Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials

Sandesh C.S. Nagamani; George A. Diaz; William Rhead; Susan A. Berry; Cynthia Le Mons; Uta Lichter-Konecki; James Bartley; Annette Feigenbaum; Andreas Schulze; Nicola Longo; William Berquist; Renata Gallagher; Dennis Bartholomew; Cary O. Harding; Mark S. Korson; Shawn E. McCandless; Wendy Smith; Jerry Vockley; David Kronn; Robert Zori; Stephen Cederbaum; J. Lawrence Merritt; Derek Wong; Dion F. Coakley; Bruce F. Scharschmidt; Klara Dickinson; Miguel Marino; Brendan H. Lee; Masoud Mokhtarani

doi:10.1016/j.ymgme.2015.08.002

Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials

Sandesh C.S. Nagamani
, George A. Diaz
, William Rhead
, Susan A. Berry
, Cynthia Le Mons
, Uta Lichter-Konecki
, James Bartley
, Annette Feigenbaum
, Andreas Schulze
, Nicola Longo
, William Berquist
, Renata Gallagher
, Dennis Bartholomew
, Cary O. Harding
, Mark S. Korson
, Shawn E. McCandless
, Wendy Smith
, Jerry Vockley
, David Kronn
, Robert Zori

Stephen Cederbaum, J. Lawrence Merritt, Derek Wong, Dion F. Coakley, Bruce F. Scharschmidt, Klara Dickinson, Miguel Marino, Brendan H. Lee, Masoud Mokhtarani

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Background: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. Methods: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB). Results: After 3. months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p < 0.0001), the number of symptoms per patient (2.5 vs. 1.1; p < 0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p < 0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose. Conclusions: The reduction in symptoms following 3. months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.

Original language	English (US)
Pages (from-to)	29-34
Number of pages	6
Journal	Molecular Genetics and Metabolism
Volume	116
Issue number	1-2
DOIs	https://doi.org/10.1016/j.ymgme.2015.08.002
State	Published - Sep 1 2015

Funding

The authors gratefully acknowledge and thank the efforts of the study staff who made this study possible, including N. Schrager (Icahn School of Medicine at Mount Sinai), A. Donovan, J. Crawford, Pediatric TRU Staff, K. Defouw, J. Balliet (The Medical College of Wisconsin), M. Keuth, N. O'Donnell (Long Beach Memorial Hospital), M. Hussain, E. Bailey, A. Orton, M. Ambreen (The Hospital for Sick Children, University of Toronto, ON, Canada), C. Bailey, M.J. Dunkley (The University of Utah), J. Perry, V. de Leon, A. Niemi, K. Cusmano (Stanford University), T. Carlson, J. Parker (University of Minnesota), S. Burr (Children's Hospital Colorado), K. Simpson (Children's National Medical Center), K. Regis (Nationwide Children's Hospital), A. Behrend, T. Marrone (Oregon Health & Sciences University), N. Dorrani (University of California, Los Angeles), C. Heggie (Case Western Reserve University), S. Mortenson (Maine Medical Center), S. Deward (Children's Hospital of Pittsburgh), K. Bart, C. Duggan (SNBL), K. Murray, C. Dedomenico (Tufts Medical Center), C. Gross (University of Florida), L. Brody (Seattle Children's Hospital), M. Mullins, S. Carter, A. Tran, J. Stuff, TCH General Clinical Research Center nursing staff (Baylor), Kathy Lisam (Hyperion), as well as the Clinical and Translational Science Awards/General Clinical Research Center Grants (Baylor College of Medicine, M01RR00188; Case Western Reserve University, NIDDK 1K08DK074573; Clinical and Translational Science Institute at Children's National Medical Center NIH/NCRR, UL1RR31988; Medical College of Wisconsin, UL1RR31973; Mount Sinai School of Medicine, UL1RR29887; Oregon Health & Science University, UL1RR24140; Stanford University, UL1RR25744; Tufts University, UL1RR25752; University of California, Los Angeles, UL1RR33176; University of Colorado, UL1RR25780; University of Florida, UL1RR29890; University of Minnesota, UL1RR33183; University of Pittsburgh, NIH UL1TR000005; University of Utah, UL1RR25764; University of Washington,UL1TR000423), the Urea Cycle Disorders Consortium (NIH Grant U54RR019453) and grants from the O'Malley Foundation, Kettering Fund, and Rotenberg Fund which provided support. SCS Nagamani is an awardee of the National Urea Cycle Disorders Foundation Research Fellowship and is supported by the Clinical Scientist Development Award by the Doris Duke Charitable Foundation. Appendix A

Funders	Funder number
Clinical and Translational Science Institute at Children's National Medical Center NIH/NCRR	UL1RR31973
NIH UL1TR000005	UL1TR000005, UL1RR25764
National Urea Cycle Disorders Foundation Research
O'Malley Foundation
Rotenberg Family Fund
Urea Cycle Disorders Consortium	U54RR019453
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	UL1RR025780, UL1RR024140, M01RR000188, R01DK102641, UL1RR031988, UL1RR025752, UL1RR033176
National Center for Research Resources	UL1RR029887
Doris Duke Charitable Foundation
Department of Biological Sciences Stanford University Stanford	UL1RR25744
Oregon Health Sciences University Oregon Regional Primate Research Center
Oregon State University/Oregon Health and Science University	UL1RR24140
National Center for Medical Rehabilitation Research
New England Eye Center, Tufts Medical Center, Tufts University
University of California Los Angeles
University of Minnesota, Minnesota Supercomputing Institute
Icahn school of Medicine at Mount Sinai
Nationwide Children's Hospital
University of Southern Florida	Baylor
University of Utah, Utah Poison Control Center	Utah
Genome Center at Washington University, Washington University School of Medicine	UL1TR000423
One Baylor Plaza, Baylor College of Medicine
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
New England Eye Center, Tufts Medical Center, Tufts University	UL1RR25752, UL1RR33176
Case-Western Reserve University	NIDDK 1K08DK074573
Society for Classical Studies
School of Medicine	UL1RR29887
Medical College of Wisconsin
Center for Clinical and Translational Research
University of Colorado Colorado Springs	UL1RR25780, UL1RR33183, UL1RR29890
Toronto Western Hospital and University of Toronto
Hospital for Sick Children

Keywords

Ammonia
Glycerol phenylbutyrate
Health-related quality of life
Patient-reported outcomes
Sodium phenylbutyrate
Treatment-related symptoms

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Molecular Biology
Genetics
Endocrinology

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10.1016/j.ymgme.2015.08.002

Cite this

Nagamani, S. C. S., Diaz, G. A., Rhead, W., Berry, S. A., Le Mons, C., Lichter-Konecki, U., Bartley, J., Feigenbaum, A., Schulze, A., Longo, N., Berquist, W., Gallagher, R., Bartholomew, D., Harding, C. O., Korson, M. S., McCandless, S. E., Smith, W., Vockley, J., Kronn, D., ... Mokhtarani, M. (2015). Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials. Molecular Genetics and Metabolism, 116(1-2), 29-34. https://doi.org/10.1016/j.ymgme.2015.08.002

Nagamani, SCS, Diaz, GA, Rhead, W, Berry, SA, Le Mons, C, Lichter-Konecki, U, Bartley, J, Feigenbaum, A, Schulze, A, Longo, N, Berquist, W, Gallagher, R, Bartholomew, D, Harding, CO, Korson, MS, McCandless, SE, Smith, W, Vockley, J, Kronn, D, Zori, R, Cederbaum, S, Lawrence Merritt, J, Wong, D, Coakley, DF, Scharschmidt, BF, Dickinson, K, Marino, M, Lee, BH & Mokhtarani, M 2015, 'Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials', Molecular Genetics and Metabolism, vol. 116, no. 1-2, pp. 29-34. https://doi.org/10.1016/j.ymgme.2015.08.002

@article{7f3d7b6e0fce4ea08ddac449411df7fb,

title = "Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials",

abstract = "Background: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. Methods: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB). Results: After 3. months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69\% vs. 46\%; p < 0.0001), the number of symptoms per patient (2.5 vs. 1.1; p < 0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p < 0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose. Conclusions: The reduction in symptoms following 3. months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.",

keywords = "Ammonia, Glycerol phenylbutyrate, Health-related quality of life, Patient-reported outcomes, Sodium phenylbutyrate, Treatment-related symptoms",

author = "Nagamani, \{Sandesh C.S.\} and Diaz, \{George A.\} and William Rhead and Berry, \{Susan A.\} and \{Le Mons\}, Cynthia and Uta Lichter-Konecki and James Bartley and Annette Feigenbaum and Andreas Schulze and Nicola Longo and William Berquist and Renata Gallagher and Dennis Bartholomew and Harding, \{Cary O.\} and Korson, \{Mark S.\} and McCandless, \{Shawn E.\} and Wendy Smith and Jerry Vockley and David Kronn and Robert Zori and Stephen Cederbaum and \{Lawrence Merritt\}, J. and Derek Wong and Coakley, \{Dion F.\} and Scharschmidt, \{Bruce F.\} and Klara Dickinson and Miguel Marino and Lee, \{Brendan H.\} and Masoud Mokhtarani",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc..",

year = "2015",

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doi = "10.1016/j.ymgme.2015.08.002",

language = "English (US)",

volume = "116",

pages = "29--34",

journal = "Molecular Genetics and Metabolism",

issn = "1096-7192",

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TY - JOUR

T1 - Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials

AU - Nagamani, Sandesh C.S.

AU - Diaz, George A.

AU - Rhead, William

AU - Berry, Susan A.

AU - Le Mons, Cynthia

AU - Lichter-Konecki, Uta

AU - Bartley, James

AU - Feigenbaum, Annette

AU - Schulze, Andreas

AU - Longo, Nicola

AU - Berquist, William

AU - Gallagher, Renata

AU - Bartholomew, Dennis

AU - Harding, Cary O.

AU - Korson, Mark S.

AU - McCandless, Shawn E.

AU - Smith, Wendy

AU - Vockley, Jerry

AU - Kronn, David

AU - Zori, Robert

AU - Cederbaum, Stephen

AU - Lawrence Merritt, J.

AU - Wong, Derek

AU - Coakley, Dion F.

AU - Scharschmidt, Bruce F.

AU - Dickinson, Klara

AU - Marino, Miguel

AU - Lee, Brendan H.

AU - Mokhtarani, Masoud

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Background: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. Methods: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB). Results: After 3. months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p < 0.0001), the number of symptoms per patient (2.5 vs. 1.1; p < 0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p < 0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose. Conclusions: The reduction in symptoms following 3. months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.

AB - Background: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. Methods: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB). Results: After 3. months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p < 0.0001), the number of symptoms per patient (2.5 vs. 1.1; p < 0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p < 0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose. Conclusions: The reduction in symptoms following 3. months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.

KW - Ammonia

KW - Glycerol phenylbutyrate

KW - Health-related quality of life

KW - Patient-reported outcomes

KW - Sodium phenylbutyrate

KW - Treatment-related symptoms

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C2 - 26296711

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ER -

Self-reported treatment-associated symptoms among patients with urea cycle disorders participating in glycerol phenylbutyrate clinical trials

Abstract

Funding

Keywords

ASJC Scopus subject areas

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