Clinical Trials Register

Summary
EudraCT Number:	2015-002310-72
Sponsor's Protocol Code Number:	0201/DEV
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-04-29
Trial results	View 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

Czechia - SUKL

A.2

EudraCT number

2015-002310-72

A.3

Full title of the trial

Open-label, uncontrolled trial to evaluate pharmacokinetics of naloxone in children from 4 to less than 18 years of age with opioid-induced constipation

Otevřené nekontrolované klinické hodnocení k posouzení farmakokinetiky naloxonu u dětí ve věku od 4 do méně než 18 let se zácpou vyvolanou opioidy

A.3.1

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

Clinical trial to investigate the bioavailability of Naloxone in children with opioid induced constipation

Klinické hodnocení k posouzení biologické dostupnosti naloxonu u dětí se zácpou vyvolanou opioidy

A.4.1

Sponsor's protocol code number

0201/DEV

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/146/2018

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Develco Pharma Schweiz AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Develco Pharma Schweiz AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Develco Pharma Schweiz AG
B.5.2	Functional name of contact point	Sponsor Clinical Team
B.5.3	Address:
B.5.3.1	Street Address	Hohenrainstr. 12 D
B.5.3.2	Town/ city	Pratteln
B.5.3.3	Post code	4133
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41614255020
B.5.5	Fax number	+41614255029
B.5.6	E-mail	info@develco.ch

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	No
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	Naloxone Hydrochloride Prolonged Release Tablets
D.3.4	Pharmaceutical form	Film-coated 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.3.8	INN - Proposed INN	Naloxone Hydrochloride Prolonged Release
D.3.9.1	CAS number	357-08-4
D.3.9.3	Other descriptive name	NALOXONE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03382MIG
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	6
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	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	No
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	Naloxone Hydrochloride Prolonged Release Tablets
D.3.4	Pharmaceutical form	Film-coated 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.3.8	INN - Proposed INN	Naloxone Hydrochloride Prolonged Release
D.3.9.1	CAS number	357-08-4
D.3.9.3	Other descriptive name	NALOXONE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03382MIG
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	12
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

Opioid induced constipation

E.1.1.1

Medical condition in easily understood language

Constipation, defined as "the evacuation of hard stools less frequently
than is normal for the individual", is an almost inevitable side effect of
opioid use.

E.1.1.2

Therapeutic area

Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10071128
E.1.2	Term	Opioid induced constipation
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To characterise the pharmacokinetics (PK) of naloxone-3-glucuronide (NLX-3-G) in children (4 to less than 18 years) with opioid-induced constipation (OIC) after single oral dose of one naloxone (NLX) HCl prolonged release (PR) tablet.

E.2.2

Secondary objectives of the trial

To assess the safety (in terms of maintenance of analgesia, occurrence of opioid withdrawal symptoms and standard safety assessments), acceptability/palatability and tolerability of NLX HCl PR tablets in children (4 to less than 18 years) with OIC.

To assess the efficacy (descriptive activity; number of bowel movements (BMs), use of laxative rescue medication) of NLX HCl PR tablets in children (4 to less than 18 years) with OIC

To assess the PK of naloxone (NLX) and 6β-naloxole (NXOL) after single oral dose of one NLX HCl PR tablet, and optionally including steady state parameters for NLX 3 G, NLX and NXOL after multiple doses.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Male and female paediatric patients, from 4 years (provided that they are able to swallow the tablet) to less than 18 years of age.

-Subjects with malignant or non-malignant pain who are requiring (or are about to require) short-term or long-term treatment with opioids (i.e. start of opioid treatment on the day of screening at the latest).

-In the investigator’s judgement, subjects must be either newly diagnosed with OIC or subjects must have a history of OIC treated with laxatives or are expected to develop constipation after initiation of opioid treatment.

-Female subjects of childbearing potential (postmenarchal) must have a negative urine pregnancy test at screening. Females of childbearing potential must either not be sexually active or be using an adequate birth control method throughout the duration of the study.

E.4

Principal exclusion criteria

- Currently active medical conditions or ongoing treatments (e.g. irinotecan or any other chemotherapy) that may result in diarrhoea or intermittent loose stools or intractable vomiting during the screening or treatment period.

- Evidence of impaired hepatic function (total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), or alkaline phosphatase (AP) >3 times the upper limit of normal, unless known to be due to Gilbert’s syndrome or sickle-cell disease).

- Evidence of impaired renal function (glomerular filtration rate [GFR] <60 mL/min/1.73 m2, using the updated "bedside" Schwartz formula) or subjects with renal failure who are on any form of dialysis.

- Any suspected or known physiologic, neurogenic, endocrinic, metabolic, anatomic or other causes of constipation, such as functional constipation, Hirschsprung’s disease, spinal or anal/rectal abnormalities, inflammatory bowel diseases, gastrointestinal perforation or obstruction, other drugs or any gastrointestinal pathology or surgery, likely to significantly influence drug absorption. Faecal impaction at screening.

- Pregnancy or breast-feeding.

- Any other condition of the subject that, in the opinion of the investigator, may compromise evaluation of the trial treatment or jeopardize subject’s safety, compliance or adherence to protocol requirements.

- Administration of any other investigational products, currently or within the last 30 days, unless it is a labelled therapy (adult or paediatric), which is not expected to interfere with the pharmacokinetics/drug absorption of NLX HCl PR tablets.

- Employees of the investigator, trial centre, sponsor, CRO and trial consultants, when employees are directly involved in the trial or other studies under the direction of this investigator or trial centre, and their family members.

E.5 End points

E.5.1

Primary end point(s)

Pharmacokinetic parameters of NLX-3-G on Day 1 after single oral dose. Blood samples for PK assessments will be taken pre-dose (prior to NLX PR intake), 30 min, 60 min, 90 min 2 hours and 9 hours (Day 1) as well as 24 hours (Day 2) after intake of NLX HCl PR tablets. The following PK parameters will be calculated for NLX-3-G:

- Area under the plasma concentration time curve from the first time point [t=0] until last measured time point [t(last)] (AUC(0-t ))
- Maximum plasma concentration after first dose (Cmax)
- Time until Cmax (tmax)
- If feasible, area under the plasma concentration-time curve from the time point [t=0] to infinity [∞], (AUC(0-∞) ), elimination half life t1/2 and elimination rate constant λz.

PK parameters will also be calculated normalised to body weight and normalised to IMP dose.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of the trial; in addition, to optionally re-evaluate sample size, an interim analysis will be performed as soon as evaluable PK data are available for approximately 50% of subjects (approximately 18 subjects completed PK sampling after single dose.

E.5.2

Secondary end point(s)

- Pain intensity (PI) scores assessed by the revised Faces Pain Scale (FPS-R) (daily diaries)
- Acceptability/palatability assessed via questionnaire
- Adverse events (AEs) reporting
- Signs and symptoms of potential opioid withdrawal as assessed by site staff via modified Sophia Observation withdrawal Symptoms scale (mSOS)
- Vital signs and physical examination
- Standard safety laboratory evaluations
- Number of bowel movements (BMs) (daily diaries)
- Use of laxative rescue medication (daily diaries)
- Pharmacokinetic parameters of naloxone (NLX) and 6β-naloxole (NXOL) after single oral dose, including at least Cmax, AUC(0-t), tmax and, if feasible, AUC(0-∞), t1/2 and λz; normalised to IMP dose and body weight.
- Optional: pharmacokinetic parameters at steady state (at Visit 4 or any other day of week 2-12 of the extension period) of NLX-3-G, NLX and NXOL over 12 hours after IMP administration; normalised to IMP dose and body weight. Blood samples for PK assessments will be taken pre-dose (prior to NLX PR intake) as well as 30 min, 60 min, 2 hours, 4 hours and 12 hours after IMP intake (but still prior to next IMP intake).

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the trial.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Acceptability/Palatability

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

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

Yes

E.8.1.7.1

Other trial design description

two parallel groups with different IMP dose

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Minors

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	o.k.ids - Medicines for Children Research Organisation
G.4.3.4	Network Country	Austria
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Swiss PedNet - Swiss Research Network of Clinical Pediatric Hubs
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	NIHR CRN National Coordinating Centre
G.4.3.4	Network Country	United Kingdom

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-06-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-12-27

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