<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04460521</url>
  </required_header>
  <id_info>
    <org_study_id>ACTS Trial</org_study_id>
    <nct_id>NCT04460521</nct_id>
  </id_info>
  <brief_title>The ACTS Trial: N-acetylcysteine (NAC) and Night-splinting as a Non-operative Treatment for Carpal Tunnel Syndrome</brief_title>
  <acronym>ACTS</acronym>
  <official_title>The Use of N-acetylcysteine Supplementation in Addition to Night Splinting for Treatment of Mild to Moderate Carpal Tunnel Syndrome: A Randomized, Double-blind, Placebo-controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>David Tang</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Nova Scotia Health Authority</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Carpal tunnel syndrome (CTS) is the most common nerve compression syndrome worldwide, causing&#xD;
      significant chronic pain, functional impairment, and lowered quality of life for individuals&#xD;
      of various backgrounds. CTS is caused by chronic compression of the median nerve in the&#xD;
      carpal tunnel of the wrist, causing numbness and pain in the palm, thumb, index, and middle&#xD;
      fingers and eventual weakness of the hand. Many different treatments for CTS have been&#xD;
      proposed and studied, including but not limited to non-operative treatments such as wrist&#xD;
      splinting, steroid injections, and lifestyle modifications as well as operative treatments,&#xD;
      such as surgical carpal tunnel release (CTR). To date, very few oral medications have been&#xD;
      shown to be effective as conservative treatments for CTS. In this study the investigators&#xD;
      will examine whether there is any benefit to using oral N-acetylcysteine (NAC) as an&#xD;
      adjunctive treatment for mild to moderate CTS in addition to a standard 8-week trial of night&#xD;
      splinting. NAC has been used in humans for various purposes, is extremely safe and has very&#xD;
      few side effects, and has been shown to have anti-inflammation properties which may help&#xD;
      treat CTS. The investigators will study this by performing a randomized controlled trial,&#xD;
      comparing patients receiving oral NAC and standard night splinting to patients receiving an&#xD;
      identical placebo and standard night splinting. Both patient groups will be assessed using a&#xD;
      questionnaire to assess for severity of their CTS symptoms both before and after the 8-week&#xD;
      treatment. The primary objective will be to determine whether supplementation with oral NAC&#xD;
      in addition to night splinting has any significant impact on patient-reported symptoms and&#xD;
      functional impairment when compared to night splinting alone. The investigators will also&#xD;
      measure secondary outcomes including whether patients decide to have surgery for their CTS&#xD;
      after treatment and/or continued use of other treatments. This study has the potential to&#xD;
      have a significant positive impact on patients by identifying a safe, inexpensive,&#xD;
      accessible, and well tolerated conservative treatment for mild to moderate carpal tunnel&#xD;
      syndrome, and potentially preventing the need for additional, more invasive treatments such&#xD;
      as surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction: Carpal tunnel syndrome (CTS) is the most prevalent and widely studied&#xD;
      peripheral nerve entrapment syndrome, with estimates between 10-20% of the general population&#xD;
      having clinical symptoms of CTS at least once in their lifetime. Classically, it presents&#xD;
      with symptoms of nocturnal numbness and tingling in the distribution of the median nerve,&#xD;
      often progressing to more constant parasthesias, weakness, and pain in the hand and/or wrist,&#xD;
      and eventually thenar muscle atrophy. There is a robust and continuously growing body of&#xD;
      research available on the clinical presentation, diagnosis, and management of CTS.&#xD;
      Conservative, non-operative management strategies, including night splinting and&#xD;
      corticosteroid injections, have shown significant clinical benefit in improving the severity&#xD;
      of CTS symptoms and preventing the need for carpal tunnel release (CTR) surgery. However,&#xD;
      many patients with mild-moderate CTS will still go on to have CTR due to failure of&#xD;
      conservative measures or lack of long-term efficacy. N-acetylcysteine (NAC) is a safe and&#xD;
      extremely well tolerated compound which acts as a powerful antioxidant and has been utilized&#xD;
      in the treatment of many conditions including, but not limited to acetaminophen toxicity,&#xD;
      various psychiatric disorders, Alzheimer's disease, and polycystic ovarian syndrome. Of note,&#xD;
      some studies using animal models have shown NAC to be effective in reducing oxidative stress&#xD;
      and potentially expediting the recovery of peripheral nerve injuries. This warrants&#xD;
      consideration of the potential of NAC to impact peripheral nerve recovery in the&#xD;
      non-operative treatment of mild to moderate carpal tunnel syndrome. Given the safety of NAC,&#xD;
      and promising hypotheses to suggest neuroprotective and neuronal growth promoting effects on&#xD;
      peripheral nerves, The investigators propose the following project to examine whether&#xD;
      supplementation with oral NAC in addition to standard night splinting significantly improves&#xD;
      functional outcomes for mild to moderate CTS when compared to splinting alone.&#xD;
&#xD;
      Methods: This study will be a randomized, double-blind, parallel-group, placebo-controlled&#xD;
      human clinical trial. Participants for this study will be recruited by staff, residents, and&#xD;
      research assistants on a voluntary basis from both the outpatient Plastic Surgery clinic,&#xD;
      Plastic Surgery clinic waiting list, and the Neurology clinic at the Queen Elizabeth II&#xD;
      Health Sciences Center, Halifax Infirmary, in Nova Scotia, Canada. These will include&#xD;
      patients both waiting for consultation with a hand surgeon for consideration of carpal tunnel&#xD;
      release and patients who have already been assessed by a hand surgeon but have yet to undergo&#xD;
      a trial of night splinting.&#xD;
&#xD;
      For the purposes of this study, a diagnosis of mild to moderate CTS will be primarily&#xD;
      determined by clinical history of any intermittent or persistent numbness in the distribution&#xD;
      of the median nerve and/or pain in the hand or wrist. Clinical exam findings consistent with&#xD;
      a diagnosis of CTS will be determined by a CTS-6 score of 12 or higher, indicating at least&#xD;
      an 80% chance of a diagnosis of CTS.&#xD;
&#xD;
      After identification of eligible participants, they will be informed of the nature of the&#xD;
      study and the proposed intervention and consented both verbally and in writing to participate&#xD;
      in the study by a research assistant. They will undergo permutated block randomization to&#xD;
      either the placebo controlled or experimental group in a 1:1 ratio. The participants and&#xD;
      physicians/assessors will be masked to participant group allocation.&#xD;
&#xD;
      Baseline variables will be collected from each participant including age, gender, smoking&#xD;
      status, previous diagnoses of carpal tunnel syndrome, which side is affected or bilateral&#xD;
      disease, which side will undergo splinting as determined by severity, previous treatments for&#xD;
      carpal tunnel syndrome on both the study and non-study limb (if bilateral disease), clinical&#xD;
      and electrodiagnostic severity of CTS, duration of symptoms, nature of onset, any current&#xD;
      pain medications for both CTS symptoms and non-CTS related pain, employment status, and&#xD;
      comorbidities.&#xD;
&#xD;
      Pre-treatment Evaluation: Once the participants have given informed consent and been&#xD;
      randomized, they will be asked to complete a baseline Boston Carpal Tunnel Questionnaire&#xD;
      (BCTQ). All patients will receive a prescription for a wrist splint and 8 weeks supply of&#xD;
      either NAC tablets or a placebo.&#xD;
&#xD;
      Post-treatment Evaluation: Follow-up will take place at eight weeks by the surgeon to whom&#xD;
      the patient was referred for consideration of carpal tunnel release. Participants will be&#xD;
      asked to complete another BCTQ to be compared to their baseline score. At this time, patients&#xD;
      can decide if they wish to proceed with carpal tunnel release surgery or defer surgical&#xD;
      treatment.&#xD;
&#xD;
      For patients that do not decide to proceed with carpal tunnel release surgery, a secondary&#xD;
      outcome measure will include a follow up at 6 months, at which time The investigators will&#xD;
      collect patient reported outcomes including conversion to surgery, continued use of&#xD;
      conservative treatment modalities including night splinting or other treatment modalities,&#xD;
      and patient-reported outcomes in the way of a final BCTQ if surgery was not pursued.&#xD;
&#xD;
      Outcome Measures: The primary outcome measure in this study will be the overall score for&#xD;
      symptom severity and hand function limitations as determined by the BCTQ at eight weeks post&#xD;
      initiation of night splinting therapy. A secondary outcome will be ratio of conversion to&#xD;
      surgery versus continuation of conservative treatment or no treatment at all.&#xD;
&#xD;
      Data Analysis: For baseline demographic variables, The investigators will use descriptive&#xD;
      statistics (means with standard deviations for continuous variables or frequency with&#xD;
      percentages for categorical variables) and assess between group similarities. T-test and&#xD;
      chi-square tests, where appropriate, will be used to determine significant differences in&#xD;
      baseline demographics. The primary between group analysis will be done with multiple linear&#xD;
      regression with adjustments made for age at randomization, gender, symptom duration, and&#xD;
      baseline BCTQ score, with an aim to identify significant differences in improvements in the&#xD;
      BCTQ score between the treatment and control group at eight weeks and six months, where&#xD;
      applicable. The investigators will also examine for significance in the ratio of conversion&#xD;
      to surgery at eight weeks and six months. Significance will be set as a p-value &lt;0.05.&#xD;
&#xD;
      Sample Size: Based on the INSTINCTS trial by Chesterson and colleagues, this study will&#xD;
      require 240 total participants (120 per group). The investigators will aim to detect a 15% or&#xD;
      greater improvement in the BCTQ from assumed baseline value of 2.9 (scale 1-5, SD 1.0). This&#xD;
      would mean a 0.9 point (30%) reduction in the NAC plus splinting group and a 0.45 point (15%)&#xD;
      reduction in the placebo plus splinting group, with a pooled SD of 1.0 and mean difference of&#xD;
      0.45. Power will be set at 90%, two-tailed significance at 5%, and a 15% loss to follow up&#xD;
      will be anticipated. Recruitment of 120 participants for both the placebo-controlled and NAC&#xD;
      groups will primarily be from the practice of a single hand surgeon (DT) and the practices of&#xD;
      several local neurologists. The primary hand surgeon (DT) has completed a preliminary audit&#xD;
      of his practice and has determined that in the last year, he completed 200 CTRs in the minor&#xD;
      procedure clinic.&#xD;
&#xD;
      Strengths and Limitations: This study will have a robust sample size, minimal potential for&#xD;
      participant loss, and strong clinical applications in the way of a minimally invasive adjunct&#xD;
      to night splinting as a conservative treatment for mild to moderate carpal tunnel syndrome.&#xD;
      This study is limited in that the primary outcome measure is relatively subjective, despite&#xD;
      the fact that the BCTQ is a validated tool that has been applied clinically in reputable&#xD;
      trials. Additionally, despite controlling for between group variability in baseline function,&#xD;
      severity of disease prior to treatment can certainly impact the degree of response to&#xD;
      conservative measures and may confound results.&#xD;
&#xD;
      Ethical Considerations: Given that the participants in this study will have already decided&#xD;
      to pursue investigations and treatment for their carpal tunnel syndrome prior to being&#xD;
      informed of and consented for our trial, there is a negligible ethical conflict of exposing a&#xD;
      patient to tests and treatments that they would not have otherwise had. Eligible participants&#xD;
      will be given the standard information regarding the risks and benefits of both pursuing and&#xD;
      delaying carpal tunnel release surgery and will not be delayed or denied surgery should they&#xD;
      choose not to participate in the trial. It is, however, acknowledged that there is a remote&#xD;
      possibility of placing patients at risk by administering a medication. NAC has been found to&#xD;
      be a safe, non-toxic substance with little-to-no reported short or long-term side effects.&#xD;
      Participants will be given as much information about the possible intervention as is needed&#xD;
      and will be offered the right to withdraw from the study at any point in time without any&#xD;
      repercussion to their medical care.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 1, 2021</start_date>
  <completion_date type="Anticipated">May 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomized, double-blind, placebo-controlled trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Participants will undergo permutated block randomization to either the placebo controlled or experimental group in a 1:1 ratio. This method will be computer-generated. The allocation sequence will be concealed to research staff. The participants, clinic nurses, research assistants, and physician investigators as well as outcome assessors will be masked to participant group allocation. Unblinding will be permissible in extenuating circumstances only, such as if a participant experiences a severe adverse reaction secondary to the tablet and requires confirmation of the contents.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change from baseline Boston Carpal Tunnel Questionnaire (BCTQ) at 8 weeks</measure>
    <time_frame>8 weeks</time_frame>
    <description>The Boston Carpal Tunnel Questionnaire (BCTQ) is a validated tool for patient-reported outcomes with respect to symptoms and functional impact of carpal tunnel syndrome. It consists of both a symptom severity scale (SSS) (11 items) and functional status scale (FSS) (8 items). Each item on both of these scales is scored on a 5-point rating system, with higher numbers indicating more severe symptoms and higher functional disability. The possible range of both the FSS and SSS combined is from 19-95. A baseline BCTQ will be administered at the first visit, which will be used to calculate the overall change in BCTQ score at 8 weeks.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants who elect to have surgical carpal tunnel decompression after 8 weeks</measure>
    <time_frame>8 weeks</time_frame>
    <description>The participant's decision to continue with conservative treatment or to elect to have a carpal tunnel release procedure at 8-weeks post-treatment will be a secondary outcome measure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants who elect to have surgical carpal tunnel decompression after 6 months</measure>
    <time_frame>6 months</time_frame>
    <description>If at 8-weeks, the participant decides not to have carpal tunnel release surgery, an additional follow up visit will be scheduled at 6 months time. At this point in time, the participants decision to have carpal tunnel release surgery or to continue to conservative modalities will be a subgroup analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline Boston Carpal Tunnel Questionnaire (BCTQ) at 6 months</measure>
    <time_frame>6 months</time_frame>
    <description>If the participant decides not have have a carpal tunnel release at 8 weeks, an additional follow up visit will be scheduled in 6 months. At this time, a third BCTQ will be completed to assess change in long-term BCTQ compared to baseline.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">240</enrollment>
  <condition>Carpal Tunnel Syndrome</condition>
  <condition>Hand Injuries and Disorders</condition>
  <condition>Nerve Compression</condition>
  <condition>Splints</condition>
  <condition>Carpal Tunnel</condition>
  <condition>Carpal Tunnel Release</condition>
  <arm_group>
    <arm_group_label>NAC Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in this group will given an N-acetylcysteine 500mg oral tablet daily in addition to wearing a standard carpal tunnel splint nightly (worn approximately 6-8 hours/day). Both interventions will take place concurrently for a total of 8 consecutive weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants in this group will be given a placebo table to be taken orally daily in addition to wearing a standard carpal tunnel splint nightly (worn approximately 6-8 hours/day). Both interventions will take place concurrently for a total of 8 consecutive weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>N-Acetyl cysteine</intervention_name>
    <description>In addition to splinting, both groups will receive an oral tablet to take daily for 8 weeks. Participants assigned to the experimental group will receive oral NAC (500 mg PO daily for eight weeks; based on recommended daily dose for use as an antioxidant and dosing in previous human clinical trials and animal studies), and those assigned to the control group will be given a similar looking placebo with identical instructions. Tablets will be provided in a blister pack to assist with compliance.</description>
    <arm_group_label>NAC Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Wrist Splint</intervention_name>
    <description>Participants in both arms will be given a standard prescription for a prefabricated night splint which keeps the wrist in a neutral position and instructed on proper use and the importance of consistent use. To limit splint variability, we will ensure that splint prescriptions are written such that a MedSpec Wrist Lacer II splint is obtained from the patient's pharmacy. This is the most commonly available brand locally and meets the criteria for wrist, metacarpophalangeal, and interphalangeal joint positioning. They will be advised to wear the splint consistently during sleeping hours on their affected wrist for eight weeks, as is the standard of practice.</description>
    <arm_group_label>NAC Group</arm_group_label>
    <arm_group_label>Placebo Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The patient has a confirmed diagnosis of mild to moderate idiopathic unilateral or&#xD;
             bilateral CTS as determined by both clinical exam findings and electrodiagnostic nerve&#xD;
             conduction studies (median nerve distal motor latency ≥ 4.3 milliseconds and/or median&#xD;
             nerve sensory distal latency ≥ 3.5 milliseconds at the wrist) performed within the&#xD;
             preceding year prior to enrollment&#xD;
&#xD;
          2. Symptoms of CTS must have been present for ≥ 6 weeks&#xD;
&#xD;
          3. The patient must be ≥ 18 years of age.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any previous carpal tunnel release procedure on the ipsilateral limb&#xD;
&#xD;
          2. Any previous trial of night splinting or corticosteroid injection in the last 6 months&#xD;
             on the ipsilateral limb&#xD;
&#xD;
          3. Severe CTS/signs of median nerve denervation with axonal loss determined by constant&#xD;
             wrist or hand pain, constant parasthesias in the median nerve distribution, or thenar&#xD;
             muscle atrophy in the ipsilateral limb&#xD;
&#xD;
          4. Any known or suspected allergy to NAC&#xD;
&#xD;
          5. Any current medications which preclude use of NAC including antibiotics or&#xD;
             nitroglycerin&#xD;
&#xD;
          6. Breastfeeding patients or patients with nephrolithiasis&#xD;
&#xD;
          7. Any history of proximal ipsilateral neck or proximal limb injury&#xD;
&#xD;
          8. Secondary CTS related to pregnancy&#xD;
&#xD;
          9. Unable for financial reasons to obtain a night splint (i.e. lack of insurance coverage&#xD;
             or lack of financial means).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael Bezuhly, MD</last_name>
    <role>Study Director</role>
    <affiliation>NSHA</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Anna M Duncan, MD</last_name>
    <phone>506-651-9368</phone>
    <email>anna.duncan@dal.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>David Tang, MD</last_name>
    <phone>902-473-1740</phone>
    <email>dt.tang@dal.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Queen Elizabeth II Health Sciences Center, Halifax Infirmary Site</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <zip>B3H3A6</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anna M Duncan, MD</last_name>
      <phone>506-651-9368</phone>
      <email>anna.duncan@dal.ca</email>
    </contact>
    <contact_backup>
      <last_name>David T Tang, MD</last_name>
      <phone>902-473-1740</phone>
      <email>dt.tang@dal.ca</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Atroshi I, Gummesson C, Johnsson R, Ornstein E, Ranstam J, Rosen I. Prevalence of carpal tunnel syndrome in a general population. JAMA. 1999 Jul 14;282(2):153-8. doi: 10.1001/jama.282.2.153.</citation>
    <PMID>10411196</PMID>
  </reference>
  <reference>
    <citation>Chesterton LS, Blagojevic-Bucknall M, Burton C, Dziedzic KS, Davenport G, Jowett SM, Myers HL, Oppong R, Rathod-Mistry T, van der Windt DA, Hay EM, Roddy E. The clinical and cost-effectiveness of corticosteroid injection versus night splints for carpal tunnel syndrome (INSTINCTS trial): an open-label, parallel group, randomised controlled trial. Lancet. 2018 Oct 20;392(10156):1423-1433. doi: 10.1016/S0140-6736(18)31572-1.</citation>
    <PMID>30343858</PMID>
  </reference>
  <reference>
    <citation>Levine DW, Simmons BP, Koris MJ, Daltroy LH, Hohl GG, Fossel AH, Katz JN. A self-administered questionnaire for the assessment of severity of symptoms and functional status in carpal tunnel syndrome. J Bone Joint Surg Am. 1993 Nov;75(11):1585-92. doi: 10.2106/00004623-199311000-00002.</citation>
    <PMID>8245050</PMID>
  </reference>
  <reference>
    <citation>Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A. A Review on Various Uses of N-Acetyl Cysteine. Cell J. 2017 Apr-Jun;19(1):11-17. doi: 10.22074/cellj.2016.4872. Epub 2016 Dec 21.</citation>
    <PMID>28367412</PMID>
  </reference>
  <reference>
    <citation>Huisstede BM, Friden J, Coert JH, Hoogvliet P; European HANDGUIDE Group. Carpal tunnel syndrome: hand surgeons, hand therapists, and physical medicine and rehabilitation physicians agree on a multidisciplinary treatment guideline-results from the European HANDGUIDE Study. Arch Phys Med Rehabil. 2014 Dec;95(12):2253-63. doi: 10.1016/j.apmr.2014.06.022. Epub 2014 Aug 12.</citation>
    <PMID>25127999</PMID>
  </reference>
  <reference>
    <citation>Page MJ, Massy-Westropp N, O'Connor D, Pitt V. Splinting for carpal tunnel syndrome. Cochrane Database Syst Rev. 2012 Jul 11;2012(7):CD010003. doi: 10.1002/14651858.CD010003.</citation>
    <PMID>22786532</PMID>
  </reference>
  <reference>
    <citation>Chan KM, Gordon T, Zochodne DW, Power HA. Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets. Exp Neurol. 2014 Nov;261:826-35. doi: 10.1016/j.expneurol.2014.09.006. Epub 2014 Sep 16.</citation>
    <PMID>25220611</PMID>
  </reference>
  <reference>
    <citation>Reid AJ, Shawcross SG, Hamilton AE, Wiberg M, Terenghi G. N-acetylcysteine alters apoptotic gene expression in axotomised primary sensory afferent subpopulations. Neurosci Res. 2009 Oct;65(2):148-55. doi: 10.1016/j.neures.2009.06.008. Epub 2009 Jun 24.</citation>
    <PMID>19559059</PMID>
  </reference>
  <reference>
    <citation>Sud V, Freeland AE. Biochemistry of carpal tunnel syndrome. Microsurgery. 2005;25(1):44-6. doi: 10.1002/micr.20071.</citation>
    <PMID>15481038</PMID>
  </reference>
  <reference>
    <citation>Kim JK, Koh YD, Kim JS, Hann HJ, Kim MJ. Oxidative stress in subsynovial connective tissue of idiopathic carpal tunnel syndrome. J Orthop Res. 2010 Nov;28(11):1463-8. doi: 10.1002/jor.21163.</citation>
    <PMID>20872582</PMID>
  </reference>
  <reference>
    <citation>Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1-100. doi: 10.1111/j.1600-0447.1987.tb10566.x. No abstract available.</citation>
    <PMID>2887090</PMID>
  </reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>June 17, 2020</study_first_submitted>
  <study_first_submitted_qc>July 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>August 3, 2021</last_update_submitted>
  <last_update_submitted_qc>August 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 9, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Nova Scotia Health Authority</investigator_affiliation>
    <investigator_full_name>David Tang</investigator_full_name>
    <investigator_title>Principal Investigator, Associate Professor, Division of Plastic Surgery, Dalhousie University</investigator_title>
  </responsible_party>
  <keyword>Wrist splint</keyword>
  <keyword>Carpal tunnel syndrome</keyword>
  <keyword>Carpal tunnel release</keyword>
  <keyword>Compression neuropathy</keyword>
  <keyword>NAC</keyword>
  <keyword>Conservative treatment</keyword>
  <keyword>Hand surgery</keyword>
  <keyword>Plastic surgery</keyword>
  <keyword>N-acetylcysteine</keyword>
  <keyword>Night splint</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carpal Tunnel Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
    <mesh_term>Hand Injuries</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetylcysteine</mesh_term>
    <mesh_term>N-monoacetylcystine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04460521
org study id: ACTS Trial
nct id: NCT04460521
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Carpal tunnel syndrome (CTS) is the most common nerve compression syndrome worldwide, causing
      significant chronic pain, functional impairment, and lowered quality of life for individuals
      of various backgrounds. CTS is caused by chronic compression of the median nerve in the
      carpal tunnel of the wrist, causing numbness and pain in the palm, thumb, index, and middle
      fingers and eventual weakness of the hand. Many different treatments for CTS have been
      proposed and studied, including but not limited to non-operative treatments such as wrist
      splinting, steroid injections, and lifestyle modifications as well as operative treatments,
      such as surgical carpal tunnel release (CTR). To date, very few oral medications have been
      shown to be effective as conservative treatments for CTS. In this study the investigators
      will examine whether there is any benefit to using oral N-acetylcysteine (NAC) as an
      adjunctive treatment for mild to moderate CTS in addition to a standard 8-week trial of night
      splinting. NAC has been used in humans for various purposes, is extremely safe and has very
      few side effects, and has been shown to have anti-inflammation properties which may help
      treat CTS. The investigators will study this by performing a randomized controlled trial,
      comparing patients receiving oral NAC and standard night splinting to patients receiving an
      identical placebo and standard night splinting. Both patient groups will be assessed using a
      questionnaire to assess for severity of their CTS symptoms both before and after the 8-week
      treatment. The primary objective will be to determine whether supplementation with oral NAC
      in addition to night splinting has any significant impact on patient-reported symptoms and
      functional impairment when compared to night splinting alone. The investigators will also
      measure secondary outcomes including whether patients decide to have surgery for their CTS
      after treatment and/or continued use of other treatments. This study has the potential to
      have a significant positive impact on patients by identifying a safe, inexpensive,
      accessible, and well tolerated conservative treatment for mild to moderate carpal tunnel
      syndrome, and potentially preventing the need for additional, more invasive treatments such
      as surgery.
Introduction: Carpal tunnel syndrome (CTS) is the most prevalent and widely studied
      peripheral nerve entrapment syndrome, with estimates between 10-20% of the general population
      having clinical symptoms of CTS at least once in their lifetime. Classically, it presents
      with symptoms of nocturnal numbness and tingling in the distribution of the median nerve,
      often progressing to more constant parasthesias, weakness, and pain in the hand and/or wrist,
      and eventually thenar muscle atrophy. There is a robust and continuously growing body of
      research available on the clinical presentation, diagnosis, and management of CTS.
      Conservative, non-operative management strategies, including night splinting and
      corticosteroid injections, have shown significant clinical benefit in improving the severity
      of CTS symptoms and preventing the need for carpal tunnel release (CTR) surgery. However,
      many patients with mild-moderate CTS will still go on to have CTR due to failure of
      conservative measures or lack of long-term efficacy. N-acetylcysteine (NAC) is a safe and
      extremely well tolerated compound which acts as a powerful antioxidant and has been utilized
      in the treatment of many conditions including, but not limited to acetaminophen toxicity,
      various psychiatric disorders, Alzheimer's disease, and polycystic ovarian syndrome. Of note,
      some studies using animal models have shown NAC to be effective in reducing oxidative stress
      and potentially expediting the recovery of peripheral nerve injuries. This warrants
      consideration of the potential of NAC to impact peripheral nerve recovery in the
      non-operative treatment of mild to moderate carpal tunnel syndrome. Given the safety of NAC,
      and promising hypotheses to suggest neuroprotective and neuronal growth promoting effects on
      peripheral nerves, The investigators propose the following project to examine whether
      supplementation with oral NAC in addition to standard night splinting significantly improves
      functional outcomes for mild to moderate CTS when compared to splinting alone.

      Methods: This study will be a randomized, double-blind, parallel-group, placebo-controlled
      human clinical trial. Participants for this study will be recruited by staff, residents, and
      research assistants on a voluntary basis from both the outpatient Plastic Surgery clinic,
      Plastic Surgery clinic waiting list, and the Neurology clinic at the Queen Elizabeth II
      Health Sciences Center, Halifax Infirmary, in Nova Scotia, Canada. These will include
      patients both waiting for consultation with a hand surgeon for consideration of carpal tunnel
      release and patients who have already been assessed by a hand surgeon but have yet to undergo
      a trial of night splinting.

      For the purposes of this study, a diagnosis of mild to moderate CTS will be primarily
      determined by clinical history of any intermittent or persistent numbness in the distribution
      of the median nerve and/or pain in the hand or wrist. Clinical exam findings consistent with
      a diagnosis of CTS will be determined by a CTS-6 score of 12 or higher, indicating at least
      an 80% chance of a diagnosis of CTS.

      After identification of eligible participants, they will be informed of the nature of the
      study and the proposed intervention and consented both verbally and in writing to participate
      in the study by a research assistant. They will undergo permutated block randomization to
      either the placebo controlled or experimental group in a 1:1 ratio. The participants and
      physicians/assessors will be masked to participant group allocation.

      Baseline variables will be collected from each participant including age, gender, smoking
      status, previous diagnoses of carpal tunnel syndrome, which side is affected or bilateral
      disease, which side will undergo splinting as determined by severity, previous treatments for
      carpal tunnel syndrome on both the study and non-study limb (if bilateral disease), clinical
      and electrodiagnostic severity of CTS, duration of symptoms, nature of onset, any current
      pain medications for both CTS symptoms and non-CTS related pain, employment status, and
      comorbidities.

      Pre-treatment Evaluation: Once the participants have given informed consent and been
      randomized, they will be asked to complete a baseline Boston Carpal Tunnel Questionnaire
      (BCTQ). All patients will receive a prescription for a wrist splint and 8 weeks supply of
      either NAC tablets or a placebo.

      Post-treatment Evaluation: Follow-up will take place at eight weeks by the surgeon to whom
      the patient was referred for consideration of carpal tunnel release. Participants will be
      asked to complete another BCTQ to be compared to their baseline score. At this time, patients
      can decide if they wish to proceed with carpal tunnel release surgery or defer surgical
      treatment.

      For patients that do not decide to proceed with carpal tunnel release surgery, a secondary
      outcome measure will include a follow up at 6 months, at which time The investigators will
      collect patient reported outcomes including conversion to surgery, continued use of
      conservative treatment modalities including night splinting or other treatment modalities,
      and patient-reported outcomes in the way of a final BCTQ if surgery was not pursued.

      Outcome Measures: The primary outcome measure in this study will be the overall score for
      symptom severity and hand function limitations as determined by the BCTQ at eight weeks post
      initiation of night splinting therapy. A secondary outcome will be ratio of conversion to
      surgery versus continuation of conservative treatment or no treatment at all.

      Data Analysis: For baseline demographic variables, The investigators will use descriptive
      statistics (means with standard deviations for continuous variables or frequency with
      percentages for categorical variables) and assess between group similarities. T-test and
      chi-square tests, where appropriate, will be used to determine significant differences in
      baseline demographics. The primary between group analysis will be done with multiple linear
      regression with adjustments made for age at randomization, gender, symptom duration, and
      baseline BCTQ score, with an aim to identify significant differences in improvements in the
      BCTQ score between the treatment and control group at eight weeks and six months, where
      applicable. The investigators will also examine for significance in the ratio of conversion
      to surgery at eight weeks and six months. Significance will be set as a p-value <0.05.

      Sample Size: Based on the INSTINCTS trial by Chesterson and colleagues, this study will
      require 240 total participants (120 per group). The investigators will aim to detect a 15% or
      greater improvement in the BCTQ from assumed baseline value of 2.9 (scale 1-5, SD 1.0). This
      would mean a 0.9 point (30%) reduction in the NAC plus splinting group and a 0.45 point (15%)
      reduction in the placebo plus splinting group, with a pooled SD of 1.0 and mean difference of
      0.45. Power will be set at 90%, two-tailed significance at 5%, and a 15% loss to follow up
      will be anticipated. Recruitment of 120 participants for both the placebo-controlled and NAC
      groups will primarily be from the practice of a single hand surgeon (DT) and the practices of
      several local neurologists. The primary hand surgeon (DT) has completed a preliminary audit
      of his practice and has determined that in the last year, he completed 200 CTRs in the minor
      procedure clinic.

      Strengths and Limitations: This study will have a robust sample size, minimal potential for
      participant loss, and strong clinical applications in the way of a minimally invasive adjunct
      to night splinting as a conservative treatment for mild to moderate carpal tunnel syndrome.
      This study is limited in that the primary outcome measure is relatively subjective, despite
      the fact that the BCTQ is a validated tool that has been applied clinically in reputable
      trials. Additionally, despite controlling for between group variability in baseline function,
      severity of disease prior to treatment can certainly impact the degree of response to
      conservative measures and may confound results.

      Ethical Considerations: Given that the participants in this study will have already decided
      to pursue investigations and treatment for their carpal tunnel syndrome prior to being
      informed of and consented for our trial, there is a negligible ethical conflict of exposing a
      patient to tests and treatments that they would not have otherwise had. Eligible participants
      will be given the standard information regarding the risks and benefits of both pursuing and
      delaying carpal tunnel release surgery and will not be delayed or denied surgery should they
      choose not to participate in the trial. It is, however, acknowledged that there is a remote
      possibility of placing patients at risk by administering a medication. NAC has been found to
      be a safe, non-toxic substance with little-to-no reported short or long-term side effects.
      Participants will be given as much information about the possible intervention as is needed
      and will be offered the right to withdraw from the study at any point in time without any
      repercussion to their medical care.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized, double-blind, placebo-controlled trial
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Participants will undergo permutated block randomization to either the placebo controlled or experimental group in a 1:1 ratio. This method will be computer-generated. The allocation sequence will be concealed to research staff. The participants, clinic nurses, research assistants, and physician investigators as well as outcome assessors will be masked to participant group allocation. Unblinding will be permissible in extenuating circumstances only, such as if a participant experiences a severe adverse reaction secondary to the tablet and requires confirmation of the contents.
measure: Change from baseline Boston Carpal Tunnel Questionnaire (BCTQ) at 8 weeks
time frame: 8 weeks
description: The Boston Carpal Tunnel Questionnaire (BCTQ) is a validated tool for patient-reported outcomes with respect to symptoms and functional impact of carpal tunnel syndrome. It consists of both a symptom severity scale (SSS) (11 items) and functional status scale (FSS) (8 items). Each item on both of these scales is scored on a 5-point rating system, with higher numbers indicating more severe symptoms and higher functional disability. The possible range of both the FSS and SSS combined is from 19-95. A baseline BCTQ will be administered at the first visit, which will be used to calculate the overall change in BCTQ score at 8 weeks.
measure: Number of participants who elect to have surgical carpal tunnel decompression after 8 weeks
time frame: 8 weeks
description: The participant's decision to continue with conservative treatment or to elect to have a carpal tunnel release procedure at 8-weeks post-treatment will be a secondary outcome measure.
measure: Number of participants who elect to have surgical carpal tunnel decompression after 6 months
time frame: 6 months
description: If at 8-weeks, the participant decides not to have carpal tunnel release surgery, an additional follow up visit will be scheduled at 6 months time. At this point in time, the participants decision to have carpal tunnel release surgery or to continue to conservative modalities will be a subgroup analysis.
measure: Change from baseline Boston Carpal Tunnel Questionnaire (BCTQ) at 6 months
time frame: 6 months
description: If the participant decides not have have a carpal tunnel release at 8 weeks, an additional follow up visit will be scheduled in 6 months. At this time, a third BCTQ will be completed to assess change in long-term BCTQ compared to baseline.
arm group label: NAC Group
arm group type: Experimental
description: Participants in this group will given an N-acetylcysteine 500mg oral tablet daily in addition to wearing a standard carpal tunnel splint nightly (worn approximately 6-8 hours/day). Both interventions will take place concurrently for a total of 8 consecutive weeks.
arm group label: Placebo Group
arm group type: Placebo Comparator
description: Participants in this group will be given a placebo table to be taken orally daily in addition to wearing a standard carpal tunnel splint nightly (worn approximately 6-8 hours/day). Both interventions will take place concurrently for a total of 8 consecutive weeks.
intervention type: Drug
intervention name: N-Acetyl cysteine
description: In addition to splinting, both groups will receive an oral tablet to take daily for 8 weeks. Participants assigned to the experimental group will receive oral NAC (500 mg PO daily for eight weeks; based on recommended daily dose for use as an antioxidant and dosing in previous human clinical trials and animal studies), and those assigned to the control group will be given a similar looking placebo with identical instructions. Tablets will be provided in a blister pack to assist with compliance.
arm group label: NAC Group
intervention type: Device
intervention name: Wrist Splint
description: Participants in both arms will be given a standard prescription for a prefabricated night splint which keeps the wrist in a neutral position and instructed on proper use and the importance of consistent use. To limit splint variability, we will ensure that splint prescriptions are written such that a MedSpec Wrist Lacer II splint is obtained from the patient's pharmacy. This is the most commonly available brand locally and meets the criteria for wrist, metacarpophalangeal, and interphalangeal joint positioning. They will be advised to wear the splint consistently during sleeping hours on their affected wrist for eight weeks, as is the standard of practice.
arm group label: NAC Group
arm group label: Placebo Group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Michael Bezuhly, MD
role: Study Director
affiliation: NSHA
last name: Anna M Duncan, MD
phone: 506-651-9368
email: anna.duncan@dal.ca
last name: David Tang, MD
phone: 902-473-1740
email: dt.tang@dal.ca
facility: 
status: Recruiting
contact: 
contact backup: 
country: Canada
citation: Atroshi I, Gummesson C, Johnsson R, Ornstein E, Ranstam J, Rosen I. Prevalence of carpal tunnel syndrome in a general population. JAMA. 1999 Jul 14;282(2):153-8. doi: 10.1001/jama.282.2.153.
PMID: 10411196
citation: Chesterton LS, Blagojevic-Bucknall M, Burton C, Dziedzic KS, Davenport G, Jowett SM, Myers HL, Oppong R, Rathod-Mistry T, van der Windt DA, Hay EM, Roddy E. The clinical and cost-effectiveness of corticosteroid injection versus night splints for carpal tunnel syndrome (INSTINCTS trial): an open-label, parallel group, randomised controlled trial. Lancet. 2018 Oct 20;392(10156):1423-1433. doi: 10.1016/S0140-6736(18)31572-1.
PMID: 30343858
citation: Levine DW, Simmons BP, Koris MJ, Daltroy LH, Hohl GG, Fossel AH, Katz JN. A self-administered questionnaire for the assessment of severity of symptoms and functional status in carpal tunnel syndrome. J Bone Joint Surg Am. 1993 Nov;75(11):1585-92. doi: 10.2106/00004623-199311000-00002.
PMID: 8245050
citation: Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A. A Review on Various Uses of N-Acetyl Cysteine. Cell J. 2017 Apr-Jun;19(1):11-17. doi: 10.22074/cellj.2016.4872. Epub 2016 Dec 21.
PMID: 28367412
citation: Huisstede BM, Friden J, Coert JH, Hoogvliet P; European HANDGUIDE Group. Carpal tunnel syndrome: hand surgeons, hand therapists, and physical medicine and rehabilitation physicians agree on a multidisciplinary treatment guideline-results from the European HANDGUIDE Study. Arch Phys Med Rehabil. 2014 Dec;95(12):2253-63. doi: 10.1016/j.apmr.2014.06.022. Epub 2014 Aug 12.
PMID: 25127999
citation: Page MJ, Massy-Westropp N, O'Connor D, Pitt V. Splinting for carpal tunnel syndrome. Cochrane Database Syst Rev. 2012 Jul 11;2012(7):CD010003. doi: 10.1002/14651858.CD010003.
PMID: 22786532
citation: Chan KM, Gordon T, Zochodne DW, Power HA. Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets. Exp Neurol. 2014 Nov;261:826-35. doi: 10.1016/j.expneurol.2014.09.006. Epub 2014 Sep 16.
PMID: 25220611
citation: Reid AJ, Shawcross SG, Hamilton AE, Wiberg M, Terenghi G. N-acetylcysteine alters apoptotic gene expression in axotomised primary sensory afferent subpopulations. Neurosci Res. 2009 Oct;65(2):148-55. doi: 10.1016/j.neures.2009.06.008. Epub 2009 Jun 24.
PMID: 19559059
citation: Sud V, Freeland AE. Biochemistry of carpal tunnel syndrome. Microsurgery. 2005;25(1):44-6. doi: 10.1002/micr.20071.
PMID: 15481038
citation: Kim JK, Koh YD, Kim JS, Hann HJ, Kim MJ. Oxidative stress in subsynovial connective tissue of idiopathic carpal tunnel syndrome. J Orthop Res. 2010 Nov;28(11):1463-8. doi: 10.1002/jor.21163.
PMID: 20872582
citation: Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl. 1987;334:1-100. doi: 10.1111/j.1600-0447.1987.tb10566.x. No abstract available.
PMID: 2887090
responsible party type: Sponsor-Investigator
investigator affiliation: Nova Scotia Health Authority
investigator full name: David Tang
investigator title: Principal Investigator, Associate Professor, Division of Plastic Surgery, Dalhousie University
mesh term: Carpal Tunnel Syndrome
mesh term: Syndrome
mesh term: Hand Injuries
mesh term: Acetylcysteine
mesh term: N-monoacetylcystine
sharing ipd: No