 weeks. | Posted | Mean | Standard Deviation | percentage of work | Week 16 |
|
|
|
|
| Primary | Fatiguability | Fatiguability was tested using bilateral knee extension with an external load equal to 40% of the maximal voluntary contraction force. Fatiguability was defined as the ratio (expressed as a percentage) of the total work in the last 3 of the 10 repetitions to that of the first 3 of the 10 repetitions, where the total work for n repetitions is defined as the sum of peak torque (FT-LBS) over n repetitions (i.e., last three reps/first three reps). The maximum of the two sides was used in the analysis. | Compliant Completers: Participants who discontinued treatment during study but who continued follow-up visits and completed a final visit at 24 weeks. | Posted | Mean | Standard Deviation | percentage of work | Week 24 |
|
|
|
|
| Secondary | Number of Participants Experiencing Any Amount of Decrease in Frailty | Number of participants experiencing any amount of decrease in frailty score from baseline to Week 8 (i.e., improvement in frailty status) | Compliant completers: participants who continued treatment during the entire 24 week study. and completed the final visit at 24 weeks. 10 out of the 18 participant who were given losartan completed the study and 15 out of 19 who received the placebo participant completed the study. | Posted | Count of Participants | Participants | from baseline to 8 weeks |
|
|
|
|
| Secondary | Number of Participants Experiencing Any Amount of Decrease in Frailty | Number of participants experiencing any amount of decrease in frailty score from baseline to Week 16 (i.e., improvement in frailty status) | Compliant completers: participants who continued treatment during the entire 24 week study. and completed the final visit at 24 weeks. 10 out of the 18 participant who were given losartan completed the study and 15 out of 19 who received the placebo participant completed the study. | Posted | Count of Participants | Participants | from baseline to 16 weeks |
|
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|
|
| Secondary | Number of Participants Experiencing Any Amount of Decrease in Frailty | Number of participants experiencing any amount of decrease in frailty score from baseline to Week 24 (i.e., improvement in frailty status) | Compliant completers: participants who continued treatment during the entire 24 week study. and completed the final visit at 24 weeks. 10 out of the 18 participant who were given losartan completed the study and 15 out of 19 who received the placebo participant completed the study. | Posted | Count of Participants | Participants | from baseline to 24 weeks |
|
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|
|
| 1 |
| 18 |
| 1 |
| 18 |
| 4 |
| 18 |
| EG001 | Placebo | For those subjects randomized to placebo, they will receive a placebo to take for 24 weeks total. Placebo: Placebo will be given to those in placebo arm | 0 | 19 | 0 | 19 | 0 | 19 |
| Hypertension | Vascular disorders | Non-systematic Assessment |
|
| Creatinine | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hyperkalemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
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| D001284 | Atrophy |
| D020763 | Pathological Conditions, Anatomical |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012816 | Signs and Symptoms |
| D010335 | Pathologic Processes |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D013777 | Tetrazoles |