Safety Study of PP-007 in Subjects With Acute Ischemic Stroke

Study Overview
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Brief Summary
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The study will evaluate the safety of a single administration of PP-007 in patients admitted to a hospital for Acute Ischemic Stroke. PP-007 is pegylated bovine carboxyhemoglobin and will be administered via IV infusion. The effects on collateral flow, infarct size and functional outcome will also be evaluated. Patients will be randomized to either standard of care excluding tPA, or PP-007. Patients may also receive thrombectomy.

Detailed Description
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The study will evaluate the safety of a single administration of PP-007 in patients admitted to a hospital for Acute Ischemic Stroke. PP-007 is pegylated bovine carboxyhemoglobin and will be administered via IV infusion. The effects on collateral flow, infarct size and functional outcome will also be evaluated. Patients will be randomized to either standard of care excluding tPA, or PP-007. Patients may also receive thrombectomy. Other measures include assessment of plasma concentration of PP-007.

Official Title
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A Randomized, Phase 1, Contemporaneously Controlled, Multicenter Study to Assess the Safety of PP-007 in Subjects With Acute Ischemic Stroke

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Biological: PP-007
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Subject or subject's LAR has provided informed consent. 2. ≥18 years of age. 3. AIS diagnosis including: CTA with evidence of anterior circulation large artery occlusion (i.e., ICA terminus, M1, M2, A1, A2). Large volumes of absolute hypo-perfused mismatch tissue (Tmax >10 s lesion - rCBF<30% lesion) >50 mL and core volumes ≤70 mL on CT Perfusion (CTP) and/or ASPECT score 5. Thrombolysis in Cerebral Infarction 0-1 flow in the intracranial internal carotid artery, M1 or M1-M2 segment of the middle cerebral artery, or carotid terminus confirmed by CTA and CTP that is accessible to thrombectomy. Last seen well ≤24 hours prior to start of investigational product (IP) infusion. Note: Onset is defined as the time point when symptoms first began, or if unknown, the last time point when the subject reported or was observed having normal neurological function. 4. Modified Rankin Score ≤2, prior to the onset of symptoms (self-reported or family/caregiver reported). 5. Subject has an anticipated life expectancy of at least three months, in the opinion of the Investigator. 6. Subject and caregiver are available for protocol required follow-up visits. 7. Contraception and pregnancy: Male subjects, and females of childbearing potential (subjects and female partners of male subjects who are ovulating, premenopausal, and not surgically sterile) must use a highly effective method of contraception consistently and correctly during study participation and up to 90 days following PP-007 infusion. Highly effective methods of contraception are those that, either alone or in combination, result in a failure rate of <1% per year when used consistently and correctly, including: i. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (i.e., oral, intravaginal, or transdermal). ii. Progesterone-only hormonal contraception associated with inhibition of ovulation (i.e., oral, injectable, or implantable). iii. Intrauterine device, intrauterine hormone-releasing system, or bilateral tubal occlusion. iv. Male sterilization performed more than six months prior to Screening. v. Sexual abstinence. c. Female subjects of non-childbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before Screening) or postmenopausal, defined as spontaneous amenorrhea for at least 12 months. d. Male subjects must abstain from sperm donation during study participation and up to 90 days following PP-007 infusion. e. Female subjects of childbearing potential must have negative results for the pregnancy test at Screening/Baseline. Exclusion Criteria: 1. ASPECTS < 5 on NCCT. 2. Bilateral middle cerebral artery stroke. 3. Evidence of intracranial hemorrhage, including subarachnoid hemorrhage, on initial CTA/CTP, or history of intracranial hemorrhage within the last 30 days. 4. Subjects who have received or are scheduled to receive tPA use for current stroke. 5. Pre-existing neurological or psychiatric disease that would confound neurological or functional evaluations in the opinion of the Investigator. 6. A seizure at stroke onset that precludes obtaining at accurate Screening NIHSS and mRS assessment. 7. History of severe head injury within 90 days of Baseline with residual neurological deficit at the time of AIS. 8. Clinically significant heart disease including: a. Symptoms or ECG evidence of acute myocardial infarction or unstable angina. b. Cardiac arrhythmia associated with hemodynamic instability. c. Heart failure (New York Heart Association Class III or IV) or known ejection fraction <30%. d. ECG with second- or third-degree heart block in the absence of a permanent pacemaker. 9. Refractory BP (systolic >200 and/or diastolic >120 mmHg). 10. Confirmed diagnosis of septic embolus or bacterial endocarditis within the past six months. 11. Aortic dissection. 12. Known history of arterial tortuosity, pre-existing stent, and/or other arterial disease which would prevent the device from reaching the target vessel and/or preclude safe recovery of a device. 13. Contraindication to radiographic imaging procedures including: Known hypersensitivity to radiographic contrast agents. Known renal insufficiency precluding repeated contrast administration. 14. Prior treatment (within the last 30 days) or planned concurrent treatment with an investigational medication or device. 15. Blood glucose <50 mg/dL (2.78 mmol) or >400 mg/dL (22.20 mmol) that is not responsive to appropriate treatment at Baseline. 16. Known bleeding disorder (e.g., coagulopathy or thrombocytopenia). a. Platelet count <50,000/μL at Baseline. b. Prothrombin Time (International Normalization Ratio [INR]) ≥2 and/or activated partial tromboplastin time (aPTT) ≥40 seconds at Baseline. c.Any anticoagulants within the previous 48 hours that leads to Prothrombin Time (International Normalization Ratio [INR]) ≥2.0 and/or activated partial thromboplastin time (aPTT) ≥40 sec at baseline. d. Any dual antiplatelet agents (e.g., aspirin plus clopidogrel) within the previous 48 hours. 17. History or current evidence of renal or hepatic disease including: Documented renal insufficiency (serum creatinine >3.0 × ULN). History of liver disease (i.e., alanine transaminase [ALT] and/or Aspartate transaminase (AST) >2 × ULN and/or conjugated bilirubin >1.5 mg/dL). Note: A subject without history or current evidence of renal or hepatic disease does not require creatinine, ALT, AST, or bilirubin results to be available prior to enrollment. 18. Mass effect or intracranial mass on NCCT defined as: a. Significant mass effect with midline shift ≥8 mm. b. Evidence of intracranial mass (except for small non-clinically significant meningioma based on the Investigator's discretion). 19. Employee of Prolong Pharmaceuticals or its designated clinical research organization or an employee or relative of the Investigator. 20. Any condition or situation which may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study in the opinion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Contemporaneously controlled, blinded safety study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard of Care<br>Patients randomized to receive this treatment will receive standard of care appropriate for the condition. | Other: Standard of care<br>* Patients randomized to this treatment will not receive the experimental treatment, but will receive the standard of care at the institution.<br>|
| Experimental: PP-007<br>Patients randomized to receive this treatment will receive a single infusion of PP-007 | Biological: PP-007<br>* PP-007 is pegylated carboxyhemoglobin<br>* Other names: Sanguinate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital Signs | Change from baseline in systolic and diastolic blood pressure in mm Hg | 90 days | 
| Heart-rate | Change from baseline in heart-rate in bpm | 90 days | 
| 12-lead ECG | Change from baseline in msec for QT, QTc, RR and PR intervals | 90 days | 
| Clinically significant change from baseline in Biochemical, hematological, coagulation and urinalysis measures | Number of subjects with clinically significant change from baseline in Biochemical, hematological, coagulation and urinalysis measures | 90 days | 
| Mortality | Number of mortalities | 90 days | 
| Symptomatic intracranial hemorrhage | Incidence of symptomatic intracranial hemorrhage, number of occurrences | 90 days | 
| Major Bleeding incidence | Number of occurrences | 90 days | 
| Adverse Events | Presence or absence | 90 days | 
| Bleeding requiring surgical intervention | Number of occurrences | 90 days | 
| Bleeding requiring intravenous vasoactive drugs | Number of occurrences | 90 days | 
| Intracranial hemorrhage | Number of occurrences | 90 days | 
| Intraocular bleed compromising vision | Number of occurrences | 90 days | 
| Fatal bleeding | Number of occurrences | 90 days | 
| AESI, Blood pressure | Number of events of systolic blood pressure [SBP] >220 mmHg or diastolic blood pressure [DBP] >120 mmHg | 90 days | 
| AESI, Liver panel | Number of events of Liver enzymes elevation >3.0 × Baseline or upper limit of normal [ULN] | 90 days | 
| AESI, neurological deterioration | Number of occurrences of Neurological deterioration (≥4-point increase from Baseline in National Institutes of Health Stroke Scale. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Activity, ASITN collateral score | American Society of Interventional and Therapeutic Neuroradiology collateral score (CT Change from baseline in angiography [CTA] Score 0-4 pre- and post-dose | 90 days | 
| Clinical Activity | Non-contrast computed tomography (NCCT 24 hours) | 90 days | 
| Clinical Activity, NIHSS and mRS | Change from baseline in NIHSS and mRS score | 90 days | 
| Plasma Concentration of PP007 | Plasma PP007 concentration in mg/mL at end of infusion and 24 h post infusion | 24 hours | 
| Clinical Activity, eTICI | Change from baseline in Expanded treatment in cerebral infarction (eTICI) score 2b or 3 post-thrombectomy change | 90 days | 
| Clinical Activity, infarct growth | Predicted infarct growth for CT/CTP and collateral score | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, Thrombectomy