Nerve Stimulation for Diabetic Neuropathy

Overseen By Ronald Triolo, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: VA Office of Research and Development

Disqualifiers: Uncontrolled diabetes, Vascular disease, Infections, Obesity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 9 months

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to help individuals who have lost a leg feel sensations in their missing limb and control a robotic leg. The study employs tiny devices, specifically an implanted multi-contact stimulating electrode and an intramuscular electromyography recording electrode, to send signals to the brain, recreating the sensation of having a foot. This approach could make using a prosthetic leg feel more natural. Ideal participants are those with a stable lower limb amputation due to diabetes who can walk with a prosthetic. As an unphased trial, this study offers participants the chance to contribute to groundbreaking research that could improve prosthetic technology and enhance quality of life.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What prior data suggests that this nerve stimulation technique is safe for individuals with limb loss?

Research has shown that implanted devices with multiple contact points have been tested in patients with conditions like diabetic nerve pain. Initially, about 77% of patients responded well to the treatment. After six months, around 59% continued to experience benefits. However, some side effects were reported. One study found 18 side effects in 14 patients, including infections, wound healing problems, and a few cases where the device required removal.

Overall, while many patients tolerated the treatment well, there is a risk of side effects. These studies provide important information about safety, but individual experiences can vary. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this treatment for diabetic neuropathy because it offers a new way to manage nerve pain, which is traditionally treated with medications like pain relievers and antidepressants. Unlike these standard treatments, this approach uses an implanted multi-contact stimulating electrode to directly stimulate nerves. This method has the potential to provide more precise pain relief by targeting specific nerve areas, potentially reducing reliance on medications and their side effects. Additionally, the combination of stimulating electrodes and intramuscular electromyography recording electrodes could lead to a better understanding of nerve function and improve treatment outcomes.

What evidence suggests that this nerve stimulation technique is effective for diabetic neuropathy?

Research has shown that implanted electrode systems can help people with limb loss regain feeling and movement. In this trial, participants will receive a multi-contact electrode implant and implanted electromyography recording electrodes. A similar study found that 77% of participants experienced successful results with the stimulation and implantation. After six months, 59% of those treated reported success, compared to only 7% in a group that did not receive the treatment. These electrodes send small electrical signals to the nerves, which then relay information to the brain. This approach is expected to help users feel sensations in their missing limbs and could improve control over prosthetic devices. ^{2 3 6 7 8}

Who Is on the Research Team?

Ronald Triolo, PhD

Principal Investigator

Louis Stokes VA Medical Center, Cleveland, OH

Are You a Good Fit for This Trial?

This trial is for individuals with lower limb loss above or below the knee due to diabetes, who can walk or stand with assistance and have healthy nerves in their remaining limbs. They should have good skin health, no autoimmune issues, seizures, heart problems, and must be able to follow the study plan. Excluded are those with uncontrolled diabetes (HbA1c ≥ 8.5%), active skin ulcers, pregnancy, language barriers (non-English speakers), balance disorders, severe obesity (BMI > 35), mental health issues that affect study participation.

Inclusion Criteria

I can walk or stand using a prosthesis or brace.

I have a stable lower limb amputation or insensate foot due to diabetes.

I do not have autoimmune deficiencies, seizures, or heart problems that prevent stimulation treatments.

Exclusion Criteria

I have arthritis near where a medical device was implanted.

You have severe mental illness or problems with memory and thinking that may make it hard for you to follow the study schedule.

You expect to need MRI scans during the study, or you have a type of medical device that makes MRI scans unsafe for you.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgical Implantation

Electrodes are surgically implanted on one to four nerves of the residual limb and intramuscular recording electrodes can be implanted in the lower limbs and hip muscles.

1-2 weeks

Treatment

Participants receive stimulation through implanted electrodes to restore sensation and develop a motor controller for a robotic prosthetic leg.

9 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of neuropathic pain and functional gait.

4 years

What Are the Treatments Tested in This Trial?

Interventions

• Implanted Multi contact stimulating electrode and intramuscular electromyography recording electrode
• Multi contact electrode implant

Trial Overview The trial tests implanted electrodes that provide sensation to nerves in the residual limb of amputees simulating natural feedback from a lost foot or leg. Additionally offered is an option for muscle recording electrodes aimed at creating intuitive control over robotic prosthetic legs through a motor controller.

How Is the Trial Designed?

Group I: Multi contact electrode implant and implanted electromyography recording electrodes Experimental Treatment 1 Intervention

Fifteen subjects with lower limb amputation will receive implanted multicontact stimulating nerve cuff electrodes connected to temporary percutaneous leads. During experimental testing, a small amount of stimulation will be applied to the nerves through the contacts of the multichannel cuff electrode.

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

The study successfully implanted a silicon-based Utah Electrode Array with 25 or 100 microelectrodes into the cat sciatic nerve, demonstrating that this high-density array can be inserted without significantly disrupting nerve function, as indicated by only slight changes in compound action potentials recorded after insertion.

The electrodes were able to reliably record neural activity and stimulate muscle contractions for up to 60 hours, suggesting their potential for use in neuroscience research and neuroprosthetic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multielectrode array for intrafascicular recording and stimulation in sciatic nerve of cats. Branner, A., Normann, RA.[2019]

A novel neural prosthesis design eliminates the need for an implanted stimulator by using surface electrodes to stimulate nerves through an insulated lead, allowing for effective nerve activation with minimal current.

The system demonstrated long-term stability in chronic implants for over 8 months, successfully producing graded muscle force without reaching contraction thresholds, indicating its potential for practical applications in restoring motor functions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new means of transcutaneous coupling for neural prostheses. Gan, LS., Prochazka, A., Bornes, TD., et al.[2019]

This review outlines a comprehensive framework for translating neural interfaces for electrical modulation of the peripheral nervous system (PNS) from design to clinical use, emphasizing the importance of following FDA guidelines for safety and efficacy.

Key steps in the translational process include quantitative human anatomy, neural modeling, acute testing, and chronic deployment, with case studies demonstrating successful applications of specific electrode designs like the spiral cuff and Flat Interface Nerve Electrode (FINE).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A translational framework for peripheral nerve stimulating electrodes: Reviewing the journey from concept to clinic. Charkhkar, H., Christie, BP., Pinault, GJ., et al.[2021]

Microchannel electrode implants successfully recorded neural activity from regenerating sciatic nerves in freely moving rats over a three-month period, demonstrating their potential for long-term monitoring of nerve regeneration.

Histological analysis showed robust regeneration of mini-nerves within the implants, and the recorded neural firing patterns correlated with different phases of gait, indicating the implants' effectiveness in interfacing with nerve activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic multichannel neural recordings from soft regenerative microchannel electrodes during gait. Musick, KM., Rigosa, J., Narasimhan, S., et al.[2018]

The novel thin-film multichannel electrode, designed for both recording and stimulating muscle activity, was successfully tested in six tremor patients and three healthy individuals, demonstrating its potential for applications in neuroprosthetics.

In one tremor patient, closed-loop stimulation using the electrode led to a significant reduction in tremor power by over 50%, indicating its efficacy in managing tremor symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A thin-film multichannel electrode for muscle recording and stimulation in neuroprosthetics applications. Muceli, S., Poppendieck, W., Hoffmann, KP., et al.[2020]

Micro-channel sieve electrodes produce significantly lower stimulation artifacts compared to thin-film transverse intrafascicular multichannel electrodes (tfTIMEs), making them more effective for providing haptic feedback in prosthetic limbs.

Using micro-channel devices allows for better simultaneous stimulation and recording of nerve signals, improving the signal-to-artifact ratio and enhancing the potential for effective motor control and sensory feedback in amputees.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Micro-channel sieve electrode for concurrent bidirectional peripheral nerve interface. Part B: stimulation. Coker, RA., Zellmer, ER., Moran, DW.[2020]

The four-contact spiral nerve-cuff electrodes demonstrated stable performance over 63 weeks, with a low stimulation charge threshold (mean 23.3 nC), indicating a reliable interface with the peripheral nervous system.

These electrodes were able to selectively stimulate different heads of the quadriceps muscle, achieving maximum twitch responses of 3.8 to 8.1 N m, which suggests their potential effectiveness for neuroprosthetic applications in individuals with spinal cord injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic stability and selectivity of four-contact spiral nerve-cuff electrodes in stimulating the human femoral nerve. Fisher, LE., Tyler, DJ., Anderson, JS., et al.[2021]

The study assessed the biocompatibility of the transverse intrafascicular multi-channel electrode (TIME) by implanting it in the median nerves of Göttingen minipigs for 33-38 days, showing no significant inflammatory response or necrosis, indicating good safety.

The presence of only a layer of fibrosis around the implant suggests that the TIME could be a promising neural interface for future use in neuroprostheses, as it demonstrates favorable biosafety characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biosafety assessment of an intra-neural electrode (TIME) following sub-chronic implantation in the median nerve of Göttingen minipigs. Kundu, A., Wirenfeldt, M., Harreby, KR., et al.[2017]

In a study of 216 patients with refractory painful diabetic neuropathy, 10 kHz spinal cord stimulation (SCS) led to a remarkable 79.9% reduction in pain over 24 months, with 90.1% of participants achieving at least 50% pain relief.

The treatment also significantly improved health-related quality of life and sleep, with 65.7% of participants showing clinically meaningful neurological improvements, indicating that 10 kHz SCS is both safe and effective for long-term management of this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy of high-frequency (10 kHz) spinal cord stimulation for the treatment of painful diabetic neuropathy: 24-Month results of a randomized controlled trial. Petersen, EA., Stauss, TG., Scowcroft, JA., et al.[2023]

The Utah Slanted Electrode Array (USEA) was implanted in human median and ulnar nerves for four weeks, showing that the current design only penetrates a small percentage of the nerve tissue, which may limit its effectiveness.

Despite some inflammatory response observed around the electrodes, the USEA was still able to successfully record nerve signals and elicit sensory responses, indicating its potential for neuroprosthetic applications, but future designs should aim for better tissue integration and reduced inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A histological analysis of human median and ulnar nerves following implantation of Utah slanted electrode arrays. Christensen, MB., Wark, HA., Hutchinson, DT.[2016]

The implantable intraorbitary device (IOD) allows for chronic delivery of solutions, recording of nerve activity, and electrical stimulation, demonstrating its multifunctional capabilities for peripheral nerve applications.

The device was successfully tested on the abducens nerve, showing that it can provide valuable electrophysiological data and deliver pharmacological substances, which could enhance research and treatment options for nerve-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A chronically implantable device for the controlled delivery of substances, and stimulation and recording of activity in severed nerves. Davis-López de Carrizosa, MA., Tena, JJ., Benítez-Temiño, B., et al.[2007]

A new multielectrode array has been developed for precise electrical stimulation of peripheral nerves, featuring twelve platinum electrodes designed to selectively stimulate individual nerve fibers in rats.

Sensitivity tests showed that the number of activated motor units increases cubically with the current amplitude, while selectivity is maximized when electrodes are spaced 200-250 microns apart, providing important insights for future device designs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sensitivity and selectivity of intraneural stimulation using a silicon electrode array. Rutten, WL., van Wier, HJ., Put, JH.[2013]

Citations

1. withpower.com withpower.com/trial/phase-diabetic-neuropathies-2-2021-4614f

Nerve Stimulation for Diabetic Neuropathy Research on similar electrode implants shows they can reliably stimulate and record nerve activity, which may help restore motor and sensory functions.

2. sciencedirect.com sciencedirect.com/science/article/pii/S1094715921001410

Invasive Electrical Neuromodulation for the Treatment of ... Slangen et al. reported 77% having successful trial stimulation and implantation, with 59% having treatment success at six months, compared to 7% for BMT (p < ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8586096/

Spinal Cord Stimulation for Painful Diabetic Peripheral ... In summary, treatment of PDN with SCS demonstrated success in several high-quality multi-center randomized controlled trials. Based on these results, spinal ...

4. journals.sagepub.com journals.sagepub.com/doi/10.1177/19322968221133795

Spinal Cord Stimulation for Painful Diabetic Neuropathy A reduction in pain by at least 50% is considered a successful trial. Such success during a trial of SCS is achieved by approximately 80% of ...

5. diabetesjournals.org diabetesjournals.org/care/article/41/1/32/36623/Severity-of-Neuropathy-Is-Associated-With-Long

Severity of Neuropathy Is Associated With Long-term Spinal ... Treatment success was observed in 55% of patients after 5 years. Median duration of SCS treatment was 60 months (minimum 1 month, maximum 60 months), and 80% of ...

6. accessdata.fda.gov accessdata.fda.gov/cdrh_docs/pdf/P840001S469B.pdf

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) 6 months follow-up. 18 adverse events in 14 subjects treated with SCS. Study related AEs: 3 Infection. 2 Wound dehiscence. 2 Explants. 1 each of impaired ...

7. accessdata.fda.gov accessdata.fda.gov/cdrh_docs/pdf/P010032S189B.pdf

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) The safety and effectiveness of the Abbott implantable neurostimulation system to treat DPN was based primarily on a systematic review of published scientific ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06290661

Clinical Trial of the Safety and Efficacy of Peripheral Nerve ... The goal of this clinical trial is to evaluate safety and efficacy of percutaneous peripheral nerve stimulation in patients with peripheral neuropathic pain ...