Progressive Desensitization Paired With Behavioral Cough Therapy for the Treatment of Chronic Cough
Laurie Slovarp | The University of Montana
This continuation proposal expands on our prior work related to chronic cough (CC), which in Montana is often caused by or exacerbated by particulate air pollution due to wildfires1-3. CC impacts 11% of Americans4 and up to 20% do not respond to standard medical treatment and are diagnosed with refractory chronic cough (RCC)2,5,6. RCC results in decreased quality of life with both physical and psychosocial burdens7,8. The negative impacts of RCC are even more debilitating currently due to the pandemic. Evidence points to peripheral and/or central hypersensitivity as the underlying condition responsible for RCC9-12. Subsequently, most research efforts to find an effective treatment for RCC are designed to directly target cough hypersensitivity.
Most researchers seek to achieve desensitization pharmaceutically. The purpose of the proposed treatment is also desensitization; however, it’s unique in that it is designed to reduce sensitivity via neuroplasticity, which has the benefit of a very low risk profile and no long-term pharmaceutical dependency. This novel treatment, called cough desensitization treatment (CDT), involves repeated exposure to a cough stimulant (capsaicin), in progressive doses, while actively suppressing cough. This treatment concept is supported by a proof-of-concept study which showed significant change in cough sensitivity in healthy individuals following 6 CDT sessions13. Similar desensitization occurs in smokers who eventually lose the urge-to-cough to inhalation of tobacco.
Earlier Montana INBRE funding (2019) supported a phase I randomized controlled pilot clinical trial of CDT (from here forward referred to as Pilot 1). In Pilot 1, 75% of the CDT participants improved, while only 33% of the control group improved. The difference between the two groups was statistically significant in one of our primary outcome measures.
- Complete a second pilot clinical trial (Pilot 2) with refinement of the protocol to optimize study design and treatment outcomes. Pilot 2 will address four issues: (1) An unforeseen error in equipment set-up resulted in inconsistent amounts of capsaicin released from the nebulizer, which compromised the reliability and validity of cough sensitivity testing during Pilot 1. (2) The equipment used to deliver the capsaicin is no longer manufactured or serviced. (3) Improvement in the control group may have been due to a desensitizing effect from the subthreshold dose of capsaicin (which was used as a placebo) or improved compliance and motivation with home cough suppression, rather than an actual placebo effect. (4) A longer treatment course would likely result in greater gains. Issues 1 and 2 have been resolved, but additional data needs to be collected following these corrections. To resolve issues 3 and 4, in Pilot 2 we will extend the treatment course, use saline as the placebo, and eliminate tracking of home cough suppression.
- Investigate feasibility of using machine learning to create an algorithm that predicts candidates of CDT based on audio recordings of cough sounds. This aim is supported by studies showing high levels of sensitivity for machine-learning algorithms to diagnose cough-related illnesses such as tuberculosis, pneumonia, and COVID-1914-17. Anecdotally, we have also observed a difference in the sound of the cough in the participants who had did not improve with CDT. We will collaborate with audio engineer Rob Maher, PhD and computer engineer Bradley Whitaker, PhD to complete this aim. Audio files already collected from participants in Pilot 1, as well audio files collected from participants in Pilot 2 will be used to create a protype and determine feasibility of this aim. If our data shows sufficient feasibility, this aim will be further expanded on in the R01 proposal.
- Submit an R01 proposal for a multi-site study of CDT. Marie Jette, PhD (University of Colorado), Amanda Gillespie, PhD (Emory University), and Julie Barkmeier-Kraemer, PhD (University of Utah) will serve as site project leaders for the multi-site clinical trial. The R01 proposal will be drafted in collaboration with these co-project leaders under the mentorship of Dr. Julie Barkmeier-Kraemer, PhD who is a nationally renowned expert in laryngeal disorders, is the PI on 3 RO1 awards, and has served as a scientific reviewer for NIH. The Bioinformatics & Biostatistics Core of Montana INBRE will provide biostatistical support. The initial draft of the R01 will be completed at least two months in advance of the deadline and submitted for mock review to Montana INBRE and/or MW-CTRIN. Final edits will be made following obtainment of review feedback. The PI has been in contact with the Scientific Review Officer of the National Heart, Lung, Blood Institute within NIH, where this proposal will likely be submitted. The pay line for early-stage investigators (such as the PI) at NHLBI is 27%.