UMIN-ICDS Clinical Trial

Public title

Benefit-risk profile in P2X3 receptor antagonists for treatment of chronic cough: Dose-response model-based network meta-analysis

Acronym

Benefit-risk profile in P2X3 receptor antagonists for treatment of chronic cough: Dose-response model-based network meta-analysis

Scientific Title

Benefit-risk profile in P2X3 receptor antagonists for treatment of chronic cough: Dose-response model-based network meta-analysis

Scientific Title:Acronym

Benefit-risk profile in P2X3 receptor antagonists for treatment of chronic cough: Dose-response model-based network meta-analysis

Region

Japan

Condition

Refractory chronic cough
Unexplained chronic cough

Classification by specialty

Pneumology

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

Chronic cough affects 4-10% of the global population, imposing significant burdens on patient quality of life (QoL) and the healthcare system. Current clinical guidelines recommend speech therapy, morphine, gabapentin, and pregabalin, which are neuromodulators, but they have dose-limiting side effects and concerns remain regarding their long-term use. The P2X3 receptor, an ATP-sensitive receptor located on airway C-fibers, contributes to the establishment of chronic cough by inducing cough reflex. P2X3 receptor antagonists are anticipated as treatments addressing these unmet needs. Gefapixant, one of these antagonists, was first shown in a 2015 RCT to reduce cough frequency, improve VAS, and enhance QoL scores by antagonizing the P2X3 receptor. To date, five such drugs (Camlipixant, Eliapixant, Filapixant, Gefapixant, Sivopixant) have been published in RCTs, each with differing clinical standings. Gefapixant 45 mg b.i.d. has been approved by Japan's PMDA and Switzerland's regulatory authorities, while deliberations continue with the US FDA, Europe's EMA, UK's MHRA, and Canada's Health Canada based on the benefit-risk profile.

Meta-analyses have revealed that Gefapixant causes taste disturbances in about 50% of cases due to cross-antagonism at the P2X2/3 receptors located on taste buds. Subsequent P2X3 receptor antagonists focus on reducing adverse effects while maintaining efficacy by enhancing selectivity between P2X3 and P2X2/3 receptors. For instance, while Gefapixant shows a 3-8 fold difference in IC50 between P2X3 and P2X2/3 receptors, Camlipixant demonstrates over 1000-fold selectivity in IC50. However, direct comparative trials evaluating the efficacy and safety of P2X3 receptor antagonists are lacking, and the differential characteristics within this class remain unclear.

Basic objectives2

Others

Basic objectives -Others

To assist clinical decision-making and policy formulation for the establishment of chronic cough Clinical practice guidelines, it is desired to compare high-quality clinical studies using P2X3 receptor antagonists. Specifically, identifying dosages where benefits outweigh risks for each drug, and understanding the characteristics of multiple P2X3 receptor antagonists through comparison, are crucial. The first step involves assessing the characteristics of each P2X3 receptor antagonist and the quality of current evidence. Integrating these evidences holds significant documentary value in the deliberations of regulatory authorities in various countries. This study aims to elucidate the differences in benefit-risk profiles of five P2X3 receptor antagonists by conducting a systematic review and dose-response meta-analysis.

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

The primary outcomes were the 24-hour cough frequency and the incidence of taste disturbances. The efficacy outcomes comprised the 24-h cough frequency (coughs per hour), evaluated as a percentage change from baseline, where a reduction indicated improvement. The minimum important difference (MID) was considered a 20% reduction. Taste disturbances with MIDs of 15 in absolute risk difference per 100 patients.

Key secondary outcomes

Secondary outcomes included cough severity using the Visual Analogue Scale (VAS), Leicester Cough Questionnaire (LCQ) total score, treatment-related adverse events (AEs), discontinuation due to AEs, and serious AEs. The VAS, ranging from 0 mm (symptom-free) to 100 mm (severe), assessed subjective characteristics. A reduction in VAS score indicated improvement, with a MID of a 30 mm reduction. The LCQ total score, ranging from 3 to 21, evaluated quality of life, with a lower score indicating greater impairment due to cough. An increase in LCQ score signified improvement, with a MID of a 1.3-point increase. Safety outcomes included serious AEs, and discontinuation due to AEs, treatment-related AEs, with MIDs of 5, 10, and 15 in absolute risk difference per 100 patients, respectively.

To gather missing or unclear data from primary studies, we (1) contacted corresponding authors and (2) referred to supplementary files or online server data. We assumed crossover trials as parallel trials following Cochrane's recommendations.

Study type

Others,meta-analysis etc

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

Not applicable

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

Eligibility criteria for our evidence-based research question included phase II-III randomized controlled trials (RCTs) that met the following criteria: (1) participants with refractory or unexplained chronic cough of any age, (2) treatment with P2X3 receptor antagonists, (3) comparison with a placebo or other P2X3 receptor antagonists, and (4) reporting of safety and efficacy outcomes.

Key exclusion criteria

We excluded studies that compared P2X3 receptor antagonists with any other active treatment, as well as animal trials, abstracts, and any study designs other than RCTs.

Target sample size

Name of lead principal investigator

1st name	Shota
Middle name
Last name	Yamamoto

Organization

Tokai University

Division name

Graduate School of Medicine

Zip code

259-1193

Address

143 Shimokasuya, Isehara, Kanagawa, Japan

TEL

0463-93-1121

Email

yamasho1113x1987@gmail.com

Name of contact person

1st name	Shota
Middle name
Last name	Yamamoto

Organization

Tokai University

Division name

Graduate School of Medicine

Zip code

259-1193

Address

143 Shimokasuya, Isehara, Kanagawa, Japan

TEL

0463-93-1121

Homepage URL

Email

yamasho1113x1987@gmail.com

Institute

Tokai University

Institute

Department

Personal name

Shota Yamamoto

Organization

Self provided

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Tokai University

Address

143 Shimokasuya, Isehara, Kanagawa, Japan

Tel

0463-93-1121

Email

yamasho1113x1987@gmail.com

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2023

Year

03

Month

20

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

No longer recruiting

Date of protocol fixation

2023

Year

03

Month

17

Day

Date of IRB

2023

Year

03

Month

18

Day

Anticipated trial start date

2023

Year

03

Month

18

Day

Last follow-up date

2024

Year

03

Month

18

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Study Overview:
We follow the guidelines provided in Cochrane's handbook of systematic reviews of interventions and adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.

Literature Search:
We conduct a comprehensive search of four electronic databases, including PubMed, Scopus, Cochrane Library, and Web of Science, using specific keywords to identify studies that meet our eligibility criteria.

Quality Assessment:
Two independent reviewers (J.H., M.S.) employ a modified Cochrane-risk of bias tool for assessing the risk of bias in RCTs. The quality of the included studies is assessed using the CINeMA. Within-study bias, reporting bias, imprecision, indirectness, heterogeneity, and incoherence in each domain are rated as low, some, or high concern.

Data Synthesis and Model Fit:
For all outcomes and drugs, we examine the presence or absence of a dose-response relationship using a random effect model NMA. Dose-response function selection is based on the Deviance Information Criterion (DIC). If no dose-response relationship is suspected for a specific outcome across all drugs, an Equal dose effect model NMA is conducted. We calculate the median effective dose (ED50) for the 24-h cough frequency using an Exchangeable dose effect model-based NMA. Dose-response curves are generated, and effect sizes and the surface under the cumulative ranking curve (SUCRA) at ED50 are compared. All analyses utilize Just Another Gibbs Sampler, Ver.4.3.1, for Markov Chain Monte Carlo (MCMC) simulations, with the R packages Rjags and MBNMAdose employed.

Sensitivity Analysis Using Meta-Regression:
Sensitivity analysis through meta-regression is conducted for three factors potentially influencing network estimates (1) Risk of Bias (2) Small-study effect and (3) Repeated exposure.

Registered date

2023

Year

03

Month

18

Day

Last modified on

2024

Year

03

Month

19

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000057667