Impact of Elosulfase Alfa on Pain in Patients with Morquio A Syndrome over 52 Weeks: MOR-008: A Randomized, Double-Blind, Pilot Study

Treadwell, Marsha; Harmatz, Paul R.; Burton, Barbara K.; Mitchell, John J.; Muschol, Nicole; Jones, Simon A.; Pastores, Gregory M.; Lau, Heather A.; Sparkes, Rebecca; Sutton, V. Reid; Meesen, Bianca; Haller, Christine A.; Shaywitz, Adam J.; Gold, Jeffrey I.

doi:10.1177/2326409817718850

Marsha Treadwell Corresponding Author: Marsha Treadwell, UCSF Benioff Children’s Hospital Oakland, 747 52nd St., Oakland, CA 94609, USA. Email: mtreadwell@mail.cho.org

UCSF Benioff Children’s Hospital Oakland, Oakland, CA, USA

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Paul R. Harmatz

UCSF Benioff Children’s Hospital Oakland, Oakland, CA, USA

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Barbara K. Burton

Ann and Robert H. Lurie Children’s Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

John J. Mitchell

Montreal Children’s Hospital, Quebec, Canada

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Nicole Muschol

University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Simon A. Jones

Willink Unit, St. Mary’s Hospital, CMFT, MAHSC, University of Manchester, Manchester, United Kingdom

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Gregory M. Pastores

University College Dublin, Mater Misericordiae University Hospital, Dublin, Ireland

New York University School of Medicine, New York, NY, USA

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Heather A. Lau

New York University School of Medicine, New York, NY, USA

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Rebecca Sparkes

Alberta Children’s Hospital, Calgary, Alberta, Canada

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

V. Reid Sutton

Baylor College of Medicine & Texas Children’s Hospital, Houston, TX, USA

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Bianca Meesen

Ismar Healthcare, Lier, Belgium

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Christine A. Haller

BioMarin Pharmaceutical Inc., Novato, CA, USA

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Adam J. Shaywitz

BioMarin Pharmaceutical Inc., Novato, CA, USA

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Jeffrey I. Gold

Department of Anesthesiology, Pediatrics, and Psychiatry & Behavioral Sciences, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Department of Anesthesiology Critical Care Medicine, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Authors’ Contributions MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin. Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion. John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire. Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus. Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium. Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire. Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer. Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin. V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium. Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx. Bianca Meesen is an employee of Ismar Healthcare NV. Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options. Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

Corresponding Author: Marsha Treadwell, UCSF Benioff Children’s Hospital Oakland, 747 52nd St., Oakland, CA 94609, USA. Email: mtreadwell@mail.cho.org

Authors’ Contributions

MT was consultant to the study, designed the plan for the pain assessment strategies used in the present study, scored and interpreted the pain assessments, and reviewed data analyses. PRH, BKB, JJM, NM, SAJ, GMP, HAL, RS, and VRS were all primary investigators of this study, contributed to the planning of the study, were involved in the clinical examinations and collection of data. JIG provided insight in the interpretation of the data. CH and AJS assisted with conduction of the study, data analyses, and development of the manuscript. All authors contributed to the writing and critical review of the manuscript and approved the final manuscript.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marsha Treadwell received consulting fees and travel and meeting reimbursement from BioMarin.

Paul R. Harmatz received consulting fees from BioMarin, Shire, Genzyme, Alexion, Chiesi, Inventiva, PTC, and ReGenX Bio; he received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion.

Barbara K. Burton received consulting fees from BioMarin, Shire, Genzyme, Horizon Pharma, Alexion, and ReGenX Bio; she received research funding from BioMarin, Shire, Ultragenyx, Genzyme, Alexion, Cytonet, and Armagen and travel and meeting reimbursement from BioMarin, Shire, Genzyme, and Alexion.

John J. Mitchell received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, and Shire.

Nicole Muschol received consulting fees, honoraria, and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Amicus.

Simon A. Jones worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received a honorarium.

Gregory M. Pastores received consulting fees from BioMarin, Genzyme, Pfizer, and Shire.

Heather A. Lau received consulting fees from Genzyme, Pfizer, and BioMarin; she received research funding from Genzyme, NTSAD, BioMarin, Ultragenyx, Pfizer, Shire, Amicus, and GSK and travel and meeting reimbursement from BioMarin, Genzyme, Shire, and Pfizer.

Rebecca Sparkes received consulting fees, research funding, and travel and meeting reimbursement from BioMarin.

V. Reid Sutton worked as consultant and study investigator for BioMarin Pharmaceutical Inc. and has received an honorarium.

Christine Haller is a former employee of BioMarin Pharmaceutical Inc. and a current employee of Ultragenyx.

Bianca Meesen is an employee of Ismar Healthcare NV.

Adam J. Shaywitz is an employee of BioMarin Pharmaceutical Inc. and holder of stock options.

Jeffrey I. Gold received speaker fees and travel reimbursement from BioMarin.

UCSF Benioff Children’s Hospital Oakland, Oakland, CA, USA

Ann and Robert H. Lurie Children’s Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Montreal Children’s Hospital, Quebec, Canada

University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Willink Unit, St. Mary’s Hospital, CMFT, MAHSC, University of Manchester, Manchester, United Kingdom

University College Dublin, Mater Misericordiae University Hospital, Dublin, Ireland

New York University School of Medicine, New York, NY, USA

Alberta Children’s Hospital, Calgary, Alberta, Canada

Baylor College of Medicine & Texas Children’s Hospital, Houston, TX, USA

Ismar Healthcare, Lier, Belgium

BioMarin Pharmaceutical Inc., Novato, CA, USA

Department of Anesthesiology, Pediatrics, and Psychiatry & Behavioral Sciences, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Department of Anesthesiology Critical Care Medicine, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

Timepoint			2.0 mg/kg/wk		4.0 mg/kg/wk	Total Study Population
Baseline		N		N		N
	Mean (SD)	12	7.2 (4.5)	9	3.7 (2.7)	21	5.7 (4.1)
	Median (IQR)	12	6.0 (3, 12)	9	2.0 (2, 5)	21	5.0 (2, 9)
Week 24
	Mean (SD)	15	5.5 (4.7)	10	3.5 (2.4)	25	4.7 (4.0)
	Mean (SD) change from baseline	12	-2.2 (4.8)	9	-0.1 (2.8)	21	-1.3 (4.1)
	Median (IQR)	15	5.0 (1, 9)	10	3.0 (2, 6)	25	3.0 (2, 6)
	Median change from baseline (IQR)	12	-2.0 (-5, 2)	9	1,0 (-1, 1)	21	0.0 (-4, 1)
Week 52
	Mean (SD)	14	6.1 (6.8)	10	3.4 (3.1)	24	5.0 (5.7)
	Mean (SD) change from baseline	11	-1.8 (6.4))	9	0.0 (3.2)	20	-1.0 (5.5)
	Median (IQR)	14	3.0 (1. 10)	10	3.0 (1, 3)	24	3.0 (1, 8)
	Median change from baseline (IQR)	11	-1.0 (-5, 0)	9	1.0 (-3, 1)	20	0.0 (-4, 1)

Timepoint			2.0 mg/kg/wk		4.0 mg/kg/wk	Total Study Population
Baseline		N		N		N
	Mean (SD)	12	5.0 (2.9)	9	4.1 (2.5)	21	4.6 (2.7)
	Median (IQR)	12	5.3 (3.3, 7.2)	9	4.5 (2.5, 5.0)	21	4.9 (3.0, 6.0)
Week 24
	Mean (SD)	15	3.2 (2.4)	9	3.0 (1.7)	24	3.2 (2.1)
	Mean (SD) change from baseline	12	-2.2 (3.7)	8	-1,2 (2.9)	20	-1.8 (3.3)
	Median (IQR)	15	3.6 (0.4, 5.3)	9	2.9 (2.2, 4.7)	24	3.0 (2.1, 5.1)
	Median change from baseline (IQR)	12	-0.7 (-3.9, 0)	8	-0.7 (-3.1, 1.1)	20	-0.7 (-3.5, 0.1)
Week 52
	Mean (SD)	14	3.4 (3.0)	10	2.9 (2.2)	24	3.2 (2.6)
	Mean (SD) change from baseline	11	-0.8 (3.4)	9	-0.8 (3.0)	20	-0,8 (3.2)
	Median (IQR)	14	2.8 (0.5, 6.0)	10	2.8 (1.0, 4.0)	24	2.8 (0.8 5.1)
	Median change from baseline (IQR)	11	0.1 (-4.0, 1.4)	9	-0.2 (-1.0, 1.0)	20	0.1 (-2.3, 1.4)

Timepoint			2.0 mg/kg/wk		4.0 mg/kg/wk	Total Study Population
Baseline		N		N		N
	Mean (SD) number of words	11	8.0 (5.2)	9	6.6 (2.5)	20	7.4 (4.2)
	Median (IQR) number of words	11	8.0 (4, 14)	9	6.0 (4, 8)	20	7.0 (4, 10)
Week 24
	Mean (SD) number of words	15	5.3 (4.3)	10	4.3 (3.9)	25	4.9 (4.1)
	Mean (SD) change from baseline in number of words	11	-2.5 (5.6)	9	-1.9 (3.6)	20	-2.3 (4.7)
	Median (IQR) number of words	15	6.0 (1, 8)	10	4.0 (1, 6)	25	5.0 (1,7)
	Median (IQR) change from baseline in number of words	11	-1.0 (-4, 1)	9	-1.0 (-5, 1)	20	-1.0 (-5, 1)
Week 52
	Mean (SD) number of words	14	5.6 (5.3)	10	4.0 (2.6)	24	4.9 (4.3)
	Mean (SD) change from baseline in number of words	10	-1.0 (7.9)	9	-2.4 (2.7)	19	-1.7 (5.9)
	Median (IQR) number of words	14	5.0 (1, 7)	10	3.0 (3, 7)	24	3.5 (2, 7)
	Median (IQR) change from baseline in number of words	10	0.5 (-6, 2)	9	-3.0 (-4, -1)	19	-1.0 (-5, 1)

Questionnaire	MPS Type	Number of Subjects; Age Range	ERT (duration)	Baseline Pain Intensity score	Final Pain Intensity Score	Reference
(C)HAQ (0-3 scale)	MPS I	N = 45; 6.3-43.3 years	Laronidase	0.93 (N = 30)	0.56 (N = 30)	³3 Clarke, LA, Wraith, JE, Beck, M. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009;123(1):229–240.
			(3.5-4 years)
(C)HAQ (0-100	MPS II	N = 96; 5-30.9 years	Not used	28.2		⁴4 Raluy-Callado, M., Chen, WH., Whiteman, DAH., Fang, J., Wiklund, I. The impact of Hunter syndrome (mucopolysaccharidosis type II) on health-related quality of life. Orphanet J Rare Dis. 2013;8(1):101.
scale)	MPS VI	N = 90; 4-18 years	Not used	31.6		⁵5 Swiedler, SJ, Beck, M, Bajbouj, M. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet. 2005;134A(2):144–150.
		N = 28; 19-56 years	Not used	38.2		⁵5 Swiedler, SJ, Beck, M, Bajbouj, M. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet. 2005;134A(2):144–150.
		N = 22; 4-18 years	Galsulfase	24.3	31.9	⁶6 Giugliani, R, Lampe, C, Guffon, N. Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)-10-year follow-up of patients who previously participated in an MPS VI survey study. Am J Med Genet A. 2014;164A(8):1953–1964.
			( ± 6.8 years)
		N = 10; >18 years	Galsulfase	35.5	22.3	⁶6 Giugliani, R, Lampe, C, Guffon, N. Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)-10-year follow-up of patients who previously participated in an MPS VI survey study. Am J Med Genet A. 2014;164A(8):1953–1964.
			(+ 6.8 years)
		N =10; 6-22 years	Galsulfase	41	55% reduction	⁷7 Harmatz, P., Ketteridge, D., Giugliani, R. Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatase. Pediatrics. 2005;115(6):e681–e689.
			(48 weeks)
		N = 9; 1.4-21.1 years	Galsulfase	NA	30.5% reduction	¹⁷17 Lin, HY, Chen, MR, Chuang, CK. Enzyme replacement therapy for mucopolysaccharidosis VI-experience in Taiwan. J Inherit Metab Dis. 2010;33(suppl 3):S421–S427.
			(2 years)
NCCPC-Revised	MPS	N = 35; <8 years or	Not used	Range 0-36		¹1 Brands, MMG, Güngör, D, van den Hout, JMP. Pain: a prevalent feature in patients with mucopolysaccharidosis. Results of a cross-sectional national survey. J Inherit Metab Dis. 2015;38(2):323–331.
(0-90 scale)		with intellectual disability		(cut-off for pain of 7 in 45.7%)
Six-face Faces Pain	MPS	N = 11; 8-18 years	Not used	Range 0-92		¹1 Brands, MMG, Güngör, D, van den Hout, JMP. Pain: a prevalent feature in patients with mucopolysaccharidosis. Results of a cross-sectional national survey. J Inherit Metab Dis. 2015;38(2):323–331.
Scale-Revised		without intellectual		(cut-off for moderate pain of 45
(0-100 scale)		disability		in 18.1%)
VAS (0-100 scale)	MPS	N = 8; >18 years	Not used	Range 10-88, median 41.5		¹1 Brands, MMG, Güngör, D, van den Hout, JMP. Pain: a prevalent feature in patients with mucopolysaccharidosis. Results of a cross-sectional national survey. J Inherit Metab Dis. 2015;38(2):323–331.
		without		(cut-off for moderate pain of 45
		intellectual disability		in 37.5%)
BPI (0-10 scale)	MPS IV	N = 19; 18-67 years	Not used	4.39		³⁹39 Ali, N, Cagle, S. Psychological health in adults with Morquio syndrome. JIMD Rep. 2015;20:87–93.
	MPS IVA	N = 27; ≥ 18 years	Not used	No WC: 1.69 (N = 4) WC when needed: 3.55 (N = 14) WC always used: 2.69 (N = 9)		²2 Hendriksz, CJ., Lavery, C., Coker, M. Burden of disease in patients with Morquio A syndrome: results from an international patient-reported outcomes survey. Orphanet J Rare Dis. 2014;9:32.
APPT (0-10 scale)	MPS IVA	N = 36; 5-17 years	Not used	No WC: 4.38 (N = 20) WC when needed: 4.00 (N = 14) WC always used: 1.00 (N = 2)		²2 Hendriksz, CJ., Lavery, C., Coker, M. Burden of disease in patients with Morquio A syndrome: results from an international patient-reported outcomes survey. Orphanet J Rare Dis. 2014;9:32.
	MPS IVA	N =25; 8-40 years	Elosulfase alfa	Pain intensity: 4.6	Pain intensity: 3.2	MOR-008
			(52 weeks)			study

		2.0 mg/kg/week (N =15)	4.0 mg/kg/week (N = 10)	Total Study Population (N = 25)
Age at enrollment, years
	Mean (SD)	14.9 (9.3)	12.0 (3.2)	13.7 (7.5)
	Median (IQR)	11.3 (9, 17)	12.2 (9, 14)	11.5 (9, 15)
Sex, n
	Female	12	4	16
	Male	3	6	9
Race, n
	White	14	9	23
	Other	1	1	2
6MWT, m
	Mean (SD)	369.6 (89.2)	376.3 (70.0)	372.2 (80.6)
	Median (IQR)	346.8 (300, 422)	393.2 (326, 444)	372.3 (321,422)
3MSCT, stairs/min
	Mean (SD)	65.5 (21.4)	64.2 (23.3)	65.0 (21.7)
	Median (IQR)	65.3 (55, 72)	63.6 (53, 84)	65.2 (55, 78)

[1] Corresponding Author: Marsha Treadwell, UCSF Benioff Children’s Hospital Oakland, 747 52nd St., Oakland, CA 94609, USA. Email: mtreadwell@mail.cho.org

Brasil

Brasil

Impact of Elosulfase Alfa on Pain in Patients with Morquio A Syndrome over 52 Weeks: MOR-008: A Randomized, Double-Blind, Pilot Study

Abstract