UMIN-CTR 臨床試験登録情報の閲覧

一般向け試験名/Public title

日本語
難治性及び原因不明の慢性咳嗽に対するP2X3受容体拮抗薬の臨床的有効性に関するシステマティックレビューと用量反応性ネットワークメタ解析

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

一般向け試験名略称/Acronym

日本語
難治性及び原因不明の慢性咳嗽に対するP2X3受容体拮抗薬の臨床的有効性に関するシステマティックレビューと用量反応性ネットワークメタ解析

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

科学的試験名/Scientific Title

日本語
難治性及び原因不明の慢性咳嗽に対するP2X3受容体拮抗薬の臨床的有効性に関するシステマティックレビューと用量反応性ネットワークメタ解析

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

科学的試験名略称/Scientific Title:Acronym

日本語
難治性及び原因不明の慢性咳嗽に対するP2X3受容体拮抗薬の臨床的有効性に関するシステマティックレビューと用量反応性ネットワークメタ解析

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

試験実施地域/Region

日本/Japan

対象疾患名/Condition

日本語
難治性慢性咳嗽
原因不明の慢性咳嗽

英語
Refractory chronic cough
Unexplained chronic cough

疾患区分1/Classification by specialty

呼吸器内科学/Pneumology

疾患区分2/Classification by malignancy

悪性腫瘍以外/Others

ゲノム情報の取扱い/Genomic information

いいえ/NO

目的1/Narrative objectives1

日本語
Please refer to the English explanation.

英語
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.

目的2/Basic objectives2

その他/Others

目的2 -その他詳細/Basic objectives -Others

日本語
Please refer to the English explanation.

英語
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.

試験の性質1/Trial characteristics_1

試験の性質2/Trial characteristics_2

試験のフェーズ/Developmental phase

主要アウトカム評価項目/Primary outcomes

日本語
Please refer to the English explanation.

英語
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.

副次アウトカム評価項目/Key secondary outcomes

日本語
Please refer to the English explanation.

英語
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.

試験の種類/Study type

その他・メタアナリシス等/Others,meta-analysis etc

基本デザイン/Basic design

ランダム化/Randomization

ランダム化の単位/Randomization unit

ブラインド化/Blinding

コントロール/Control

層別化/Stratification

動的割付/Dynamic allocation

試験実施施設の考慮/Institution consideration

ブロック化/Blocking

割付コードを知る方法/Concealment

群数/No. of arms

介入の目的/Purpose of intervention

介入の種類/Type of intervention

介入1/Interventions/Control_1

日本語

英語

介入2/Interventions/Control_2

日本語

英語

介入3/Interventions/Control_3

日本語

英語

介入4/Interventions/Control_4

日本語

英語

介入5/Interventions/Control_5

日本語

英語

介入6/Interventions/Control_6

日本語

英語

介入7/Interventions/Control_7

日本語

英語

介入8/Interventions/Control_8

日本語

英語

介入9/Interventions/Control_9

日本語

英語

介入10/Interventions/Control_10

日本語

英語

年齢（下限）/Age-lower limit

適用なし/Not applicable

年齢（上限）/Age-upper limit

適用なし/Not applicable

性別/Gender

男女両方/Male and Female

選択基準/Key inclusion criteria

日本語
Please refer to the English explanation.

英語
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.

除外基準/Key exclusion criteria

日本語
Please refer to the English explanation.

英語
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.

目標参加者数/Target sample size

責任研究者/Name of lead principal investigator

日本語

名	章太
ミドルネーム
姓	山本

英語

名	Shota
ミドルネーム
姓	Yamamoto

所属組織/Organization

日本語
東海大学

英語
Tokai University

所属部署/Division name

日本語
大学院医学研究科

英語
Graduate School of Medicine

郵便番号/Zip code

259-1193

住所/Address

日本語
神奈川県伊勢原市下糟屋143

英語
143 Shimokasuya, Isehara, Kanagawa, Japan

電話/TEL

0463-93-1121

Email/Email

yamasho1113x1987@gmail.com

試験問い合わせ窓口担当者/Name of contact person

日本語

名	章太
ミドルネーム
姓	山本

英語

名	Shota
ミドルネーム
姓	Yamamoto

組織名/Organization

日本語
東海大学

英語
Tokai University

部署名/Division name

日本語
大学院医学研究科

英語
Graduate School of Medicine

郵便番号/Zip code

259-1193

住所/Address

日本語
神奈川県伊勢原市下糟屋143

英語
143 Shimokasuya, Isehara, Kanagawa, Japan

電話/TEL

0463-93-1121

試験のホームページURL/Homepage URL

Email/Email

yamasho1113x1987@gmail.com

機関名/Institute

日本語
東海大学

英語
Tokai University

機関名/Institute
（機関選択不可の場合）

日本語

部署名/Department

日本語
大学院医学研究科

個人名/Personal name

日本語
山本章太

英語
Shota Yamamoto

機関名/Organization

日本語
自己調達

英語
Self provided

機関名/Organization
（機関選択不可の場合）

日本語

組織名/Division

日本語

組織の区分/Category of Funding Organization

自己調達/Self funding

研究費拠出国/Nationality of Funding Organization

日本語

英語

共同実施組織/Co-sponsor

日本語

英語

その他の研究費提供組織/Name of secondary funder(s)

日本語

英語

組織名/Organization

日本語
東海大学

英語
Tokai University

住所/Address

日本語
神奈川県伊勢原市下糟屋143

英語
143 Shimokasuya, Isehara, Kanagawa, Japan

電話/Tel

0463-93-1121

Email/Email

yamasho1113x1987@gmail.com

他機関から発行された試験ID/Secondary IDs

いいえ/NO

試験ID1/Study ID_1

ID発行機関1/Org. issuing International ID_1

日本語

英語

試験ID2/Study ID_2

ID発行機関2/Org. issuing International ID_2

日本語

英語

治験届/IND to MHLW

試験実施施設名称/Institutions

一般公開日（本登録希望日）/Date of disclosure of the study information

2023

年

03

月

20

日

プロトコル掲載URL/URL releasing protocol

試験結果の公開状況/Publication of results

最終結果が公表されている/Published

結果掲載URL/URL related to results and publications

https://doi.org/10.1016/j.chest.2024.05.015

組み入れ参加者数/Number of participants that the trial has enrolled

4904

主な結果/Results

日本語

英語
The gefapixant regimen demonstrated an ED50 of 90.7 mg/day for cough frequency reduction. Gefapixant showed the highest antitussive effectiveness at ED50 (reduction rate in 24-h cough frequency, median 28.1%; 95% Credible Interval 21.0 to 35.6%; ranked 1/5; moderate certainty) but the highest prevalence of taste disturbance (absolute risk difference per 100 patients, median 38; 95%CrI 27 to 51; ranked 5/5; high certainty) and the highest prevalence of discontinuation.

主な結果入力日/Results date posted

2024

年

06

月

11

日

結果掲載遅延/Results Delayed

結果遅延理由/Results Delay Reason

日本語

英語

最初の試験結果の出版日/Date of the first journal publication of results

2024

年

06

月

08

日

参加者背景/Baseline Characteristics

日本語

英語

参加者の流れ/Participant flow

日本語

英語

有害事象/Adverse events

日本語

英語

評価項目/Outcome measures

日本語

英語

個別症例データ共有計画/Plan to share IPD

日本語

英語

個別症例データ共有計画の詳細/IPD sharing Plan description

日本語

英語

試験進捗状況/Recruitment status

試験終了/Completed

プロトコル確定日/Date of protocol fixation

2023

年

03

月

17

日

倫理委員会による承認日/Date of IRB

2023

年

03

月

18

日

登録・組入れ開始（予定）日/Anticipated trial start date

2023

年

03

月

18

日

フォロー終了(予定)日/Last follow-up date

2024

年

03

月

18

日

入力終了(予定)日/Date of closure to data entry

データ固定（予定）日/Date trial data considered complete

解析終了(予定)日/Date analysis concluded

その他関連情報/Other related information

日本語
Please refer to the English explanation.

英語
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.

登録日時/Registered date

2023

年

03

月

18

日

最終更新日/Last modified on

2024

年

06

月

11

日

閲覧ページへのリンク/Link to view the page

日本語
https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000057667

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

単一の症例データURL/Single case data URL

日本語
https://center6.umin.ac.jp/ic/57667

英語
https://center6.umin.ac.jp/ice/57667