E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Functional dyspepsia (FD) |
Functionele dyspepsie (FD) |
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E.1.1.1 | Medical condition in easily understood language |
Functional dyspepsia (FD) is a gastrointestinal disorder characterized by epigastric pain or discomfort and/or bloating or early satiety. |
Functionele dyspepsie is een vaak voorkomende stoornis van het maag-darmstelsel. De kenmerken zijn ongemak of pijn in de maagstreek en/of een opgeblazen gevoel of vroege verzadiging na de maaltijd. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of an escalating dose regimen of nortriptyline as compared to placebo in FD patients without evidence of significant psychiatric disease, that have been identified as extensive metabolizers based on their CYP2D6 genotype |
Het bepalen van de effectiviteit van behandeling met nortriptyline bij FD patiënten, geïdentificeerd als CYP2D6 extensive metabolizers, zonder onderliggende psychiatrische stoornis, in vergelijking met placebo. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of treatment on quality of life, as compared to placebo. 2. To evaluate the cost-effectiveness of treatment, as compared to placebo. 3. To evaluate the effect of treatment after discontinuation, as compared to placebo. 4. To evaluate side-effects of nortriptyline as compared to placebo |
1. Het evalueren van het effect van behandelingop de kwaliteit van leven, in vergelijking met placebo. 2. Het evalueren van de kosten-effectiviteit van behandeling, in vergelijking met placebo. 3. Het evalueren van de effect van behandeling nadat deze gestaakt is, in vergelijking met placebo. 4. Het evalueren van de bijwerkingen van nortriptyline in vergelijking met placebo.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
An open label extension of the current study is specified in the study protocol in Addendum A (version 2.6, date August 12 2019):
In the sub-study we aim to offer open label nortriptyline treatment to FD patients recognized as poor or intermediate metabolizer. Ultrarapid metabolizers will not be eligible for this open label extension.
Hypothesis: We hypothesize that treatment with the second generation TCA nortriptyline (open label) results in adequate relief of symptoms in FD in patients with predicted poor or intermediate metabolizing capacity for CYP2D6.
Primary objective: 1. To explore the efficacy of low dose (10 mg) nortriptyline in FD patients without evidence of significant psychiatric disease, that have been identified as poor or intermediate metabolizers based on their CYP2D6 genotype.
Secondary objectives: In addition to the objectives described in section 2, we aim to explore the relationship between CYP2D6 genotype and nortriptyline plasma levels at week 1 of treatment, when dosages are similar in all nortriptyline regimens (i.e. 10mg)
Open label treatment Patients that are recognized as poor or abnormal metabolizers will be offered nortriptyline in a dose of 10 mg (open label), as customary in regular clinical care. No more than 10 mg dose will be administered to mitigate the occurrence of potential side effects.
Prescriptions and regular follow-up will be performed by the treating physician. Treatment duration will generally be 12 weeks, which is regarded routine clinical practice. When deemed necessary by the treating physician, treatment duration may be longer (or shorter). During the treatment period, the same study procedures as described in section 8.3 will be applicable (with the exception of randomisation). After treatment, the follow-up period will encompass the same study procedures (i.e. completion of questionnaires). After completion of the follow-up period, patients will receive the same monetary reward as patients in the randomized setting (i.e. 150 euros). Finally, the total number of inclusions will not exceed the pre-calculated sample size described in section 4.5 (i.e. 154 subjects). This open label extension is entirely exploratory and therefore no additional sample size calculation was performed.
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E.3 | Principal inclusion criteria |
- Patients with functional dyspepsia (FD), diagnosed according to the Rome IV criteria - Age 18-65 years - Predicted CYP2D6 extensive metabolizer phenotype on the basis of CYP genotyping - In the presence of alarm symptoms, patients are required to have undergone a upper gastrointestinal endoscopy (without evidence of organic disease), and have tested negative for Helicobacter pylori 2 years prior to inclusion. - Insufficient effect of first line treatment with proton pump inhibitors or prokinetics. - Women in their fertile age (<55 years old) must use contraception or be postmenopausal for at least two years.
Patients are recruited in primary and secondary/tertiary healthcare settings. |
- Diagnose functionele dyspepsie op basis van Rome IV criteria - Leeftijd tussen de 18 en 65 jaar - Voorspeld CYP2D6 extensive metabolizer fenotype op basis van genotypering - Bij alarmsymptomen: negatieve gastroduodenoscopie en negatieve helicobacter pylori test in periode 2jaar voorafgaande aan de studie. - Onvoldoende effect op eerstelijns therapie. - Vrouwen in vruchtbare levensfase worden gevraagd anticonceptie te gebruiken
Patiënten worden geïncludeerd in 1e en 2e/3e lijn zorg. |
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E.4 | Principal exclusion criteria |
- History of gastric ulcer; - Evidence of current anxiety and/or depression disorder as defined by a score ≥ 10 on the GAD-7 and/or PHQ-9 questionnaire, supported by a detailed interview by the investigator (i.e. the investigator is required to confirm suspicion of anxiety or depressive disorder); - Predicted CYP2D6 poor, intermediate or ultrarapid metabolizer phenotype on the basis of CYP genotyping - Current use or any previous use of psychotropic medication in the last 3 months prior to inclusion; - Inability to discontinue prokinetics*, NSAIDs or opioids; - Excessive alcohol consumption, defined as > 2 of 3 units per day (females and males respectively) - Using drugs of abuse; - Previous major abdominal surgery or radiotherapy interfering with gastrointestinal function: a. Uncomplicated appendectomy, cholecystectomy and hysterectomy allowed unless within the past 6 months; b. Other surgery upon judgment of the principle investigator; - History of liver disease, cholangitis, achlorhydria, gallstones or other diseases of the gallbladder/biliary system; - Pregnancy or lactation. - History of epilepsy - History of glaucoma
* Patients still using prokinetics at the time of inclusion will be asked to discontinue treatment. A wash-out period of 2 weeks before the run-in period is required. Patients that cannot discontinue prokinetic therapy will be excluded. Patients on proton pump inhibitors should continue these without altering dosage, given that rebound symptoms can occur with discontinuation. |
- Maagzweer in het verleden, - Voorspeld poor, intermediate of ultrarapid metabolizer fenotype op basis van CYP genotypering - Aanwijzingen voor angststoornis of depressie (GAD-7 of PHQ-9 score 10 of hoger, aangevuld met een interview door de onderzoeker, welke het vermoeden op een angststoornis of depressie dient te bevestigen) - Huidig gebruik van psychotrope medicatie of 3 maanden voor inclusie - Onvermogen prokinetica*, opiaten of NSAIDs te staken - Gebruik van drugs - Eerdere grotere abdominale chirurgie of radiotherapie die met de gastrointestinale functie kan interfereren. Toegestaan zijn ongecompliceerde cholecystectomie, hysterectomie of appendectomie, mits eerder dan 6 maanden voor inclusie. - zwangerschap of het geven van borstvoeding - bekend met epilepsie - bekend met glaucoom
* patienten die nog prokinetica gebruiken op het moment van inclusie worden verzocht deze te staken. Een washout van 2 weken wordt gehanteerd vooraleer patienten kunnen deelnemen aan de run-in. Voor PPIs geldt dat patienten verzocht worden deze te continueren in de dosis zoals op het moment van inclusie. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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. This is in line with the FDA guidelines on IBS treatment studies. Recorded symptoms include the five core symptoms of FD: epigastric pain, epigastric burning, postprandial fullness, early satiety and upper abdominal bloating. Weeks 1 and 2 are excluded in order to allow for establishment of steady-state drug levels |
Response gedefinieerd als een 30% reductie ten opzichte van baseline in het wekelijks gemiddelde van symptoomscores, gedurende ten minste 50% van de weken 3-12 van behandeling. De gerapporteerde symptomen zijn de 5 core symptomen van functionele dyspepsie, zoals omschreven in de recent ontwikkelde FD diary. Week 1 en 2 worden buiten beschouwing gelaten omdat gedurende deze periode eerst een "steady-state" van het medicijn bereikt moet worden. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Weekly evaluation |
Wekelijkse evaluatie |
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E.5.2 | Secondary end point(s) |
- Self-reported weekly global adequate relief of symptoms (defined as a "yes" in at least 50% of weeks 3-12 of the treatment), collected electronically. Weeks 1 and 2 are excluded in order to allow for establishment of steady-state drug levels - Quality of life, assessed with the use of the EQ-5D-5L (change from baseline). - Dyspepsia-specific quality of life, assessed with the use of the Nepean Dyspepsia Index (change from baseline). - Cost-utility, as determined by calculations incorporating total treatment costs and changes in EQ-5D-5L (QALYs gained) and MCQ/PCQ results (savings from reduced medical resource use and increased work productivity respectively). - Use of rescue medication. - Number and severity of side effects - 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. - Worst-case-analysis: imputing a non-response day for each day on which the electronic diary entry was missing (due to non-reporting of the patient) in patients assigned to nortriptyline; in patients assigned to placebo, a response day will be imputed for each day the electronic diary entry was missing. - (Negative) mood; assessed with the use of the PHQ-9 and GAD-7 (change from baseline). |
1 - Patiënt gerapporteerde globale verlichting van klachten (gedefinieerd als een "ja" in ten minste 50% van de weken 3-12 van de behandeling). De antwoorden worden elektronisch verzameld. 2 - Dyspepsie specifieke kwaliteit van leven (NDI) 3 - Kwaliteit van leven (EQ-5D-5L) 4 - Kosten effectiviteit (gebaseerd QALY toename, gezondheidszorg consumptie (MCQ) en werkproductiviteit (PCQ) en behandel kosten) 5 - Gebruik van rescue medicatie 6 - Aantal bijwerkingen 7 - Response 6 maanden na staken van behandeling (follow-up), gedefinieerd als een "ja" response op de vraag of de patient verlichting heeft ervaren van zijn/haar klachten tov baseline 8 - Worst-case analyse. Hierbij wordt een non-response ingevoerd bij patiënten op nortriptyline wanneer er geen data is; bij placebo vice versa. 9 - (negatieve stemming); beoordeeld met behulp van de PHQ-9 en de GAD-7 (verandering tov baseline). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 - Daily symptom evaluation (symptom diary) with calculation of symptom average at the end of treatment 2 Prior to initiation of the treatment period, at 12 weeks and at 3 and 6 months follow-up 3 Prior to initiation of the treatment period, at 4, 8, 12 weeks and at 3 and 6 months follow-up 4 for MCQ: Prior to initiation of the treatment period, at 12 weeks and at 3 and 6 months follow-up 4 for PCQ: Prior to initiation of the treatment period, at 4, 8, 12 weeks and at 3 and 6 months follow-up 5 + 6 - daily evaluation 7 - at follow-up 8 - end of treatment 9 - Prior to initiation of the treatment period, at 12 weeks of treatment and at 3 and 6 months follow-up |
1 - dagelijkse symptoom evaluatie met calculatie van gemiddelde aan einde van behandeling 2 - voor de start van de behandelperiode, na de behandeling (week 12) en + follow-up (3 en 6 maanden) 3 - voor de start van de behandelperiode en in week 4, 8, 12 + follow-up (3 en 6 maanden) 4 - in geval van MCQ: voor de start van de behandelperiode, na de behandeling (week 12) en + follow-up (3 en 6 maanden) 4 - in geval van PCQ: voor de start van de behandelperiode en in week 4, 8, 12 + follow-up (3 en 6 maanden) 5 + 6 - dagelijkse evaluatie 7 - bij follow-up 8 - aan het einde van de behandelperiode 9- Voor de start van de behandeling, na 12 weken behandeling + follow-up (3 en 6 maanden) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 36 |
E.8.9.1 | In the Member State concerned days | |