Safety and Tolerability of PNT001 in Patients With Acute Traumatic Brain Injury (TBI)

Phase 1, Randomized, Double-blind, Placebo-controlled, Multiple-ascending-dose Trial to Evaluate the Safety, Tolerability, Immunogenicity, and Pharmacokinetics of Intravenous PNT001 in Hospitalized Patients With Traumatic Brain Injury (TBI)

This is a Phase 1, multi-center, randomized, double-blind, placebo-controlled, multiple-ascending- dose trial to evaluate the safety, tolerability, immunogenicity, and pharmacokinetics of intravenous PNT001 in hospitalized patients with traumatic brain injury.

Study Overview

• Status: Terminated
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Biological: PNT001; Biological: %5 dextrose for infusion

Detailed Description

The Phase 1 study is a double-blind, multiple ascending dose trial evaluating a total of 64 patients across two dose cohort groups. Each cohort will include 32 patients (24 active; 8 placebo) who will be randomized to receive three doses of either PNT001 or placebo. Doses studied will be 1000mg and 4000mg.

Patients admitted to the trauma center who meet entrance criteria will receive their first dose of study drug within 24 hours of documented TBI. They will remain in the facility for at least 24 hours after initial dose. Baseline biomarker collection and cognitive assessments will be completed. Study medication will be administered as an IV infusion over 30 minutes (for 1000mg cohort) or 60 minutes (for 4000mg cohort) followed by collection of safety, tolerability, pharmacokinetic, biomarker, imaging, and cognitive data over 12 weeks. Subsequent dosing visits will be at Days 28 and 56. All visits after initial discharge will be on an outpatient basis.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Hospitalization due to documented evidence of TBI with Glasgow Coma Scale (GCS) Score 9-12 or GCS score of 13-15 with radiographic evidence of trauma.
2. Duration from documented time of TBI event to time of start of initial dose of study drug will not exceed 24 hours.
3. Signed informed consent by patient, or where applicable, patient's legally authorized representative.
4. Male and females, 18- 65 years of age at time of screening (State's legal age of majority is minimum age if higher than 18).
5. Female patients must meet protocol defined criteria for 1) non-childbearing potential, 2) post menopausal or 3) must have a negative pregnancy test and agree to contraception as outlined in the protocol.
6. Male must agree to use acceptable contraception and refrain from sperm donation during the entire study and for 200 days after dosing has been completed.
7. Has not participated in a clinical drug trial within 3 months of study start.
8. Body Mass Index (BMI) of 18.5-35.0 kg/m2 and for the 4000mg dose group only, weight greater than or equal to 44.8 kg.
9. Vision, hearing, speech, motor function, and comprehension sufficient for compliance with all testing procedures and assessments.

Exclusion Criteria:

1. TBI that does not require hospitalization.
2. TBI outside 24-hour window.
3. GCS < 9 within 2 hours of dosing.
4. History of TBI in past 12 months that resulted in patient seeking medical attention.
5. Evidence of penetrating head trauma or depressed skull fracture.
6. Clinical or radiographic evidence of mass effect, midline shift, or intracranial hypertension, requiring craniotomy/craniectomy.
7. Evidence of symptomatic cervical, thoracic, lumbar spine injury e.g. paresis, radiculopathy, that can be localized to the injury.
8. Systemic traumatic injury that would preclude participation in study or is expected to result in long-term disability.
9. Any other acute or chronic medical illness that in the judgement of the study physician results in functional impairment or impairs neuropsychiatric function.
10. Any acute intoxication that in the judgement of the study physician results in significant functional impairment or impairs neuropsychiatric function.
11. Any history of cancer within 5 years of enrollment with the exception of resected skin basal cell carcinoma.
12. Any major surgery requiring general anesthesia within 4 weeks of study drug administration.
13. Donation of blood or serum ≥500 mL to a blood bank or in a clinical study (except screening visit) within 3 months of study drug administration.
14. Known recent (within 6 months of study drug administration) drug or alcohol abuse as defined in DSM V, Diagnostic Criteria for Drug and Alcohol Abuse.
15. Evidence of any clinically significant neurological or psychiatric disorder that could interfere with study assessments as determined by investigator and sponsor.
16. Patient has history or currently has schizophrenia, schizoaffective disorder or bipolar disorder, untreated major depression (DSM-V or ICD-10 criteria).
17. Significant illness within the prior 30 days.
18. Abnormalities in creatinine, hepatic transaminases, or QT that would preclude entry into the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PNT001 1000mg; PNT001 diluted in 5% dextrose for infusion	Biological: PNT001; 30 minute infusion for PNT001 1000mg; 60 minute infusion for PNT001 4000mg
Experimental: PNT001 4000mg; PNT001 diluted in 5% dextrose for infusion	Biological: %5 dextrose for infusion; 30 min placebo infusion for 1000mg; 60 minute placebo infusion for 4000mg
Placebo Comparator: Placebo; 5% dextrose for infusion	Biological: PNT001; 30 minute infusion for PNT001 1000mg; 60 minute infusion for PNT001 4000mg; Biological: %5 dextrose for infusion; 30 min placebo infusion for 1000mg; 60 minute placebo infusion for 4000mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment Emergent Adverse Events	assess adverse events	84 day study duration
Incidence of Treatment Emergent Clinical Laboratory Test Abnormalities	measure clinical laboratory values	84 day study duration
Incidence of Treatment Emergent Abnormalities in Physical Examination Findings	perform physical examination	84 day study duration
Incidence of Treatment Emergent Abnormalities in Neurological Examination Findings	perform neurological examination	84 day study duration
Incidence of Treatment Emergent Abnormalities in Vital Signs	assess blood pressure, pulse, temperature, respiratory rate	84 day study duration
Incidence of Treatment Emergent Abnormalities in 12-lead Electrocardiogram Assessment	measure ECG parameters	84 day duration of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Properties of PNT001 in Serum	measure concentration of PNT001 in serum	84 day duration of study

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-Drug Antibodies (ADA)	number of participants with presence of anti-drug antibodies (ADA) in serum	84 day duration of study
Biomarker Measurements in Plasma	measure concentrations of total (mid-domain) tau, NfL, GFAP, UCH-L1, pT181 tau, pT231 tau total tau in plasma	84 day duration of study
Effects of PNT001 on imaging parameters	measure diffusion tensor imaging parameters	Day 3 through the remainder of the 84 day study
Effects of PNT001 on cognitive measures	scores on the Trails A and B assessments	84 day duration of study
Effects of PNT001 on health related Quality of Life	measure change in ratings across 8 categories on the NeuroQOL assessment	84 day duration of the study
Effects of PNT001 on a Global Outcome Scale	measure disability outcome based on ratings in 8 areas of the Global Outcome Scale Extended (GOSE)	84 day duration of the study
hsCRP Measurement in Serum	measure concentrations of hsCRP in serum	84 day duration of the study

Collaborators and Investigators

• Sponsor: Pinteon Therapeutics, Inc
• Collaborators: United States Department of Defense
• Investigators: Study Director: Larry Altstiel, MD, PhD, Pinteon Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2021
• Primary Completion (Actual): April 12, 2021
• Study Completion (Actual): April 12, 2021

Study Registration Dates

• First Submitted: December 6, 2020
• First Submitted That Met QC Criteria: December 16, 2020
• First Posted (Actual): December 21, 2020

Study Record Updates

• Last Update Posted (Actual): June 29, 2022
• Last Update Submitted That Met QC Criteria: June 23, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic
• Other Study ID Numbers: PNT001-002

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