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Spinal Cord InjuryPhase 2NCT03345576

Testosterone and Long Pulse Stimulation After SCI

A Phase 2 study testing Testosterone and LPWS and Testosterone and standard NMES in people with Spinal Cord Injury, run by VA Office of Research and Development at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 70 years, men only
Conditions the study is for
Spinal Cord Injury
What is being tested?
Testosterone and LPWS and Testosterone and standard NMES
Type of treatment
Medical device
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
12 participants
Where
1 siteUnited States
Study dates
1 Jul 2018to 30 Nov 2023
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • Men only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Traumatic motor complete SCI and level of injury of T10 and below
  • Only participants with lower motor neuron (LMN) denervation as determined by EMG testing
  • Participants must also have an absence of reflexes, denervation of both knee extensor muscles
  • Tolerance to LPWS paradigm
  • Both knee extensors will also have to be unresponsive (i.e., no observed tetanic contraction or twitches) to standard electrical stimulation procedures (stimulation frequency: 30 Hz; pulse duration:450 s and amplitude of the current:200 mA)
  • All participants will undergo International Standards for Neurological Classification of SCI (ISNCSCI) examination for neurological level and function and only those with American Spinal Injury Classification (AIS A and B; i.e. motor deficit below the level of injury)

Who cannot join

  • Diagnosis of neurological injury other than SCI
  • Pre-existing medical conditions will be excluded (cardiovascular disease, uncontrolled type II DM and those on insulin requirements) or other concurrent medical conditions judged to be contraindicated by the site physician.
  • Hematocrit above 50% and severe urinary tract infection or symptoms
  • Those with hyper-physiological testosterone level above 800 ng/dl
  • Those who will fail to tolerate the LPWS paradigm
  • Progressive condition that would be expected to result in changing neurological status
Show all 13Show fewer
  • Lower extremity fracture around the knee joint (distal femur or proximal tibia) within the last 2 years from enrollment in the study
  • Knee BMD < 0.60 gm/cm2
  • Total hip BMD T-scores < -3.5
  • Untreatable severe spasticity judged to be contraindicated by the site Physician
  • Untreated or uncontrolled hypertension (systolic blood pressure >140 mmHg; diastolic blood pressure >90 mmHg)
  • Pressure ulcer of the trunk, pelvic area, or lower extremities of grade 3 or more
  • Psychopathology documentation in the medical record or history that may conflict with study objectives

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Hunter Holmes McGuire VA Medical Center, Richmond, VA

    Richmond, Virginia, 23249-0001

Other trials in United States

About this study

Official title: Testosterone and Long Pulse Width Stimulation for Denervated Muscles After Spinal Cord Injury

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.

Read the detailed description

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.

Being tested
Testosterone and LPWS, Testosterone and standard NMES
Keywords
Electric Stimulation, Spinal Cord Injuries, Muscle Denervation, carbohydrate metabolism, Lipids metabolism, Basal Metabolic Rate, Muscle Proteins, Mitochondria, Muscle, RNA, Rehabilitation
Medical subject headings
Spinal Cord Injuries

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Testosterone and LPWSDevice

    Also called Testosterone and long pulse width stimulation

    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 standard NMESDrug

    Also called Testosterone and neuromuscular electrical stimulation

    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.

Study groups in NCT03345576
Study groupRoleWhat they receive
Testosterone and LPWSExperimentalTwelve 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.
Receives: Device: Testosterone and LPWS
Testosterone and standard NMESSham comparatorTwelve 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.
Receives: Drug: Testosterone and standard NMES

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: Baseline, 6 months and 12 months

Secondary outcomes (2)

  1. Basal Metabolic Rate

    Using indirect canopy after overnight 10-12 hours fast.

    Measured: Baseline, 6 months and 12 months

  2. Mitochondrial Complex Activities

    Performing a simple muscle biopsy and them muscle samples will be assayed to measure mitochondrial citrate synthase and other complexes.

    Measured: 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]

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Nov 2017
  2. Study start1 Jul 2018
  3. Primary completion30 Jun 2023
  4. Study completion30 Nov 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Participant
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03345576
Sponsor's protocol ID
B2649-R
Status last verified
Sep 2025
First submitted
13 Nov 2017
Last updated
14 Oct 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
Yes
Individual data sharing
Yes: 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.

Publications

  • 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.

    PubMed 36198461

  • 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.

    PubMed 36899099

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Testosterone and LPWS and Testosterone and standard NMES in people with Spinal Cord Injury, run by VA Office of Research and Development at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Muscle Size Change (time frame: Baseline, 6 months and 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03345576, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Oct 2025.

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