Cough as an Endpoint in IPF Trials

Why it matters

Yu Kan Au, M.D. – VP, Clinical Affairs at Strados Labs
Todd Lustine, M.D., M.S., FCCP – VP, Medical Science – Respiratory at Clario

Increased importance has been placed in recent years on the ability of idiopathic pulmonary fibrosis (IPF) treatments to impact how patients feel and function, beyond survival (Raghu, et al., 2024). In IPF, one of the most burdensome symptoms impacting how patients feel and function is a dry, persistent cough. Due to its consistent correlation with health-related quality of life (Saunders et al, 2023), reducing cough presents a significant opportunity for IPF drug developers. Despite this, sponsors historically have not consistently focused  on assessing their IPF treatment’s ability to reduce cough as a marker for efficacy. In this blog, we dive into why measuring cough in IPF trials, whether subjectively through patient reporting tools or with an objective monitoring device, may offer drug developers additional data to strengthen evidence and differentiate their clinical development program.

For IPF patients, cough is among the most significant and impactful symptoms

We’ve all experienced cough at some point, but for IPF patients, it takes over their lives and is far more than just an annoyance. This is true of many respiratory diseases, but in IPF, cough is particularly prevalent, with over 90% of patients reporting it as a symptom. [Hirons et al., 2023] The significant impact of IPF-related cough on patients’ quality of life was highlighted in “The Voice of the Patient” report by the FDA. Of the 60 patients involved, 75% described cough as one of the symptoms that mattered the most, alongside shortness of breath and fatigue. (FDA, 2015)

Patients described the acute impact of coughing bouts, but also how they impact nearly all other aspects of their lives, including sleep, exercise and socializing. 

Given cough’s severe impact on patients’ lives, sponsors are increasingly focused on reducing it, even in IPF treatments that were primarily developed to improve disease trajectory and survival. 

Severe cough may predict disease progression and survival

While features of cough directly impact patient quality of life, studies have also demonstrated a relationship to disease severity and outcomes.

In 2022, Lee et al analyzed data from the Pulmonary Fibrosis Foundation Patient Registry, which included data from 1,447 patients. They found that a 1-point decrease in Leicester Cough Questionnaire (LCQ) score (indicating greater cough burden), was associated with an increased risk of a negative clinical outcome. Specifically this indicated a 6.5% higher risk of respiratory-related hospitalization, 7.4% higher risk of death, and an 8.7% high risk of lung transplantation.

In another study of IPF patients led by Wu et al, researchers divided the 239 patients in the study into two cohorts: those with and without severe cough. They found that those with severe cough had a 2.8-fold increased risk of death versus those with less severe cough.

Although there is little to suggest a direct causal relationship, there may certainly be disease related factors driving both poor prognosis and profound symptomatic cough. It remains unclear if cough directly predicts these negative outcomes or whether it’s the cough-related decrease in QoL, but there certainly seems to be a relationship. This provides further incentive to consider cough as a clinically meaningful endpoint in future IPF clinical trials. 

Assessing Cough in IPF: Patient Reported Outcomes or Objective Cough Monitoring? 

In most IPF studies, cough is typically assessed subjectively using patient-reported outcomes (PROs). Validated questionnaires such as the Leicester Cough Questionnaire and the St. George’s Respiratory Questionnaire are valuable in capturing the patients’ perspectives on their well-being and improvement. 

PROs, however, are not without their limitations. Patients may have difficulty recalling how much better they’re feeling or how much their symptoms have improved. PROs may not fully capture timing of onset of a treatment effect. Due to their subjective nature, questionnaire answers may be influenced by patients’ moods or anxieties, versus a more objective measure. 

Cough monitoring offers a complementary way to capture cough in conjunction with PROs, that can address some of the limitations with subjective data. Cough monitoring offers an objective measure of cough frequency, intensity or bouts that is independent and unbiased. It also provides standardized data that is easy to interpret and analyze, providing an additional layer of insight and evidence. 

Summary

Cough in idiopathic pulmonary fibrosis (IPF) is a significant contributor to reduced quality of life for patients, yet historically has not been a major focus for many IPF drug developers. Recent studies however have underscored its relevance, not only as a key symptom affecting patients, but also as a potential indicator of disease severity and prognosis. Including cough as an endpoint in IPF studies offers sponsors a unique opportunity to differentiate treatments commercially while also addressing a priority concern for patients. Due to the limitations of subjective cough data from PROs and the increasingly competitive IPF treatment landscape, leveraging complementary innovative tools like objective cough monitoring can strengthen evidence and advance patient-centric drug development.