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Glycerol Phenylbutyrate (Ravicti) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 Apr.
To summarize the results from three long-term, safety studies that evaluated the safety and efficacy of glycerol phenylbutyrate (GPB) in adult and/or pediatric patients with urea cycle disorders (UCDs).
Study design and characteristics of the three long-term, open-label, non-randomized, non-comparative trials are summarized in Table 20. Both patients who were not included as well as those who completed the switch-over phase of studies HPN-100-005, HPN-100-006, and HPN-100-012 were offered the opportunity to continue in the safety-extension phase and receive open-label GPB for up to 12 months.
Summary Design and Characters of Long-Term Non-Randomized Studies.
No adjustments for covariates were made in any of the analyses in any of the long-term treatment studies. All analyses were based on the safety population, defined as all patients who received any amount of GPB. Any missing data were not imputed. No corrections were applied to adjust for multiplicity, and all efficacy end points were considered exploratory. The primary outcome in all long-term studies was safety as measured by the rate of adverse events (AEs). Other safety end points included serious adverse events (SAEs) and withdrawals due to adverse events. All efficacy end points evaluated in the long-term studies were considered secondary outcomes. The outcomes measured in the long-term treatment studies are detailed in Table 20.
The disposition of patients across the three long-term studies (HPN-100-005, HPN-100-007, and HPN-100-012) is summarized in Table 21.
Disposition of Patients in Studies HPN-100-005, HPN-100-007, and HPN-100-012.
A total of 17 patients were enrolled in the extension phase of HPN-100-005. Eleven (65%) of the 17 were patients in the switch-over phase. There was only one (6%) withdrawal during the trial; all other patients (94%) completed the trial.
A total of 60 patients were enrolled in HPN-100-007. Forty (67%) of the 60 were patients in HPN-100-006. There was a total of seven (12%) withdrawals; all other patients (88%) completed the trial.
A total of 23 patients were enrolled in the extension phase of HPN-100-012. Fifteen (65%) of the 23 were patients in the switch-over phase. There was a total of two (9%) withdrawals; all other patients (91%) completed the trial.
The main demographic and baseline characteristics of patients were variable across studies and are summarized in Table 22. The extension phases of HPN-100-005 and HPN-100-012 included a younger population than the patients included in HPN-100-007 ▬ Generally, all long-term studies included more females than males and more white patients than other ethnic groups. Both the extension phase of HPN-100-005 and HPN-100-007 included more patients with UCDs with ornithine transcarbamylase (OTC) deficiency ▬ whereas HPN-100-012 included more patients with the arginosuccinate lyase deficiency. Both the extension phase of HPN-100-005 and HPN-100-007 included patients with childhood or adult UCD onset ▬ whereas HPN-100-012 included more patients with neonatal UCD onset ▬ Sodium phenylbutrate (NaPBA) exposure, NaPBA daily dose, and the number of hypoammonemic crises varied across the long-term studies.
Demographics and Main Baseline Characteristics in Studies HPN-100-005, HPN-100-007, and HPN-100-012.
A summary of the AEs during the studies is presented in Table 23. ▬
Adverse Events Reported in Studies HPN-100-005, HPN-100-007, and HPN-100-012 (≥ 10%).
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A summary of the blood ammonia and glutamine levels during the long-term studies is presented in Table 24. ▬
Change in Blood Ammonia and Glutamine Levels in Studies HPN-100-005, HPN-100-007, and HPN-100-012.
A summary of the number of hyperammonemic crises (HACs) during the long-term studies is presented in Table 25. ▬
Hyperammonemic Crises in Studies HPN-100-005, HPN-100-007, and HPN-100-012.
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Two long-term studies, HPN-100-007 and the extension phase of HPN-100-005, evaluated quality of life (QoL) using the Pediatric Quality of Life Inventory Generic Core Scales SF15 (PedsQL SF15) version 4 and/or the Short Form (36) Health Survey (SF-36) version 2, ▬ A summary of the quality of life data is presented in Table 26 and Table 27. The PedsQL SF15 quality of life measure was evaluated in children in both HPN-100-007 and the extension phase of HPN-100-005▬ The SF-36 QoL measure was evaluated in adults in HPN-100-007. ▬
Pediatric Quality of Life Inventory Generic Core Scales SF15 Quality of Life Data in Studies HPN-100-005 and HPN-100-007 in Children.
Short Form (36) Health Survey (SF-36) Quality of Life Data in Studies HPN-100-007 in Adults.
All long-term studies performed neuropsychological testing, ▬ The Wechsler Abbreviated Scale of Intelligence was evaluated in both HPN-100-007 and the extension phase of HPN-100-005. ▬ Mean estimated full intelligence quotient (IQ) scores were also evaluated in adults in HPN-100-007 ▬ A summary of the Wechsler Abbreviated Scale of Intelligence data is presented in Table 28.
Wechsler Abbreviated Scale of Intelligence Second Edition.
The Child Behavior Checklist was evaluated in all three long-term studies. ▬ A summary of the Child Behavior Checklist data is presented in Table 29.
Child Behavior Checklist.
The Behavior Rating Inventory of Executive Function (BRIEF) was also evaluated in all three long-term studies in children only. ▬ A summary of the Behavior Rating Inventory of Executive Function data is presented in Table 30.
Behavior Rating Inventory of Executive Function.
Study HPN-100-012 also evaluated the Wechsler Preschool and Primary Scale of Intelligence. ▬ A summary of the Wechsler Preschool and Primary Scale of Intelligence data is presented in Table 31.
Wechsler Preschool and Primary Scale of Intelligence Third Edition.
Study HPN-100-007 also evaluated the California Verbal Learning Test, Digit Span Test, and Grooved Pegboard Test in adults only. ▬ Summaries of the California Verbal Learning Test, Digit Span Test, and Grooved Pegboard Test data are presented in Table 32 and Table 33.
California Verbal Learning Test Second Edition.
Digit Span and Grooved Pegboard Tests.
There are several limitations to these long-term, open-label, non-randomized, non-comparative safety studies. First, given that they were uncontrolled studies, it remains unclear whether the changes observed in the safety profile were due to a natural course of the disease or were attributed to long-term treatment with GPB. Open-label trial designs in which both the investigators and the patients are unblinded to treatment allocation may have an impact on subjective outcomes, such as some patient-reported AEs. Additionally, dose adjustments were permitted during the studies; this makes it difficult to isolate the safety profile of GPB. In addition, all efficacy end points were considered exploratory and no corrections were applied to adjust for multiplicity; therefore, any efficacy results are susceptible to inflated type I error, which can lead to uncertainty. Furthermore, no minimal clinically important differences for any of the QoL or neuropsychological scales were identified in the UCD population, making it difficult to interpret the results and whether they are clinically meaningful. Finally, patients included in all three long-term studies were mainly female, with OTC deficiency and childhood-to-adult UCD onset, which may suggest the inclusion of a less severe UCD population. Consequently, the generalizability of the results to the Canadian population is unclear.
Results from three long-term, open-label, non-randomized, non-comparative studies suggested that the effects of GPB on blood ammonia and glutamine levels appear to be maintained after 12 months of treatment in both children and adults. In addition, the number of hyperammonemic episodes per patient appears to be reduced compared with the values 12 months before screening when treated with GPB. Generally, QoL appears to increase in children when assessed with the PedsQL SF15 questionnaire. By contrast, QoL appears to decrease in adults when assessed with the SF-36 questionnaire. Generally, neuropsychological testing results were inconsistent across trials, age groups, and assessment tools. Almost all patients experienced AEs after one year of treatment with GPB. Infections and infestations (i.e., gastroenteritis, nasopharyngitis, and upper respiratory tract infection) and gastrointestinal (GI) disorders (i.e., vomiting, diarrhea, and abdominal pain) were reported as the most frequently experienced AEs. Newly emerging AEs included nervous system disorders and general disorders as well as administration-site conditions. However, because of the uncontrolled design, it is unclear whether any difference truly exists.
Considering the exploratory nature of all efficacy outcomes and the limitations of the long-term studies, the results should be interpreted with caution.
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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