NBP in Adult Patients With Acute Ischemic Stroke (AIS)

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Add-On to Standard Of-Care Study of n Butylphthalide (NBP) Softgel Capsules for Treatment of Mild to Moderate Acute Ischemic Stroke (AIS) in Adult Subjects

This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, add-on to standard of care study of NBP softgel capsules for the treatment of mild to moderate AIS in adults.

Study Overview

• Status: Completed
• Conditions: AIS
• Intervention / Treatment: Drug: Placebo; Drug: NBP Softgel Capsules

Detailed Description

This is a randomized, double-blind, placebo-controlled, add-on to standard-of-care study with a primary objective to assess the safety of NBP treatment in patients with mild to moderate acute ischemic stroke. The secondary objectives include determination of pharmacokinetic (PK) profile and exploratory evaluation for the efficacy of NBP treatment in stroke patients.

All randomized subjects will also receive standard supportive medical care for treatment of AIS throughout the study. The overall duration of the study will be approximately 90 days, including 30 days of treatment and an additional 60 days for follow up assessments. Subjects will be hospitalized long enough to receive the first four doses of study drug. After discharge from the hospital, subjects will continue to take study treatment daily through Day 30 and have scheduled assessments completed.

To maintain the blind, all subjects will take 4 softgel capsules BID, which will contain either 100 mg NBP or matching placebo. The first dose must be taken within 12 hours of the onset of the AIS defined as the last known normal.

• Study Type: Interventional
• Enrollment (Actual): 177
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Investigative Site
    • Los Angeles, California, United States, 90095
      • Investigative Site
  • Florida
    • Jacksonville, Florida, United States, 32209
      • Investigative Site
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Investigative Site
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Investigative Site
  • Minnesota
    • Golden Valley, Minnesota, United States, 55422
      • Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Investigative Site
  • Nebraska
    • Omaha, Nebraska, United States, 68123
      • Investigative Site
  • New York
    • Buffalo, New York, United States, 14202
      • Investigative Site
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Investigative Site
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Investigative Site
  • Oregon
    • Hillsboro, Oregon, United States, 97123
      • Investigative Site
    • Portland, Oregon, United States, 97213
      • Investigative Site
    • Portland, Oregon, United States, 97225
      • Investigative Site
    • Portland, Oregon, United States, 97239
      • Investigative Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Investigative Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Investigative Site
    • Columbia, South Carolina, United States, 29203
      • Investigative Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • Investigative Site
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Males or females aged ≥ 18 and ≤ 85 years.
2. Women of childbearing potential (WOCBP) must have a negative urine human chorionic gonadotropin (HCG) pregnancy test at Screening and be practicing a medically acceptable method of contraception with an annual failure rate of less than 1% until the completion of the trial or 60 days after discontinuation of study treatment. Women are considered not childbearing if they are > 1 year postmenopausal or surgically sterile (ie, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy tubal ligation). If serum beta human chorionic gonadotropin (bHCG) is the standard of care, then this value can be used to determine eligibility.
3. A clinical diagnosis of mild to moderate cortical or subcortical AIS.
4. Able to swallow the softgel capsules as defined by the investigator.
5. Completes screening procedures such that study treatment is first administered within 24 hours of stroke onset. The stroke onset time will be defined as the last known normal.
6. If Tissue Plasminogen Activator (tPA) is given as part of standard of care, the first dose of NBP must be administered no sooner than 4 hours after the end of the tPA infusion.
7. A standard NIHSS score of 4 to 17, inclusive. If patients receive tPA and/or endovascular treatment (EVT), the NIHSS score must be obtained after the infusion and/or procedure is completed. If sedation is used for EVT, then the NIHSS score must be obtained after sedation no longer confounds the assessment. All subjects must meet a NIHSS consciousness score of 0-1 in order to meet eligibility.
8. Functionally independent, as defined by a Modified Rankin Scale (mRS) score of 0 to 1 before their present illness as determined by the subject or provided by a representative if the subject is unable to participate at the time of study entry (determined by retrospective assessment by the Investigator).
9. Capable of understanding the purpose and risk of the study and has signed, in writing, the Informed Consent Form (ICF). If the subject is not capable of this at the time of enrollment, a legally authorized representative (LAR) will provide written informed consent in accordance with all regulations.
10. Ability to comply with study requirements.

Exclusion Criteria:

1. Female subjects who are pregnant, lactating/breast-feeding, or plan to become pregnant within the next 3 months.
2. Suspected diagnosis of stroke isolated to brainstem or brain areas other than cortical or subcortical AIS that may have caused the present symptoms, based on the opinion of the Investigator.
3. Rapidly improving or resolving symptoms, suggesting a possible transient ischemic attack (TIA) rather than a qualifying stroke.
4. Signs of acute intracranial hemorrhage or symptomatic hemorrhagic transformation of AIS defined by a 4-point worsening in NIHSS from presentation, or other cause of acute stroke symptoms (other than early ischemic findings) on cranial imaging at Screening.
5. History of intracranial hemorrhage.
6. Seizure at onset of stroke.
7. A previous clinical diagnosis of stroke within 6 months of current AIS. A previously undiagnosed stroke evidenced on screening CT or MRI may be enrolled provided it does not affect neurological and functional assessments based on the opinion of the Investigator.
8. Uncontrolled severe hypertension defined as a systolic blood pressure (SBP) ≥ 220 mm Hg or diastolic blood pressure (DBP) ≥ 110 mm Hg.
9. Treatment with intensive antihypertensive therapy within 4 hours of randomization.
10. SBP < 100 mm Hg, temperature > 38.0º C, or heart rate < 40 beats/minute or > 120 beats/minute at Screening or prior to randomization.
11. A glucose level of < 50 mg/dL at Screening.
12. An international normalized ratio (INR) ≥ 1.5 if not being treated with anticoagulant therapy, or an INR ≥ 3.5 if being treated with an acceptable anticoagulant therapy.
13. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level > 1.5 × Upper Limits of Normal (ULN), or bilirubin > 1.5 ULN (except in setting of known Gilbert's disease) at Screening.
14. Clinically significant renal dysfunction (including serum creatinine level > 2.0 mg/dL or 177 µmol/L) at Screening.
15. A hemoglobin level < 10 g/dL at Screening.
16. Current or within the last 6 months prior to Screening, New York Heart Association Class III/IV heart failure, severe uncorrected valve disease, known or suspected infective/vegetative endocarditis, ventricular tachycardia, or torsade de pointes.
17. Corrected QTcF (Fridericia) > 450 ms for male subjects or > 470 ms for female subjects (average of 3 ECG tracings) prior to randomization.
18. Current diagnosis of cancer or is being treated or has received any treatments for cancer within the last 5 years except basal cell carcinoma or curatively resected squamous cell carcinoma.
19. Known life expectancy < 6 months (for any reason).
20. Known allergy or hypersensitivity to celery or soybeans.
21. Received treatment with any other investigational drug within 30 days before Baseline, was previously treated with NBP, is currently taking celery seed extract, or is currently participating in another clinical study.
22. Known or suspected history of alcohol or drug dependence within the past 6 months, or is known to have abused alcohol (eg, been intoxicated) within the last 24 hours.
23. Known history of hepatitis B, hepatitis C, HIV, or tuberculous (TB).
24. Any other reasons that, in the opinion of the investigator, make the subject unsuitable for enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Interventions: Placebo (NBP placebo softgel capsules, 0 mg NBP, BID)	Drug: Placebo; Take 4 capsules BID on an empty stomach at least 1 hour before food intake, and remain fasting at least 1 hour after dosing; Other Names: NBP Placebo Softgel Capsules
Active Comparator: 800 mg of NBP daily; Interventions: 800 mg NBP softgel capsules daily (400 mg BID)	Drug: NBP Softgel Capsules; Take 4 capsules BID on an empty stomach at least 1 hour before food intake, and remain fasting at least 1 hour after dosing.; Other Names: NBP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence rate of treatment-emergent adverse events (TEAEs)	Safety will be evaluated through the collection of TEAEs, serious adverse events (SAEs), clinical laboratory assessments, vital sign measurements, 12-lead ECGs, and physical and neurologic examinations. Suicidality will be evaluated at each clinical visit using the Columbia-Suicide Severity Rating Scale (C-SSRS).	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK profile of NBP treatment in subjects with AIS	Peak and trough levels of NBP and metabolites	1 day
Exploratory efficacy outcome: mRS	Improvement of disability as measured by the mRS at Day 30 and Day 90	90 days
Exploratory efficacy outcome: Barthel Index (BI) Assessment	Stroke recovery as measured by the BI Assessment at Day 30 and Day 90	90 days
Exploratory efficacy outcome: NIHSS	Stroke recovery as measured by the NIHSS at Day 30 and Day 90	90 days
Exploratory efficacy outcome: Stroke Impact Scale (SIS) Assessment	SIS-16 on study Day 30 and 90	90 days

Collaborators and Investigators

• Sponsor: CSPC-NBP Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Wayne Clarke, MD, Oregon Health and Science University

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2018
• Primary Completion (Actual): August 7, 2020
• Study Completion (Actual): August 7, 2020

Study Registration Dates

• First Submitted: August 23, 2016
• First Submitted That Met QC Criteria: September 14, 2016
• First Posted (Estimate): September 19, 2016

Study Record Updates

• Last Update Posted (Actual): September 17, 2020
• Last Update Submitted That Met QC Criteria: September 16, 2020
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Safety; Efficacy; Double-Blind; Randomized; Placebo-Controlled; Multicenter; Add-On to Standard-of-Care
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: CSPC-NBP-2001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No