Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP)

Bernard J Smilde; Clemens Stockklausner; Richard Keen; Andrew Whittaker; Alex N Bullock; Annette von Delft; Natasja M van Schoor; Paul B Yu; E Marelise W Eekhoff

doi:10.1186/s12891-022-05471-x

Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP)

Bernard J Smilde
, Clemens Stockklausner
, Richard Keen
, Andrew Whittaker
, Alex N Bullock
, Annette von Delft
, Natasja M van Schoor
, Paul B Yu
, E Marelise W Eekhoff

Department of Paediatrics
Royal National Orthopaedic Hospital
Emerging Innovations Unit
Medical Research Council Molecular Haematology Unit, Oxford Centre for Haematology, University of Oxford and Oxford University Hospitals National Health Service Trust, Oxford, United Kingdom.
Cardiovascular Research Center

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

51 Downloads (Pure)

Abstract

BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP.

METHODS: The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include 18F NaF PET activity and patient reported outcome measures.

DISCUSSION: Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients.

TRIAL REGISTRATION: EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL .

CLINICALTRIALS: gov , NCT04307953 . Registered 13 March 2020.

Original language	English
Article number	519
Pages (from-to)	519
Journal	BMC musculoskeletal disorders
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s12891-022-05471-x
Publication status	Published - Dec 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

AZD0530
Clinical trial
Drug repositioning
Drug repurposing
Fibrodysplasia Ossificans Progressiva
Saracatinib

Access to Document

10.1186/s12891-022-05471-x

Smilde-2022-Protocol paper-a multi-center double-blindedFinal published version, 1.54 MBLicence: CC BY
Protocol-paper.pdfFinal published version, 1.54 MBLicence: CC BY

Fingerprint

Dive into the research topics of 'Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP)'. Together they form a unique fingerprint.

Cite this

Smilde, B. J., Stockklausner, C., Keen, R., Whittaker, A., Bullock, A. N., von Delft, A., van Schoor, N. M., Yu, P. B., & Eekhoff, E. M. W. (2022). Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP). BMC musculoskeletal disorders, 23(1), 519. Article 519. https://doi.org/10.1186/s12891-022-05471-x

Smilde, Bernard J ; Stockklausner, Clemens ; Keen, Richard et al. / Protocol paper : a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP). In: BMC musculoskeletal disorders. 2022 ; Vol. 23, No. 1. pp. 519.

@article{df2b26f9ff7648218515cb882540cc92,

title = "Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP)",

abstract = "BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP.METHODS: The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include 18F NaF PET activity and patient reported outcome measures.DISCUSSION: Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients.TRIAL REGISTRATION: EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL .CLINICALTRIALS: gov , NCT04307953 . Registered 13 March 2020.",

keywords = "AZD0530, Clinical trial, Drug repositioning, Drug repurposing, Fibrodysplasia Ossificans Progressiva, Saracatinib",

author = "Smilde, \{Bernard J\} and Clemens Stockklausner and Richard Keen and Andrew Whittaker and Bullock, \{Alex N\} and \{von Delft\}, Annette and \{van Schoor\}, \{Natasja M\} and Yu, \{Paul B\} and Eekhoff, \{E Marelise W\}",

note = "Funding Information: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821600. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s12891-022-05471-x",

language = "English",

volume = "23",

pages = "519",

journal = "BMC musculoskeletal disorders",

publisher = "BioMed Central Ltd.",

number = "1",

}

Smilde, BJ, Stockklausner, C, Keen, R, Whittaker, A, Bullock, AN, von Delft, A, van Schoor, NM, Yu, PB & Eekhoff, EMW 2022, 'Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP)', BMC musculoskeletal disorders, vol. 23, no. 1, 519, pp. 519. https://doi.org/10.1186/s12891-022-05471-x

Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP). / Smilde, Bernard J; Stockklausner, Clemens; Keen, Richard et al.
In: BMC musculoskeletal disorders, Vol. 23, No. 1, 519, 12.2022, p. 519.

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

TY - JOUR

T1 - Protocol paper

T2 - a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP)

AU - Smilde, Bernard J

AU - Stockklausner, Clemens

AU - Keen, Richard

AU - Whittaker, Andrew

AU - Bullock, Alex N

AU - von Delft, Annette

AU - van Schoor, Natasja M

AU - Yu, Paul B

AU - Eekhoff, E Marelise W

N1 - Funding Information: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821600. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP.METHODS: The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include 18F NaF PET activity and patient reported outcome measures.DISCUSSION: Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients.TRIAL REGISTRATION: EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL .CLINICALTRIALS: gov , NCT04307953 . Registered 13 March 2020.

AB - BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP.METHODS: The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include 18F NaF PET activity and patient reported outcome measures.DISCUSSION: Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients.TRIAL REGISTRATION: EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL .CLINICALTRIALS: gov , NCT04307953 . Registered 13 March 2020.

KW - AZD0530

KW - Clinical trial

KW - Drug repositioning

KW - Drug repurposing

KW - Fibrodysplasia Ossificans Progressiva

KW - Saracatinib

UR - https://www.scopus.com/pages/publications/85131041686

U2 - 10.1186/s12891-022-05471-x

DO - 10.1186/s12891-022-05471-x

M3 - Article

VL - 23

SP - 519

JO - BMC musculoskeletal disorders

JF - BMC musculoskeletal disorders

IS - 1

M1 - 519

ER -

Smilde BJ, Stockklausner C, Keen R, Whittaker A, Bullock AN, von Delft A et al. Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP). BMC musculoskeletal disorders. 2022 Dec;23(1):519. 519. doi: 10.1186/s12891-022-05471-x

Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP)

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this