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Efficacy of crisugabalin (HSK16149) for refractory chronic cough: study protocol for a randomized, double-blind, placebo-controlled trial

This paper outlines the protocol for a single-centre, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of the third-generation alpha2delta ligand crisugabalin (HSK16149) in reducing cough frequency and improving quality of life for adults with refractory chronic cough over an 8-week treatment period.

Original authors: Xu Ju, Yaxing Zhou, Bingxian Sha, Yunfeng Zhang, Tiantian Cen, Shengyuan Wang, Jiaying Yuan, Haodong Bai, Tongyangzi Zhang, Li Yu, Xianghuai Xu

Published 2026-08-12

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CC BY 4.0

Original authors: Xu Ju, Yaxing Zhou, Bingxian Sha, Yunfeng Zhang, Tiantian Cen, Shengyuan Wang, Jiaying Yuan, Haodong Bai, Tongyangzi Zhang, Li Yu, Xianghuai Xu

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Imagine your body's nervous system as a massive, high-tech security network. Usually, this system is smart; it knows the difference between a gentle breeze and a real intruder, like a virus or a speck of dust. It only sounds the alarm when absolutely necessary. But for some people, this security system gets a little too jumpy. It starts treating harmless things—like a cool draft of air or a tiny tickle in the throat—as if they were dangerous invaders. This overreaction triggers a relentless, uncontrollable cough that just won't stop, even after doctors have checked for common causes like asthma or infections. Doctors call this "refractory chronic cough," which is just a fancy way of saying "a stubborn cough that refuses to go away."

To fix this, scientists are looking at a class of drugs called "neuromodulators." Think of these drugs as the system administrators for your nervous system. Instead of just patching the holes, they try to recalibrate the sensitivity of the security sensors, turning the volume down on the false alarms. While there are some existing medications that do this, they can sometimes be slow to work or cause side effects like drowsiness, making them tricky to use for long periods. So, the big question in the medical world is: Can we find a newer, smarter administrator that calms the cough without knocking the patient out?

This paper is the blueprint for a new experiment designed to answer that question. It doesn't report the final results of a finished study; rather, it lays out the detailed game plan for a clinical trial testing a new drug called crisugabalin (also known as HSK16149). The researchers are setting up a "face-off" between this new drug and a fake pill (a placebo) to see which one actually works better at stopping the cough.

Here is how the experiment is set up to play out:

The Players: The study will recruit 70 adults who have been suffering from this stubborn, refractory cough for a while.
The Teams: These 70 people will be split into two equal groups. One group will take the real crisugabalin, and the other will take a placebo that looks and tastes exactly the same. Neither the patients nor the doctors will know who is getting which pill until the very end—this is called a "double-blind" setup to keep things fair and honest.
The Game Plan: The participants will take their pills twice a day for 8 weeks. After that, there will be a 4-week follow-up period to see how things hold up.
The Scoreboard: The main thing they are measuring is the actual number of coughs. They won't just ask the patients, "Do you feel better?" Instead, they will have the participants wear a special digital recorder for 24 hours to count every single cough, day and night. This gives them a hard, objective number to compare. They will also check how the patients feel using questionnaires about their quality of life, sleep, and mood, and they will test how sensitive the patients' airways are to a mild irritant (capsaicin).

The researchers are hoping that crisugabalin will act like a master reset button for the nervous system, reducing the number of coughs and making life easier for these patients. They expect the drug to be safe, though they are watching closely for common side effects like dizziness or sleepiness, which are known to happen with similar drugs.

However, it is important to keep in mind that this paper is just the plan, not the final score. The study is still in the early stages (it's an "exploratory" trial), and because it involves a relatively small number of people (70) and is happening in just one hospital in Shanghai, the results might not tell the whole story yet. The authors admit that this study might not be big enough to spot rare side effects or to prove exactly how the drug compares to older treatments. But if the experiment goes according to this protocol, it will provide the first real, scientific evidence on whether crisugabalin is a promising new tool for taming the un-tamable cough. If it works, it could pave the way for bigger, more widespread studies in the future.

Technical Summary: Efficacy of Crisugabalin (HSK16149) for Refractory Chronic Cough

Problem Statement
Refractory Chronic Cough (RCC) represents a significant unmet clinical need, defined as a cough persisting for ≥8 weeks despite systematic evaluation revealing no clear cause, or despite adequate treatment of identified causes. RCC is associated with impaired quality of life, sleep disturbance, and increased psychological burden. While the concept of Cough Hypersensitivity Syndrome (CHS) suggests that RCC involves central and peripheral neural sensitization, current neuromodulatory treatments (e.g., gabapentin, pregabalin) face limitations including slow onset of action, central nervous system adverse effects (somnolence, dizziness), and potential relapse upon discontinuation. There is a need for neuromodulators with faster onset, better tolerability, and sustained efficacy. Crisugabalin (HSK16149), a third-generation $\alpha_2\delta$ ligand with enhanced affinity and potency, has demonstrated efficacy in chronic pain but lacks evaluation in RCC populations.

Methodology
This document outlines the protocol for a single-centre, randomized, double-blind, placebo-controlled trial conducted at Tongji Hospital, Shanghai, China.

Study Design: The trial enrolls 70 adults (aged 18–70) with RCC. Participants are allocated 1:1 to receive either oral crisugabalin (20 mg twice daily) or a matching placebo for 8 weeks, followed by a 4-week follow-up period.
Eligibility: Inclusion requires a Cough Visual Analog Scale (VAS) score ≥40 mm and a diagnosis of RCC per Chinese Medical Association guidelines. Key exclusion criteria include current smoking (or cessation within 2 years), recent respiratory infection, significant liver/kidney disease, hypertension, cardiovascular disease, and use of specific cough treatments (macrolides, PPIs, ACEIs, or other neuromodulators) within specified windows prior to enrollment.
Intervention: The experimental group receives HSK16149; the control group receives an inert placebo identical in appearance, odor, and taste. Concomitant medications affecting cough are prohibited, while stable long-term medications for comorbidities are permitted.
Primary Outcome: The change from baseline to Week 4 in objectively measured 24-hour cough frequency. Cough counts are captured via continuous 24-hour audio monitoring using digital voice recorders and analyzed using a deep-learning model (C-BiLSTM) followed by blinded manual adjudication to exclude false positives.
Secondary Outcomes: These include patient-reported cough severity (VAS), quality of life (Leicester Cough Questionnaire), cough sensitivity (capsaicin challenge C2/C5 thresholds), airway reflux (HARQ), laryngeal hypersensitivity (NLHQ), cough hypersensitivity assessment (CHAT), and psychological measures (PHQ-9, GAD-7). Safety outcomes include adverse events (AEs) and serious adverse events (SAEs).
Statistical Analysis: The primary analysis utilizes a repeated-measures generalized linear mixed model (GLMM) with a negative binomial distribution to account for overdispersed count data. Analyses follow an intention-to-treat (ITT) principle. A responder analysis (≥30% reduction in cough frequency) is also planned.

Key Contributions and Claims
As a study protocol, this paper does not report experimental results but defines the framework for generating preliminary evidence. Its primary contributions are:

Trial Design: It establishes a rigorous, placebo-controlled methodology to evaluate a novel third-generation $\alpha_2\delta$ ligand (crisugabalin) specifically for RCC, addressing the high placebo response rates common in cough trials.
Objective Measurement: It employs advanced, validated objective cough monitoring (24-hour audio recording with AI-assisted analysis and manual adjudication) to reduce measurement bias, rather than relying solely on subjective diaries.
Safety and Efficacy Framework: It outlines a comprehensive plan to assess not only cough frequency but also patient-reported outcomes, cough sensitivity, and psychological comorbidities, which are integral to the CHS framework.
Transparency: The protocol details strict randomization, allocation concealment, blinding procedures, and a Data Monitoring Committee (DMC) to ensure data integrity and participant safety.

Significance and Limitations
The authors posit that this trial will provide the first randomized evidence regarding the efficacy and safety of crisugabalin for RCC. If successful, it could support the development of a better-tolerated, faster-acting neuromodulator for a condition with limited treatment options.

However, the paper explicitly acknowledges several limitations inherent to this exploratory design:

Generalizability: As a single-centre study in China with strict inclusion criteria, the findings may not be immediately generalizable to broader, more heterogeneous real-world populations.
Sample Size and Power: With 70 participants, the study is powered for preliminary estimates and may lack the statistical power to detect small effect sizes, rare adverse events, or subgroup differences.
Duration: The 8-week treatment and 4-week follow-up period may be insufficient to fully assess the durability of symptom improvement after discontinuation or long-term safety profiles.
Comparators: The lack of an active comparator (e.g., gabapentin or pregabalin) means the study cannot directly establish the relative efficacy or tolerability of crisugabalin compared to existing standard-of-care neuromodulators.

The authors conclude that while modest in scope, this study is intended to inform the design of future larger, multicentre confirmatory and mechanistic studies.

Technical Summary: Efficacy of Crisugabalin (HSK16149) for Refractory Chronic Cough

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