Here is the article from the November issue of the "CURRENT"...

Here is the article from the November issue of the "CURRENT" Newsletter of the Neurocritical Society.

Clinical Trials Monitor

INTREPID-2566 Trial to Study Neuroprotection and Seizure Reduction after TBI

By Matthew A. Koenig MD

The INTREPID-2566(Investigating TREatments for the Prevention of secondary Injury and Disability following TBI) trial is planned to begin patient enrollment on January 15, 2010. INTREPID is the first major, multi-center trial of a neuroprotective therapy for improving outcomes after traumatic brain injury (TBI) in over a decade.
The trial(clinicaltrials.gov NCT00805818) will investigate the safety and efficacy of the insulin-like growth factor-1 (IGF-1) analog NNZ2566 for improving functional outcomes and reducing seizures after TBI.

The multi-center trial is being carried out through a collaborative effort between the Department of Defense(DOD) and Neuren Pharmaceuticals. The principal investigators are Ross R. Bullock, MD, PhD from the University of Miami and Paul Vespa, MD from the Ronald Reagan UCLA Medical Center.
“Neuren created the drug, a synthetic analog of the n-terminal tripeptide of IGF-1. Since late 2004, Neuren and the Army have collaborated on preclinical development,” says Dr. Vespa.

In preclinical studies, NNZ-2566 has been shown to improve functional outcome measures after blunt and penetrating brain injuries, as well as reduction of stroke volume in ischemic injury models. Although the exact mechanisms and receptors remain to be clarified, the drug appears to act through several pathways to reduce apoptosis, inflammatory cytokines, and microglial activation. Animal models also suggested a reduction in post-TBI seizures in those treated with NNZ2566.

The multi-mechanistic properties and anticonvulsant effects raise hopes that NNZ-2566 will succeed where other neuroprotective agents have failed.
“This drug blocks post-traumatic seizures in animal models and that blockade is linked to better neurological outcomes. Post-traumatic seizures have never been a target in any TBI trial, per se. Hence, this is a novel approach.
Additionally, the drug inhibits up-regulation of inflammatory cytokine and apoptotic gene expression for at least 24 hours thereby preventing secondary neuronal loss following brain injury,” says Dr. Vespa.

“We are looking for the incidence of seizures in each arm, drug versus placebo, as the primary EEG outcome variable … We have created a centralized database that will pipe the EEG to the central warehouse, and be monitored by my team.”



INTREPID-2566 is seeking to enroll 260 male patients admitted to the hospital after moderate-to-severe, non-penetrating TBI (initial GCS 4-12). Patients must be able to be randomized within 7 hours of injury and receive the drug within 8 hours of injury. Patients with penetrating or spinal cord injuries will be excluded. Additional exclusion criteria are a history of pre-morbid neurological or psychiatric disorder or baseline QT prolongation.

Enrolled patients will be randomized to receive either the active drug or placebo as a bolus followed by a continuous infusion for 72 hours in a sequential, dose-escalation design. Enrollment will be paused for evaluation of safety
endpoints between the three dosing tiers, prior to dose escalation. In phase I studies, adverse effects included
injection site irritation and asymptomatic prolongation of the QT interval.

The primary endpoint of the study is safety of drug administration. The secondary therapeutic endpoints are
improvement in 1-month and 3-month global outcome, activities of daily living, and neuropsychological measures. In addition, continuous EEG recording will be undertaken during the first week of hospitalization. The incidence of epileptiform discharges and quantitative EEG measures will be compared between the active and placebo arms.

“We are looking for the incidence of seizures in each arm, drug versus placebo, as the primary EEG outcome variable … We have created a centralized database that will pipe the EEG to the central warehouse, and be monitored by my team. A variety of automated and quantitative algorithms will be used,” says Dr. Vespa.

The study is being funded and administered through the combined efforts of Neuren and the DOD.
“Neuren developed the drug and will retain all rights and intellectual property for the drug. The Army is providing the majority of funding for the trial—$4 million through a grant to the Geneva Foundation through the Congressionally Directed Medical Research Program and $14 million through a direct grant to Neuren from the US Army Medical Research and Material Command. Neuren is responsible for managing the trials and regulatory affairs,” says Dr. Vespa.



This looks to have sparked some "off shore" interest recently in NEU.

Cheers

The Rocket