Clinical trial NCT04677777: Safety Study of PP-007 in Subjects With Acute Ischemic Stroke
Official title: A Randomized, Phase 1, Contemporaneously Controlled, Multicenter Study to Assess the Safety of PP-007 in Subjects With Acute Ischemic Stroke (HEMERA-1)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Acute Ischemic Stroke
Keywords: Stroke
Thrombectomy
Intravenous Thrombolysis
NIHSS, mRS, ASPECTS
Lead sponsor: Prolong Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2020-12-21
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Contemporaneously controlled, open-label safety study
Primary purpose: TREATMENT

Brief summary: The HEMERA-1 Extension (Part III) is a prospective, open-label, multicenter study to evaluate safety of two doses of PP-007 in Acute Ischemic Stroke (AIS) subjects receiving Intravenous Thrombolysis (IVT) or mechanical thrombectomy (MT) or IVT+MT as standard of care (SOC). Subjects will receive two doses of PP-007 infusion 24 ± 6 hours apart in addition to the site-specific SOC protocol. PP-007 is PEGylated bovine carboxyhemoglobin and will be administered via IV infusion. The effects on collateral flow, infarct size and functional outcomes will be evaluated.

Detailed description: Part III of the HEMERA study evaluates safety after extended drug exposure of PP-007 in subjects with AIS. Subjects would receive two PP-007 doses administered 24±6 hours apart, in addition to the site's SOC protocol of IVT or MT or IVT+MT. PP-007 is PEGylated bovine carboxyhemoglobin and will be administered via IV infusion. The effects on collateral flow, infarct size and functional outcomes (NIHSS and mRS) will also be evaluated. Other measures include assessment of plasma concentration of PP-007.

Eligibility criteria: Inclusion Criteria:

1. Subject or subject's LAR has provided informed consent.
2. ≥18 years of age.
3. If the patient were to receive MT, patient must have a history of last seen well ≤ 24 hours prior to start of MT
4. If the patient were to receive IVT, patient must have a history of last seen well ≤ 4.5 hours prior to start of IVT or as per Institution SOC 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 (baseline) neurological function.
5. AIS patient with ASPECTS ≥ 3 to 10
6. AIS patient with life expectancy of 90 days, as determined by the investigator
7. Patient with disabling stroke defined as baseline NIHSS ≥ 6 prior to IP administration
8. mRS ≤ 2 (pre-morbid), prior to onset of symptoms (self-reported or family/caregiver reported)
9. At the time of stroke, patient must be living in their own home, apartment or seniors lodge where no nursing care/support is required
10. Subject and caregiver are available for protocol-required follow-up visits
11. Contraception and pregnancy:

    1. 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.
    2. 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:

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1. ASPECTS \< 3 on NCCT
2. Multi-arterial territorial strokes (e.g. bilateral, anterior and posterior circulation)
3. Evidence of symptomatic intracranial hemorrhage, including subarachnoid hemorrhage, on initial CTA/CTP, or history of intracranial hemorrhage within the last 30 days.
4. Pre-existing neurological or psychiatric disease that would confound neurological or functional evaluations in the opinion of the Investigator.
5. A seizure at stroke onset that precludes obtaining an accurate screening NIHSS and mRS assessment
6. Clinical history, past imaging, or clinical judgment suggests that the intracranial occlusion is chronic
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. Contraindication to radiographic imaging procedures including:

    a. Known hypersensitivity to radiographic contrast agents. b. Known renal insufficiency precluding repeated contrast administration.
13. Prior treatment (within the last 30 days) or planned concurrent treatment with an investigational medication or device.
14. Blood glucose \<50 mg/dL (2.78 mmol) or \>400 mg/dL (22.20 mmol) that is not responsive to appropriate treatment at Baseline.
15. Known bleeding disorder (e.g., coagulopathy or thrombocytopenia).

    a. Platelet count \<50,000/μL at Baseline b. 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.

    c. Any dual antiplatelet agents (e.g., aspirin plus clopidogrel) within the previous 48 hours that leads to Prothrombin Time (INR ≥ 2.0 and or aPTT ≥ 40 sec at baseline)
16. Known history or current evidence of renal or hepatic disease including:

    1. Documented renal insufficiency (serum creatinine \>3.0 × ULN).
    2. 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.

17. Mass effect or intracranial mass on NCCT defined as:

1. Significant mass effect with midline shift ≥8 mm.
2. Evidence of intracranial mass (except for small non-clinically significant meningioma based on the Investigator's discretion).

   18. Employee of Prolong Pharmaceuticals or its designated clinical research organization or an employee or relative of the Investigator.

   19. 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.

   20. Intracranial neoplasm, arteriovenous malformation, or aneurysm 21. Participation in another clinical trial investigating a drug, medical device, or a medical procedure in the 30 days preceding study inclusion Note: LVO and/or SVO will be allowed as long as the respective study subject meets the inclusion and exclusion criteria defined above.

   Inclusion/Exclusion criteria for 2nd PP-007 dose: Prior to administering the second dose of PP-007, the subject, must be evaluated for the following:

   Inclusion Criteria for 2nd dose:
   1. AIS patient with ASPECTS ≥ 3 to 10

   Exclusion Criteria for 2nd dose:
   1. Multi-arterial territorial strokes (e.g. bilateral, anterior and posterior circulation)
   2. Evidence of symptomatic intracranial hemorrhage, including subarachnoid hemorrhage, on NCCT or CTA/CTP.
   3. 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.

4. Refractory BP (systolic \>200 and/or diastolic \>120 mmHg). 5. Confirmed diagnosis of septic embolus or bacterial endocarditis. 6. Aortic dissection. 7. Blood glucose \<50 mg/dL (2.78 mmol) or \>400 mg/dL (22.20 mmol). 8. Known bleeding disorder (e.g., coagulopathy or thrombocytopenia).

a. Platelet count \<50,000/μL at Baseline b. For 2nd dose, patient fully anti-coagulated (heparinized) will be excluded (DBT prophylaxis is allowed) 9. Evidence of renal or hepatic disease including:

1. Documented renal insufficiency (serum creatinine \>3.0 × ULN).
2. Documented 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.

10. 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).

11. Intracranial neoplasm, arteriovenous malformation, or aneurysm 12. 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.

1. Parenchymal hematoma (PH-1 and PH-2)
2. Symptomatic intracranial hemorrhage
3. Hemicraniectomy
4. Midline shift ≥ 8 mm
5. Mass effect
6. Significant cerebral edema Note: LVO and/or SVO will be allowed as long as the respective study subject meets the inclusion and exclusion criteria defined above. The decision to administer the 2nd dose will be based on subject's safety and PI's discretion.

Primary outcomes:
measure: Vital Signs
timeFrame: 90 days
measure: Heart-rate
timeFrame: 90 days
measure: 12-lead ECG
timeFrame: 90 days
measure: Clinically significant change from baseline in Biochemical, hematological, coagulation and urinalysis measures
timeFrame: 90 days
measure: Cardiovascular Adverse Events (MI, myocardial injury, hypertension. hypertensive crisis, pulmonary hypertension) & Mortality
timeFrame: 90 days
measure: Symptomatic intracranial hemorrhage
timeFrame: 90 days
measure: Major Bleeding incidences
timeFrame: 90 days
measure: Adverse Events
timeFrame: 90 days
measure: Bleeding requiring surgical intervention
timeFrame: 90 days
measure: Bleeding requiring intravenous vasoactive drugs
timeFrame: 90 days
measure: Intracranial hemorrhage
timeFrame: 90 days
measure: Intraocular bleed compromising vision
timeFrame: 90 days
measure: Fatal bleeding
timeFrame: 90 days
measure: AESI, Blood pressure
timeFrame: 90 days
measure: AESI, Liver panel
timeFrame: 90 days
measure: AESI, neurological deterioration
timeFrame: 90 days
Secondary outcomes:
measure: Clinical Activity, ASITN collateral score
timeFrame: 90 days
measure: Clinical Activity
timeFrame: 90 days
measure: Clinical Activity, NIHSS and mRS
timeFrame: 90 days
measure: Plasma Concentration of PP007
timeFrame: 24 hours
measure: Clinical Activity, eTICI
timeFrame: 90 days
measure: Clinical Activity, infarct growth
timeFrame: 90 days
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Baptist Health Research Institute
state: Florida
city: Miami
country: United States
facility: Baptist Health Miami Cardiac & Vascular Institute (MCVI)
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Kansas City
country: United States
facility: Saint Luke's Hospital
state: Missouri
city: Toledo
country: United States
facility: Mercy Health - St. Vincent Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Stroke Center at Oregon Health & Science University (OHSU)
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC Stroke Institute
state: Pennsylvania
Study officials:
affiliation: Prolong Pharmaceuticals, LLC
name: Kirsten Gruis, MD
role: STUDY_DIRECTOR
References: