Case Studies

EEG Case Study – Worldwide Clinical Trial with EEG as a Safety Endpoint

With over 150 subjects to enroll, this Phase IIb study is being performed at 45 sites across Europe, North & South America, and Asia. Due to the compound’s mechanism of action, it was necessary to set up EEG monitoring in order to detect any proepileptic abnormalities prior to and during the trial.

In terms of therapeutic areas, our clinical research experience covers:

  • Digital EEG equipment supply and shipment on site
  • Training of the site staff and help desk during the trial
  • Collection of the EEG recordings via a secured web platform
  • Review of the EEG recordings with a pool of neurologists
  • Reporting to the site for subject management

Within a few months, all the study sites were initiated and a high-quality EEG platform has been implemented. Using remote training tools (webex, video clips), site staff have received clear and detailed instructions enabling them to perform high-quality EEG recordings (even for sites with no prior experience in EEG capture). With a highly skilled pool of neurologists, comprehensive feedback is provided quickly to the site. An EEG reading platform is available 24/7 and is used by Biotrial’s neurologists and the sponsor. Due to services delivered by Biotrial’s Core Lab, the patients’ safety is ensured and the sponsor can rely on high quality data to support the development of the compound.

A Recent TQT Trial

Biotrial Core Lab was chosen by a mid-sized pharma company to carry out all ECG activities for a TQT trial conducted on a new antihypertensive drug. The clinical site was located in the UK and Biotrial was in charge of the ECG equipment set up, ECG data collection and QT measurement.

The study parameters:

    • 4-way cross over design (placebo/positive control/therapeutic dose/supratherapeutic dose)
    • 64 healthy volunteers, 18 to 55 years of age, male and female
    • 5 ECG days, 13 ECG timepoints per ECG day, triplicate ECGs at each time point
    • 24-hour 12-lead Holter recording with further ECG extraction
    • Overall number of 12-lead 10-second ECGs: 12480

 

State-of-the-art equipment was shipped to the site along with all necessary supplies and on-site training sessions were organized. Three weeks after the study award, the site was ready to perform Holter recordings. Throughout the TQT Study, Holter recordings were transferred regularly to Biotrial and upon reception, full Quality Control was conducted. The site was notified any time a technical issue was identified and Biotrial provided the clinical staff with support in order to maintain a high level of quality for all recordings.

A team of 4 board-certified cardiologists was involved in the ECG reading: 

      • Semi-automated method for ECG interval measurements
      • All ECGs for each subject were reviewed by the same cardiologist under blind conditions
      • Intra & inter reader variability monitored on a continual basis
      • Query process was performed to ensure 100% error-free data

 

Two weeks after the last Holter recording, ECG reading was completed and a 100% validated database was transferred including annotated ECG fi les for submission (FDA/XML fi le format).

The statistical analysis showed no effect for the therapeutic dose or for the supra-therapeutic dose, and the positive control effect was clearly demonstrated. With a very low variability of the QTc interval (less than 7msec), the TQT study was a success for the sponsor and for Biotrial!

 

“ Biotrial’s Core Lab has a very effi cient operational approach – the team worked hand-in-hand with the Clinical Site and they provided reliable results – on time!” Client feedback

 

In recent years, the amyloid-ß lowering capacity of anti-Aß antibodies has been demonstrated in models of Alzheimer's Disease (AD) and in AD patients. This study was a Phase I study of a humanized monoclonal antibody against amyloid Aß in elderly healthy volunteers.

The Use of MRI in Screening and Selecting Suitable Subjects in the Context of AD Studies

The context: in a previous FIM study micro-hemorrhages were observed in some trial participants. Therefore in this study a full MRI brain assessment was requested for each subject before enrollment in the trial.

The Phase I trial was conducted in the Biotrial Unit located in Rennes, France. 150 subjects (healthy volunteers, 50-70 years old) were screened during a 3-month time period.

The MRI scan was conducted to exclude subjects with evidence of clinically significant MRI findings (Biotrial Core Lab Imaging central reading) including lacunar infarct, territorial infarct or macroscopic hemorrhage, micro bleed or area of leptomeningohemo-siderosis, or deep white matter lesions corresponding to an overall Fazekas score of ≥ 2.

Central Reading

Imaging sequences were recorded on a 3 Tesla MRI (Siemens Magnetom Verio), operated by the Neurinfo platform, located next to the Biotrial Clinical Unit. The imaging protocol was designed to cover all possible issues and detect exclusion criteria:

  • T1 3D for anatomical assessment
  • AXIAL FLAIR to detect any white matter lesions
  • AXIAL T2* for micro bleeding detection
  • DIFF 3 DIR for recent stroke detection

The radiological assessments were conducted by the Biotrial Imaging Core Lab, using a Siemens Syngo (VB17) imaging workstation, board-certified neuroradiologists independently assessed both native and processed MRI data for the evaluation of eligibility as in this case, but also for safety and efficacy endpoints. Conducting remote reading sessions can significantly increase the efficiency of central reading activities while minimizing the inherent costs. The image evaluation results are made available at the sponsor’s site in a real-time manner to facilitate the tracking of operations and allowing decisions to be made quickly when it comes to patient monitoring, in case of safety findings.

Analysis & Interpretation

7.5% of the healthy subjects were excluded from the trial due to MRI issues:

Microbleeding 2.7%
Cerebral venous abnormality + probable lacunar lesion 0.5%
Deep white matter lesions with Fazekas score >2 0.5%
Frontal abnormality 0.5%
Hypophysis abnormality 0.5%
Microbleeding + telangiectasia 0.5%
Possible cerebellar cavernoma 0.5%
Probable frontal lobe meningioma 0.5%
Right parietal lobe lacune 0.5%
Sequellae of infratentorial neurosurgery 0.5%

2.5% of the pre-selected healthy volunteer’s population was considered as normal from an MRI perspective.