Efficacy, Safety and Tolerability of BAF312 Compared to Placebo in Patients With Intracerebral Hemorrhage (ICH).

• ClinicalTrials.gov Identifier: NCT03338998
• Recruitment Status: Completed
• First Posted: November 9, 2017
• Results First Posted: June 7, 2021
• Last Update Posted: August 12, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This is a randomized, placebo-controlled, subject and investigator-blinded study to evaluate efficacy, safety and tolerability of BAF312 in participants with intracerebral hemorrhage (ICH)

Condition or disease	Intervention/treatment	Phase
Hemorrhagic Stroke; Intracerebral Hemorrhage (ICH)	Drug: BAF312 solution; Drug: Matching Placebo for BAF312 solution; Drug: BAF312 tablet; Drug: Matching Placebo for BAF312 tablet	Phase 2

Detailed Description:

This was the first trial of BAF312 in ICH patients to evaluate if BAF312 had the potential to limit brain inflammation after ICH, and thereby improve neurological outcome for stroke patients when administered in addition to standard of care.

ICH patients meeting study criteria were randomized at 1:1 ratio into either active or placebo group. Patients received an intravenous infusion (i.v.) treatment within 24 hours of an ICH event and were up titrated for 7 days. Following the i.v. treatment, participants received 10 mg BAF312 or placebo in tablet form (taken daily orally) for an additional 7 days. Participants were followed for an additional 76 days after treatment for neurological and safety conditions during three clinic visits.

Recruitment for the trial was put on hold due to the COVID-19 pandemic. Thirty-two patients had been enrolled in the trial and completed the protocol as planned. After seven months of the trial being on hold, an Interim analysis was conducted and reviewed by the Data Monitoring Committee. Novartis terminated the trial due to lack of potential efficacy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This is a randomized, patient- and investigator-blinded, placebo-controlled, parallel group study of BAF312 on top of standard-of-care for ICH, consisting of 3 epochs: Screening/Baseline, Treatment (Day 1-14), and Follow-Up (to Day 90)
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Patient- and Investigator-blinded, Randomized, Placebo-controlled Study to Evaluate Efficacy, Safety and Tolerability of BAF312 (Siponimod) in Patients With Stroke Due to Intracerebral Hemorrhage (ICH)
• Actual Study Start Date: December 24, 2017
• Actual Primary Completion Date: May 13, 2020
• Actual Study Completion Date: May 13, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: BAF312; Days 1 - 7, IV up titration; days 8 - 14, 10 mg (5 x 2 mg tablets) taken daily orally	Drug: BAF312 solution; Solution for intravenous (IV) infusion - 4.5mg/4.5mL; Other Name: Siponimod; Drug: BAF312 tablet; 2 mg film-coated tablet; Other Name: Siponimod
Placebo Comparator: Placebo; Days 1 - 7, IV up titration; days 8 - 14, 10 mg (5 x 2 mg tablets) taken daily orally - matching placebo	Drug: Matching Placebo for BAF312 solution; Solution for intravenous (IV) infusion - 0mg/4.5mL matching placebo; Drug: Matching Placebo for BAF312 tablet; 0 mg film-coated tablet matching placebo

Outcome Measures

Primary Outcome Measures :

1. Absolute Perihematoma Edema (aPHE) Volume Measured by Computed Tomography (CT) Scan After Intracerebral Hemorrhage (ICH) [ Time Frame: On Day 14 following ICH ]
   Following the initial diagnostic CT, repeat CT images were obtained between 24-48 h after the diagnostic scan, and on Day 7 and Day 14 to capture the trajectory of PHE increase and plateau after ICH. Only non-contrast study CT scans were obtained on Day 7 and Day 14. The non-contrast scan acquired on each patient at first follow-up (i.e. 24-48 h after the diagnostic scan) served as the baseline for our analysis. All CT scans were uploaded through a secure server, and edema and hematoma volumes were measured in a semi-automated manner by one Central Reader.

Secondary Outcome Measures :

1. Plasma BAF312 Concentrations [ Time Frame: Days 1, 8, and 14 ]
   Blood samples will be collected to assess plasma concentrations.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

ICH patients eligible for inclusion in this study must fulfill all of the following criteria:

1. Male or female patients aged 18 to 85 years (inclusive).
2. Written informed consent obtained before any study assessment is performed. If the patient is not able to give the informed consent personally, consent by a relative or legal representative is acceptable.
3. Spontaneous, supratentorial intracerebral hemorrhage in cerebral cortex or deep brain structures (putamen, thalamus, caudate, and associated deep white matter tracts) with a volume ≥ 10 mL but ≤ 60 mL (calculated by the ABC/2 method, after Kothari et al 1996) determined by routine clinical MRI or CT.
4. Patients with the onset of ICH witnessed and/or last seen healthy no longer than 24 hrs previously.
5. Patients with Glasgow Coma Scale (GCS) best motor score no less than 5 (brings hands above clavicle on stimulus to head or neck).

Exclusion Criteria:

ICH patients fulfilling any of the following criteria are not eligible for inclusion in this study:

1. Use of other investigational drugs within 5 half-lives of enrollment, or until the expected pharmacodynamic effect has returned to baseline (for biologics), whichever is longer.
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes (e.g., fingolimod).
3. Current use of concomitant medications with potent CYP2C9/3A4 inhibitory or induction potential.
4. Infratentorial (midbrain, pons, medulla, or cerebellum) ICH.
5. Candidates for surgical hematoma evacuation or other urgent surgical intervention (i.e., surgical relief of increased intracranial pressure) on initial presentation. If during the treatment period surgical hematoma evacuation or surgical intervention to lower intracranial pressure becomes indicated, the investigational treatment should be stopped.
6. Patients with intraventricular hemorrhage (IVH) having a Graeb score of >3 on initial presentation. Patients must not have blood in the 4th ventricle and may only have blood in the 3rd ventricle in the absence of ventricular expansion. Trace or mild hemorrhage in either or both lateral ventricles is permitted. Patients with hydrocephalus determined radiologically on initial presentation are excluded regardless of Graeb score.

7. Secondary ICH due to:

   • aneurysm
   • brain tumor
   • arteriovenous malformation
   • thrombocytopenia, defined as platelet count of <150,000/µl
   • known history of coagulopathy
   • acute sepsis
   • traumatic brain injury (TBI)
   • disseminated intravascular coagulation (DIC)
8. Prior disability due to other disease compromising mRS evaluation, thereby interfering with the primary outcome, operationally defined as an estimated mRS score (by history) of ≥ 3 before ICH for patients less than or equal to 80 years of age. For ICH patients 81-85 years of age, estimated mRS by history prior to ICH must be less than or equal to 1 (no significant disability despite symptoms).
9. Preexisting unstable epilepsy.
10. Patients with active systemic bacterial, viral or fungal infections.

11. Concomitant drug-related exclusion criteria:

    • Intravenous immunoglobulin, immunosuppressive and/or chemotherapeutic medications.
    • Moderate immunosuppressives (e.g. azathioprine, methotrexate) and/or fingolimod within 2 months prior to randomization.
    • Stronger immunosuppressives (e.g. cyclophosphamide, immunosuppressive mAb) within (minimally) 6 months prior to randomization, or longer with long-lasting immunosuppressive medications as determined by the investigator.

12. Cardiovascular exclusion criteria:

    • Cardiac conduction or rhythm disorders including sinus arrest or sino-atrial block, heart rate <50 bpm, sick-sinus syndrome, Mobitz Type II second degree AV block or higher grade AV block, or preexisting atrial fibrillation (either by history or observed at screening).
    • PR interval >220 msec. Long QT syndrome or QTcF prolongation >450 msec in males or >470 msec in females on screening electrocardiogram (ECG).
    • Patients receiving treatment with QT-prolonging drugs having a long half-life (e.g., amiodarone).

13. Any of the following abnormal laboratory values prior to randomization:

    • White blood cell (WBC) count < 2,000/μl (< 2.0 x 109/L)
    • Lymphocyte count < 800/μl (< 0.8 x 109/L)
14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
15. Patients with any other medically unstable condition or serious laboratory abnormality as determined by the investigator.

Contacts and Locations

Locations

United States, California

Novartis Investigative Site

Palo Alto, California, United States, 94304

United States, Connecticut

Novartis Investigative Site

New Haven, Connecticut, United States, 06520

United States, Georgia

Novartis Investigative Site

Atlanta, Georgia, United States, 30303

United States, Maryland

Novartis Investigative Site

Baltimore, Maryland, United States, 21201

United States, Michigan

Novartis Investigative Site

Detroit, Michigan, United States, 48202

United States, Ohio

Novartis Investigative Site

Cincinnati, Ohio, United States, 45219

United States, Oregon

Novartis Investigative Site

Portland, Oregon, United States, 97239

United States, Pennsylvania

Novartis Investigative Site

Philadelphia, Pennsylvania, United States, 19104-4283

United States, Texas

Novartis Investigative Site

Houston, Texas, United States, 77024

Novartis Investigative Site

Houston, Texas, United States, 77030-3900

United States, Virginia

Novartis Investigative Site

Charlottesville, Virginia, United States, 22908

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Principal Investigator: Kevin N. Sheth, MD; Yale University

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] March 25, 2019

Statistical Analysis Plan  [PDF] March 29, 2021

More Information

Additional Information:

A Plain Language Trial Summary is available on novctrd.com 

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03338998
• Other Study ID Numbers: CBAF312X2207
• First Posted: November 9, 2017
• Results First Posted: June 7, 2021
• Last Update Posted: August 12, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• URL: https://www.clinicalstudydatarequest.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

stroke; intracerebral hemorrhage; ICH; BAF312; siponimod; sphingosine-1-phosphate receptor; adult

Additional relevant MeSH terms:

Stroke; Cerebral Hemorrhage; Hemorrhagic Stroke; Hemorrhage; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Intracranial Hemorrhages; Pharmaceutical Solutions; Siponimod; Sphingosine 1 Phosphate Receptor Modulators; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs