A clinical trial to judge the safety, tolerability and effects on abnormal bone formation of reseach medication AZD 0530 (sarcatinib) in patients with FOP

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stichting Amsterdam UMC

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

8 Jan 2020 → ongoing

Decision date (initial)

2025-01-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Innovative Medicines Initiative EU · AstraZeneca

External identifiers

EU CT number

2024-515186-33-00

EudraCT number

2019-003324-20

ClinicalTrials.gov

NCT04307953

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Others, Pharmacodynamic, Therapy, Safety

To assess the effectivity of treatment with AZD0530 on HO formation

Secondary objectives 1

1. To assess the safety and tolerability of AZD0530 and to further assess effectivity by functional and other radiological/nuclear imaging endpoints

Conditions and MedDRA coding

Fibrodyplasia Ossificans Progressiva (FOP)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

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. 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. 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 18

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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary Safety: Incidence and severity of treatment- emergent adverse events through the end of the Treatment Period 1 at week 26 (RCT). Primary Efficacy: Number of new lesions in the RCT defined as: Number of individual new active HO lesions assessed by [18F]-NaF PET at week 26 in placebo vs. drug arms of the RCT; and number of individual new HO lesions detected by CT at week 26 in placebo vs. drug arms of the RCT

Secondary endpoints 9

1. 1. The incidence and severity of adverse events (AE) a. During the 6-month RCT b. During 6-month open label extension of AZD0530
2. 2. Number of new lesions after one year of cross-over therapy, defined as: Number of individual new active HO lesions assessed by [18F]-NaF PET between the placebo arm at week 26 and the subsequent open-label phase at week 52 among pa-tients receiving placebo during the RCT; Number of individual new HO lesions detected by CT be-tween the placebo arm at week 26 and the subsequent open-label arm at week 52 among patients receiving placebo during the RCT
3. 3. Difference in [18F] NaF PET activity of individual active lesion(s) by PET at week 26 between the placebo and drug arms of the RCT, or between the placebo arm at week 26 and its subsequent open label arm at week 52 among cross-over patients.
4. 4. Difference in volume of individual active lesions as assessed by [18F] NaF PET at week 26 between the placebo and drug arm of the RCT, or between the placebo arm at week 26 and its subsequent open label arm at week 52 among cross-over patients.
5. 5. Change in volume of individual HO lesions as assessed by by CT at week 26 between the placebo and drug arm of the RCT, or between the placebo arm at week 26 and its subsequent open label arm at week 52 among cross-over patients.
6. 6. Change in functional mobility outcomes from baseline to week 26 between the place-bo versus drug arm of the RCT, or change between baseline and week 26 in the pla-cebo arm versus the change between week 26 and week 52 among cross-over pa-tients initially treated with placebo in the RCT, as assessed by:
7. 6. (Continued) a. Change in the cumulative analogue joint involvement scale for FOP (CAJIS); b. Change in the quantitative detailed multi-joint assessment by goniometry, c. Change in interincisal distance (mouth opening, mm.) d. Change in forced vital capacity (FVC) as percent of predicted based on age, sex, and body mass index.
8. 7. Change in functional mobility outcomes at week 52, 104, and week 156 of drug treat-ment compared to baseline measurements, in reference to Ipsen natural history data (NCT02322255) and/or other history data on rate of progression of these measure-ments in an untreated FOP population where available.
9. 7. (Continued) a. Change in the cumulative analogue joint involvement scale for FOP (CAJIS); b. Change in the quantitative detailed multi-joint assessment by goniometry; c. Change in interincisal distance (mouth opening, mm.); d. Change in forced vital capacity (FVC) as percent of predicted based on age, sex, and body mass index.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stichting Amsterdam UMC

Sponsor organisation

Stichting Amsterdam UMC

Address

De Boelelaan 1117

City

Amsterdam

Postcode

1081 HV

Country

Netherlands

Scientific contact point

Organisation

Stichting Amsterdam UMC

Contact name

E.M.W. Eekhoff

Public contact point

Organisation

Stichting Amsterdam UMC

Contact name

E.M.W. Eekhoff

Third parties 1

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications