Nortriptyline for the Treatment of Functional Dyspepsia (TENDER)

Tailored Treatment of Functional Dyspepsia With Nortriptyline: a Multi-center Double-blind Placebo-controlled Trial

Functional dyspepsia (FD) is a common functional gastrointestinal disorder characterized by upper abdominal discomfort/pain and/or symptoms of meal-related fullness/satiety. There is currently no definitive therapy that is beneficial for all FD patients. Accumulating evidence suggests efficacy of tricyclic antidepressants (TCAs) in FD. However, no firm conclusion can be drawn currently due to the relatively small amount of studies and large heterogeneity between studies. In addition, TCAs are often associated with side effects, which occur early after initiation of therapy preceding the therapeutic effect and often result in discontinuation of the therapy. These side effects are related to drug metabolism, which depend on polymorphisms of the cytochrome P (CYP) enzyme system. It is therefore hypothesized that pre-treatment assessment of CYP genotype and subsequent exclusion of abnormal metabolizers limits the occurrence of side-effects and as such improves compliance and efficacy.

Study Overview

• Status: Terminated
• Conditions: Functional Dyspepsia
• Intervention / Treatment: Drug: Placebo; Drug: Nortriptyline

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • AMC
  • Amsterdam, Netherlands
    • VUMC
  • Arnhem, Netherlands
    • Rijnstate
  • Den Bosch, Netherlands
    • Jeroen Bosch Ziekenhuis
  • Ede, Netherlands
    • Gelderse Vallei
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Groningen, Netherlands
    • Martini ziekenhuis
  • Hilversum, Netherlands
    • Tergooi Hilversum
  • Leeuwarden, Netherlands
    • Medisch Centrum Leeuwarden
  • Leiden, Netherlands
    • Alrijne Ziekenhuis
  • Maastricht, Netherlands
    • Maastrich University Medical Center
  • Uden, Netherlands
    • Bernhoven
  • Utrecht, Netherlands
    • Diakonessenhuis
  • Veldhoven, Netherlands
    • MMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-65 years;
• A diagnosis of FD according to the Rome IV criteria;
• Predicted CYP2D6 extensive metabolizer phenotype on the basis of CYP genotyping
• Insufficient effect of first line treatment with proton pump inhibitors (twice daily) or prokinetics;
• In the presence of alarm symptoms, patients are required to have undergone an upper gastrointestinal endoscopy (without evidence of organic disease), and have tested negative for Helicobacter pylori 2 years prior to inclusion;
• Women in their fertile age (<55 years old) must use contraception or be postmenopausal for at least two years.

Exclusion Criteria:

• Predicted CYP2D6 poor, intermediate or ultrarapid metabolizer phenotype on the basis of CYP genotyping
• Evidence of current anxiety and/or depression disorder as defined by a score ≥ 10 on the GAD-7 and/or PHQ-9 questionnaire;
• Current use or any previous use of psychotropic medication in the last 3 months prior to inclusion;
• Inability to discontinue prokinetics, NSAIDs or opioids;
• Using drugs of abuse;
• Using more than 2 or 3 units of alcohol per day (females and males respectively)

• Previous major abdominal surgery or radiotherapy interfering with gastrointestinal function:

  1. Uncomplicated appendectomy, cholecystectomy and hysterectomy allowed unless within the past 6 months;
  2. Other surgery upon judgment of the principle investigator;
• History of gastric ulcer;
• History of liver disease, cholangitis, achlorhydria, gallstones or other diseases of the gallbladder/biliary system;
• History of epilepsy
• History of glaucoma
• Pregnancy or lactation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo
Experimental: Nortriptyline; Nortriptyline in an escalating dose regimen: Week 1-2: 10mg daily Week 3-4: 25mg daily Week 5-12: 50mg daily	Drug: Nortriptyline; Nortriptyline escalating dose regimen: Week 1-2: 10mg Week 3-4: 25mg Week 5-12: 50mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptom response	Response to therapy, as defined by a 30% reduction from baseline (i.e. the run-in period) in the weekly average of daily symptom scores, during at least 50% of weeks 3-12 of treatment. Symptoms will be assessed daily using a digital diary (mobile phone application). Recorded symptoms include the five core symptoms of FD: epigastric pain, epigastric burning, postprandial fullness, early satiety and upper abdominal bloating.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adequate relief	Self-reported adequate relief. Adequate relief is defined as a 'yes' response in at least 50% of weeks 3-12 of the treatment. Reported via digital diary (mobile phone application)	12 weeks
General quality of life	Assessed with the use of the Euro-Qol-5D (EQ-5D; change from baseline).	12 weeks, 3 & 6 months
Dyspepsia-specific quality of life	Dyspepsia-specific quality of life, assessed with the use of the Nepean Dyspepsia Index (NDI; change from baseline).	12 weeks, 3 & 6 months
Cost-utility	Cost-utility, as determined by calculations incorporating total treatment costs and changes in EQ-5D-5L (QALYs gained), and results from the Medical Consumption Questionnaire (MCQ) and Productivity Cost Questionnaire (PCQ) [savings from reduced medical resource use and increased work productivity respectively].	12 weeks, 3 & 6 months
Use of rescue medication.	As reported via digital diary (mobile phone application)	12 weeks
Number and severity of side effects.	As reported via digital diary (mobile phone application)	12 weeks
Responder rates following discontinuation	Responder rates following discontinuation of treatment at 6 months follow-up, as defined by a "Yes" to the query regarding adequate relief from baseline symptoms.	6 months
Negative mood - anxiety	Assessed with the use of the Generalized Anxiety Disorder-7 (GAD-7; change from baseline)	12 weeks, 3 & 6 months
Negative mood - depression	Assessed with the use of the Patient Health Questionnaire-9 (PHQ-9; change from baseline)	12 weeks, 3 & 6 months

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: Ad A.A.M Masclee, Prof, Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2018
• Primary Completion (Actual): August 1, 2024
• Study Completion (Actual): August 1, 2024

Study Registration Dates

• First Submitted: August 17, 2018
• First Submitted That Met QC Criteria: August 28, 2018
• First Posted (Actual): August 29, 2018

Study Record Updates

• Last Update Posted (Actual): July 3, 2025
• Last Update Submitted That Met QC Criteria: June 30, 2025
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Dyspepsia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Membrane Transport Modulators; Psychotropic Drugs; Adrenergic Agents; Neurotransmitter Uptake Inhibitors; Antidepressive Agents; Adrenergic Uptake Inhibitors; Antidepressive Agents, Tricyclic; Nortriptyline
• Other Study ID Numbers: 848016005; NL62932.068.17 / METC173051 (Other Identifier: METC azM/UM); 2017-003307-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No