- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02687191
Safety and Tolerability of PF-05230907 in Intracerebral Hemorrhage
A PHASE 1B MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND TOLERABILITY AND DETERMINE THE MAXIMUM TOLERATED DOSE OF PF-05230907 IN SUBJECTS WITH INTRACEREBRAL HEMORRHAGE (ICH)
This study employs a modified continual reassessment method (mCRM) design to estimate the maximum tolerated dose (MTD) of PF-05230907, defined as a target toxicity rate of 15% based on treatment emergent thromboembolic and/or ischemic events (TIEs). The mCRM design utilizes Bayesian methodology to continuously learn the dose-toxicity relationship, which is characterized by a parametric model.
Subjects with a diagnosis of ICH (determined by computed tomography) will be enrolled in cohorts of 3. The total length of time planned for study participation is approximately 3 months; 6.0 hours for screening, a single dose administration with a 4-day minimum hospital confinement period and follow-up visits through Day 91.
Severity of adverse events (AEs) and serious adverse events (SAEs) will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All subjects who receive PF-05230907 are evaluable for TIEs. The determination of MTD using mCRM modeling will be based on TIEs which occur through 7 days post-dose (Day 8).
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Ontario
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Ottawa, Ontario, Canada, K1Y4E9
- The Ottawa Hospital
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Quebec
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Montreal, Quebec, Canada, H3A2B4
- Montreal Neurological Institute and Hospital
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Barcelona, Spain, 08035
- Hospital Vall d'Hebron, Unidad de Ictus
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Girona, Spain, 17007
- Hospital Universitari Dr. Josep Trueta IDIBGI, Department Neurology
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Madrid, Spain, 28034
- Hospital Universitario Ramon Y Cajal
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Barcelona
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Badalona, Barcelona, Spain, 08916
- Hospital Universitari Germans Trias i Pujol
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LA Coruna
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Santiago de Compostela, LA Coruna, Spain, 15706
- Hospital Clínico Universitario de Santiago de Compostela, Area Neurovascular-Neurologia
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London, United Kingdom, NW1 2BU
- University College Hospital
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Missouri
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Saint Louis, Missouri, United States, 63110
- Barnes Jewish Hospital
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Saint Louis, Missouri, United States, 63110
- Washington University,
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Ohio
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Columbus, Ohio, United States, 43210
- The Ohio State University Wexner Medical Center
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Columbus, Ohio, United States, 43210
- James Cancer Hospital and Solove Research Institute
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Columbus, Ohio, United States, 43221
- Martha Morehouse Medical Plaza
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- ICH as documented by CT scan within 6.0 hours of symptom onset
- Baseline ICH volume > 5mL and < 60 mL
Exclusion Criteria:
- Deep coma (Glasgow Coma Scale < 6)
- Modified Rankin Score > 3 prior to ICH onset
- Known history of schemic, vaso-occlusive or thrombotic events within 6 months prior to screening
- Known prothrombotic disorders
- Known secondary ICH related to aneurysm, arteriovenous malformation, subarachnoid hemorrhage, trauma, or other causes. CT angiography, MR, or other diagnostic studies obtained as part of the standard of care may be used to assess eligibility.
- Known use of oral anticoagulant(s)
- Known use of low-molecular weight heparin or heparin
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: PF-05230907 (Cohort 1)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 2)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 3)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 4)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 5)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 6)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 7)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 8)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 9)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 10)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 11)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 12)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 13)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 14)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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Experimental: PF-05230907 (Cohort 15)
PF-05230907 IV bolus injection
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PF-05230907 IV bolus injection
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Treatment-Emergent Thromboembolic and/or Ischemic Events (TIEs)
Time Frame: Day 1 through day of discharge (Day 8)
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Thromboembolic and/or ischemic events (TIEs) were defined as any of the following events: disseminated intravascular coagulation (Grade [Gr]>=3); acute coronary syndrome (Gr >=3); cardiac arrest (Gr >=4); myocardial infarction (Gr >=3); Cardiac troponin I increased (Gr 3); ischemia cerebrovascular (Gr >=1 and associated with lesion[s]); portal vein thrombosis (Gr >=2); ischemic stroke (Gr >=1 and associated with lesion[s]); transient ischemic attacks (Gr 2); purpura (Gr >=2); superior vena cava syndrome (Gr >=1); thromboembolic event (Gr >=2); visceral arterial ischemia (Gr >=2); peripheral arterial ischemia (Gr >=3).
TIEs were graded based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
For the respective event to count as a treatment-emergent TIE, onset or worsening of the event must have occurred following treatment with PF-05230907 and during the interval between Day 1 dosing through Day 8.
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Day 1 through day of discharge (Day 8)
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Number of Participants With Treatment-Emergent Serious Adverse Events (SAEs)
Time Frame: Day 1 through follow-up visit (Day 43)
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A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; or was life threatening (immediate risk of death); or required inpatient hospitalization or prolongation of existing hospitalization; or resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); or resulted in congenital anomaly/birth defect.
Any such events occurring following the start of treatment or increasing in severity were counted as treatment-emergent.
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Day 1 through follow-up visit (Day 43)
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Number of Participants With Treatment-Emergent Adverse Events (AEs)
Time Frame: Day 1 through day of discharge (Day 8)
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An adverse event (AE) was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship.
For the respective event to count as a treatment-emergent AE, onset or worsening of the event must have occurred following treatment with PF-05230907 and during the interval between Day 1 dosing through Day 8.
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Day 1 through day of discharge (Day 8)
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Number of Participants With Treatment-Emergent Laboratory Abnormalities
Time Frame: Day 1 through Day 8 (or discharge) for D-dimer laboratory test and urinalysis; Day 1 through Day 4 for all other laboratory tests
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Laboratory safety parameters included hematology, blood chemistry, prothrombin time/international normalized ratio (PT/INR), fibrinogen, antithrombin III (ATIII), Protein S level, Protein C activity, cardiac troponin I, D-dimer, and urinalysis.
The number of participants with laboratory test abnormalities meeting specified criteria without regard to baseline abnormality was assessed.
Any abnormalities occurring after the administration of treatment and increasing in severity from baseline value were counted as treatment-emergent.
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Day 1 through Day 8 (or discharge) for D-dimer laboratory test and urinalysis; Day 1 through Day 4 for all other laboratory tests
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Number of Participants With Changes From Baseline in Physical Examination
Time Frame: Baseline (pre-dose), Day 2, Day 3, Day 4, Day 8/discharge
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Comprehensive and targeted physical examinations included general appearance, HEENT (head, eyes, ears, nose and throat), skin, heart (auscultation), lungs (auscultation), abdomen (palpitation and auscultation), and extremities with attention to swelling, general or localized tenderness, entire leg or calf swelling, edema, and collateral superficial veins.
The results of the comprehensive and targeted physical examinations were combined to evaluate the changes from baseline through Day 8 (or discharge) for each site parameter according to the categories: positive change (abnormal to normal); no change (normal to normal or abnormal to abnormal); negative change (normal to abnormal).
Parameters with at least 1 participant meeting the positive/negative change from baseline criteria are presented here.
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Baseline (pre-dose), Day 2, Day 3, Day 4, Day 8/discharge
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Change From Baseline for Body Temperature
Time Frame: Baseline (pre-dose), Day 1 (5 and 45 minutes [min] post-dose), Day 2, Day 3, Day 4, Day 8/discharge
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Body temperature was measured by oral, tympanic, axillary or temporal method.
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Baseline (pre-dose), Day 1 (5 and 45 minutes [min] post-dose), Day 2, Day 3, Day 4, Day 8/discharge
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Change From Baseline for Supine Respiratory Rate
Time Frame: Baseline (pre-dose), Day 1 (5 and 45 minutes [min] post-dose), Day 2, Day 3, Day 4, Day 8/discharge
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Respiratory rate was measured after 5 minutes rest in supine position by observing and counting the respirations of the participant for 30 seconds and multiplied by 2. The use of an automated device for measuring respiratory rate was acceptable.
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Baseline (pre-dose), Day 1 (5 and 45 minutes [min] post-dose), Day 2, Day 3, Day 4, Day 8/discharge
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Change From Baseline for Supine Systolic and Diastolic Blood Pressure
Time Frame: Baseline (pre-dose), Day 1 (5 and 45 minutes [min] post-dose), Day 2, Day 3, Day 4, Day 8/discharge
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Supine blood pressure (BP, systolic and diastolic) was measured with the participant's arm supported at the level of the heart and recorded to the nearest milliliters of mercury (mmHg) after 5 minutes of rest whenever possible and as permitted by the participant's medical condition.
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Baseline (pre-dose), Day 1 (5 and 45 minutes [min] post-dose), Day 2, Day 3, Day 4, Day 8/discharge
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Change From Baseline for Supine Pulse Rate
Time Frame: Baseline (pre-dose), Day 1 (5 and 45 minutes [min] post-dose), Day 2, Day 3, Day 4, Day 8/discharge
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The use of an automated device for measuring pulse rate was acceptable, although, when done manually, pulse rate was measured in the brachial/radial artery for at least 30 seconds.
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Baseline (pre-dose), Day 1 (5 and 45 minutes [min] post-dose), Day 2, Day 3, Day 4, Day 8/discharge
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Number of Participants With Electrocardiogram (ECG) Qualitative Results
Time Frame: Baseline (pre-dose), Day 2, Day 4, Day 8/discharge
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The electrocardiogram (ECG) results over time were compared to baseline and assessed by the investigator as "less abnormal", "no significant change", or "more abnormal".
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Baseline (pre-dose), Day 2, Day 4, Day 8/discharge
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum Changes From Baseline for Activated Partial Thromboplastin Time (aPTT)
Time Frame: Baseline (pre-dose), Day 2
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Maximum changes from baseline were calculated for activated partial thromboplastin time (aPTT) after dosing with PF-05230907 through Day 2.
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Baseline (pre-dose), Day 2
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Maximum Changes From Baseline for Prothrombin Fragment 1+2 (PF1+2)
Time Frame: Baseline (pre-dose), Day 2
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Maximum changes from baseline were calculated for prothrombin fragment 1+2 (PF1+2) after dosing with PF-05230907 through Day 2.
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Baseline (pre-dose), Day 2
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Number of Participants With Anti-Drug Antibody (ADA) Production
Time Frame: Day 1 up to follow-up visit (Day 43 and/or Day 91)
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Participants with anti-drug antibody (ADA) production were those with at least 1 positive result from Day 1 through follow-up visit (Day 43 and/or Day 91).
ADA positive: titer value >=1.88.
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Day 1 up to follow-up visit (Day 43 and/or Day 91)
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Number of Participants With Neutralizing Antibody (NAb) Production
Time Frame: Day 1 up to follow-up visit (Day 43 and/or Day 91)
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ADA positive samples were planned to be further characterized for neutralizing antibody (NAb).
Participants with NAb production were those with at least 1 positive result from Day 1 through follow-up visit (Day 43 and/or Day 91).
As all ADA samples were negative (titer value <1.88), NAb analysis was not conducted.
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Day 1 up to follow-up visit (Day 43 and/or Day 91)
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Number of Participants With Depletion of Coagulation Factor X
Time Frame: Baseline (pre-dose), Day 43, Day 91
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Depletion of coagulation factor X was defined as >50% reduction relative to baseline (pre-dose).
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Baseline (pre-dose), Day 43, Day 91
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change From Baseline in Intracerebral Hemorrhage (ICH) Volume at 24 Hours
Time Frame: Baseline (pre-dose), 24 hours
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Change from baseline in intracerebral hemorrhage (ICH) volume was calculated at 24 hours.
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Baseline (pre-dose), 24 hours
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PF-05230907 Concentration in Plasma
Time Frame: Day 1 pre-dose, 5 and 45 minutes post-dose
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Day 1 pre-dose, 5 and 45 minutes post-dose
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Number of Participants With Anti-Chinese Hamster Ovary (CHO) Protein Antibody Production
Time Frame: Day 1, Day 43
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Participants with anti-Chinese hamster ovary (CHO) antibody production were those with positive results.
Positive: titer value >=2.00.
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Day 1, Day 43
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Number of Participants With Anti-Paired Basic Amino Acid Cleaving Enzyme (PACE) Furin Antibody Production
Time Frame: Day 1, Day 43
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Participants with anti-paired basic amino acid cleaving enzyme (PACE) antibody production were those with positive results.
Positive: titer value >=2.00.
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Day 1, Day 43
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Neurological Function as Assessed by the National Institute of Health Stroke Scale (NIHSS)
Time Frame: Screening, Day 1, Day 2, Day 4, Day 43, and Day 91
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The National Institute of Health Stroke Scale (NIHSS) is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss.
The total NIHSS score range is from 0 (normal) to 42 (severe impairment), with higher values indicating greater level of neurological impairment.
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Screening, Day 1, Day 2, Day 4, Day 43, and Day 91
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Health Resource Utilization Surrogate Measures - Maximum Duration
Time Frame: Day 1 up to Day 91
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Maximum duration for 4 types of hospital or health care unit: Intensive Care Unit (ICU), general ward, rehabilitation center, and other hospital units.
This was an exploratory endpoint to evaluate information for designing future studies, which were no longer planned.
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Day 1 up to Day 91
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Collaborators and Investigators
Sponsor
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- B2341002
- 2015-005703-83 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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