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IMPAACT 2017

IMPAACT 2017.

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IMPAACT 2017

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  1. IMPAACT 2017 Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable Rilpivirinein Virologically Suppressed HIV-Infected Children and AdolescentsMOCHAMore Options for Children and Adolescents

  2. MOCHA study-specific training Self-review module: Electrocardiogram(ECG/EKG)

  3. Training Objectives To provide an overview and establish a common understanding of the following: ECG and QTc basics Overview of protocol specifications ECG procedures Management of QTc prolongation

  4. Protocol References See MOP Section 5.2.3, Performing an ECG, for additional details and operational guidance

  5. ECG Terms

  6. QT Interval Basics The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle The QT interval represents electrical depolarization and repolarization of the ventricles. A lengthened QT interval is a marker for the potential of ventricular tachyarrhythmias like torsades de pointes and a risk factor for sudden death QTc (QT corrected): The QTc is the QT interval with a formulated correction based on the patient's heart rate (HR). The faster the HR the shorter the QT interval Since 2005, the FDA and European regulators have required that nearly all new molecular entities be evaluated in a thorough QT study to determine a drug's effect on the QT interval

  7. Background QTc in IMPAACT 2017 Cabotegravir (CAB) has no reported significant effect on cardiac repolarization Rilpivirine (RPV) at the recommended, approved oral dose of 25 mg is not associated with a clinically relevant effect on QTc Higher doses of RPV (75 and 300 mg q.d) were associated with mean maximum QTcF prolongations > 10 ms, which were dose and plasma concentration dependent No clinically relevant increase in QTcF is expected with the plasma concentrations achieved with RPV LA At screening, QTc interval (automated machine readout or calculated using either Bazett or Fredericia) < 500 msec is an inclusion criteria for both Cohort 1 and Cohort 2

  8. QTc in IMPAACT 2017 At screening, QTc interval (automated machine readout or calculated using either Bazett or Fredericia) < 500 msecis an inclusion criteria for both Cohort 1 and Cohort 2

  9. ECG Timepoints • At the Cohort 1 Screening and Cohort 2 Screening visits, the ECG reading should be done in triplicate such that three, single automated QTc readings will be done, each separated by at least 2 minutes, with the mean value establishing baseline. • The triplicate ECG reading must be conducted within 2 weeks (14 days) of the participant’s Entry visit; the triplicate ECG conducted at the Screening may be repeated to maintain this timeframe. • Cohort 1 Week 13 and Week 16 – single ECG with QTc compared to baseline • If a single ECG QTc > 500 msec OR a >60 msec increase from baseline averaged value ECG should be repeated in triplicate

  10. ECG Method and QTc Calculation • The ECG should be conducted using a 12-lead ECG with the participant in a semi-supine position • An ECG machine that automatically calculates the heart rate and measures QTc (QT corrected) intervals is preferred • If automated QTc calculations are not available, an appropriately qualified ECG reader must interpret the results • The IoR or designee can review the ECG reading; a cardiologist reading is not required • The same QT correction formula (e.g. Bazett’s or Fridericia's) must be used for each individual participant to determine eligibility for and discontinuation from the study. This formula may not be changed or substituted once the participant has been enrolled.

  11. Documentation All ECG readings should be source documented Individual ECG QTc values and mean value of triplicate readings (as applicable) should be entered into the DGW10019: Abbreviated Electrocardiogram (ECG) Results Log

  12. Management of QTc Prolongation • During follow-up, if a single automated reading results in a QTc interval > 500 msec, or a >60 msec increase from baseline averaged value, repeat the reading in triplicate (i.e. three tracings separated by at least 2 minutes). • If any one of the repeated readings confirm a QTc interval > 500 msec, or a > 60 msec increase from baseline, temporarily hold study product and assess participant for concomitant medications known to cause prolonged QT or Torsades de pointes. • Study product may be resumed in consultation with the CMC, and if the prolonged QTc is assessed as not related to study product. • If the prolonged QTc is assessed as related, or no other likely cause identified, permanently discontinue study product • For any other abnormal or irregularity reported by the automated read or by the qualified site clinician, a cardiologist should be consulted, and the CMC notified.

  13. Thank you for viewing this self-review module! Please remember to document your completion of this training component Per the DAIDS policy on Requirements for Manual of Operational Procedures, all sites must establish and follow a standard operation procedure (SOP) for personnel training and certification documentation Each site is responsible for preparing attendance documentation for this self-review module in accordance with this SOP.

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