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| Name | Class |
|---|---|
| Hunter Holmes McGuire VA Medical Center | FED |
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Denervation following spinal cord injury (SCI) limits beneficial application of neuromuscular electrical stimulation (NMES). SCI with denervation results in extensive muscle atrophy that is accompanied with several cardio-metabolic health risks. The current proposal provides a novel intervention by examining the effects of long pulse width stimulation (LPWS) and testosterone replacement therapy (TRT) on restoring muscle size and leg lean mass after denervation in persons with SCI. This intervention will be rewarding for Veterans and Civilians with SCI who do not benefit from exercising their lower extremity muscles because denervation has limited the response to standard surface NMES. The investigators will study the biochemical mechanisms that contribute to changes in muscle size following this novel training. Combing both pharmaceutical and physical-therapeutic interventions will optimize restoration of muscle size after SCI.
The long-term goal is to develop a rehabilitation strategy to mitigate the deleterious changes in muscle size and lower leg lean mass in persons with denervation following spinal cord injury (SCI). Currently, there is no available rehabilitation intervention following lower motor neuron (LMN) denervation. More than 46,000 Veterans are affected with SCI and may experience profound skeletal muscle atrophy and loss of lean mass and about 20-25% experience LMN denervation. Skeletal muscle cross-sectional area is 6 times smaller following LMN denervation compared to the innervated muscles. Denervation atrophy may be accompanied by several SCI health-related consequences.
Twelve weeks of twice weekly of surface neuromuscular electrical stimulation (NMES) resistance training (RT) can elicit more than a 35% increase in skeletal muscle size, decreased ectopic adipose tissue accumulation, increased insulin sensitivity after SCI. Moreover, the applicant's CDA-2 preliminary findings showed that 16 weeks of NMES-RT and testosterone replacement therapy (TRT) increased leg lean mass by 1.5 kg with no changes in the TRT group only. This was accompanied by an increase in the basal metabolic rate (BMR) of 218 kcal/day in the NMES-RT+TRT with no changes in the TRT group. During the course of recruitment for the study, 20% of individuals with SCI were excluded and could not benefit from exercising their lower extremity muscles, presumably because of LMN denervation.
Long pulse width stimulation (LPWS; 120-150 ms) has the potential to stimulate denervated muscles and to restore muscle size in people with SCI. The previous paradigm has focused on daily activation of the denervated muscles without applying progressive loading similar to RT. Daily training is not a clinically feasible approach in persons with SCI. Moreover, previous trials did not focus on enhancing the neuromuscular homeostasis by promoting the increase in lean mass independent of LMN denervation. Testosterone replacement therapy (TRT) has been shown to increase lean mass and basal metabolic rate in hypogonadal men with SCI. The investigators will determine if TRT+LPWS would increase skeletal muscle size, leg lean mass and improve overall metabolic health in SCI persons with LMN denervation. The investigators hypothesize that the one year TRT+LPWS protocol will upregulate protein synthesis pathways, down-regulate protein degradation pathways and increase overall mitochondrial health. Three specific aims will address these hypotheses. Aim 1 will assess the effects of TRT+LPWS compared to TRT+ standard neuromuscular electrical stimulation (NMES; as a control group) on the size of thigh skeletal muscle, intramuscular fat (IMF) and leg lean mass. Aim 2 will determine the association between the changes in skeletal muscle size, leg lean mass and the metabolic profile as determined by measuring BMR, serum lipids and carbohydrate profile. Aim 3 will investigate the cellular mechanisms responsible for evoking skeletal muscle hypertrophy following TRT+LPWS. This study is novel because it provides a feasible rehabilitation intervention by combining two approaches; which are likely to improve the quality of life in SCI persons with LMN denervation. If proven successful, the intervention will be easily translated into clinical practice for persons with SCI.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Testosterone and LPWS | Experimental | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury. |
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| Testosterone and standard NMES | Sham Comparator | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Testosterone and LPWS | Device | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury. |
| Measure | Description | Time Frame |
|---|---|---|
| Muscle Size Change | Magnetic resonance imaging (MRI): The skeletal muscle area will be measured at baseline 6 months and 12 months after training (post-intervention). | Baseline, 6 months and 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Basal Metabolic Rate | Using indirect canopy after overnight 10-12 hours fast. | Baseline, 6 months and 12 months |
| Mitochondrial Complex Activities | Performing a simple muscle biopsy and them muscle samples will be assayed to measure mitochondrial citrate synthase and other complexes. |
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Inclusion Criteria:
Exclusion Criteria:
Only men with SCI, women will not be included in the current study because administering testosterone replacement therapy (TRT) is neither appropriate nor safe.
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| Name | Affiliation | Role |
|---|---|---|
| Ashraf Gorgey, PhD PT | Hunter Holmes McGuire VA Medical Center, Richmond, VA | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hunter Holmes McGuire VA Medical Center, Richmond, VA | Richmond | Virginia | 23249-0001 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36198461 | Background | Gorgey AS, Khalil RE, Alrubaye M, Gill R, Rivers J, Goetz LL, Cifu DX, Castillo T, Caruso D, Lavis TD, Lesnefsky EJ, Cardozo CC, Adler RA. Testosterone and long pulse width stimulation (TLPS) for denervated muscles after spinal cord injury: a study protocol of randomised clinical trial. BMJ Open. 2022 Oct 5;12(10):e064748. doi: 10.1136/bmjopen-2022-064748. | |
| 36899099 |
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The target audiences for dissemination of the results from this study include the VHA and its practitioners, the national SCI/D Services Office, the general healthcare community, and the Veteran population. The investigators will share findings with the SCI community. The SCI/D Services and PVA publish a quarterly newsletter that is sent to SCI practitioners across the VA system. The investigators will inform the VA community of the impact of these findings. The investigators will report findings to the scientific community via the American Congress of Rehab Medicine, American College of Sports Medicine and American Spinal Cord Injury Association (ASIA). The investigators will publish reports in different scientific journals.
Throughout the study and at the completion of the study.
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Each participant underwent a detailed history and physical exam by a certified study medical provider to ensure eligibility. This was followed by electrodiagnosis to ensure denervation of the knee extensor muscle groups.
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| ID | Title | Description |
|---|---|---|
| FG000 | Testosterone and LPWS | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury. Testosterone and LPWS: Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury. |
| FG001 | Testosterone and Standard NMES | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. Testosterone and standard NMES: Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Testosterone and LPWS | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury. Testosterone and LPWS: Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Two participants withdrew after signing consent and being randomized without performing any intervention or study procedures. |
| 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 | Muscle Size Change | Magnetic resonance imaging (MRI): The skeletal muscle area will be measured at baseline 6 months and 12 months after training (post-intervention). | We are reporting the results of magnetic resonance imaging analysis of the right whole thigh muscle cross-sectional area (CSA, cm^2) and knee extensor CSA (CSA, cm^2) at baseline, 6 months and 12 months of completion of Testosterone and LPWS or Testosterone and standard NMES. | Posted | Mean | Standard Deviation | Muscle CSA (cm^2) | Baseline, 6 months and 12 months |
|
through study completion during the entire course of the intervention until the end of the study or until withdrawal from the trial up to 12 months.
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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 | Testosterone and LPWS | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury. Testosterone and LPWS: Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and long pulse width stimulation (LPWS) in persons with denervated spinal cord injury. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cellulitis | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Skin irritations as result of using testosterone patches | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Participant reported skin irritation as result of using testosterone patches. Study medical provider recommended over the counter corticosteroid cream to reduce or decrease skin irritation. However, participant decided to withdraw from the trial. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ashraf S. Gorgey | Richmond VAMC | 8046755000 | 3386 | ashraf.gorgey@va.ogv |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 31, 2018 | Jun 25, 2024 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Feb 22, 2022 | Jun 25, 2024 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D013119 | Spinal Cord Injuries |
| ID | Term |
|---|---|
| D013118 | Spinal Cord Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D020196 | Trauma, Nervous System |
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| ID | Term |
|---|---|
| D013739 | Testosterone |
| ID | Term |
|---|---|
| D000737 | Androstenols |
| D000736 | Androstenes |
| D000731 | Androstanes |
| D013256 | Steroids |
| D000072473 |
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Participant will be masked to the type of electrical stimulation (LPWS vs. standard NMES)
|
| Testosterone and standard NMES | Drug | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. |
|
|
| Mitochondrial measurements were conducted over 1 year period at baseline [BL, before starting any intervention], Post-intervention 1 [ P1; 6 months after starting interventions] and Post-intervention 2 [P2-12 months after starting interventions] |
| Alazzam AM, Goldsmith JA, Khalil RE, Khan MR, Gorgey AS. Denervation impacts muscle quality and knee bone mineral density after spinal cord injury. Spinal Cord. 2023 Apr;61(4):276-284. doi: 10.1038/s41393-023-00885-3. Epub 2023 Mar 10. |
| BG001 | Testosterone and Standard NMES | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. Testosterone and standard NMES: Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. |
| BG002 | Total | Total of all reporting groups |
| Count of Participants |
| Participants |
|
| Age, Continuous | Two participants withdrew prior to performing any study procedures. | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Two participants withdrew after signing consent forms without conducting any study procedures. | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Testosterone and Standard NMES | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. Testosterone and standard NMES: Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. |
|
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| Secondary | Basal Metabolic Rate | Using indirect canopy after overnight 10-12 hours fast. | The numbers in P2 or at 12 months were different because of earlier withdrawal of participants from the study. | Posted | Mean | Standard Deviation | Basal Metabolic Rate (BMR; Kcal/day) | Baseline, 6 months and 12 months |
|
|
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| Secondary | Mitochondrial Complex Activities | Performing a simple muscle biopsy and them muscle samples will be assayed to measure mitochondrial citrate synthase and other complexes. | Three participants withdrew from Testosterone and LPWS before P2 as well as two participants withdrew from testosterone and standard NMES group before conducting P2. | Posted | Mean | Standard Deviation | nmol/min/mg | Mitochondrial measurements were conducted over 1 year period at baseline [BL, before starting any intervention], Post-intervention 1 [ P1; 6 months after starting interventions] and Post-intervention 2 [P2-12 months after starting interventions] |
|
|
|
| 0 |
| 6 |
| 2 |
| 6 |
| 1 |
| 6 |
| EG001 | Testosterone and Standard NMES | Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. Testosterone and standard NMES: Twelve patients will undergo 1 year of supervised training examining the effects of testosterone replacement therapy (TRT) and standard surface neuromuscular electrical stimulation (NMES) in persons with denervated spinal cord injury. | 0 | 6 | 0 | 6 | 0 | 6 |
|
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| D014947 | Wounds and Injuries |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D045165 | Testosterone Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| BMR- 6 Months |
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| BMR- 12 Months |
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| Complex II-Post-intervention 1 |
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| Complex II-Post-intervention 2 |
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