E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with complaints of dysphagia and poor esophageal motility |
patienten met zwakke of afwezige slokdarmperistaltiek |
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E.1.1.1 | Medical condition in easily understood language |
Patients with complaints of dysphagia and poor esophageal motility |
patienten met zwakke of afwezige slokdarmperistaltiek |
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E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
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 investigate the effect of buspirone on high resolution manometry parameters (specifically: distal contractile integral, DCI) in patients with poor esophageal motility during a high resolution impedance manometry with 3 types of boluses (on liquid bolus, 5mL) |
Het effect van buspirone op slokdarmperistaltiek onderzoeken met behulp van hoge resolutie manometrie in patienten met zwakke of afwezige slokdarmperistaltiek |
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E.2.2 | Secondary objectives of the trial |
To investigate the effect of buspirone vs. placebo on several esophageal and EGJ pressure flow parameters (PCI es., DCI, Largest Break Size, DL, IRP4s, PFI, IR, DPA, DPE, RP, CSI, BPT, BFT, EGJ Rest.P, EGJCI, LES-CD) as measured by high resolution impedance manometry To investigate the influence of buspirone on changes in symptoms using the validated Mayo Dysphagia Questionnaire To investigate the influence of buspirone on changes in overall treatment evaluation (OTE) and overall symptom severity (OSS)
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Het effect van buspirone nagaan op * slokdarm contractiliteitsparameters * druk-bolusvloed parameters * symptomen van dysfagie |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. A minimum of 18 years old; 2. Ineffective Esophageal Motility (IEM) or absent contractility, as determined on HRM in the last three months before inclusion in the study, using the Chicago classification v4.0. IEM is defined as >70% ineffective or ≥50% failed swallows with a normal integrated relaxation pressure (IRP4). IEM includes a weak contraction (DCI ≥ 100 mmHg·s·cm and <450 mmHg·s·cm), failed peristalsis (DCI < 100 mmHg·s·cm), or fragmented peristalsis (a large break (>5 cm length) in the 20-mmHg isobaric contour with DCI > 450 mmHg·s·cm). Absent contractility is defined as 100% failed swallows (DCI < 100 mmHg·s·cm), with a normal IRP4. 3. No hiatal hernia ≥3 cm 4. Have completed a gastro-duodenoscopy, within 12 months, showing no anatomical abnormality of the stomach or esophagus, which can explain the patients’ symptoms. 5. History of dysphagia for at least 2 months, at least twice per week in the last month. 6. Sexually active women of child bearing potential participating in the study must be using an appropriate form contraception. Medically acceptable forms of contraception include oral contraceptives, injectable or implantable methods, intrauterine devices, or properly used barrier contraception. If the female patient has not been on oral, injectable, implantable or intrauterine contraception, a urinary pregnancy test will be performed prior to administration of Buspirone/Placebo. 7. Subjects must be capable of understanding and be willing to provide signed and dated written voluntary informed consent before any protocol-specific screening procedures are performed.
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1. minimaal 18 jaar 2. ineffectieve of afwezige slokdarmperistaltiek, bewezen op hoge resolutie manometrie in de drie maanden voorafgaand aan inclusie 3. Geen hernia van ≥3 cm 3. geen abnormaliteiten van maag of slokdarm die de symptomen kunnen verklaren (obv gastro-duodenoscopie) 4. geschiedenis van dysfagie symptomen voor minstens 2 maanden, minstens 2 keer per week in de afgelopen maand 5. vrouwen die zwanger kunnen worden moeten een geschikte vorm van anticonceptie nemen. Een zwangerschapstest zal afgenomen worden aan het begin van de studie. |
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E.4 | Principal exclusion criteria |
1. Endoscopic signs of severe erosive esophagitis (grade C or D, Los Angeles classification) on endoscopy performed during PPI treatment in the 12 months prior to screening, or ≥ grade B when endoscopy is performed off PPI treatment. 2. Systemic diseases, known to affect esophageal motility (i.e. systemic sclerosis) 3. Surgery in the thorax or in the upper part of the abdomen (appendectomy and cholecystectomy are allowed). 4. QT c>450 ms. 5. Use of medication that effect cholinergic function such as anticholinergics, tricyclic antidepressants. 6. Concomitant promotility agents such as prucalopride or domperidone. 7. Concomitant use of benzodiazepines. 8. Significant neurological, respiratory, hepatic, renal, hematological, cardiovascular, metabolic or gastrointestinal cerebrovascular disease as judged by the investigator. 9. Major psychiatric disorder. 10. Pregnancy or breastfeeding. 11. History of poor compliance. 12. History of/or current psychiatric illness that would interfere with ability to comply with protocol requirements or give informed consent. 13. History of alcohol or drug abuse that would interfere with ability to comply with protocol requirements.
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1. Erosieve esofagitis (graad C of D) gedurende endoscopie in de laatste 12 maanden wanneer inname van een proton pomp inhibitor, of graad B of meer wanneer geen maagmedicatie. 2. systeemlijden 3. voorafgaande chirurgie in thorax of bovenste gedeelte van het abdomen 4. QTc >450 ms 5. gelijktijdig gebruik van medicatie met cholinerge effecten (antidepressiva etc) 6. gelijktijdig gebruik van medicatie die motiliteit bevorderend werken 7. gelijktijdig gebruik van benzodiazepines 8. belangrijke neurologische, respiratoire, hepatische, renale, hematologische, cardiovasculaire, metabole, gastrointestinale of cerebrovasculaire ziekte 9. belangrijke psychiatrische aandoening 10. zwangerschap of lactatie 11. geschiedenis van slechte compliantie |
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E.5 End points |
E.5.1 | Primary end point(s) |
Changes in distal contractile integral (DCI, in mm Hg*s*cm) between buspirone and placebo. DCI is established on HRiM. As primary endpoint, we will focus on the values for DCI for the liquid bolus, 5 ml. |
verandering in distal contractile integral (DCI, in mm Hg*s*cm) tussen buspirone and placebo. DCI wordt gemeten aan de hand van een HRiM. We zullen focussen op DCI voor de vloeibare bolus van 5 ml. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
DCI is measured after intake of buspirone or placebo for 4 weeks. |
DCI wordt gemeten na inname van buspirone en placebo gedurende 4 weken. |
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E.5.2 | Secondary end point(s) |
Bolus passage score A Likert score applied during all swallows: 1-Normal, 2-Slow passage of bolus, 3-Stepwise passage, 4-Partial Blockage, 5-Complete Blockage. a) Mean score for each type of swallow b) Percentage of swallows with a score ≥4, averaged for each type of swallow. High-resolution impedance manometry ESOPHAGUS Proximal Contractile Integral (PCI es., mmHg.s.cm) Distal Contractile Integral (DCI, mmHg.s.cm) Largest Break Size (cm) Distal Latency (DL, s) Integrated Relaxation Pressure 4s (IRP4s, mmHg) Pressure Flow Index (PFI) Impedance Ratio (IR) Distension Pressure Accommodation (DPA, mmHg) Distension Pressure Emptying (DPE, mmHg) Ramp Pressure (RP, mmHg/s) Contractile Segment Impedance (CSI, Ohms) Bolus Presence Time (BPT, s) Bolus Flow Time (BFT, s)
ESOPHAGO-GASTRIC JUNCTION (EGJ) Esophago-Gastric Junction Resting Pressure (EGJ Rest.P, mmHg) Esophago-Gastric Junction Contractile Integral (EGJCI, mmHg.cm) Lower Esophageal Sphincter – Crural Diaphragm (LES-CD, mm)
a) Mayo Dysphagia Questionnaires b) Overall Treatment Evaluation (OTE) c) Overall Symptom Severity (OSS)
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Bolus doorgang score A Likert score toegepast op elke slik: 1-Normaal, 2-Trage passage van de bolus, 3-Stapsgewijse passage, 4-Gedeeltelijke Blokkage, 5-Volledige Blokkage. a) Gemiddelde score voor elk type slik b) Percentage van slikken met een score ≥4, gemiddeld genomen voor elk type slik Hoge-resolutie impedantie manometrie SLOKDARM Proximal Contractile Integral (PCI es., mmHg.s.cm) Distal Contractile Integral (DCI, mmHg.s.cm) Largest Break Size (cm) Distal Latency (DL, s) Integrated Relaxation Pressure 4s (IRP4s, mmHg) Pressure Flow Index (PFI) Impedance Ratio (IR) Distension Pressure Accommodation (DPA, mmHg) Distension Pressure Emptying (DPE, mmHg) Ramp Pressure (RP, mmHg/s) Contractile Segment Impedance (CSI, Ohms) Bolus Presence Time (BPT, s) Bolus Flow Time (BFT, s)
OESOFAGOGASTRISCHE OVERGANG overgang (EGJ) Esophago-Gastric Junction Resting Pressure (EGJ Rest.P, mmHg) Esophago-Gastric Junction Contractile Integral (EGJCI, mmHg.cm Lower Esophageal Sphincter – Crural Diaphragm (LES-CD, mm)
Symptoom vragenlijsten a) Mayo Dysphagia vragenlijst b) Algemene behandelingsevaluatie (OTE) c) Algemene Symptoom ernst (OSS)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All parameters are measured after intake of buspirone or placebo for 4 weeks. |
Alle parameters worden gemeten na inname van buspirone en placebo gedurende 4 weken. |
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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 | No |
E.6.5 | Efficacy | No |
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 | No |
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 | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |