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Nortriptyline for the Treatment of Functional Dyspepsia (TENDER)

Primary Purpose

Functional Dyspepsia

Status
Unknown status
Phase
Phase 3
Locations
Netherlands
Study Type
Interventional
Intervention
Nortriptyline
Placebo
Sponsored by
Maastricht University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Functional Dyspepsia

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • AMC
  • VUmc
  • Rijnstate
  • Jeroen Bosch ziekenhuis
  • Gelderse Vallei
  • Medisch Spectrum Twente
  • Martini Ziekenhuis
  • Tergooi Hilversum
  • Medisch Centrum Leeuwarden
  • Alrijne ziekenhuis
  • Maastrich University Medical CenterRecruiting
  • Bernhoven
  • Diakonessenhuis
  • MMC

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Nortriptyline

Placebo

Arm Description

Nortriptyline in an escalating dose regimen: Week 1-2: 10mg daily Week 3-4: 25mg daily Week 5-12: 50mg daily

Placebo

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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)
General quality of life
Assessed with the use of the Euro-Qol-5D (EQ-5D; change from baseline).
Dyspepsia-specific quality of life
Dyspepsia-specific quality of life, assessed with the use of the Nepean Dyspepsia Index (NDI; change from baseline).
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].
Use of rescue medication.
As reported via digital diary (mobile phone application)
Number and severity of side effects.
As reported via digital diary (mobile phone application)
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.
Negative mood - anxiety
Assessed with the use of the Generalized Anxiety Disorder-7 (GAD-7; change from baseline)
Negative mood - depression
Assessed with the use of the Patient Health Questionnaire-9 (PHQ-9; change from baseline)

Full Information

First Posted
August 17, 2018
Last Updated
September 4, 2018
Sponsor
Maastricht University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03652571
Brief Title
Nortriptyline for the Treatment of Functional Dyspepsia
Acronym
TENDER
Official Title
Tailored Treatment of Functional Dyspepsia With Nortriptyline: a Multi-center Double-blind Placebo-controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Unknown status
Study Start Date
September 1, 2018 (Actual)
Primary Completion Date
September 1, 2020 (Anticipated)
Study Completion Date
September 1, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Maastricht University Medical Center

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Functional Dyspepsia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
154 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Nortriptyline
Arm Type
Experimental
Arm Description
Nortriptyline in an escalating dose regimen: Week 1-2: 10mg daily Week 3-4: 25mg daily Week 5-12: 50mg daily
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Nortriptyline
Intervention Description
Nortriptyline escalating dose regimen: Week 1-2: 10mg Week 3-4: 25mg Week 5-12: 50mg
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Symptom response
Description
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.
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Adequate relief
Description
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)
Time Frame
12 weeks
Title
General quality of life
Description
Assessed with the use of the Euro-Qol-5D (EQ-5D; change from baseline).
Time Frame
12 weeks, 3 & 6 months
Title
Dyspepsia-specific quality of life
Description
Dyspepsia-specific quality of life, assessed with the use of the Nepean Dyspepsia Index (NDI; change from baseline).
Time Frame
12 weeks, 3 & 6 months
Title
Cost-utility
Description
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].
Time Frame
12 weeks, 3 & 6 months
Title
Use of rescue medication.
Description
As reported via digital diary (mobile phone application)
Time Frame
12 weeks
Title
Number and severity of side effects.
Description
As reported via digital diary (mobile phone application)
Time Frame
12 weeks
Title
Responder rates following discontinuation
Description
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.
Time Frame
6 months
Title
Negative mood - anxiety
Description
Assessed with the use of the Generalized Anxiety Disorder-7 (GAD-7; change from baseline)
Time Frame
12 weeks, 3 & 6 months
Title
Negative mood - depression
Description
Assessed with the use of the Patient Health Questionnaire-9 (PHQ-9; change from baseline)
Time Frame
12 weeks, 3 & 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: Uncomplicated appendectomy, cholecystectomy and hysterectomy allowed unless within the past 6 months; 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bram Beckers, MD
Phone
0031 43 388 1844
Email
tender-intmed@maastrichtuniversity.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Daniel Keszthelyi, MD, PhD
Email
daniel.keszthelyi@maastrichtuniversity.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ad A.A.M Masclee, Prof
Organizational Affiliation
Maastricht University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
AMC
City
Amsterdam
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A.J. Bredenoord
Facility Name
VUmc
City
Amsterdam
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
R.J.F Felt-Bersma
Facility Name
Rijnstate
City
Arnhem
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
D.P. Hirsch
Facility Name
Jeroen Bosch ziekenhuis
City
Den Bosch
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
K van Hee
Facility Name
Gelderse Vallei
City
Ede
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
B.J.M Witteman
Facility Name
Medisch Spectrum Twente
City
Enschede
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
J.J. Kolkman
Facility Name
Martini Ziekenhuis
City
Groningen
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
L.A. van der Waaij
Facility Name
Tergooi Hilversum
City
Hilversum
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
B.D.J. van den Elzen
Facility Name
Medisch Centrum Leeuwarden
City
Leeuwarden
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
H.J.A. Jebbink
Facility Name
Alrijne ziekenhuis
City
Leiden
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
C.H.M. Clemens
Facility Name
Maastrich University Medical Center
City
Maastricht
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Daniel Keszthelyi
Facility Name
Bernhoven
City
Uden
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
B.J.T. Haarhuis
Facility Name
Diakonessenhuis
City
Utrecht
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
A.H. Oberndorff-Klein Woolthuis
Facility Name
MMC
City
Veldhoven
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
J.W.A. Straathof

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Nortriptyline for the Treatment of Functional Dyspepsia

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