Clinical Trials Register

Summary
EudraCT Number:	2019-002187-26
Sponsor's Protocol Code Number:	neostigmine2019
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-08-02
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2019-002187-26

A.3

Full title of the trial

A Prospective evaluation of the effect of a single dose of neostigmine in patients with patients with weak or absent esophageal peristalsis

Prospectieve evaluatie naar het effect van een enkelvoudige dosis neostigmine in patiënten met zwakke of afwezige slokdarmperistaltiek

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Neostigmine for patients with weak or absent esophageal peristalsis

Neostigmine voor patiënten met zwakke of afwezige slokdarmperistaltiek

A.4.1

Sponsor's protocol code number

neostigmine2019

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	KU Leuven - TARGID
B.1.3.4	Country	Belgium
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	TARGID
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	KU Leuven - TARGID
B.5.2	Functional name of contact point	Ans Pauwels
B.5.3	Address:
B.5.3.1	Street Address	Herestraat 49 - box 701
B.5.3.2	Town/ city	Leuven
B.5.3.3	Post code	3000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	3216343385
B.5.5	Fax number	3216345939
B.5.6	E-mail	ans.pauwels@kuleuven.be

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Prostigmine
D.2.1.1.2	Name of the Marketing Authorisation holder	Mylan
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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

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

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

E.2 Objective of the trial

E.2.1

Main objective of the trial

Investigate the symptomatic and manometric factors associated with the use of neostigmine in patients with complaints of dysphagia due to poor esophageal motility

Het effect van neostigmine op symptomen en slokdarmperistaltiek onderzoeken met
behulp van hoge resolutie manometrie in patienten met zwakke of
afwezige slokdarmperistaltiek

E.2.2

Secondary objectives of the trial

• To investigate the effect of neostigmine on other esophageal contractility parameters (distal latency, integrated relaxation pressure in 4s, EGJ pressures, number and size of defect in the 30 mm Hg isobaric contour) as measured by HRiM
• To investigate the effect of neostigmine on symptoms during HRiM
• To investigate several pressure flow parameters (integrated manometry and impedance) after administration of neostigmine: pressure flow index, impedance ratio, distal ramp pressure, intra-bolus pressure, pressure at nadir impedance, time from nadir impedance to peak pressure, distension pressure compartmentalized transport, distension pressure emptying, distension pressure accommodation, contractile segment impedance

Het effect van neostigmine nagaan op
* slokdarm contractiliteitsparameters
* druk-bolusvloed parameters
* symptomen van dysfagie gedurende de manometrie

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. A minimum of 18 years old;
2. Ineffective Esophageal Motility (IEM), fragmented peristalsis or absent contractility, as determined on HRM in the last three months before inclusion in the study, using the Chicago classification v3.0 (1). IEM is defined as ≥50% of 5ml liquid swallows being weak or failed (DCI < 450 mmHg·s·cm) with a normal integrated relaxation pressure (IRP4). Fragmented peristalsis is defined as ≥50% of 5ml liquid swallows being fragmented (large break (>5 cm length) in the 20-mmHg isobaric contour with DCI >450 mmHg·s·cm) and not ineffective, with a normal IRP4. Absent contractility is defined a 100% failed swallows (DCI < 100 mmHg·s·cm), with a normal IRP4.
3. Have completed a gastro-duodenoscopy, within 12 months, showing no anatomical abnormality of the stomach or esophagus which can explain the patients symptoms.
4. History of dysphagia for at least 2 months, at least twice per week in the last month.
5. Sexually active women of child bearing potential participating in the study must be on 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 neostigmine.
6. 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.

1. minimaal 18 jaar
2. ineffectieve , gefragmenteerde of afwezige slokdarmperistaltiek,
bewezen op hoge resolutie manometrie in de drie maanden voorafgaand
aan inclusie
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.

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. Myasthenia Gravis or Eaton Lambert Syndrome.
6. Use of medication which effect cholinergic function such as anticholinergics, tricyclic antidepressants, calcium channel blockers.
7. Concomitant promotility agents such as: prucalopride or domperidone.
8. Aminoglycoside antibiotics.
9. Corticosteroids.
10. A cardiac disorder effecting electrical conductivity of the heart OR uninvestigated chest pain OR uninvestigated shortness of breath OR uninvestigated syncope.
11. An ECG finding or a new conductive abnormality which has not been previously identified (i.e. heart block, LBBB).
12. Significant neurological, respiratory, hepatic, renal, hematological, cardiovascular, metabolic or gastrointestinal cerebrovascular disease as judged by the investigator.
13. Major psychiatric disorder.
14. Pregnancy or breast-feeding.
15. History of poor compliance.
16. History of/or current psychiatric illness that would interfere with ability to comply with protocol requirements or give informed consent.
17. History of alcohol or drug abuse that would interfere with ability to comply with protocol requirements.

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. myasthenia gravis of eaton lambert syndroom
6. gelijktijdig gebruik van medicatie met cholinerge effecten
(antidepressiva etc)
7. gelijktijdig gebruik van medicatie die motiliteit bevorderend werken
8. aminoglycosed antibiotica
9. corticosteroiden gebruik
10. een hartafwijking/aandoening
11. abnormale bevindingen op ECG
12. belangrijke neurologische, respiratoire, hepatische, renale,
hematologische, cardiovasculaire, metabole, gastrointestinale of
cerebrovasculaire ziekte
13. belangrijke psychiatrische aandoening
14. zwangerschap of lactatie
15. geschiedenis van slechte compliantie
16. geschiedenis van of huidige psychiatrische aandoening waardoor informed consent geven onmogelijk is
17. geschiedenis van alcohol of drug gebruik

E.5 End points

E.5.1

Primary end point(s)

Mean change of distal contractile integral (DCI, mm Hg*s*cm) between pre- and post-neostigmine for the liquid boluses of 5 ml.

verandering in distal contractile integral (DCI, in mm Hg*s*cm) na neostgimine. DCI wordt gemeten aan de hand van een HRiM.
We zullen focussen op DCI voor de vloeibare bolus van 5 ml.

E.5.1.1

Timepoint(s) of evaluation of this end point

DCI is measured at baseline (which is a standard of care HRM) and after a one time application of neostigmine.

DCI wordt gemeten op baseline (standard of care) en na een eenmalige toediening van neostigmine.

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 manometry
a) Distal latency (s)
b) Integrated relaxation pressure in 4 seconds (mm Hg)
c) EGJ basal tone (mm Hg)
d) EGJ residual pressure (mm Hg)
e) Length of defect in the 30 mm Hg isobaric contour of the distal esophageal segment above proximal LES border (cm)
Pressure Flow Analysis
a) Pressure Flow Index (PFI)
b) Impedance Ratio (IR)
c) Distal ramp pressure (RP, mmHg/s)
d) Intra-bolus pressure (IBP, mmHg)
e) Pressure at nadir impedance (PNI, mmHg)
f) Time from nadir impedance to peak pressure (TNIPP, s)
g) Contractile segment impedance (CSI, Ohms)
h) Distension pressure emptying (DPE, mmHg)
i) Distension pressure compartmentalized transport (DPCT, mmHg)
j) Distension pressure accommodation (DPA, mmHg)

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 manometrie
a) Distal latency (s)
b) Integrated relaxation pressure in 4 seconden (mm Hg)
c) EGJ basale druk (mm Hg)
d) EGJ rustdruk (mm Hg)
e) Lengte van defect in de 30 mm Hg isobaar van het distale slokdarm
segment boven de proximale grens van de lage esofagale sphincter
(LES) (cm)
Pressure Flow Analyse
a) Pressure Flow Index (PFI)
b) Impedance Ratio (IR)
c) Distal ramp druk (RP, mmHg/s)
d) Intra-bolus druk (IBP, mmHg)
e) Druk bij laagste impedantie (PNI, mmHg)
f) Tijd van laagste impedantie tot hoogste druk (TNIPP, s)
g) Contractile segment impedantie (CSI, Ohms)
h) Distensie druk lediging (DPE, mmHg)
i) Distensie druk compartmentalized transport (DPCT, mmHg)
j) Distensie druk accommodatie (DPA, mmHg)

E.5.2.1

Timepoint(s) of evaluation of this end point

All parameters are measured at baseline (which is a standard of care HRM) and after a one time application of neostigmine.

Alle parameters worden gemeten op baseline (standard of care) en na een eenmalige toediening van neostigmine.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

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

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-08-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-08-28

P. End of Trial
P.	End of Trial Status	Ongoing

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