This study has been transitioned to CTIS with ID 2024-515186-33-00 check the CTIS register for the current data. The three key outcome measurements and challenges of this proof of concept study are to achieve a decrease in ongoing HO bone formation…
ID
Source
Brief title
Condition
- Musculoskeletal and connective tissue disorders congenital
- Musculoskeletal and connective tissue disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Objectives: To assess the effectivity and safety of treatment with
AZD0530 on HO formation.
The primary endpoint of the study is:
Incidence and severity of treatment-emergent adverse events
The objective change between the two arms in number of new heterotopic bone
lesions measured by [18F]NaF PET/low-dose whole body computer tomography (CT)
over the initial 6 month RCT;
Secondary outcome
Secondary Objectives: To assess the safety and tolerability of AZD0530 and to
further assess effectivity by functional and other radiological/nuclear imaging
endpoints.
The secondary endpoints are, summarised:
1. The incidence and severity of adverse events (AE)
2. Change in new heterotopic bone lesions over six and/or twelve months
treatment during open label expension of AZD 0530 as measured by [18F] NaF
PET/CT compared to the previous placebo arm RCT and compared to historical data
as of Clemetia
3. Change in [18F] NaF PET, an imaging biomarker, that will be performed in
addition to the whole body low-dose CT between time of enrolment and after 6
and 12 months treatment to measure the clinical efficacy of the compound
AZD0530 on magnitude and localization of the osteogenic activity;
4. Change in functional, clinical and patient-reported outcome measures
including:
a. the cumulative analogue joint involvement scale for FOP (CAJIS),
b. the quantitative detailed multi-joint assessment,
c. the 36-item Short Form Health Survey (SF-36) and
d. FOP Independent Activity of Daily Living (FOP I-ADL) will provide the effect
of the compound AZD0530 on general physical function, flare-ups (as measured by
swelling, pain and other features as reported in the International Clinical
Counsel (ICC) on FOP
(https://www.ifopa.org/international_clinical_council_on_foparticle),
5. Change and percent change from baseline in biomarkers of bone formation
levels in serum over time, including Total Procollagen Type 1 N-Terminal
Propeptide (P1NP), Alkaline Phosphatase (AP) fasting cross-linked C-terminal
telopeptide of type I colla-gen (βCTX) and selected miRNA*s.
A detailed description of the endpoints can be found in section 8 of the
protocol.
Background summary
Fibrodysplasia ossificans progressiva (FOP) is a genetic chronic and
devastating disease characterized by severe heterotopic ossifications (HO),
severe contractures and early death. There are no approved medications yet. Our
STOPFOP team (Paul Yu and Alex Bullock) identified AZD0530 (saracatinib) as a
potent, low nanomolar inhibitor of the ALK2 kinase. The goal of this phase 2A
study is to redress the activating mutations in the ALK2 kinase that cause the
orphan indication of FOP, prevalence 1 in 1.5 million people, by repurposing
the compound AZD0530 (saracatinib) as a low nanomolar ALK2 kinase inhibitor.
AZD0530 has been shown to prevent heterotopic bone formation in an authentic
genetic model of FOP. In vivo safety of AZD0530 was assessed during the
efficacy experiments in the FOP mouse model.
These data strongly support the concept that AZD0530 would be effective in
inhibiting ALK2 activity and HO in patients with FOP. If proven to be safe and
effective in clinical trials, AZD0530 would represent a rapidly translatable
therapy for FOP, having the significant advantage of extensive safety data from
over 28 registered clinical trials with AZD0530 involving approximately 608
subjects (187 healthy volunteers and 421 patients with
advanced cancer)
Study objective
This study has been transitioned to CTIS with ID 2024-515186-33-00 check the CTIS register for the current data.
The three key outcome measurements and challenges of this proof of concept
study are to achieve a decrease in ongoing HO bone formation, decrease in
numbers of disease *flare-up* episodes and to prevent the continuation of FOP
induced contractures. A successful study would lead to a larger phase 2b or
phase 3 study and potential licensing to an existing partner of new entity. The
long term future goal of the consortium is to develop safe and effective
pharmacotherapies for patients with FOP, including using such medications at
the time of surgical release of disabling contractures to prevent the
trauma/surgically induced HO recur-rence and exacerbation.
Study design
This is a phase 2a study, designed as an European multicentre 6-month double
blind random-ized controlled trial (RCT) of AZD0530 versus placebo, followed by
a 12 month trial compar-ing open-label extended AZD0530 treatment with
historical control data as from the Clementia Natural History Study. In
addition, the open label extension group that followed after the pla-cebo arm
of the RCT will be compared to the placebo arm.
Intervention
Patients will be randomized to receive either AZD0530 100mg once daily or
matched place-bo, taken orally for the first 6 months, immediately followed by
an open-label extension in which all patients will receive AZD0530 100mg (=2
tablets of 50mg) once daily oral dose for a further 12 months.
Study burden and risks
-Known and unknown side effect from medication
-Venapuncture: bruising, infection, fainting, if applied incorrectly: local
disease activity (Will therefore be performed by an experienced
anaesthesiologist)
-Radiation exposure PET/CT
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
1. Male or female aged 18-65 with a clinical diagnosis of FOP at screening,
including congenital malformation of the great toes and a history of
spontaneous or injury-induced heterotopic ossification (HO), and have a
confirmed classic-like FOP phenotype by the documentation of an ACVR1R206H/+ or
variant genomic sequence.
a. Female participants who are women of child-bearing potential will be
required to use a highly effective method of contraception as defined in
section 5.4, in combination with a condom or diaphragm or cervical/vault caps
with spermicidal foam/gel/film/suppository), from the time of enrolment until 4
weeks after final dose of study drug, unless practicing true sexual abstinence
as defined in section 5.4.
b. Male participants will be required to avoid procreative sexual intercourse
with women of child-bearing potential from time of enrollment until 4 weeks
after final dose of study drug through use of highly effective contraceptive
methods. Male participants with a pregnant female partner will be required to
use a condom for the duration of the study and for 4 weeks final dose of study
drug. Male study participants will not be permitted to donate sperm for from
the time of enrolment and until 4 weeks after final dose of study drug.
2. Participants will have to be able to understand and complete study and
willing to sign informed consent (IC). They have to be able to attend and
comply with the study visits and related activities, adhere to all
study-related restrictions, and able to undergo pro-cedures such as PET and CT
imaging.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
1. Not willing to strictly adhere to the reproductive restrictions as defined
in section 5.4
2. Women who are pregnant or breast-feeding (from the time 3 months prior to 4
weeksafter completion of participation in the study)
3. The presence of significant concomitant illness or history of significant
illness such as cardiac, respiratory, renal, rheumatologic, neurologic,
psychiatric, endocrine, metabolic, lymphatic disease, or infectious disease,
that might confound the results of the study or pose additional risk to the
patient;
4. Evidence of active bleeding (including hematuria or hematochezia,) acute or
chronic gastrointestinal illness, inflammatory bowel disease, or mucositis
5. Malignant disease / cancer requiring treatment in the past 3 years (except
some primary non melanoma skin cancer);
6. Severely impaired renal function defined as estimated glomerular filtration
rate <30 mL/min/1.73 m2 calculated by the Modification of Diet in Renal Disease
equation;
7. Showing uncontrolled diabetes mellitus with an HbA1C > 9%;
8. Significant viral illness or active infections at screening or
randomisation; Subjects should not have subacute or acute fevers of >101*F at
time of screening or randomisation
9. Evidence of prolonged QT interval at screening or randomization (defined as
QTc of >450 ms) .or known congenital long-QT syndrome.
10. Neutropenia defined as an absolute neutrophil count of <1,500/µl,
11. Thrombocytopenia defined as platelet count <100 × 103/µl,
12. Current blood clotting or bleeding disorder, or significantly abnormal
INR-prothrombin time or partial thromboplastin time at screening, or clinically
significant abnormalities in other screening laboratories, including
significant abnormalities in vitamin B12 or thyroid function tests would be
cause for exclusion.-
13. Abnormal liver function test results defined as aspartate aminotransferase
(AST) >2.0 x upper limit of normal (ULN); alanine aminotransferase (ALT) >2.0 x
ULN; and / or total bilirubin >1.5 x ULN;
14. Known allergy or intolerance to AZD0530 or any excipients used in the
investigational medicinal products.
15. Simultaneous participation in another interventional clinical study or a
non-interventional study with imaging measures or invasive procedures (eg.
collection of blood or tissue samples); Participation in the FOP Connection
Registry (www.fopconnection.org) or other studies in which patients completed
study questionnaires are possible.
16. Treatment with another investigational or drug that might interfere with HO
formation and the interpretation of the study drug in the last 90 days
17. Current use or history of regular alcohol consumption exceeding 14
units/week (6 glasses of 13.0% wine (175ml), 6 pints of 4.0% lager or ale
(568ml), 5 pints of 4.5% cider (568 ml) or 14 glasses of 10.0% spirits (25ml))
within 6 months of screening.
18. Currently active metabolic bone disease, other than FOP.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-515186-33-00 |
| EudraCT | EUCTR2019-003324-20-NL |
| CCMO | NL71401.029.19 |