Respiratory Training vs Interoceptive Exposure in the Treatment of Transdiagnostic Pathological Anxiety

• ClinicalTrials.gov Identifier: NCT05427708
• Recruitment Status: Recruiting
• First Posted: June 22, 2022
• Last Update Posted: November 21, 2023
• Sponsor: University of Texas at Austin
• Collaborator: Freespira, Inc.
• Information provided by (Responsible Party): Michael J. Telch, University of Texas at Austin

Tracking Information

• First Submitted Date: March 1, 2022
• First Posted Date: June 22, 2022
• Last Update Posted Date: November 21, 2023
• Actual Study Start Date: August 22, 2022
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 16, 2022)

• Overall Anxiety Severity and Impairment Scale [ Time Frame: Pre-Treatment (Week 0), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) ]
  Change from baseline in self-reported transdiagnostic anxiety symptoms (range = 0 - 20, with higher scores indexing more symptoms).
• Computerized Hamilton Anxiety Scale [ Time Frame: Pre-Treatment (Week 0), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) ]
  Change from baseline in anxiety symptom severity. Each item is assessed both in terms of frequency and severity. Scores on these probes are summed and divided by the number of response options. Higher scores index higher severity.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 16, 2022)

• Sheehan Disability Scale [ Time Frame: Pre-Treatment (Week 0), Weekly Assessments (Weeks 1 - 4), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) ]
  Change from baseline in overall disability (range = 0 - 30, with higher scores indexing more disability).
• PROMIS - Global Health (Mental Health Subdomain) [ Time Frame: Pre-Treatment (Week 0), Weekly Assessments (Weeks 1 - 4), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) ]
  Change from baseline in quality of life (range = 4 - 20, with higher scores indexing higher quality of life).
• Anxiety Sensitivity Composite Measure [ Time Frame: Pre-Treatment (Week 0), Weekly Assessments (Weeks 1 - 4), Post-treatment (Week 5), 2-Month Follow-Up (Week 13) ]
  This composite measure will incorporate scores on the Anxiety Sensitivity Index-3 (ASI-3), Body Sensations Questionnaire (BSQ), and Texas Multi-Factor Anxiety Sensitivity Scale (TMASS). Scores on each of these individual measures will be transformed into z scores and then averaged to derive this composite index. We will measure change from baseline in anxiety sensitivity.
• Modified DIAMOND [ Time Frame: Pre-Treatment (Week 0), 2-Month Follow-Up (Week 13) ]
  Change from baseline in DIAMOND Diagnostic Interview + Health Anxiety Questionnaire scores.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Respiratory Training vs Interoceptive Exposure in the Treatment of Transdiagnostic Pathological Anxiety
• Official Title: Respiratory Training vs Interoceptive Exposure in the Treatment of Transdiagnostic Pathological Anxiety: A Randomized Clinical Trial
• Brief Summary: Purpose of the Research: The primary aim of the proposed study is to conduct a randomized parallel-group 3-arm clinical trial comparing two mechanistically distinct interventions for pathological anxiety - (1) Interoceptive Exposure (IE) utilizing graduated exposure to somatic cues (respiratory, cardiac, vestibular) with the primary aim of reducing fear responding to the presence of interoceptive perturbations; (2) Capnometry-Guided Respiratory Intervention (CGRI) aimed at raising end-tidal CO2 levels thereby lowering hyperventilation-induced respiratory alkalosis and its associated fear-eliciting somatic reactions; and (3) Psycho-education about anxiety and its effects (PsyEd), which will serve as a credible control comparator.

Detailed Description

Anxiety sensitivity - the tendency to perceive anxiety as threatening - is a widely recognized risk factor for the development of panic disorder and other anxiety-related psychopathology. Interoceptive exposure therapy consisting of repeated exposure to interoceptive cues using respiratory provocation challenges such as hyperventilation and inhalation of various concentrations of CO2-enriched air have shown promise in reducing AS and are often included in cognitive-behavioral treatments of panic disorder with or without agoraphobia.However, some patients are unwilling to undergo exposure-based treatments, while others who do show only partial response or subsequent relapse.

Alternatively, low end-tidal CO2 (ETCO2), which is an accompanying feature of hyperventilation, has been associated with a variety of anxiety disorders, including panic disorder and social phobia. More recently, researchers have examined the efficacy of capnometry-guided respiratory intervention (CGRI) as a method for increasing ETCO2 and thereby reducing hyperventilation-induced anxiety/panic symptoms. Promising preliminary efficacy studies have shown that CGRI results in decreased panic symptom frequency and severity at a rate comparable to that of cognitive therapy. A recent uncontrolled proof-of-concept study showed that CGRI led to significant reductions in trauma symptoms in a sample of patients meeting DSM-5 criteria for PTSD. However, neither IE or CGRI has been adequately evaluated in the treatment of anxiety disorders other than panic disorder with or without agoraphobia.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

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

This study will utilize a 3 x 3 randomized controlled trial design with intervention type as a between-subjects factor with three levels (IE, CGRI, PsyEd) and time points (baseline, posttreatment, 2-month follow-up) as a three-level within-subjects factor.

Masking: Single (Outcomes Assessor)
Masking Description:

Participants will be randomized by the undergraduate student coordinator for the project who is uninvolved with (1) running subjects through treatment; and (2) with data analysis. The study personnel involved in completing participants' treatment will not be blind. However, these personnel will not be involved in data maintenance or analysis.

Primary Purpose: Treatment

Condition

• Anxiety Disorders
• Trauma
• Generalized Anxiety Disorder
• Panic Disorder
• Agoraphobia
• Illness Anxiety Disorder
• Social Anxiety Disorder
• Posttraumatic Stress Disorder
• Acute Stress Disorder
• Adjustment Disorder With Anxious Mood

Intervention

• Behavioral: Interoceptive Exposure
  See: Arm/group descriptions
  Other Name: IE
• Device: Capnometry-Guided Respiratory Intervention
  See: Arm/group descriptions
  Other Name: CGRI
• Behavioral: Psycho-Education
  See: Arm/group descriptions
  Other Name: PsyEd

Study Arms

• Experimental: Interoceptive Exposure (IE)
  Participants assigned to the interoceptive exposure condition will receive twice-weekly 90-minute in-person treatment sessions for four weeks. This treatment will include education about anxiety and factors that maintain anxiety symptoms. In addition, participants will be asked to perform exercises designed to activate potentially distressing - but harmless - bodily sensations that are commonly associated with stress and anxiety. Participants will also be encouraged to practice these exercises daily at home.
  Intervention: Behavioral: Interoceptive Exposure
• Experimental: Capnometry-Guided Respiratory Intervention (CGRI)
  If assigned to this condition, participants will be expected to complete twice-daily 17-minute tablet-assisted breathing exercises at home for four weeks. They will also receive brief phone check-ins with their study therapist weekly to review progress and troubleshoot any problems they may be experiencing. Last, these participants will have access to a paced-breathing app that provides audio recordings to maintain specified breathing rates for up to 10 minutes.
  Intervention: Device: Capnometry-Guided Respiratory Intervention
• Active Comparator: Psycho-Education (PsyEd)
  If assigned to the psycho-education condition, participants will undergo once-weekly 20-minute video conferencing session with a therapist for four weeks. During these sessions, they will be provided information about the nature and causes of anxiety-related disorders and learn tips for coping with anxiety symptoms when they arise. At the end of their sessions with the therapist, they will receive handouts that will help reinforce what they've learned.
  Intervention: Behavioral: Psycho-Education

Publications *

• Reiss S, Peterson RA, Gursky DM, McNally RJ. Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behav Res Ther. 1986;24(1):1-8. doi: 10.1016/0005-7967(86)90143-9. No abstract available.
• Li W, Zinbarg RE. Anxiety sensitivity and panic attacks: a 1-year longitudinal study. Behav Modif. 2007 Mar;31(2):145-61. doi: 10.1177/0145445506296969.
• Maller RG, Reiss S. Anxiety sensitivity in 1984 and panic attacks in 1987. J Anxiety Disord. 1992;6(3):241-247.
• Schmidt NB, Lerew DR, Jackson RJ. Prospective evaluation of anxiety sensitivity in the pathogenesis of panic: replication and extension. J Abnorm Psychol. 1999 Aug;108(3):532-7. doi: 10.1037//0021-843x.108.3.532.
• Telch MJ, Rosenfield D, Lee HJ, Pai A. Emotional reactivity to a single inhalation of 35% carbon dioxide and its association with later symptoms of posttraumatic stress disorder and anxiety in soldiers deployed to Iraq. Arch Gen Psychiatry. 2012 Nov;69(11):1161-8. doi: 10.1001/archgenpsychiatry.2012.8.
• Cobb AR, Lancaster CL, Meyer EC, Lee HJ, Telch MJ. Pre-deployment trait anxiety, anxiety sensitivity and experiential avoidance predict war-zone stress-evoked psychopathology. Journal of Contextual Behavioral Science. 2017;6(3):276-287.
• Schmidt NB, Telch MJ. Role of fear of fear and safety information in moderating the effects of voluntary hyperventilation. Behav Ther. 1994;25(2):197-208.
• Beck JG, Shipherd JC, Zebb BJ. How does interoceptive exposure for panic disorder work? An uncontrolled case study. J Anxiety Disord. 1997 Sep-Oct;11(5):541-56. doi: 10.1016/s0887-6185(97)00030-3.
• Craske MG, Barlow DH. Mastery of Your Anxiety and Panic: Therapist Guide. Published online 2006. doi:10.1093/med:psych/9780195311402.001.0001
• Margraf J, Barlow DH, Clark DM, Telch MJ. Psychological treatment of panic: work in progress on outcome, active ingredients, and follow-up. Behav Res Ther. 1993 Jan;31(1):1-8. doi: 10.1016/0005-7967(93)90036-t.
• Telch MJ, Lucas JA, Schmidt NB, Hanna HH, LaNae Jaimez T, Lucas RA. Group cognitive-behavioral treatment of panic disorder. Behav Res Ther. 1993 Mar;31(3):279-87. doi: 10.1016/0005-7967(93)90026-q.
• Ley R. Blood, breath, and fears: A hyperventilation theory of panic attacks and agoraphobia. Clin Psychol Rev. 1985;5(4):271-285.
• Studer RK, Danuser B, Hildebrandt H, Arial M, Wild P, Gomez P. Hyperventilation in anticipatory music performance anxiety. Psychosom Med. 2012 Sep;74(7):773-82. doi: 10.1097/PSY.0b013e31825e3578. Epub 2012 Jul 23.
• Kaplan A, Mannarino AP, Nickell PV. Evaluating the Impact of Freespira on Panic Disorder Patients' Health Outcomes and Healthcare Costs within the Allegheny Health Network. Appl Psychophysiol Biofeedback. 2020 Sep;45(3):175-181. doi: 10.1007/s10484-020-09465-0.
• Meuret AE, Wilhelm FH, Ritz T, Roth WT. Feedback of end-tidal pCO2 as a therapeutic approach for panic disorder. J Psychiatr Res. 2008 Jun;42(7):560-8. doi: 10.1016/j.jpsychires.2007.06.005. Epub 2007 Aug 3.
• Tolin DF, McGrath PB, Hale LR, Weiner DN, Gueorguieva R. A Multisite Benchmarking Trial of Capnometry Guided Respiratory Intervention for Panic Disorder in Naturalistic Treatment Settings. Appl Psychophysiol Biofeedback. 2017 Mar;42(1):51-58. doi: 10.1007/s10484-017-9354-4.
• Meuret AE, Rosenfield D, Seidel A, Bhaskara L, Hofmann SG. Respiratory and cognitive mediators of treatment change in panic disorder: evidence for intervention specificity. J Consult Clin Psychol. 2010 Oct;78(5):691-704. doi: 10.1037/a0019552.
• Ostacher MJ, Fischer E, Bowen ER, Lyu J, Robbins DJ, Suppes T. Investigation of a Capnometry Guided Respiratory Intervention in the Treatment of Posttraumatic Stress Disorder. Appl Psychophysiol Biofeedback. 2021 Dec;46(4):367-376. doi: 10.1007/s10484-021-09521-3.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 1, 2023): 180
• Original Estimated Enrollment (submitted: June 16, 2022): 102
• Estimated Study Completion Date: May 2025
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Clinically elevated anxiety as indicated by an eight or higher on the Overall Anxiety Severity and Impairment Scale (OASIS).

2. Meets DSM-5 criteria for one or more of the following anxiety or trauma-related disorders as their "primary" mental disorder:

   • Generalized Anxiety Disorder
   • Panic Disorder
   • Health Anxiety
   • Agoraphobia
   • Social Anxiety Disorder
   • Posttraumatic Stress Disorder
   • Acute Stress Disorder
   • Adjustment Disorder with primary anxious mood
   • Anxiety disorder not otherwise specified
3. No current use of psychotropic medications or stable on current medications for at least 6 weeks
4. Age 18+.
5. Able to arrange transportation to our laboratory for study appointments.
6. Fluent in English.

Exclusion Criteria:

1. No history of medical conditions that would contraindicate participation in fear-provocation or respiratory challenges, including:

   • Cardiovascular or respiratory disorders
   • High blood pressure
   • Epilepsy
   • Strokes
   • Seizures
   • History of fainting
   • Pregnant or lactating
2. Not currently receiving other psychological treatment for anxiety.
3. No history of a suicide attempt within the past 6 months.
4. No history of psychosis within the past 6 months.
5. No history of moderate to severe alcohol or substance use disorder (with the exception of nicotine) within the past 3 months.
6. Does not endorse COVID-19 symptoms during the screening phase.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Michael J Telch, PhD; 512-814-5480; telch@austin.utexas.edu

Contact: Cate Fischer, MA; 512-522-6216; utinterventionstudy@gmail.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05427708
• Other Study ID Numbers: STUDY00002306
• 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: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Michael J. Telch, University of Texas at Austin
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Texas at Austin
• Original Study Sponsor: Same as current
• Collaborators: Freespira, Inc.
• Investigators: Not Provided
• PRS Account: University of Texas at Austin
• Verification Date: November 2023