Guideline Recommendation for Endpoints Used in Clinical Trials for Functional Dyspepsia

Han Hee Lee; Hye-Kyung Jung; Myung-Gyu Choi

doi:10.4166/kjg.2018.72.4.170

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Lee, Jung, and Choi: Guideline Recommendation for Endpoints Used in Clinical Trials for Functional Dyspepsia

Review Article

Korean J Gastroenterol 2018;72(4):170-178.

Published online: 4 October 2018

DOI: https://doi.org/10.4166/kjg.2018.72.4.170

Guideline Recommendation for Endpoints Used in Clinical Trials for Functional Dyspepsia

Han Hee Lee^1,², Hye-Kyung Jung³, Myung-Gyu Choi^1,²

¹Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea

²Catholic Photomedicine Research Institute, Division of Gastroenterology, Seoul, Korea

³Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea

Correspondence to: Myung-Gyu Choi, Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. Tel: +82-2-2258-2083, Fax: +82-2-2258-2089, E-mail: choim@catholic.ac.kr, ORCID: https://orcid.org/0000-0003-4083-5187

Received 3 September 2018 Revised 12 October 2018 Accepted 16 October 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Functional dyspepsia is a disease, in which there is no organic lesion but chronic and repetitive postprandial fullness, early satiation, epigastric pain, and epigastric burning. Functional dyspepsia is not life-threatening but its symptoms are relapsing and remitting and persist over a lifetime, limiting the social life and reducing the quality of life. Therefore, the treatment for acute relapsing period may help improve the short-term symptoms. Continuous medication may be needed to improve the long-term symptoms. Research designs to demonstrate the short-term efficacy of therapeutic agents may differ from clinical trials to demonstrate long-term efficacy. There are many difficulties in clinical trial design, implementation, and screening because there are no international standards of clinical trials for functional dyspepsia. The purpose of this guideline recommendation is to develop a standard for clinical trials, such as clinical trial subjects and evaluation methods, in the development of therapeutic agents for functional dyspepsia. The ultimate aim is to enhance the safety and efficacy of therapeutic agents for functional dyspepsia and promote the development of new therapeutic agents.

Keywords: Dyspepsia, Gastrointestinal diseases, Clinical trial, Endpoint determination, Patient reported outcome measures

References

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Table 1.

Diagnostic Criteria for Functional Dyspepsia in Rome III ^a

1. One or more of the following:

A. Bothersome postprandial fullness

B. Bothersome early satiation

C. Bothersome epigastric pain

D. Bothersome epigastric burning

2. No evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms

^a Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.

Table 2.

Pharmacotherapy for Functional Dyspepsia

Type	Efficacy	KFDA permits	Usage status
Helicobacter pylori eradication	Superiority over placebo	No
Acid-suppressive drugs
Proton pump inhibitors	Superiority over placebo (in EPS)	No
H₂-receptor antagonists	Superiority over placebo (in EPS)	No	Indication for gastritis and GERD
Gastric acid neutralizing drugs	Not proven superiority over placebo	Yes	Can be prescribed for dyspepsia
Prokinetics
Mosapride	Not proven superiority over placebo	Yes
Itopride	Not proven superiority over placebo	Yes
Domperidone	Some proofs of superiority over placebo	Yes	Usage restriction duo to QT prolongation
Metoclopramide, levopride	Not proven superiority over placebo	Yes	Risk of pseudo-parkinsonism
Acotiamide	Superiority over placebo (in PDS)	No	Permits in Japan/not yet introduced in Korea
Psychotropic drugs
Buspirone	Superiority over placebo (in PDS)	No	patients with lots of psychosocial factors
Antidepressants-TCAs	Superiority over placebo (in EPS)	No	patients with lots of psychosocial factors
Antidepressants-SSRI	Not proven superiority over placebo	No	patients with lots of psychosocial factors
Herbal medicines
Motilitone	Not proven superiority over placebo	Yes	Non-inferiority compared to Itopride
Iberogast	Superiority over placebo
Rikkunshito	Not proven superiority over placebo

KFDA, Korea Food & Drug Administration; EPS, epigastric pain syndrome; GERD, gastroesophageal reflux disease; PDS, postprandial distress syndrome; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor.

Table 3.

Developing PROs for FGIDs

1. For FGID registration trials, the FDA and EMA require fit-for-purpose PROs that are specifically designed for the precise target population being studied.

2. As FGIDs are an international phenomenon, it is important to create PROs that can be accurately translated into different languages.

3. All items in a PRO should be carefully tested in cognitive interviews with FGID patients who are representative of the target population.

4. For clinical trials, it is generally recommended to use endpoints with a 1 day recall or less.

5. For FGID registration trials, PROs must have empirical evidence of validity and reliability and must have a priori MCID benchmarks and responder definitions.

PROs, patient reported outcomes; FGID, functional gastrointestinal disease; FDA, Food and Drug Administration; EMA, European Medicines Agency; MCID, minimal clinically important difference.

Table 4.

Defining MCID and Responder Status

1. The main result of the study must be based on the evaluation of the primary outcome measure, as stated in the protocol before the study begins. The primary outcome should be stated in absolute numbers and should include a 95% CI.

2. When trial results are expressed in terms of the proportion of responders in each are of the study, a responder should be defined as someone showing an improvement equal to or greater than the MCID.

3. When continuous measures are used to assess trial results, the differences between treatment arms should be compared with the MCID.

4. When reporting p-values, actual values and not thresholds should be provided. Investigators are encouraged to report the NNT in clinical trials, and the NNH can be calculated based on the risk of adverse effects and can be weighed against the NNT.

5. The primary analysis should be an ITT analysis and must include all patients randomized.

MCID, minimal clinically important difference; CI, confidence interval; NNT, number needed to treat; NNH, number needed to harm; ITT, intention-to-treat.

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ORCID iDs: Myung-Gyu Choi
https://orcid.org/0000-0003-4083-5187
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