BevacizuMAV : Evaluation of the efficacy and safety of anti-angiogenic treatment with intravenous bevacizumab in patients with symptomatic cerebral arteriovenous malformations

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hopital Fondation Adolphe De Rothschild

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

24 Oct 2024 → ongoing

Decision date (initial)

2024-02-06

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Ministry of solidarity and health

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Evaluate the 6-month efficacy of IV injections of bevacizumab 5mg/kg every 14 days for 3 months (6 injections) on disabling symptoms in patients with symptomatic cerebral arteriovenous malformations ineligible for interventional therapy.

Secondary objectives 17

1. Improvement in cognitive impairment between M0 and M6 between the two arms (bevacizumab and placebo)
2. Improvement in neurological signs between M0 and M6 between the two arms (bevacizumab and placebo)
3. Improvement in epileptic symptoms between M0 and M6 between the two arms (bevacizumab and placebo)
4. Headache improvement between M0 and M6 between the two arms (bevacizumab and placebo)
5. Cerebral hemorrhage rate at 6 months between the two arms (bevacizumab and placebo)
6. Change in diameter of AVM drainage veins between M0 and M6 between the two arms (bevacizumab and placebo)
7. Evolution of peri-AVM edema between M0 and M6 between the two arms (bevacizumab and placebo)
8. Rate of favorable neurological functional prognosis at 6 months between the two arms (bevacizumab and placebo)
9. Evolution of neurological functional prognosis between M0 and M6 between the two arms (bevacizumab and placebo)
10. Change in quality of life between M0 and M6 between the two arms (bevacizumab and placebo)
11. All-cause mortality at 6 months between the two arms (bevacizumab and placebo)
12. Changes in plasma VEGF levels between M0 and M6 between the two arms (bevacizumab and placebo)
13. Description, in each arm, of the evolution up to M12: Disabling symptoms (cognitive disorders, neurological signs, epilepsy, headaches)
14. Description, in each arm, of the evolution up to M12: Neurological functional prognosis
15. Description, in each arm, of the evolution up to M12: Quality of life
16. Description, in each arm, of the evolution up to M12: Cerebral hemorrhage rate
17. Description, in each arm, of the evolution up to M12: Occurrence of adverse events

Conditions and MedDRA coding

cerebral arteriovenous malformations

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Patient over 18 years
2. With a symptomatic cerebral AVM (chronic headache, focal neurological deficit, cognitive impairment, epilepsy) of Spetzler and Martin grade III, IV or V
3. Whose symptoms are sufficiently severe to allow significant improvement with treatment: MoCA score ≤ 25 and/or ; NIHSS score ≥ 4 and/or ; Epilepsy Balance Score ≥ 2 and/or ; HIT-6 score ≥ 48
4. With functional signs and symptoms not sequellar to a previous bleeding episode AND disabling (mRS>1)
5. Ineligible for therapeutic intervention (endovascular or neurosurgery or radiosurgery)
6. With normal bone marrow, liver and kidney function
7. For women of childbearing potential: negative pregnancy test within 14 days prior to inclusion and effective contraception for up to 6 months after the end of treatment
8. Fluency in the french language
9. Having received informed consent to participate in the study
10. Affiliated or beneficiary of a social security plan

Exclusion criteria 21

1. Known allergy to bevacizumab or an excipient
2. Symptomatic peripheral vascular disease
3. Vascular disease (aortic aneurysm, aortic dissection)
4. Major surgery, open biopsy or significant traumatic lesion within 4 weeks prior to inclusion, or anticipation of need for major surgery during study period
5. Biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to inclusion
6. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of inclusion
7. Significant unhealed wound, ulcer or bone fracture
8. Thrombotic episode within 6 months prior to inclusion
9. Atrial fibrillation
10. Patient under legal protection
11. Pregnant or breast-feeding women
12. Hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanized antibodies
13. Contraindication to cerebral MRI (claustrophobia, pacemaker or other implantable device contraindicating MRI)
14. Absolute or relative contraindication to gadolinium injection (history of true allergic reaction or intolerance to gadobutrol, renal failure with creatinine clearance <15mL/min, pregnant or breast-feeding woman)
15. Proteinuria ≥ 2+ on urine dipstick (patients with proteinuria ≥2+ on urine dipstick will need to have proteinuria ≤ 1g protein on 24-hour urine to be eligible)
16. Uncontrolled hypertension (PAS >150 and/or PAD > 100 mmHg)
17. History of hypertensive crisis or hypertensive encephalopathy
18. Congestive heart failure (New York Heart Association Grade II or higher)
19. Previous myocardial infarction or unstable angina in the preceding 12 months
20. Patient with balanced blood pressure on quadritherapy
21. Patients with severe coronary artery disease or recent ACS

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Comparison between the two arms of the proportion of patients showing at least one of the following improvements at 6 months: Increase of at least 5 points in MoCA score / Reduction of at least 4 points in NIHSS score / Improvement of at least one stage in epilepsy balance score - Reduction of at least 12 points on HIT-6 headache score

Secondary endpoints 17

1. Increase of at least 5 points in MoCA score between M0 and M6
2. Reduction of at least 4 points in NIHSS score between M0 and M6
3. Reduction of at least one stage in epilepsy balance score between M0 and M6
4. Reduction of at least 12 points in HIT-6 score between M0 and M6
5. Cerebral hemorrhage diagnosed by cerebral MRI at 6 months
6. Percentage reduction in diameter of AVM drainage veins between brain MRI at M0 and M6
7. Evolution of peri-MAV edema on brain MRI between M0 and M6 according to the following categorization: improvement, stable or worsening
8. Modified Rankin score (mRS) <2 at M6
9. Change in modified Rankin score (mRS) between M0 and M6
10. Change in EQ-5D-5L score from M0 to M6
11. All-cause mortality at 6 months
12. Evolution of plasma VEGF concentration between M0 and M6
13. MoCA, HIT-6, NIHSS and epilepsy balance scores at 12 months
14. mRS score at 12 months
15. EQ-5D-5L score at 12 months
16. Rate of occurrence of cerebral haemorrhage diagnosed by cerebral MRI at 12 months
17. Rate of occurrence of adverse events at 12 months

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hopital Fondation Adolphe De Rothschild

Sponsor organisation

Hopital Fondation Adolphe De Rothschild

Address

29 Rue Manin

City

Paris

Postcode

75019

Country

France

Scientific contact point

Organisation

Hopital Fondation Adolphe De Rothschild

Contact name

Clinical Research Department

Public contact point

Organisation

Hopital Fondation Adolphe De Rothschild

Contact name

Clinical Research Department

Locations

1 EU/EEA country · 1 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 12 files

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

Application history

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