First-in-Human Trial
This case study describes a first-in-human trial that highlights Clinilabs’ ability to work collaboratively with sponsors to complete early-phase studies. This integrated, dose escalation trial evaluated the safety, tolerability, and pharmacokinetics of a compound in healthy volunteers. The protocol required EEG monitoring, the collection of PK and multiple other biomarkers (blood and urine), and food and drug interaction cohorts. Thirty-nine subjects, divided into 4 treatment cohorts, were randomized into the trial in a 3-month period.
The protocol directed Clinilabs to start the dosing with a full cohort of 9 subjects at the initial dose level. However, recognizing the risks associated with this drug, Clinilabs was able to negotiate a different dosing schedule with the Sponsor. We proposed a schedule that allowed us to start the study quickly, and then employ more frequent dosing dates. We scheduled 2, then 3, and then 4 subjects for dosing at the initial dose before accelerating to the standard schedule of a full cohort exposed on a single day. Thus we were able to minimize subjects’ exposure to risk, and still complete the program within the Sponsor’s timeline.
Pre-clinical data suggested that there may be both seizure and cardiovascular risks associated with this drug. Therefore, Clinilabs worked closely with the sponsor to design a protocol that included extensive electroencephalographic (EEG) monitoring at screening and after study drug exposure, with photic stimulation and hyperventilation employed as provocative stimuli. Clinilabs also developed a plan to include frequent assessments of orthostatic vital signs, which proved informative when we noted several episodes of syncope at higher doses of drug.
As with all studies, Clinilabs’ staff completed protocol-specific training prior to study start-up. This training included a thorough review of the protocol, its rationale and design, and hands-on training on all required procedures, including EEG monitoring, photic stimulation, and hyperventilation procedures. This enabled us to complete the project with very few deviations.
Proof-of-Concept for a CNS Indication
Another example of the capabilities of our staff was demonstrated in a complex study of blind subjects. This Phase II double-blind, placebo-controlled trial evaluated a compound for the treatment of circadian rhythm disturbances often observed in blind persons who do not perceive light at all.
The recruitment of subjects for this study was challenging, and required an aggressive community outreach effort in more than one state. In order to be included in the study, subjects were required to have no perception of light documented by Visual Evoked Potential (VER) testing. VER was performed using lighted electronic display (LED) stimuli at variable frequencies and intensity in dichotomous bursts while EEG was monitored for N75, P100, and N175 discharges. Testing was performed by certified neurophysiologists. Subjects were randomized and followed on an outpatient basis for several weeks.
This multicenter study employed competitive enrollment, allowing Clinilabs to complete 300% of its targeted enrollment goal and enabling the Sponsor to complete the study in a timely fashion.
Implementation of CDR Battery of Tests in Phase I PK/PD Study
Clinilabs has used the Cognitive Drug Research (CDR) test battery in multiple studies. One exemplary study was a single center, double-blind, randomized, placebo-controlled, 4-way cross-over study in which the psychomotor and cognitive residual effects of a sedative-hypnotic were evaluated in healthy volunteers. Forty-two subjects, divided into 3 treatment cohorts, were randomized at Clinilabs in a 3-month time period (the shortest time achievable given the study design). Subsequent to administration of study drug, subjects completed the CDR test battery at several specific time points.
The CDR test battery included:
- Choice reaction time
- Tracking
- DSST
- LSEQ
- Digit vigilance
- Word recall
- Critical Flicker Fusion (CFF) Threshold
Following completion of this study, Clinilabs worked closely with the Sponsor to analyze the data and prepare the Clinical Study Report (CSR).
Complex Phase I PK/PD Protocol
This case study describes Clinilabs’ involvement in a complex randomized, double-blind, double-dummy, placebo-controlled comparative study of the PK and PD effects of 2 hypnotic formulations using frequent PK sampling, psychometric assessment, self-report measures, observer ratings, and QEEG assessments. The primary outcome measure of the study was post-dose β EEG activity.
The sponsor contacted Clinilabs to discuss the feasibility of this project in early August. A draft of the protocol synopsis was available for review at that time. The scientific and operational teams at Clinilabs determined that the protocol was feasible, finalized contract and budget negotiations, and completed the final draft of the protocol by mid September. One important factor in the latter was Clinilabs’ ability to form a collaboration between its thought leaders and Key Opinion Leaders (KOLs) from an academic institution (Tufts University School of Medicine).
Following completion of the final draft of the protocol, Clinilabs’ operations team worked closely with the Sponsor to obtain institutional review board (IRB) approval, and to identify and engage vendors who would provide clinical supplies, clinical laboratory services, and automated assessment tools (an electronic system for the collection of self-report and psychometric test data). At the same time, Clinilabs’ subject recruitment team began a campaign to identify candidates who met inclusion/exclusion criteria for this study.
The first-patient-in (FPI) date was October 10, approximately 8 weeks following the Sponsor’s first contact with Clinilabs. Eighty-one healthy adults between the ages of 19 and 45 years were enrolled over a 5-week period, resulting in 70 completed subjects. All completers participated in a thorough screening visit followed by 3 treatment days separated by a 7 to 14-day washout period. On the evening prior to each treatment day, subjects reported to the Phase I unit for admission and pre-treatment procedures. They were dosed the following morning, after which they remained under constant observation. Twenty-two PK samples were obtained on each treatment day, and most samples were associated with PD assessments, including EEG assessments. The staffing ratio for this study was 3 staff to 1 subject.
One of the challenges of this study was the coordination and timing of PK and PD assessments, which had to be performed in accordance with a strict schedule that allowed assessment windows of approximately ± 2 minutes. Clinilabs’ team was able to adhere to this schedule without significant deviation in 4,620 samples. Following the completion of the study, Clinilabs’ team worked with the Sponsor and KOLs to produce posters for presentation at academic meetings, as well as abstracts and a manuscript for publication. The manuscript was published in the Journal of Clinical Psychopharmacology in 2006.
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