Cargando…

Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial

BACKGROUND: Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of mult...

Descripción completa

Detalles Bibliográficos
Autores principales: Baig, Shanat, Veeranna, Vishy, Bolton, Shaun, Edwards, Nicola, Tomlinson, Jeremy W., Manolopoulos, Konstantinos, Moran, John, Steeds, Richard P., Geberhiwot, Tarekegn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258144/
https://www.ncbi.nlm.nih.gov/pubmed/30477455
http://dx.doi.org/10.1186/s12902-018-0315-6
_version_ 1783374449767088128
author Baig, Shanat
Veeranna, Vishy
Bolton, Shaun
Edwards, Nicola
Tomlinson, Jeremy W.
Manolopoulos, Konstantinos
Moran, John
Steeds, Richard P.
Geberhiwot, Tarekegn
author_facet Baig, Shanat
Veeranna, Vishy
Bolton, Shaun
Edwards, Nicola
Tomlinson, Jeremy W.
Manolopoulos, Konstantinos
Moran, John
Steeds, Richard P.
Geberhiwot, Tarekegn
author_sort Baig, Shanat
collection PubMed
description BACKGROUND: Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS. METHODS: This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests. DISCUSSION: This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217, February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015–001625-16, Sept 2015). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12902-018-0315-6) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-6258144
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-62581442018-11-29 Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial Baig, Shanat Veeranna, Vishy Bolton, Shaun Edwards, Nicola Tomlinson, Jeremy W. Manolopoulos, Konstantinos Moran, John Steeds, Richard P. Geberhiwot, Tarekegn BMC Endocr Disord Study Protocol BACKGROUND: Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS. METHODS: This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests. DISCUSSION: This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217, February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015–001625-16, Sept 2015). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12902-018-0315-6) contains supplementary material, which is available to authorized users. BioMed Central 2018-11-26 /pmc/articles/PMC6258144/ /pubmed/30477455 http://dx.doi.org/10.1186/s12902-018-0315-6 Text en © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Study Protocol
Baig, Shanat
Veeranna, Vishy
Bolton, Shaun
Edwards, Nicola
Tomlinson, Jeremy W.
Manolopoulos, Konstantinos
Moran, John
Steeds, Richard P.
Geberhiwot, Tarekegn
Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial
title Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial
title_full Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial
title_fullStr Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial
title_full_unstemmed Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial
title_short Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial
title_sort treatment with pbi-4050 in patients with alström syndrome: study protocol for a phase 2, single-centre, single-arm, open-label trial
topic Study Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258144/
https://www.ncbi.nlm.nih.gov/pubmed/30477455
http://dx.doi.org/10.1186/s12902-018-0315-6
work_keys_str_mv AT baigshanat treatmentwithpbi4050inpatientswithalstromsyndromestudyprotocolforaphase2singlecentresinglearmopenlabeltrial
AT veerannavishy treatmentwithpbi4050inpatientswithalstromsyndromestudyprotocolforaphase2singlecentresinglearmopenlabeltrial
AT boltonshaun treatmentwithpbi4050inpatientswithalstromsyndromestudyprotocolforaphase2singlecentresinglearmopenlabeltrial
AT edwardsnicola treatmentwithpbi4050inpatientswithalstromsyndromestudyprotocolforaphase2singlecentresinglearmopenlabeltrial
AT tomlinsonjeremyw treatmentwithpbi4050inpatientswithalstromsyndromestudyprotocolforaphase2singlecentresinglearmopenlabeltrial
AT manolopouloskonstantinos treatmentwithpbi4050inpatientswithalstromsyndromestudyprotocolforaphase2singlecentresinglearmopenlabeltrial
AT moranjohn treatmentwithpbi4050inpatientswithalstromsyndromestudyprotocolforaphase2singlecentresinglearmopenlabeltrial
AT steedsrichardp treatmentwithpbi4050inpatientswithalstromsyndromestudyprotocolforaphase2singlecentresinglearmopenlabeltrial
AT geberhiwottarekegn treatmentwithpbi4050inpatientswithalstromsyndromestudyprotocolforaphase2singlecentresinglearmopenlabeltrial