Randomized Controlled Study of Optical 3D Navigated Repetitive Transcranial Magnetic Stimulation for Achalasia.

Esophageal Achalasia Clinical Trial

Official title:

To Investigate the Clinical Efficacy of Optical 3D Navigation Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Achalasia, Optimize the Treatment Parameters, and Provide a Noninvasive Treatment Strategy for Achalasia

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06027190
• Other study ID #: 2023-160-02
• Status: Not yet recruiting
• Phase: N/A
• Start date: January 1, 2024
• Est. completion date: December 31, 2026

Study information

• Verified date: September 2023
• Source: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Contact: Nina Zhang
• Phone: 18652782446
• Email: zhangnina[@]njglyy.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to investigate the clinical efficacy of repetitive transcranial magnetic stimulation in the treatment of achalasia in patients diagnosed with achalasia by comprehensive evaluation of clinical symptoms, HREM, and barium meal examination, optimize rTMS treatment parameters, and provide an effective and noninvasive new treatment strategy for achalasia. The main questions it aims to answer are: 1. To investigate the clinical efficacy of individualized treatment of achalasia with optical 3D navigation repetitive transcranial magnetic stimulation. 2. Optimize rTMS parameters to achieve the best clinical treatment. Participants will need to fill out the Eckardt score scale and SF-36 quality of life scale, undergo cranial T1 structural magnetic resonance for functional connectivity analysis, and select the brain region with the strongest positive functional connectivity to the DMV as the rTMS target. All patients were randomly divided into four groups: sham-rTMS group, 5Hz-rTMS group, 10Hz-rTMS group, and 30Hz-rTMS group, and each group received acute and chronic stimulation, respectively. In the acute stimulation stage, patients only need to do rTMS once, and HREM and HRV detection are given before and after rTMS (stimulation for 1s, interval for 4s, 10 pulses per second, receiving a total of 3000 pulses); in the chronic stimulation stage, patients receive 25 minutes of rTMS actual stimulation or sham stimulation each time, lasting for 20 times, which is completed within 30 days, and the actual stimulation parameters are the same as those of acute stimulation, and the sham stimulation coil is consistent with the appearance and sound of proper stimulation, but there is no substantial stimulation. High-definition esophageal manometry, timed barium meal, heart rate coefficient of variation, and serum neurotransmitters were performed before and after chronic stimulation. Finally, a weekly telephone follow-up was performed for 12 weeks, including Eckardt score and SF-36 quality of life scale.

Description:

Study hypothesis: By analyzing the strongest resting-state functional connectivity between DMV and right precentral gyrus, left postcentral gyrus, and left brain leads in achalasia patients, individualized rTMS treatment with optical 3D navigation was applied to relax LES and relieve the clinical symptoms of dysphagia. Statistical methods: SPSS 25.0 software was used to process the data, symptom score, manometry parameters, serum transmitters and other quantitative indicators. If they met the normal distribution, they were expressed as Mean ± SD. The t-test was performed for the comparison between the two groups; if they did not obey the normal distribution, the median (quartile) was used for statistical description. The rank sum test was used for the comparison between the two groups. Enumeration data were described using number of cases (percentage), and X2 test, corrected X2 test, or Fisher exact test were performed for comparison between the 2 groups.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 112
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Aged more than 18 years old, less than 75 years old;
• Clinical symptoms evaluation, HREM, esophageal barium meal examination confirmed the diagnosis of achalasia;
• Willing to sign informed consent.

Exclusion Criteria:

• Presence of metal hardware in close contact with the discharge coil (e.g., cochlear implant, internal pulse generator, or drug pump). Note: Cochlear implants include electrodes, magnets, loop antennas, and electronic chips under the scalp implanted in the cochlea;
• Intracranial metal implants;
• Patients with cardiac pacemakers, vagal nerve stimulation (VNS) systems, spinal cord stimulators, and deep brain stimulation implanted with pulse generators should be used with caution;
• People at higher risk of noisy hearing loss and patients with hypoacusis symptoms should be used with caution;
• Pregnancy;
• Severe or recent heart disease;
• Personal history of epilepsy, use of known drugs that lower the seizure threshold, and other factors that may lower the seizure threshold (e.g., lack of sleep, infection, and alcohol abuse);
• Increased intracranial pressure;
• Acute phase of intracranial infection and hemorrhagic disease;
• Contraindications to MRI examination or claustrophobia;
• Refusal to sign informed consent.

Related Conditions & MeSH terms

• Esophageal Achalasia
• Functional Magnetic Resonance Imaging
• Motor Disorders
• Transcranial Magnetic Stimulation, Repetitive
• Vagus Nerve Diseases

Intervention

Device:
• Repetitive transcranial magnetic stimulation
Intervention Name and Specification Transcranial magnetic stimulator (M-100 Ultimate, Yingzhi Technology Co., Ltd., China) . 70-mm-diameter figure-of-eight coil (BY90A, Yingzhi Technology Co., Ltd., China). 3) Placebo coil (Magstim Company, Whitland, UK): the appearance and sound were consistent with the true coil, but no current stimulation was produced.
• Sham
Placebo coil (Magstim Company, Whitland, UK):

Locations

Country	Name	City	State
China	Nanjing Drum Tower Hospital	Nanjing

Sponsors (1)

Lead Sponsor	Collaborator
Zhang Nina

Country where clinical trial is conducted

China, 

References & Publications (19)

Abrahams TP, Partosoedarso ER, Hornby PJ. Lower oesophageal sphincter relaxation evoked by stimulation of the dorsal motor nucleus of the vagus in ferrets. Neurogastroenterol Motil. 2002 Jun;14(3):295-304. doi: 10.1046/j.1365-2982.2002.00329.x. — View Citation

Algladi T, Harris M, Whorwell PJ, Paine P, Hamdy S. Modulation of human visceral sensitivity by noninvasive magnetoelectrical neural stimulation in health and irritable bowel syndrome. Pain. 2015 Jul;156(7):1348-1356. doi: 10.1097/j.pain.0000000000000187. — View Citation

Browning KN, Carson KE. Central Neurocircuits Regulating Food Intake in Response to Gut Inputs-Preclinical Evidence. Nutrients. 2021 Mar 11;13(3):908. doi: 10.3390/nu13030908. — View Citation

Clyburn C, Travagli RA, Browning KN. Acute high-fat diet upregulates glutamatergic signaling in the dorsal motor nucleus of the vagus. Am J Physiol Gastrointest Liver Physiol. 2018 May 1;314(5):G623-G634. doi: 10.1152/ajpgi.00395.2017. Epub 2018 Jan 25. — View Citation

Farre R, Sifrim D. Regulation of basal tone, relaxation and contraction of the lower oesophageal sphincter. Relevance to drug discovery for oesophageal disorders. Br J Pharmacol. 2008 Mar;153(5):858-69. doi: 10.1038/sj.bjp.0707572. Epub 2007 Nov 12. — View Citation

Goyal RK, Padmanabhan R, Sang Q. Neural circuits in swallowing and abdominal vagal afferent-mediated lower esophageal sphincter relaxation. Am J Med. 2001 Dec 3;111 Suppl 8A:95S-105S. doi: 10.1016/s0002-9343(01)00863-4. — View Citation

Gregersen H, Lo KM. Pathophysiology and treatment of achalasia in a muscle mechanical perspective. Ann N Y Acad Sci. 2018 Dec;1434(1):173-184. doi: 10.1111/nyas.13711. Epub 2018 May 14. — View Citation

Hornby PJ, Abrahams TP. Central control of lower esophageal sphincter relaxation. Am J Med. 2000 Mar 6;108 Suppl 4a:90S-98S. doi: 10.1016/s0002-9343(99)00345-9. — View Citation

Li J, Xu K, Guo Y, Chen X, Li G, Qi L, Che X. Case evidence of repetitive transcranial magnetic stimulation in the management of refractory irritable bowel syndrome with comorbid depression. Brain Stimul. 2022 Mar-Apr;15(2):434-436. doi: 10.1016/j.brs.2022.01.020. Epub 2022 Feb 11. No abstract available. — View Citation

Magnus CJ, Lee PH, Bonaventura J, Zemla R, Gomez JL, Ramirez MH, Hu X, Galvan A, Basu J, Michaelides M, Sternson SM. Ultrapotent chemogenetics for research and potential clinical applications. Science. 2019 Apr 12;364(6436):eaav5282. doi: 10.1126/science.aav5282. Epub 2019 Mar 14. — View Citation

Mari A, Abu Baker F, Pellicano R, Khoury T. Diagnosis and Management of Achalasia: Updates of the Last Two Years. J Clin Med. 2021 Aug 16;10(16):3607. doi: 10.3390/jcm10163607. — View Citation

Nagai Y, Miyakawa N, Takuwa H, Hori Y, Oyama K, Ji B, Takahashi M, Huang XP, Slocum ST, DiBerto JF, Xiong Y, Urushihata T, Hirabayashi T, Fujimoto A, Mimura K, English JG, Liu J, Inoue KI, Kumata K, Seki C, Ono M, Shimojo M, Zhang MR, Tomita Y, Nakahara J, Suhara T, Takada M, Higuchi M, Jin J, Roth BL, Minamimoto T. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. Nat Neurosci. 2020 Sep;23(9):1157-1167. doi: 10.1038/s41593-020-0661-3. Epub 2020 Jul 6. — View Citation

Pomenti S, Blackett JW, Jodorkovsky D. Achalasia: Diagnosis, Management and Surveillance. Gastroenterol Clin North Am. 2021 Dec;50(4):721-736. doi: 10.1016/j.gtc.2021.07.001. Epub 2021 Oct 2. — View Citation

Roth BL. DREADDs for Neuroscientists. Neuron. 2016 Feb 17;89(4):683-94. doi: 10.1016/j.neuron.2016.01.040. — View Citation

Schlottmann F, Neto RML, Herbella FAM, Patti MG. Esophageal Achalasia: Pathophysiology, Clinical Presentation, and Diagnostic Evaluation. Am Surg. 2018 Apr 1;84(4):467-472. — View Citation

Schlottmann F, Patti MG. Esophageal achalasia: current diagnosis and treatment. Expert Rev Gastroenterol Hepatol. 2018 Jul;12(7):711-721. doi: 10.1080/17474124.2018.1481748. Epub 2018 Jun 8. — View Citation

Shiwaku H, Sato H, Shimamura Y, Abe H, Shiota J, Sato C, Ominami M, Sakae H, Hata Y, Fukuda H, Ogawa R, Nakamura J, Tatsuta T, Ikebuchi Y, Yokomichi H, Hasegawa S, Inoue H. Risk factors and long-term course of gastroesophageal reflux disease after peroral endoscopic myotomy: A large-scale multicenter cohort study in Japan. Endoscopy. 2022 Sep;54(9):839-847. doi: 10.1055/a-1753-9801. Epub 2022 Feb 16. Erratum In: Endoscopy. 2022 Mar 01;: — View Citation

Travagli RA, Anselmi L. Vagal neurocircuitry and its influence on gastric motility. Nat Rev Gastroenterol Hepatol. 2016 Jul;13(7):389-401. doi: 10.1038/nrgastro.2016.76. Epub 2016 May 25. — View Citation

Urban DJ, Roth BL. DREADDs (designer receptors exclusively activated by designer drugs): chemogenetic tools with therapeutic utility. Annu Rev Pharmacol Toxicol. 2015;55:399-417. doi: 10.1146/annurev-pharmtox-010814-124803. Epub 2014 Sep 25. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Eckardt score	The Eckardt scoring system is used to assess the severity of symptoms, with 0 to 1 in grade 0, 2 to 3 in grade I., 4 to 6 in grade II., and > 6 in grade III. The more severe the symptoms, the higher the score, and can also be used for efficacy assessment.	Measured immediately after intervention.
Primary	Real-time esophageal barium meal examination	The severity of the patient 's condition and the therapeutic effect were evaluated by defining the height and maximum width of the residual barium area.	Measured immediately after intervention.
Primary	High-resolution esophageal manometry(HREM)	HREM is the gold standard for the diagnosis of achalasia of cardia (AC), which can assess the relaxation ability of the lower esophageal sphincter (LES) and the contraction ability of the esophageal body. HREM dynamically collects the mean pressure data of multiple parts of the whole esophagus in real time, and converts the linear manometry pattern into color pressure topography. The basic manometry parameters include integrated relaxation pressure (IRP) and lower esophageal sphincter pressure (LESP), which can more truly reflect the relaxation function of the gastroesophageal junction (EGJ) and are the key indicators for the diagnosis of AC.	Measured immediately after intervention.
Secondary	Heart rate variability assessment	Dynamic electrocardiogram recording analysis of sympathetic vagal activity.	Measured immediately after intervention.
Secondary	Neurotransmitter detection analysis	Serum ACh, NO and VIP	Measured immediately after intervention.