Effect of Electroacupuncture on Sensitive Symptoms of Distal Diabetic Peripheral Neuropathy (EA&DPN)

• ClinicalTrials.gov Identifier: NCT05521737
• Recruitment Status: Recruiting
• First Posted: August 30, 2022
• Last Update Posted: September 29, 2023
• Sponsor: Instituto Mexicano del Seguro Social
• Collaborators: National Polytechnic Institute, Mexico; Instituto Nacional de Salud Publica, Mexico; Escuela Superior de Medicina, Instituto Politécnico Nacional; Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional; Universidad Nacional Autonoma de Mexico; Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico; Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de Mexico; Facultad de Medicina, UNAM
• Information provided by (Responsible Party): José de Jesús Peralta Romero, Instituto Mexicano del Seguro Social

Tracking Information

• First Submitted Date: August 22, 2022
• First Posted Date: August 30, 2022
• Last Update Posted Date: September 29, 2023
• Actual Study Start Date: November 1, 2021
• Estimated Primary Completion Date: February 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 7, 2023)

Nerve Conduction Velocity [ Time Frame: Baseline evaluation, after the first and second cycle of intervention, respectively, and three months after the end of the intervention. ]

Measured by Nerve Conduction Velocity Study using the VIKING LIFE-SAVING EQUIPMENT, to determine Motor and Sensitive Nerve Conduction Velocity of common peroneal nerve, sural nerve, and tibial nerve. Sensitive Nerve Conduction (SCV). Distance between the receiving point and the stimulus point. SCV normal values: Peroneal nerve ≥ 41 m/s, tibial nerve ≥ 44 m/s, sural nerve ≥ 50 m/s. Motor Conduction Velocity (MCV). Distance between two points and the difference in incubation between them after superstimulation of the corresponding nerve branch. MCV normal values: Peroneal nerve ≥ 41 m/s, tibial nerve ≥ 44 m/s, sural nerve ≥ 60 m/s. *Values below those stipulated above indicate that NCV has slowed down, and is abnomal. The investigators expect a diminishment of SCV and MCV in sham acupuncture group from the first cycle of intervention whereas electroacupuncture group remains unchanged or even increases SCV and MCV.

Original Primary Outcome Measures (submitted: August 26, 2022)

• Michigan Neuropathy Screening Instrument (MNSI). Sensitive symptoms. [ Time Frame: Two months ]
  It will be assessed with the application of the Michigan Neuropathy Screening Instrument (MNSI), a 15-item self-administered questionnaire, to assess location, duration and severity of clinical signs and symptoms of diabetic peripheral neuropathy. Responses are added to obtain a total score. 'Yes' responses to questions 1-3, 5-6, 8-9, 11-12. Responses of 14-15 questions are each counted as one point. 'No' responses to questions 7 and 13 each count as one point. Question 4 is considered to be a measure of impaired circulation and question 10 a measure of general asthenia. A score of ≥ 7 is considered as abnormal Expecting a decrease of neuropathic symptoms and clinical impairment, and changes of post-treatment score.
• Michigan Neuropathy Screening Instrument (MNSI). Clinical Inspection. [ Time Frame: Two months ]
  It will be assessed with the application of the Michigan Neuropathy Screening Instrument (MNSI), with a lower extremity examination by a health professional that inspects each foot for deformities, dry skin, calluses, infections and fissures. Each foot with any abnormality receives a score of 1. Each foot is also inspected for ulcers and each foot with an ulcer receives a score of 1. Expecting changes of foot appearance and clinical inspection scores at the end of the intervention.
• Michigan Neuropathy Screening Instrument (MNSI). Vibratory sensation. [ Time Frame: Two months ]
  It will be tested in the great toe using a 128-Hz tuning fork. In general, the examiner should be able to feel vibration in his or her hand for 5 seconds longer than a normal subject can at the great toe. Vibration is scored as: Present, if the examiner senses the vibration for < 10 s longer than the subject feels it . Decreased, if sensed for ≥ 10 s (scored as 0.5). Absent (scored as 1). The total possible score is 8 points and, a score ≥ 2.5 is considered abnormal. Expecting changes of vibration sensation score at the end of the intervention.
• Michigan Neuropathy Screening Instrument (MNSI). Ankle reflexes. [ Time Frame: Two months ]
  Ankle reflexes are elicited, tapping Achilles tendon while foot is dorsiflexed. If the reflex is absent, the patient is asked to perform the Jendrassic manoeuver. If present, the reflex is designated as present with reinforcement and is scored as 0.5. If the reflex is absent with the Jendrassic manoeuver, the reflex is designated as absent and is scored as 1. Expecting changes of ankle reflexes score at the end of the intervention.
• Semmes-Weinstein monofilament (10 g monofilament test). [ Time Frame: Two months. ]
  To assess pressure sensation, patients should close their eyes while being tested. The sensation of pressure with the buckling 10-g monofilament should first be demonstrated to the patient on a proximal site, such as the upperarm. Ten sites of the foot may then be examined by asking the patient to respond "yes" or "no" when asked whether the monofilament is being applied to the particular site; so the patient recognizes the perception of pressure on the correct site. Tested on the plantar surface of the hallux and centrally at the heel. Areas of callus should always be avoided. Sensation at all sites tested of each foot with a maximum score of 10 points. People with six points or less are considered to show abnormal reactions. Expecting changes at pressure sensation and Semmes-Weinstein monofilament score at the end of the intervention.
• Neuropathy Deficit Score (NDS). [ Time Frame: Two months. ]
  A neurological examination score aimed at anatomical levels in the legs and arms. The instrument examines cranial nerves, muscle weakness, reflexes, and sensation of upper and lowerlimbs. Lowerlimb items are complemented with 2 muscle power items (toe extension and toe flexion). The scale consists of 35 items for testing the left and right sides of the body and scores range from 0 to 4. A sum score is obtained with a maximum of 280 points. A NDS of six points or more is considered as an abnormal reaction. Expecting changes of NDS at the end of the intervention.

Current Secondary Outcome Measures (submitted: August 7, 2023)

• Michigan Neuropathy Screening Instrument (MNSI). [ Time Frame: Baseline evaluation, after the first and second cycle of intervention, respectively, and three months after the end of the intervention. ]
  It will be assessed with a lower extremity examination by a health professional of both feet in search of deformities, dry skin, calluses, infections, fissures and ulcers. Complemented with measurement of vibratory sensation, ankle reflexes, and Semmes-Weinstein monofilament test. The investigators expect improvement in the physical aspect of the foot in the electroacupuncture group, while in the sham acupuncture group the complication progresses.
• Michigan Diabetic Neuropathy Score (MDNS) [ Time Frame: Baseline evaluation, after the first and second cycle of intervention, respectively, and three months after the end of the intervention. ]
  Composed of three items where the sensory compromise is evaluated with the perception of vibration, 10 gr. monofilament and pin prick, in addition to the muscular strength of the toes, and the bicipital, tricipital, quadriceps and achilles muscle reflexes. The investigators expect a diminishment of MDNS score and clinical improvement in the electroacupuncture group and progression of clinical manifestations in the sham group.
• Douleur Neuropathique en 4 Questions (DN-4) [ Time Frame: Baseline evaluation, after the first and second cycle of intervention, respectively, and three months after the end of the intervention. ]
  A screening tool for neuropathic pain consisting of 10 interview questions (DN4-interview) and physical tests. A score greater than 4 points suggests neuropathic pain. The investigators expect decreased scores in the electroacupuncture group and increased or persistent scores in the sham group.
• Numerical Pain Rating Scale (NRS) [ Time Frame: Baseline evaluation, after the first and second cycle of intervention, respectively, and three months after the end of the intervention. ]
  Patients are only asked to circle the number between 0 and 10, 0 and 20 or 0 and 100 that best matches the intensity of their pain currently and in the last 7 days, where zero usually represents "no pain", while the upper limit represents "the worst pain of their life". The investigators expect diminishment of rating scale in electroacupuncture group and an increase in sham acupuncture group.
• Quality life (SF-36) [ Time Frame: Baseline evaluation, after the first and second cycle of intervention, respectively, and three months after the end of the intervention. ]
  It will be measured by The Short Form-36 Health Survey (SF-36) a measure of health status that consists of eight scaled scores (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health), which are the weighted sums of the questions in their section. The investigators expect quality life improvement in electroacupuncture group while in sham acupuncture group might worsen.
• Oxidative Stress [ Time Frame: Baseline evaluation, after the first and second cycle of intervention, respectively, and three months after the end of the intervention. ]
  Determined by quantifying the concentrations of the lipoperoxidation product Malondialdehyde (MDA). An increase of MDA is expected in the sham group, while in the electroacupuncture group it is expected to decrease.
• Inflammatory response [ Time Frame: Baseline evaluation, after the first and second cycle of intervention, respectively, and three months after the end of the intervention. ]
  Assessed by changes in serum concentrations of proinflammatory (IL-6, IL1β, TNF-α and IL-18) and anti-inflammatory (IL-10) cytokines determined by quantitative ELISA by flow cytometry. The investigators expect increase of anti-inflammatory cytokine and decrease of proinflammatory cytokines in the electroacupuncture group, while in the sham group this is inversely presented.
• Genetic expression [ Time Frame: Baseline evaluation, after the first and second cycle of intervention, respectively, and three months after the end of the intervention. ]
  mRNA expression of 5-HT1AR, Neurokinin 1, α-adrenoreceptors, NGF (Nerve growth factor), CX3CR1, GAP-43 (Growth associated protein 43) and Neurotrophin (NT3), (Chemoline receptor 1) genes quantified by real-time PCR. The investigators expect an increase in gene expression in patients with electroacupuncture while in sham patients it is decreased or even unchanged.

Original Secondary Outcome Measures (submitted: August 26, 2022)

• Nerve Conduction Velocity. [ Time Frame: Two months ]
  Measured by electromyogram (EMG), carried out by a EMG specialist to ensure the accuracy of EMG reading. Electromyographic detection is to be performed using VIKING LIFE-SAVING EQUIPMENT, to determine Motor Conduction Velocity and Sensation Conduction Velocity of the bilateral median nerve, ulnar nerve, common peroneal nerve, sural nerve, and tibial nerve. The room should be kept quiet, and the temperature should remain at about 25 °C. Skin temperature must remain between 28 °C and 30 °C, and hyperthermic treatment should be provided to patients with low body surface temperature. Changes in sensory and motor conduction velocity of each nerve will be compared before and after intervention.
• Sensory Testing Nerve Conduction (SCV). [ Time Frame: Two months ]
  Determined using the reverse method, with a proximal stimulus and remote reception. The sensory waveform is derived from the average deconvolution by machine automatically. SCV value is the measured distance between the receiving point and the stimulus point. The SCV normal value refers to the clinical electromyography standard: For the median nerve, SCV normal values must be ≥ 50 m/second. For the ulnar nerve, SCV normal values must be ≥ 40 m/second. SCV normal values of peroneal nerve must be ≥ 41 m/second. For tibial nerve SCV normal values must be ≥ 44 m/second. SCV normal values for sural nerve must be ≥ 50 m/second. Values below those stipulated above indicate that SCV has slowed down, that means SCV is abnomal. The changes in SCV of each nerve will be compared before and after intervention.
• Motor Conduction Velocity (MCV). [ Time Frame: Two months ]
  MCV, is determined in the corresponding distal muscles of both arms and legs. The corresponding nerve branch is superstimulated to elicit two action potentials: far end and near end. MCV is the distance between two points and the difference in incubation between those points. For the median nerve and ulnar nerve, MCV normal values must be ≥ 50 m/second, individually. MCV normal values of peroneal nerve must be ≥ 41 m/second. For tibial nerve MCV normal values must be ≥ 44 m/second. MCV normal values for sural nerve must be ≥ 60 m/second. Values below those stipulated above indicate that MCV has slowed down, that means MCV is abnomal. The changes in MCV of each nerve will be compared before and after intervention.
• Quality life [ Time Frame: Two months ]
  It will be measured by The Short Form-36 Health Survey (SF-36) a measure of health status that consists of eight scaled scores (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health), which are the weighted sums of the questions in their section.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effect of Electroacupuncture on Sensitive Symptoms of Distal Diabetic Peripheral Neuropathy
• Official Title: Effect of Electroacupuncture on Sensitive Symptoms of Distal Diabetic Peripheral Neuropathy and Its Correlation With Nerve Conduction Changes
• Brief Summary: This is a controlled clinical trial with the aim to study the effects of electroacupuncture on neuropathic pain reduction, quality of life and changes in sensory and motor nerve conduction velocity in patients with type 2 diabetes mellitus, beneficiaries of the familiar medical centers 20, 40 and 41 of the Instituto Mexicano del Seguro Social, at north of Mexico City, in colaboration with the human acupuncture specialty of the Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico.

Detailed Description

Controlled clinical trial to evaluate the effect of electroacupuncture on the reduction of neuropathic pain, quality of life; electrophysiological, inflammatory response, oxidative stress, and genetic expression, in patients with type 2 diabetes mellitus, beneficiaries from the family medical centers 20 , 40 and 41 of the Instituto Mexicano del Seguro Social, at north of Mexico City.

Once the acceptance letter has been signed, a series of questionnaires (MNSI, MDNS, DN-4, NRS, and SF-36), and a physical examination will be carried out to meet the necessary criteria to continue participating.

Only candidates with clinical diagnosis of diabetic polyneuropathy will have an electrophysiological examination by nerve conduction velocity study, if so, patients will be randomized to the electroacupunture or sham acupuncture groups.

Before intervention, laboratory studies will be taken after fasting for 8 to 10 hours, to determine biochemichal profile (glucose, urea, creatinine, uric acid , triglycerides, total cholesterol, HDL and LDL), oxidative stress (Malondialdehyde), inflammatory response (IL-6, IL1β, TNF-α, IL-10 and IL-18 cytokines), and gene expression (5-HT1AR, Neurokinin 1, α-adrenoreceptors, NGF, CX3CR1, GAP-43, and NT3).

Intervention will be applied in a total of 32 acupuncture sessions, divided into two intervention cycles, that is, 16 sessions over two months, with a rest period of one month in between.

At the end of both cycles of interventions, the questionnaires, the nerve conduction velocity study the biochemical and molecular studies will be re-assessed. Finally, this will be re-evaluated after three months post-intervention in order to evaluate the effect of intervention over time.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The protocol consists of two study groups, including a control group of sham acupuncture, and an interventional group of Electroacupuncture. Both interventions will be applied in a total of 32 sessions, divided into two intervention cycles, that is, 16 sessions over two months, with a rest period of one month in between. ,Acupuncture points are Zusanli (E36), Fenlong (E40), Yinlingquan (B9), Sanyinjiao (B6), Taichong (H3) and Zulinqi (VB41).

Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:

Patient masking: During the application of the intervention, a bandage is placed over the patients eyes so that the participants cannot see the type of therapy applied (electroacupuncture or sham acupuncture).

Statistical masking: The researcher in charge of the statistical analysis is unaware of the type of intervention received by the patients and delivers the results to the responsible researcher.

Primary Purpose: Treatment

Condition

• Electroacupuncture
• Acupuncture
• Diabetic Polyneuropathy
• Diabetic Peripheral Neuropathy
• Diabetic Peripheral Neuropathic Pain
• Nerve Conduction

Intervention

• Procedure: Electroacupuncture
  Intervention consists of a total of 32 sessions, divided into two intervention cycles, that is, 16 sessions over two months, with a rest period of one month in between. EA is applied for 20 minutes at an alternating frequency of 2 Hz. Acupunctural points are Zusanli (E36), Fenlong (E40), Yinlingquan (B9), Sanyinjiao (B6), Taichong (H3) and Zulinqi (VB41).
  Other Name: EA
• Procedure: Sham Acupuncture
  Intervention consists of a total of 32 sessions, divided into two intervention cycles, that is, 16 sessions over two months, with a rest period of one month in between. Sham acupuncture will be applied using a nonpuncture device without electrical stimulation at the same acupunctural points as in the EA group.
  Other Name: Sham

Study Arms

• Sham Comparator: Sham group
  Sham acupuncture will be administered in a total of 32 sessions within five months.
  Intervention: Procedure: Sham Acupuncture
• Experimental: Interventional group
  Electroacupuncture will be administered in a total of 32 sessions within five months.
  Intervention: Procedure: Electroacupuncture

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 4, 2023): 200
• Original Estimated Enrollment (submitted: August 26, 2022): 262
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: February 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients with type 2 diabetes.
• Patients with clinical diabetic peripheral polyneuropathy.
• Patients with electrophysiological diagnosis of diabetic peripheral polyneuropathy in its different types of classification.

Exclusion Criteria:

• Type 1 Diabetes or gestational diabetes.
• Systemic autoimmune diseases.
• Hematological disorders.
• HIV diagnosis.
• Cancer in treatment.
• Pregnancy.
• Other types of neurological disorders or neuropathies.
• Intervention with acupuncture six months previously.
• Patients with pacemarkers.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: José de Jesús Peralta Romero, PhD; 5532318563; drjjperalta@gmail.com

Contact: María Fernanda Pérez Hernández, MD; 5574021093; marferperezh@gmail.com

• Listed Location Countries: Mexico

Administrative Information

• NCT Number: NCT05521737
• Other Study ID Numbers: R-2020-785-070; 09-CEI-009-20160601 ( Other Identifier: CONBIOÉTICA ); 17 CI 09 015 006 ( Other Identifier: COFEPRIS )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: José de Jesús Peralta Romero, Instituto Mexicano del Seguro Social
• Original Responsible Party: José de Jesús Peralta Romero, Instituto Mexicano del Seguro Social, Researcher attached to the Medical Research Unit in Biochemistry, High Specialty Medical Unit "Dr. Bernardo Sepúlveda", National Medical Center Siglo XXI, IMSS, Mexico City
• Current Study Sponsor: Instituto Mexicano del Seguro Social
• Original Study Sponsor: Same as current

Collaborators

• National Polytechnic Institute, Mexico
• Instituto Nacional de Salud Publica, Mexico
• Escuela Superior de Medicina, Instituto Politécnico Nacional
• Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional
• Universidad Nacional Autonoma de Mexico
• Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico
• Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de Mexico
• Facultad de Medicina, UNAM

Investigators

• Principal Investigator: José de Jesús Peralta Romero, PhD; Instituto Mexicano del Seguro Social

• PRS Account: Instituto Mexicano del Seguro Social
• Verification Date: September 2023