Clinical Trial Results:
Open-label, uncontrolled trial to evaluate pharmacokinetics of naloxone in children from 4 to less than 18 years of age with opioid-induced constipation
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Summary
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EudraCT number |
2015-002310-72 |
Trial protocol |
DE HU CZ |
Global end of trial date |
27 Dec 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Sep 2020
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First version publication date |
19 Sep 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
0201/DEV
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Develco Pharma Schweiz AG
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Sponsor organisation address |
Hohenrainstr. 12D, Pratteln, Switzerland, 4133
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Public contact |
Sponsor Clinical Team, Develco Pharma Schweiz AG, +41 614255020, info@develco.ch
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Scientific contact |
Clinical Development, Develco Pharma Schweiz AG, +41 614255020, clinicaldevelopment@develco.ch
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001567-PIP01-13 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Apr 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 Dec 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Dec 2019
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Was the trial ended prematurely? |
Yes
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General information about the trial
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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) HCI prolonged release (PR) tablet.
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Protection of trial subjects |
The trial was conducted in compliance with the protocol, by trial personnel, who are qualified by education, training, and experience in their roles, with adherence to Good Clinical Practice (GCP), the applicable regulatory requirements and ethical principles based on the Declaration of Helsinki.
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Background therapy |
The individual opioid therapy, i.e. any opioid (WHO step II and III) including low level opioids, except any combination formulations (including morphine and naloxone) for the treatment of pain. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Oct 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Czech Republic: 1
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Country: Number of subjects enrolled |
Germany: 6
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Country: Number of subjects enrolled |
Hungary: 1
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Worldwide total number of subjects |
8
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EEA total number of subjects |
8
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
3
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Adolescents (12-17 years) |
5
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||
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Pre-assignment
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Screening details |
Subjects between 4 to less than 18 years of age with pain due to underlying malignant or non malignant disease, requiring or about to require opioid treatment and diagnosed with OIC or expected to develop constipation after initiation of opioid treatment were included in this trial. | |||||||||
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Period 1
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Period 1 title |
PK Day
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Group A | |||||||||
Arm description |
NLX HCl PR, 6 mg tablets At Visit 2 the subjects were centrally distributed to achieve a 1:1 ratio for evaluation of PK data After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (6 mg twice daily [TDD 12 mg]) | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Naloxone HCl 6 mg PR tablets
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Prolonged-release tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects took one single oral dose of NLX HCl PR tablets at their assigned tablet strength on Day 1.
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Arm title
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Group B | |||||||||
Arm description |
NLX HCl PR, 12 mg tablets At Visit 2 the subjects were centrally distributed to achieve a 1:1 ratio for evaluation of PK data After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (12 mg twice daily [TDD 24 mg]). | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Naloxone HCl 12 mg PR tablets
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Prolonged-release tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects took one single oral dose of NLX HCl PR tablets at their assigned tablet strength on Day 1.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 8 subjects were enrolled in the study (signed ICF, Enrolled Set). Out of these, 2 subjects were screening failures. |
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Period 2
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Period 2 title |
Extension Period
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Is this the baseline period? |
No | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Group A | |||||||||
Arm description |
NLX HCl PR, 6 mg tablets At Visit 2 the subjects were centrally distributed to achieve a 1:1 ratio for evaluation of PK data After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (6 mg twice daily [TDD 12 mg]) | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Naloxone HCl 6 mg PR tablets
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Prolonged-release tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects took one single oral dose of NLX HCl PR tablets at their assigned tablet strength on Day 1.
After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (Group A: 6 mg twice daily [TDD 12 mg]).
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Arm title
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Group B | |||||||||
Arm description |
NLX HCl PR, 12 mg tablets At Visit 2 the subjects were centrally distributed to achieve a 1:1 ratio for evaluation of PK data After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (12 mg twice daily [TDD 24 mg]). | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Naloxone HCl 12 mg PR tablets
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Prolonged-release tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects took one single oral dose of NLX HCl PR tablets at their assigned tablet strength on Day 1.
After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (Group B: 12 mg twice daily [TDD 24 mg]).
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| Notes [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Extension period was optional. Out of 6 subjects that completed the PK day, 3 subjects entered and completed the extension period as intended (i.e. as long as individual opioid treatment was ongoing). |
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Baseline characteristics reporting groups
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Reporting group title |
PK Day
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
PK Set
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Subject analysis set type |
Per protocol | |||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The pharmacokinetics set is defined as all safety set subjects for whom at least one evaluable PK parameter is available.
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Subject analysis set title |
Safety Set
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Subject analysis set type |
Safety analysis | |||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The safety set is defined as all subjects who received at least one dose of IMP.
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End points reporting groups
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Reporting group title |
Group A
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Reporting group description |
NLX HCl PR, 6 mg tablets At Visit 2 the subjects were centrally distributed to achieve a 1:1 ratio for evaluation of PK data After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (6 mg twice daily [TDD 12 mg]) | ||
Reporting group title |
Group B
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Reporting group description |
NLX HCl PR, 12 mg tablets At Visit 2 the subjects were centrally distributed to achieve a 1:1 ratio for evaluation of PK data After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (12 mg twice daily [TDD 24 mg]). | ||
Reporting group title |
Group A
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Reporting group description |
NLX HCl PR, 6 mg tablets At Visit 2 the subjects were centrally distributed to achieve a 1:1 ratio for evaluation of PK data After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (6 mg twice daily [TDD 12 mg]) | ||
Reporting group title |
Group B
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Reporting group description |
NLX HCl PR, 12 mg tablets At Visit 2 the subjects were centrally distributed to achieve a 1:1 ratio for evaluation of PK data After completion of PK blood sampling, the subjects entering the extension period started with IMP intake twice daily on Day 2 (12 mg twice daily [TDD 24 mg]). | ||
Subject analysis set title |
PK Set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The pharmacokinetics set is defined as all safety set subjects for whom at least one evaluable PK parameter is available.
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Subject analysis set title |
Safety Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The safety set is defined as all subjects who received at least one dose of IMP.
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End point title |
AUC(0-t ) of naloxone [1] | ||||||||
End point description |
Area under the plasma concentration time curve from the first time point [t=0] until last measured time point [t(last)] (AUC(0-t )), measured in ng/ml h
Adjusted to 6 mg dose and 50 kg weight
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End point type |
Primary
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End point timeframe |
Single dose PK (starting on Day 1/Visit 2) during 24 hours (at pre-dose and 30 min, 60 min, 90 min, 2 h, 9 h and 24 h, after intake of NLX HCl PR tablets
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistic was foreseen. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Cmax of naloxone [2] | ||||||||
End point description |
Maximum plasma concentration after first dose (Cmax)
adjusted to 6mg dose and 50 kg weight
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End point type |
Primary
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End point timeframe |
Single dose PK (starting on Day 1/Visit 2) during 24 hours (at pre-dose and 30 min, 60 min, 90 min, 2 h, 9 h and 24 h, after intake of NLX HCl PR tablets
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistic was foreseen. |
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| No statistical analyses for this end point | |||||||||
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End point title |
tmax of naloxone [3] | ||||||||
End point description |
Time until Cmax (tmax)
adjusted to 6 mg dose and 50 kg weight
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End point type |
Primary
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End point timeframe |
Single dose PK (starting on Day 1/Visit 2) during 24 hours (at pre-dose and 30 min, 60 min, 90 min, 2 h, 9 h and 24 h, after intake of NLX HCl PR tablets
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistic was foreseen. |
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| No statistical analyses for this end point | |||||||||
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End point title |
AUC(0-t ) of naloxone-3-glucuronide [4] | ||||||||
End point description |
Adjusted to 6 mg dose and 50 kg weight
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End point type |
Primary
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End point timeframe |
Single dose PK (starting on Day 1/Visit 2) during 24 hours (at pre-dose and 30 min, 60 min, 90 min, 2 h, 9 h and 24 h, after intake of NLX HCl PR tablets
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistic was foreseen. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Cmax of naloxone-3-glucuronide [5] | ||||||||
End point description |
Adjusted to 6 mg dose and 50 kg weight
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End point type |
Primary
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End point timeframe |
Single dose PK (starting on Day 1/Visit 2) during 24 hours (at pre-dose and 30 min, 60 min, 90 min, 2 h, 9 h and 24 h, after intake of NLX HCl PR tablets
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistic was foreseen. |
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| No statistical analyses for this end point | |||||||||
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End point title |
tmax of naloxone-3-glucuronide [6] | ||||||||
End point description |
Adjusted to 6 mg dose and 50 kg weight
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End point type |
Primary
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End point timeframe |
Single dose PK (starting on Day 1/Visit 2) during 24 hours (at pre-dose and 30 min, 60 min, 90 min, 2 h, 9 h and 24 h, after intake of NLX HCl PR tablets
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistic was foreseen. |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
AEs with onset or worsening after first intake of IMP until 14 days after last intake of IMP
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Safety Set
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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12 Jul 2018 |
The main changes of the Clinical Trial Protocol (CTP), Final Version 2.0, 12-JUL-2018 were: the subjects’ age range broadened to range from 4 to less than 18 years, the primary objective was changed from steady state PK to PK of naloxone-3-glucuronide after single dose, as a result the treatment period was reduced to one PK day. Standardised laxative rescue medication was removed, instead subjects were allowed to take concomitant laxatives according to their individual standard of care. Study endpoints and objectives as well as statistical methods were adapted accordingly. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| As a matter of the challenging and unsuccessful recruitment on CTP Final Version 1.0, 11-NOV-2015, a RfM was submitted to the EMA (PDCO) to agree on potential changes of the CTP, to improve recruitment and facilitate the conduct of the clinical trial | |||||||
