Clinical Trials Register

Summary
EudraCT Number:	2012-005063-28
Sponsor's Protocol Code Number:	Emend2
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-11-09
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

Sweden - MPA

A.2

EudraCT number

2012-005063-28

A.3

Full title of the trial

Release of substance P during peritoneal dialysis: effects of intervention. Controlled cross-over study of the neurokinin-1 receptor antagonist Aprepitant

Frisättning av substans P under peritonealdialys: effekter av intervention. Kontrollerad studie i cross-overdesign av neurokinin-1-receptorhämmaren Aprepitant

A.3.1

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

Is peritoneal inflammation during peritoneal dialysis inhibited by drugs that block effects of substance P?

Kan läkemedel som blockerar substans P förhindra inflammation i bukhinnan under peritonealdialys?

A.4.1

Sponsor's protocol code number

Emend2

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	University of Gothenburg
B.1.3.4	Country	Sweden
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	University of Gothenburg
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	VG-regionen
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Gothenburg
B.5.2	Functional name of contact point	Institute of Biomedicine
B.5.3	Address:
B.5.3.1	Street Address	Box 420
B.5.3.2	Town/ city	Göteborg
B.5.3.3	Post code	SE40530
B.5.3.4	Country	Sweden
B.5.4	Telephone number	4631786 3310
B.5.6	E-mail	Magnus.Braide@gu.se

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	Emend
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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.3.1	Product name	Emend
D.3.2	Product code	EMEA/H/C/000527
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Emend
D.3.9.3	Other descriptive name	APREPITANT
D.3.9.4	EV Substance Code	SUB20017
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	80 to 125
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	TrioBe
D.2.1.1.2	Name of the Marketing Authorisation holder	Recip
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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.3.1	Product name	TrioBe
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	FOLIC ACID
D.3.9.4	EV Substance Code	SUB07774MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.8
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PYRIDOXINE HYDROCHLORIDE
D.3.9.1	CAS number	58-56-0
D.3.9.4	EV Substance Code	SUB15062MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	CYANOCOBALAMIN
D.3.9.4	EV Substance Code	SUB06837MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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

End stage renal disease under treatment with peritoneal dialysis

Njursvikt under behandling med peritonealdialys

E.1.1.1

Medical condition in easily understood language

End stage renal disease under treatment with peritoneal dialysis

Njursvikt under behandling med peritonealdialys

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]

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

In an earlier study in rats we demonstrated that experimental peritoneal dialysis (PD) induced a neurogenic inflammatory response in the peritoneum, leading to the release of neuropeptides substance P (SP) and CGRP.
By blocking the effects of SP (NK1 receptor blockade) we were able to reduce plasma protein loss (leakage of albumin from blood to the peritoneal cavity) by half.
Our primary hypothesis is that NK1 receptor blockade has corresponding effects in humans and thus substantially reduces loss of plasma albumin during dialysis.

I en tidigare djurexperimentell studie påvisade vi att experimentell peritonealdialys (PD) i råtta startade en neurogen inflammation som resulterade i en frisättning av neuropeptiderna substans P (SP) och CGRP.
Genom att blockera effekterna av SP (NK1-receptorblockad) kunde vi halvera förlusterna av plasmaprotein (läckaget av albumin från blodet till PD-vätskan).
Vår primära hypotes är att NK1-receptorblockad ger likvärdiga effekter i människa som i råtta vilket i så fall påtagligt minskar albuminförlusterna.

E.2.2

Secondary objectives of the trial

Secondary objectives involve other known effects of neuropeptide release. Substance P propagates an inflammatory response by inducing the release of inflammatory cytokines. Hypothetically NK1 receptor blockade will also inhibit this effect, thereby reducing the negative long-term effects of PD on peritoneal structure and function.

Substans P orsakar också frisättning av inflammatoriska cytokiner vilket propagerar den neurogena inflammationen. Vår sekundärhypotes är att NK1-receptorblockad hämmar även frisättningen av inflammatoriska mediatorer under PD och härigenom minskar de negativa långtidseffekterna av PD på bukhinnans struktur och funktion.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Included persons are treated with PD since at least 3 months and are males aged 20-90 or post-menopausal females up to age 90.
Included persons must have positive ultrafiltration (ultrafiltration volume larger than 0 ml/24 hours measured not more than one month earlier).

Man i åldern 20-90 år eller kvinna i postmenopausal ålder upp till 90 år som lämnat skriftligt samtycke, har PD-behandling sedan minst tre månader och positiv ultrafiltration (ultrafiltrationsvolym större än 0 ml/dygn uppmätt tidigast för en månad sedan).

E.4

Principal exclusion criteria

Moderate to serious liver damage, potential or known damage to the blood-brain barrier (e.g. brain tumor, meningitis, encephalitis), peritonitis during the last two months and treatment with any of the following drugs: warfarin, corticosteroider, pimozid, terfenadin, astemizol, cisaprid, ciklosporin, takrolimus, sirolimus, everolimus, alfentanil, diergotamin, ergotamin, fentanyl, kinidin, rifampicin, fenytoin, karbamazepin, fenobarbital och metotrexat.

Måttligt till gravt nedsatt leverfunktion, potentiell eller känd skada på blod-hjärnbarriären (t.ex. hjärntumör, meningit, encefalit), peritonit under de två senaste månaderna och behandling med något av följande läkemedel: warfarin, corticosteroider, pimozid, terfenadin, astemizol, cisaprid, ciklosporin, takrolimus, sirolimus, everolimus, alfentanil, diergotamin, ergotamin, fentanyl, kinidin, rifampicin, fenytoin, karbamazepin, fenobarbital och metotrexat.

E.5 End points

E.5.1

Primary end point(s)

Measurements are performed according to the PDC (Personal Dialysis Capacity) protocol whis is a clinical routine applied to PD patients. PDC quantitates the transperitoneal transport of water and solutes, including proteins, during dialysis in terms of the three-pore model. In addition, concentrations of the cytokines IL-1 beta, IL-6, IL-8, TNF alfa, NGF are measured in plasma and dialysate.
Primary end points are transperitoneal albumin transport and peritoneal release of IL-1 beta, IL-6, IL-8, TNF alfa, NGF.

Mätningarna görs som PDC (Personal Dialysis Capacity) vilket patienterna normalt utför under ordinarie klinisk PD-behandling. PDC karakteriserar transperitoneal transport av vatten och lösta substanser, inklusive proteiner, under dialysen. Dessutom görs koncentrationsbestämningar i plasma och dialysat av cytokinerna (IL-1 beta, IL-6, IL-8, TNF alfa, NGF).
Primära end points är albumintransport över bukhinnan och intraperitoneal frisättning av IL-1 beta, IL-6, IL-8, TNF alfa, NGF.

E.5.1.1

Timepoint(s) of evaluation of this end point

Transperitoneal albumin transport is evaluated as part of the PDC evaluation within two weeks after the finalization of each treatment time period.
Evaluations of intraperitoneal cytokine release are performed whenever measurements of pooled samples are available, typically every three to six months.

Transperitoneal albumin transport utvärderas som en del av PDC-utvärderingen inom två veckor efter avslutad behandlingsperiod.
Intraperitoneal cytokinfrisättning utvärderas när tillräckligt antal prover samlats för att motivera en omgång mätningar, normalt med 3-6 månaders mellanrum.

E.5.2

Secondary end point(s)

Secondary end points are the other measurements obtained from the PDC, i.e. peritoneal diffusion surface area, hydraulic conductivity and reabsorption.

Sekundära end points är övriga mätresultat från PDC-mätningen, d.v.s. peritoneal diffusionsyta, hydralisk konduktivitet och reabsorption.

E.5.2.1

Timepoint(s) of evaluation of this end point

PDC evaluation is performed within two weeks after the finalization of each treatment time period.

PDC-utvärderingen görs inom två veckor efter avslutad behandlingsperiod.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

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

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

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

A follow-upp visit 30 days after finishing the last treatment of the study.

Ett uppföljande återbesök 30 dagar efter avslutad behandling.

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

E.8.9.2

In all countries concerned by the trial years

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

Inga

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

2013-07-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-02

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-11-14

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