Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial

Lakshminarayan R. Ranganath; Eftychia Eirini Psarelli; Jean Baptiste Arnoux; Daniela Braconi; Michael Briggs; Anders Bröijersén; Nadia Loftus; Helen Bygott; Trevor F. Cox; Andrew S. Davison; Jane P. Dillon; Michael Fisher; Richard FitzGerald; Federica Genovese; Helena Glasova; Anthony K. Hall; Andrew T. Hughes; Juliette H. Hughes; Richard Imrich; Jonathan C. Jarvis; Milad Khedr; Dinny Laan; Kim Hanh Le Quan Sang; Emily Luangrath; Ol'ga Lukáčová; Anna M. Milan; Alpesh Mistry; Vanda Mlynáriková; Brendan P. Norman; Birgitta Olsson; Nicholas P. Rhodes; Jozef Rovenský; Mattias Rudebeck; Annalisa Santucci; Ella Shweihdi; Ciarán Scott; Jana Sedláková; Nicolas Sireau; Roman Stančík; Johan Szamosi; Sophie Taylor; Christa van Kan; Sobhan Vinjamuri; Eva Vrtíková; Chris Webb; Elizabeth West; Elizabeth Záňová; Andrea Zatkova; James A. Gallagher

doi:10.1016/S2213-8587(20)30228-X

Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial

Lakshminarayan R. Ranganath, Eftychia Eirini Psarelli, Jean Baptiste Arnoux, Daniela Braconi, Michael Briggs, Anders Bröijersén, Nadia Loftus, Helen Bygott, Trevor F. Cox, Andrew S. Davison, Jane P. Dillon, Michael Fisher, Richard FitzGerald, Federica Genovese, Helena Glasova, Anthony K. Hall, Andrew T. Hughes, Juliette H. Hughes, Richard Imrich, Jonathan C. JarvisMilad Khedr, Dinny Laan, Kim Hanh Le Quan Sang, Emily Luangrath, Ol'ga Lukáčová, Anna M. Milan, Alpesh Mistry, Vanda Mlynáriková, Brendan P. Norman, Birgitta Olsson, Nicholas P. Rhodes, Jozef Rovenský, Mattias Rudebeck, Annalisa Santucci, Ella Shweihdi, Ciarán Scott, Jana Sedláková, Nicolas Sireau, Roman Stančík, Johan Szamosi, Sophie Taylor, Christa van Kan, Sobhan Vinjamuri, Eva Vrtíková, Chris Webb, Elizabeth West, Elizabeth Záňová, Andrea Zatkova, James A. Gallagher

University of Liverpool

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

63 Citations (Scopus)

57 Downloads (Pure)

Abstract

BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit.

METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA 24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA 24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382).

FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA 24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred.

INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression.

FUNDING: European Commission Seventh Framework Programme.

Original language	English
Pages (from-to)	762-772
Number of pages	11
Journal	The Lancet Diabetes and Endocrinology
Volume	8
Issue number	9
Early online date	18 Aug 2020
DOIs	https://doi.org/10.1016/S2213-8587(20)30228-X
Publication status	Published - 1 Sept 2020
Externally published	Yes

Keywords

Adult
Aged
Alkaptonuria/diagnosis
Cyclohexanones/administration & dosage
Drug Administration Schedule
Enzyme Inhibitors/administration & dosage
Female
Homogentisic Acid/metabolism
Humans
Internationality
Longitudinal Studies
Male
Middle Aged
Nitrobenzoates/administration & dosage
Single-Blind Method
Treatment Outcome

Access to Document

10.1016/S2213-8587(20)30228-X

SONIA2_Author_Accepted_version_manuscript_tables_figure_supplAccepted author manuscript, 3.18 MBLicence: CC BY-NC-ND

Cite this

Ranganath, L. R., Psarelli, E. E., Arnoux, J. B., Braconi, D., Briggs, M., Bröijersén, A., Loftus, N., Bygott, H., Cox, T. F., Davison, A. S., Dillon, J. P., Fisher, M., FitzGerald, R., Genovese, F., Glasova, H., Hall, A. K., Hughes, A. T., Hughes, J. H., Imrich, R., ... Gallagher, J. A. (2020). Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial. The Lancet Diabetes and Endocrinology, 8(9), 762-772. Advance online publication. https://doi.org/10.1016/S2213-8587(20)30228-X

@article{fd1be83df4c04a8fa2ff8f54f392d3ed,

title = "Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial",

abstract = "BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit.METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA 24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA 24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA 24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression.FUNDING: European Commission Seventh Framework Programme.",

keywords = "Adult, Aged, Alkaptonuria/diagnosis, Cyclohexanones/administration & dosage, Drug Administration Schedule, Enzyme Inhibitors/administration & dosage, Female, Homogentisic Acid/metabolism, Humans, Internationality, Longitudinal Studies, Male, Middle Aged, Nitrobenzoates/administration & dosage, Single-Blind Method, Treatment Outcome",

author = "Ranganath, {Lakshminarayan R.} and Psarelli, {Eftychia Eirini} and Arnoux, {Jean Baptiste} and Daniela Braconi and Michael Briggs and Anders Br{\"o}ijers{\'e}n and Nadia Loftus and Helen Bygott and Cox, {Trevor F.} and Davison, {Andrew S.} and Dillon, {Jane P.} and Michael Fisher and Richard FitzGerald and Federica Genovese and Helena Glasova and Hall, {Anthony K.} and Hughes, {Andrew T.} and Hughes, {Juliette H.} and Richard Imrich and Jarvis, {Jonathan C.} and Milad Khedr and Dinny Laan and {Le Quan Sang}, {Kim Hanh} and Emily Luangrath and Ol'ga Luk{\'a}{\v c}ov{\'a} and Milan, {Anna M.} and Alpesh Mistry and Vanda Mlyn{\'a}rikov{\'a} and Norman, {Brendan P.} and Birgitta Olsson and Rhodes, {Nicholas P.} and Jozef Rovensk{\'y} and Mattias Rudebeck and Annalisa Santucci and Ella Shweihdi and Ciar{\'a}n Scott and Jana Sedl{\'a}kov{\'a} and Nicolas Sireau and Roman Stan{\v c}{\'i}k and Johan Szamosi and Sophie Taylor and {van Kan}, Christa and Sobhan Vinjamuri and Eva Vrt{\'i}kov{\'a} and Chris Webb and Elizabeth West and Elizabeth Z{\'a}{\v n}ov{\'a} and Andrea Zatkova and Gallagher, {James A.}",

note = "Funding Information: We thank the European Commission for the Seventh Framework Programme grant (DevelopAKUre, project number 304985) that was crucial to conduct the SONIA 2 study. We thank all patients in SONIA 2 for their participation, and the patient societies for supporting the patients in the study and for their efforts in successfully recruiting many patients. We thank the following people for their support during SONIA 2: Pam Neagle, Heather Rogers, Julia West, Hollie Washington, Leanne A Evans, Shirley Judd (Royal Liverpool University Hospital, Liverpool, UK), Matthew Gornall, Rebecca Griffin (Liverpool Clinical Trials Centre, Liverpool, UK), Serge Sireau, Simone Sireau (Association pour la Lutte Contre l'Alcaptonurie, L'{\'E}tang-la-Ville, France), Na An, Julien Tavet, Christine Broissand, Chantal Deslandre, Laurent Sabbah, Charlotte Celerier, Matthieu Robert (H{\^o}pital Necker-Enfants Malades, Paris, France), Florence Tenenbaum, Catherine Cormier (H{\^o}pital Cochin, Paris, France), Lucia Chal{\'a}sov{\'a}, Miroslav Borovsk{\'y}, Miroslav Kone{\v c}n{\'y} (National Institute of Rheumatic Diseases, Pie{\v s}t'any, Slovakia), Oliver Timmis, Sorsha Roberts, Hana Ayoob, Eve Whitley, Lesley Harrison (AKU Society, Cambridge, UK), Kristin {\"O}nnestam, Carin Junestrand, Karin Gr{\"u}nbaum, Sirkka Thome, Ingrid Palmgren, Erik Sparve, Kristina Lindsten (Swedish Orphan Biovitrum, Stockholm, Sweden), Mohammed Alsbou (Jordanian Alkaptonuria Society, Al-Karak, Jordan), Enrico Selvi (Department of Rheumatology, University of Siena, Italy), and Dennis Omtzigt and Jolanda Overweel (PSR Group, Hoofddorp, Netherlands). We thank the independent data monitoring committee, chaired by Robert Moots, Theresa Barnes, Andy Vail, Patrick McKiernan. Finally, we thank the trial steering committee, chaired by Alan Shenkin, Wendy Introne, Virginia Kraus, and Duncan Batty. Funding Information: LRR reports grants from the European Commission. AB reports personal fees from Swedish Orphan Biovitrum. FG reports grants from the EU, and is an employee and stock owner of Nordic Bioscience. AKH reports grants from the European Commission and is a shareholder of Cudos and PSR Group. BO, MR, and JSz are employees and shareholders of Swedish Orphan Biovitrum. CS and NS report that the AKU Society received a £10 000 grant from Swedish Orphan Biovitrum towards organising an alkaptonuria patient workshop. All other authors declare no competing interests. Funding Information: We thank the European Commission for the Seventh Framework Programme grant (DevelopAKUre, project number 304985) that was crucial to conduct the SONIA 2 study. We thank all patients in SONIA 2 for their participation, and the patient societies for supporting the patients in the study and for their efforts in successfully recruiting many patients. We thank the following people for their support during SONIA 2: Pam Neagle, Heather Rogers, Julia West, Hollie Washington, Leanne A Evans, Shirley Judd (Royal Liverpool University Hospital, Liverpool, UK), Matthew Gornall, Rebecca Griffin (Liverpool Clinical Trials Centre, Liverpool, UK), Serge Sireau, Simone Sireau (Association pour la Lutte Contre l'Alcaptonurie, L'?tang-la-Ville, France), Na An, Julien Tavet, Christine Broissand, Chantal Deslandre, Laurent Sabbah, Charlotte Celerier, Matthieu Robert (H?pital Necker-Enfants Malades, Paris, France), Florence Tenenbaum, Catherine Cormier (H?pital Cochin, Paris, France), Lucia Chal?sov?, Miroslav Borovsk?, Miroslav Kone?n? (National Institute of Rheumatic Diseases, Pie?t'any, Slovakia), Oliver Timmis, Sorsha Roberts, Hana Ayoob, Eve Whitley, Lesley Harrison (AKU Society, Cambridge, UK), Kristin ?nnestam, Carin Junestrand, Karin Gr?nbaum, Sirkka Thome, Ingrid Palmgren, Erik Sparve, Kristina Lindsten (Swedish Orphan Biovitrum, Stockholm, Sweden), Mohammed Alsbou (Jordanian Alkaptonuria Society, Al-Karak, Jordan), Enrico Selvi (Department of Rheumatology, University of Siena, Italy), and Dennis Omtzigt and Jolanda Overweel (PSR Group, Hoofddorp, Netherlands). We thank the independent data monitoring committee, chaired by Robert Moots, Theresa Barnes, Andy Vail, Patrick McKiernan. Finally, we thank the trial steering committee, chaired by Alan Shenkin, Wendy Introne, Virginia Kraus, and Duncan Batty. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = sep,

day = "1",

doi = "10.1016/S2213-8587(20)30228-X",

language = "English",

volume = "8",

pages = "762--772",

journal = "The Lancet Diabetes and Endocrinology",

issn = "2213-8587",

publisher = "Elsevier BV",

number = "9",

}

Ranganath, LR, Psarelli, EE, Arnoux, JB, Braconi, D, Briggs, M, Bröijersén, A, Loftus, N, Bygott, H, Cox, TF, Davison, AS, Dillon, JP, Fisher, M, FitzGerald, R, Genovese, F, Glasova, H, Hall, AK, Hughes, AT, Hughes, JH, Imrich, R, Jarvis, JC, Khedr, M, Laan, D, Le Quan Sang, KH, Luangrath, E, Lukáčová, O, Milan, AM, Mistry, A, Mlynáriková, V, Norman, BP, Olsson, B, Rhodes, NP, Rovenský, J, Rudebeck, M, Santucci, A, Shweihdi, E, Scott, C, Sedláková, J, Sireau, N, Stančík, R, Szamosi, J, Taylor, S, van Kan, C, Vinjamuri, S, Vrtíková, E, Webb, C, West, E, Záňová, E, Zatkova, A & Gallagher, JA 2020, 'Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial', The Lancet Diabetes and Endocrinology, vol. 8, no. 9, pp. 762-772. https://doi.org/10.1016/S2213-8587(20)30228-X

Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial. / Ranganath, Lakshminarayan R.; Psarelli, Eftychia Eirini; Arnoux, Jean Baptiste et al.
In: The Lancet Diabetes and Endocrinology, Vol. 8, No. 9, 01.09.2020, p. 762-772.

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

TY - JOUR

T1 - Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial

AU - Ranganath, Lakshminarayan R.

AU - Psarelli, Eftychia Eirini

AU - Arnoux, Jean Baptiste

AU - Braconi, Daniela

AU - Briggs, Michael

AU - Bröijersén, Anders

AU - Loftus, Nadia

AU - Bygott, Helen

AU - Cox, Trevor F.

AU - Davison, Andrew S.

AU - Dillon, Jane P.

AU - Fisher, Michael

AU - FitzGerald, Richard

AU - Genovese, Federica

AU - Glasova, Helena

AU - Hall, Anthony K.

AU - Hughes, Andrew T.

AU - Hughes, Juliette H.

AU - Imrich, Richard

AU - Jarvis, Jonathan C.

AU - Khedr, Milad

AU - Laan, Dinny

AU - Le Quan Sang, Kim Hanh

AU - Luangrath, Emily

AU - Lukáčová, Ol'ga

AU - Milan, Anna M.

AU - Mistry, Alpesh

AU - Mlynáriková, Vanda

AU - Norman, Brendan P.

AU - Olsson, Birgitta

AU - Rhodes, Nicholas P.

AU - Rovenský, Jozef

AU - Rudebeck, Mattias

AU - Santucci, Annalisa

AU - Shweihdi, Ella

AU - Scott, Ciarán

AU - Sedláková, Jana

AU - Sireau, Nicolas

AU - Stančík, Roman

AU - Szamosi, Johan

AU - Taylor, Sophie

AU - van Kan, Christa

AU - Vinjamuri, Sobhan

AU - Vrtíková, Eva

AU - Webb, Chris

AU - West, Elizabeth

AU - Záňová, Elizabeth

AU - Zatkova, Andrea

AU - Gallagher, James A.

N1 - Funding Information: We thank the European Commission for the Seventh Framework Programme grant (DevelopAKUre, project number 304985) that was crucial to conduct the SONIA 2 study. We thank all patients in SONIA 2 for their participation, and the patient societies for supporting the patients in the study and for their efforts in successfully recruiting many patients. We thank the following people for their support during SONIA 2: Pam Neagle, Heather Rogers, Julia West, Hollie Washington, Leanne A Evans, Shirley Judd (Royal Liverpool University Hospital, Liverpool, UK), Matthew Gornall, Rebecca Griffin (Liverpool Clinical Trials Centre, Liverpool, UK), Serge Sireau, Simone Sireau (Association pour la Lutte Contre l'Alcaptonurie, L'Étang-la-Ville, France), Na An, Julien Tavet, Christine Broissand, Chantal Deslandre, Laurent Sabbah, Charlotte Celerier, Matthieu Robert (Hôpital Necker-Enfants Malades, Paris, France), Florence Tenenbaum, Catherine Cormier (Hôpital Cochin, Paris, France), Lucia Chalásová, Miroslav Borovský, Miroslav Konečný (National Institute of Rheumatic Diseases, Piešt'any, Slovakia), Oliver Timmis, Sorsha Roberts, Hana Ayoob, Eve Whitley, Lesley Harrison (AKU Society, Cambridge, UK), Kristin Önnestam, Carin Junestrand, Karin Grünbaum, Sirkka Thome, Ingrid Palmgren, Erik Sparve, Kristina Lindsten (Swedish Orphan Biovitrum, Stockholm, Sweden), Mohammed Alsbou (Jordanian Alkaptonuria Society, Al-Karak, Jordan), Enrico Selvi (Department of Rheumatology, University of Siena, Italy), and Dennis Omtzigt and Jolanda Overweel (PSR Group, Hoofddorp, Netherlands). We thank the independent data monitoring committee, chaired by Robert Moots, Theresa Barnes, Andy Vail, Patrick McKiernan. Finally, we thank the trial steering committee, chaired by Alan Shenkin, Wendy Introne, Virginia Kraus, and Duncan Batty. Funding Information: LRR reports grants from the European Commission. AB reports personal fees from Swedish Orphan Biovitrum. FG reports grants from the EU, and is an employee and stock owner of Nordic Bioscience. AKH reports grants from the European Commission and is a shareholder of Cudos and PSR Group. BO, MR, and JSz are employees and shareholders of Swedish Orphan Biovitrum. CS and NS report that the AKU Society received a £10 000 grant from Swedish Orphan Biovitrum towards organising an alkaptonuria patient workshop. All other authors declare no competing interests. Funding Information: We thank the European Commission for the Seventh Framework Programme grant (DevelopAKUre, project number 304985) that was crucial to conduct the SONIA 2 study. We thank all patients in SONIA 2 for their participation, and the patient societies for supporting the patients in the study and for their efforts in successfully recruiting many patients. We thank the following people for their support during SONIA 2: Pam Neagle, Heather Rogers, Julia West, Hollie Washington, Leanne A Evans, Shirley Judd (Royal Liverpool University Hospital, Liverpool, UK), Matthew Gornall, Rebecca Griffin (Liverpool Clinical Trials Centre, Liverpool, UK), Serge Sireau, Simone Sireau (Association pour la Lutte Contre l'Alcaptonurie, L'?tang-la-Ville, France), Na An, Julien Tavet, Christine Broissand, Chantal Deslandre, Laurent Sabbah, Charlotte Celerier, Matthieu Robert (H?pital Necker-Enfants Malades, Paris, France), Florence Tenenbaum, Catherine Cormier (H?pital Cochin, Paris, France), Lucia Chal?sov?, Miroslav Borovsk?, Miroslav Kone?n? (National Institute of Rheumatic Diseases, Pie?t'any, Slovakia), Oliver Timmis, Sorsha Roberts, Hana Ayoob, Eve Whitley, Lesley Harrison (AKU Society, Cambridge, UK), Kristin ?nnestam, Carin Junestrand, Karin Gr?nbaum, Sirkka Thome, Ingrid Palmgren, Erik Sparve, Kristina Lindsten (Swedish Orphan Biovitrum, Stockholm, Sweden), Mohammed Alsbou (Jordanian Alkaptonuria Society, Al-Karak, Jordan), Enrico Selvi (Department of Rheumatology, University of Siena, Italy), and Dennis Omtzigt and Jolanda Overweel (PSR Group, Hoofddorp, Netherlands). We thank the independent data monitoring committee, chaired by Robert Moots, Theresa Barnes, Andy Vail, Patrick McKiernan. Finally, we thank the trial steering committee, chaired by Alan Shenkin, Wendy Introne, Virginia Kraus, and Duncan Batty. Publisher Copyright: © 2017 Elsevier Ltd Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit.METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA 24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA 24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA 24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression.FUNDING: European Commission Seventh Framework Programme.

AB - BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit.METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA 24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA 24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA 24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression.FUNDING: European Commission Seventh Framework Programme.

KW - Adult

KW - Aged

KW - Alkaptonuria/diagnosis

KW - Cyclohexanones/administration & dosage

KW - Drug Administration Schedule

KW - Enzyme Inhibitors/administration & dosage

KW - Female

KW - Homogentisic Acid/metabolism

KW - Humans

KW - Internationality

KW - Longitudinal Studies

KW - Male

KW - Middle Aged

KW - Nitrobenzoates/administration & dosage

KW - Single-Blind Method

KW - Treatment Outcome

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UR - http://www.scopus.com/inward/citedby.url?scp=85089498775&partnerID=8YFLogxK

U2 - 10.1016/S2213-8587(20)30228-X

DO - 10.1016/S2213-8587(20)30228-X

M3 - Article (journal)

C2 - 32822600

SN - 2213-8587

VL - 8

SP - 762

EP - 772

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

IS - 9

ER -

Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial

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