Holter ECG from the IQ-CSRC Study Waveform Data Sharing Program

IDENTIFICATION : E-HOL-12-0118-023

 

The access to this database requires a submission to the Cardiac Safety Research Consortium (CSRC) using the Project Submission Form available here. The form must be submitted to the Duke Cardiac Research Institute (DCRI) to Dr. Cinthia Lea Green by email (cindy.green@duke.edu). One recomends the data user to review the slides summarizing the IQ-CSRC results and the associated data sharing program here.

Currently, the registration to the data sharing program is limited:

 

Program Description:

The Waveform Data Sharing Program from the study conducted by the Innovation and Quality in Pharmaceutical Develpment and the Cardiac Safety Research Consortium (IQ-CSRC) Study [1] allows any organization to access a validation dataset of 24-hour Holter ECG recordings to test the ability of their QT technology(ies) to accurately characterize QT effects in a manner consistent with the proposed alternative approach to the Thorough QT study (TQT).

Each participating core lab will be blinded to treatment information, and the statistical analysis based on the ECG measurements done by each registered organization will be conducted by the Duke Clinical Research Institute (Duke University, Durham, NC, USA). The statistical analysis will be based on an exposure response analysis of the data and follow an almost identical statistical analysis plan as the original IQ-CSRC study (see [1]). 

The goal of this validation exercise is to foster understanding and confidence among sponsors in the use of this new approach, results from each participating core lab will be shared with the CSRC Scientific Oversight Committee.

How to Register to the program:
1) Complete the attached CSRC Project Submission form to obtain the documents necessary to participate in the Waveform Sharing Program.
2) Review and sign the IQ-CSRC Study Waveform Sharing Program Agreement (download here);
3) Review and sign the THEW Data Use Agreement (THEW-DUA). (download PDF here);
4) Send the signed THEW DUA to the Project Coordinator Betty Mykins (betty.mykins@heart.rochester.edu), an invoice for $5,000 for data access will be sent in response to the signature of the THEW DUA.

5) Make payment to the THEW by check for support and access to the blinded ECG waveforms and blinded subject information.
6) Make payment to the CSRC in the amount of $5,000 U.S. for the statistical review and reporting related to participation in the Program.

Once the steps above are completed, the following steps will be followed by the Participant to complete the Program (full details are given in the Program Agreement):

1) The Participant will be given secured access on February 1, 2016 (online and mailed using an external hard drive if requested) to the raw ISHNE and annotation files, as well as to the Study Protocol, relevant subject demographic data, and dosing time information (collectively the “Study Data”). The access will be granted to the list of individuals described in the THEW DUA (each indvidual name should be associated with a valid email adress). There is a limit of 10 individuals per registered organization.

2) Once Study Data is released to an organization, that orgnaization must complete analysis of such Study Data and submit the results, per the specifications of the Program Agreement, to the CSRC within six (6) weeks; :

The results from the participants must be submitted to CSRC by March 14, 2016. 

3) The Participant will submit timepoint-level interval measurements for QT, QTcF, RR, PR and QRS, as well as a general, non-confidential description of its analysis methodology, which shall, at minimum, describe how many replicates were analyzed per timepoint and whether such analysis was done in a manual, semi-automated or fully automated manner (the interval measurement data and methodology description being collectively referred to herein as “Participant Analysis Results”) to the CSRC in the format structure set forth by the CSRC.  If the Participant does not submit the final Participant Analysis Results within the allotted 6-week timeline, then those results will not be analyzed by the CSRC. The Participant will not be provided another opportunity to submit the Participant Analysis Results or to further participate in the Program; further, the Participant will not be eligible for a refund of amounts paid to the THEW or to the CSRC hereunder.

4)      Once the Participant has submitted the Participant Study Result, the CSRC statistician will perform statistical analysis on the timepoint-level data as outlined in the approved analysis plan agreed to by the CSRC ECG Data Warehouse Committee.

5)      The CSRC statistician will provide applicable statistical results as detailed in the SAP to the Participant within an agreed-upon timeframe.  It is acknowledged by the Participant, that it shall at no time receive a randomization code from any organization (CSRC or iCardiac Technologies Inc.) that would enable the Participant to know which drugs subjects were administered.

6)      In addition to providing statistical results to the Participant, the CSRC statistician shall provide such full statistical results to the CSRC Scientific Oversight Committee.  By agreeing to participate in this Program, and in fairness to other participants and for the general benefit of the clinical trials industry, each Participant acknowledges and agrees that full statistical results relating to the Participant Analysis Results will be provided to all members of the CSRC Scientific Oversight Committee. If Participant initiates involvement in this Program by receiving Study Data but does not complete and submit its results in a timely manner, then in fairness to other participants it shall be noted to the CSRC Scientific Oversight Committee that the Participant voluntarily discontinued its efforts to analyze Study Data.

7)    While it is not mandatory or a condition of participation in the Program that  Participant actively take part in the drafting and review of a joint publication based on the results submitted by all participants, it is encouraged that each participating company do so.  If a Participant takes part in such a publication, it may assign one person to collaborate on the joint publication and to be listed as a co-author.

8)      The Participant may voluntarily choose to submit results from more than one methodology that the Participant used to analyze Study Data.  However, the Participant agrees that each methodology shall be treated as a separate submission hereunder, meaning that for each submission Participant must: pay a $5,000 analysis fee to the CSRC and describe the analysis methodology that was used.  However, the Participant shall be provided only one 6-week period from its initial receipt of Study Data during which to complete and submit all analyses, no matter how many different methodologies each Participant wishes to use hereunder.  All and each Participant Analysis Results submitted as part of the Program may be published or publicly reported about as further outlined herein.
       
Any questions related to the program must be directed to Dr. Cinthia Lea Green by email (cindy.green@duke.edu).

Any technical questions about the data access, i.e., reading the ECG and annotation file format and clarification about data definion must be adressed to the Project Coordinator Betty Mykins (betty.mykins@heart.rochester.edu).

Study and data description

Background:

During the fall of 2013, it was agreed between the IQ-CSRC Steering Committee and the sponsor of the IQ/CSRC study (iCardiac) that ECG waveforms should be made accessible for algorithm testing through the CSRC ECG warehouse will allow other ECG acquisition and measurement techniques to be tested on the same waveforms. The ECG waveforms are shared through the THEW to allow blinded ECG measurements. The analysis will be performed by independent statisticians (Duke University).

The primary Objective of the study is to study the effect of 6 marketed drugs on the QTc interval using concentration effect modeling. The Secondary Objectives is to evaluate the safety of the two single doses of 6 marketed drugs in healthy subjects, and to evaluate the effect of the two single doses of 6 marketed drugs on heart rate, QTc, PR and QRS intervals using a descriptive statistical analysis by time point by dose. Finaly, the evaluation of the pharmacokinetics of 6 marketed drugs in healthy subjects: ondansetron, quinine, dolasetron, maxofloxacin, dofetilide, levocetirizine.
Primary endpoint:
Change-from-baseline QTcF (∆QTcF)
Secondary endpoints:
∆∆QTcF by time point
Categorical analysis of the QTc outliers
Effects on heart rate, PR and QRS intervals.

Study Design:

- Subject cohort: 20 male and female healthy subjects
3 treatment periods
9 subjects were to receive each drug, 6 on placebo

-Study drugs:
5 ‘QT-positive’ drugs, well characterized from previous studies
1 QT negative
Placebo

-Dosing on 2 days:
Day 1: Dose intended to give app. 10 to 12 ms QTc effect
Day 2: Dose intended to give app. 15 to 20 ms effect

-24-hour Holter with ECGs schedule:
Day 1: Predose (3 timepoints), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours
Day 2: 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (i.e., 21 timepoints in total).

Discontinuations:
1 subject prior to Dosing on Day 1 of Period 3 due to unknown criminal record (completed periods 1 and 2)
2 subjects before Day 2 due to prolonged QTc (returned for next period)
1 subject withdrew the evening of Day 1 (Period 3) prior to the 16hr PD dose The subject was experiencing AEs of nausea, vomiting, and dizziness.

Number of Leads: Holter 12-lead ECGs

Sampling Frequency : 1000 Hz

 

Publications:

[1] Darpo B, Benson C, Dota C et al. Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase. Clin Pharmacol Ther 2015 April;97(4):326-35. download PDF