Clinical Trial Results:
A Phase 2, Fixed-Sequence, Open-Label, Switch-Over Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children
6-17 Years of Age with Urea Cycle Disorders, with a Long-Term Safety Extension
Summary
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EudraCT number |
2014-003246-26 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
01 Aug 2011
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Jun 2016
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First version publication date |
09 Jun 2016
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Other versions |
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 |
HPN-100-005
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00947544 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Horizon Therapeutics Inc.
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Sponsor organisation address |
150 S. Saunders Road, Lake Forest, United States, 60045
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Public contact |
Elizabeth Robinson, Horizon Therapeutics Inc., clinicaltrials@horizonpharma.com
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Scientific contact |
Tom Vescio, Horizon Therapeutics Inc., clinicaltrials@horizonpharma.com
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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-000297-PIP02-12 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Mar 2010
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Aug 2011
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Protocol HPN-100-005 was the first study of HPN-100 in pediatric subjects with urea cycle disorders (UCDs) and was a fixed-sequence, open-label, switch over study of HPN-100 with a long-term (12 month) safety extension designed to assess the safety of HPN-100 and to prospectively assess its ability to control blood ammonia as compared with Sodium Phenylbutyrate (NaPBA). Upon DSMB review of the first ten subjects who completed the switch over part of the study, and with DSMB approval, up to an additional 20 subjects were enrolled into the safety extension part of the study. The extension part of the study was a separate study (HPN-100-005SE). HPN-100 is a triglyceride that has a similar mechanism of action as NaPBA. It is a liquid with minimal taste and odor. Three teaspoons of HPN-100 (~17.4mL) delivers an equivalent amount of PBA to 40 tablets of NaPBA.
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Protection of trial subjects |
The protocol and consent/assent forms were submitted by each investigator to an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. The study was conducted in accordance with legal and regulatory requirements including Guidance for Good Clinical Practice (International Conference on Harmonization [ICH] 1996), and the Declaration of Helsinki (World Medical Association 2008). Only participants who met the inclusion criteria and none of the exclusion criteria were enrolled to this study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Mar 2010
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United States: 10
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Country: Number of subjects enrolled |
Canada: 1
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Worldwide total number of subjects |
11
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EEA total number of subjects |
0
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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) |
7
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Adolescents (12-17 years) |
4
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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 |
- | ||||||
Pre-assignment
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Screening details |
The study was to assess if HPN-100 could control blood ammonia compared with NaPBA. Subjects received NaPBA three times daily with meals during the first week and the same PBA mole-equivalent dose of HPN-100 during the second week. | ||||||
Period 1
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Period 1 title |
Switch-Over Period (2 weeks) (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Arms
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Arm title
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HPN-100 and NaPBA | ||||||
Arm description |
1 week of NaPBA treatment followed by 1 week of HPN -100 treatment. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Glycerol phenylbutyrate
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Investigational medicinal product code |
HPN-100
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Other name |
GT4P, Glyceryl tri-(4-phenylbutyrate)
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
g/mL gram(s) millitre 3 teaspoons of HPN-100 (approximately 17.4mL). Subjects dosed three times daily with meals during the first week and the same PBA mole-equivalent dose of HPN-100 during the second week.
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Investigational medicinal product name |
NaPBA
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Investigational medicinal product code |
sodium phenylbutyrate
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Other name |
AMMONAPS
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Pharmaceutical forms |
Powder and solvent for oral solution, Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
NaPBA was to be administered as either tablets or powder. The dosing was in grams. Subjects dosed three times daily with meals. The dose level recommended by the investigator for
each individual subject was not to exceed 20 g per day as recommended in the approved product labeling.
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Baseline characteristics reporting groups
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Reporting group title |
HPN-100 and NaPBA
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Reporting group description |
1 week of NaPBA treatment followed by 1 week of HPN -100 treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
HPN-100 and NaPBA
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Reporting group description |
1 week of NaPBA treatment followed by 1 week of HPN -100 treatment. | ||
Subject analysis set title |
HPN-100
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
HPN-100: Subjects treated with HPN-100
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Subject analysis set title |
NaPBA
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
NaPBA: Subjects treated with NaPBA
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End point title |
Rate of Adverse Events during the switchover part (number of participants showing Adverse Events) [1] | ||||||||||||
End point description |
To evaluate the safety and PK characteristics of HPN-100 compared with sodium phenylbutyrate (NaPBA) in pediatric patients with urea cycle disorders.
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End point type |
Primary
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End point timeframe |
1 week on each treatment for a total of 2 weeks.
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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: Data are summarized for this endpoint per protocol. |
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No statistical analyses for this end point |
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End point title |
Blood ammonia control | ||||||||||||
End point description |
To evaluate control of blood ammonia by HPN-100 compared with NaPBA in pediatric patients with urea cycle disorders. Results are for 24 hour ammonia levels.
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End point type |
Secondary
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End point timeframe |
Day 7 (NaPBA) and Day 14 (HPN-100)
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No statistical analyses for this end point |
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End point title |
NH3 Cmax on NaPBA vs. HPN-100 on the last day of treatment with each drug | ||||||||||||
End point description |
Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
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End point type |
Secondary
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End point timeframe |
Day 7 (NaPBA) and Day 14 (HPN-100)
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No statistical analyses for this end point |
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End point title |
Average ammonia values on NaPBA vs. HPN-100 on the last day of treatment with each drug (switch over) | ||||||||||||
End point description |
Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
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End point type |
Secondary
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End point timeframe |
Day 7 (NaPBA) and Day 14 (HPN-100)
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No statistical analyses for this end point |
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End point title |
Rate (percentage) of ammonia values above upper limit of normal (ULN) on NaPBA vs. HPN-100 | ||||||||||||
End point description |
Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100). The percentages are the number of ammonia values above the upper limit of normal/ the total number of ammonia samples (76).
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End point type |
Secondary
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End point timeframe |
Day 7 (NaPBA) and Day 14 (HPN-100)
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No statistical analyses for this end point |
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End point title |
Urinary PAGN 24-hour excretion values on NaPBA vs. HPN-100 (switch over) | ||||||||||||
End point description |
Urinary PAGN (phenylacetylglutamine) 24-hour excretion. Urine was collected during 0-12 hrs and 12-24 hrs.
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End point type |
Secondary
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End point timeframe |
Day 7 (NaPBA) and Day 14 (HPN-100)
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No statistical analyses for this end point |
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End point title |
Plasma PAA (phenylacetate) AUC0-24 values on NaPBA vs. HPN-100 on on the last day of treatment with each drug | ||||||||||||
End point description |
Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
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End point type |
Secondary
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End point timeframe |
Day 7 (NaPBA) and Day 14 (HPN-100)
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No statistical analyses for this end point |
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End point title |
Plasma PBA (phenylbutyrate) AUC0-24 values on NaPBA vs. HPN-100 on on the last day of treatment with each drug | ||||||||||||
End point description |
Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
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End point type |
Secondary
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End point timeframe |
Day 7 (NaPBA) and Day 14 (HPN-100)
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No statistical analyses for this end point |
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End point title |
Plasma PAGN AUC0-24 values on NaPBA vs. HPN-100 on on the last day of treatment with each drug | ||||||||||||
End point description |
Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
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End point type |
Secondary
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End point timeframe |
Day 7 (NaPBA) and Day 14 (HPN-100)
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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 |
All treatment emergent adverse events (TEAE) were defined as an AE that began (or a pre-existing AE that worsened) after receiving study drug on Day 1 and at any time through 7 days after the last dose of study drug.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
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Reporting groups
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Reporting group title |
HPN-100 and NaPBA
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Reporting group description |
HPN-100: Patient treated with HPN-100 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
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. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/24144944 |