Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

B darpo so c december 4 2014 - kopia

415 views

Published on

  • Be the first to comment

  • Be the first to like this

B darpo so c december 4 2014 - kopia

  1. 1. IQ-CSRC Study Results - Presentation to the CSRC Scientific Oversight Committee December 4, 2014 Borje Darpo MD, PhD Co-chair SoC iCardiac Technologies
  2. 2. • CSRC has entered a collaboration with the IQ-consortium to prospectively evaluate whether ‘Early QT assessment’ can be used to generate QT data with the same confidence as the TQT study • A prospective study in healthy volunteers has been conducted in a setting designed to provide similarities with a routine single ascending dose (SAD) study • The objective of the study is to evaluate whether ECG assessment in early phase clinical studies can replace, or serve as an alternative to the TQT study Background
  3. 3. History of Project CSRC Think Tank Meeting (Feb 2012) • https://www.cardiac-safety.org/think-tanks/november-2011/thinktank- meeting-on-qt-assessment-in-early-clinical-development FDA-IQ Clinical Pharmacology Leadership Meetings • May 2012. FDA’s retrospective analysis was presented and prospective study was discussed as a path forward. • Sep 2012. Study design concepts and analyses were discussed. FDA agreed to select drugs to be tested. CSRC-IQ Clinical Pharmacology Collaboration (Dec 2012) • September 2013: FTF meeting with FDA at which design and analyses were agreed.
  4. 4. CSRC-IQ Steering Committee IQ Consortium Clinical Pharmacology Leadership Group •Nenad Sarapa (Bayer) •Venkat Jarugula (Novartis) •Jim Keirns (Astellas) •Charles Benson (Lilly) CSRC •Christine Garnett (Certara) •Borje Darpo (iCardiac) •Catherine Ortemann-Renon (Sanofi) •Corina Dota (AstraZeneca) OQT Working Group (SAP) •Steve Riley (Pfizer) •Georg Ferber (Consultant) • DCRI •Cindy Green FDA • Kevin Krudys • Lars Johannesen
  5. 5. • 20 male and female healthy subjects • 3 treatment periods • 9 subjects were to receive each drug, 6 on placebo • Target to have at least 6 on active and 5 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 • ECG methodology as in TQT studies • Primary analysis: Based on exposure response IQ-CSRC prospective study - Design
  6. 6. Study treatments (1) Drug TQT Study Design and Results Dose Justification Day 1 Day 2 ZOFRAN (ondansetron HCl) QTc interval prolongation was studied in a TQT study. The maximum mean (95% upper CI) difference in QTcF from placebo after baseline-correction was 19.5(21.8) ms and 5.6 (7.4) ms after 15 minute intravenous infusions of 32 mg and 8 mg ZOFRAN, respectively. 52 mg oral** Dose has not been tested in TQT study. Anticipated effect is 10 to 12 ms. Expected Cmax: 281 ng/mL 32 mg given by 15 min IV infusion Based on TQT study results, mean ΔΔQTc= 19.5 ms. QUALAQUIN (quinine sulphate) QTc interval prolongation was studied in a double-blind, multiple dose, placebo- and positive-controlled crossover study in young (N=13, 20 to 39 years) and elderly (N=13, 65 to 78 years) subjects. After 7 days of dosing with QUALAQUIN 648 mg three times daily, the maximum mean (95% upper confidence bound) differences in QTcI from placebo after baseline correction was 27.7 (32.2) ms. 648 mg oral** In a PK study in HV (n=24) the mean change from baseline QTc at Tmax was 12 ms (from old Qualaquin label). The Cmax on day 1 is about 3.9 µg/mL with an expected increase in QTc of 12 ms based on the PK/PD model. 648 mg q8h x 4 After the 4th dose (75% of Cmax), the anticipated concentration is 5.1 µg/mL and the anticipated QTc is 19 ms. ANZEMET (dolasetron) QTcF interval was evaluated in a TQT study with IV dolasetron. The maximum mean (95% upper confidence bound) differences in QTcF from placebo after pre-dose baseline-correction were 14.1 (16.1) and 36.6 (38.6) ms for 100 mg and supratherapeutic 300 mg ANZEMET administered intravenously, respectively. 100 mg PO** Target Cmax for hydrodolasetron ~ 278 ng/mL. 150 mg IV by 15 min infusion Target Cmax ~ 440 ng/mL **Dose suggested by FDA
  7. 7. Study treatments (2) Drug TQT Study Design and Results Dose Justification Day 1 Day 2 Moxifloxacin NA 400 mg po** Mean ΔΔQTc = 10-14 ms Target Cmax ~ 2.95 µg/mL 800 mg IV given by 60 min IV infusion Mean ΔΔQTc = ~20 ms, Tikosyn (dofetilide) Increase in QT interval is directly related to dofetilide dose and plasma concentration. The relationship in normal volunteers between dofetilide plasma concentrations and change in QTc is linear, with a positive slope of approximately 15-25 ms per ng/mL after the first dose. 0.125 mg oral ΔQTc = 10 to 11 ms Target Cmax ~ 0.7 ng/mL 0.25 mg oral ΔQTc = 20 ms Xyzal (levocetirizine) (negative drug) A QT/QTc study using a single dose of 30 mg of levocetirizine did not demonstrate an effect on the QTc interval. 5 mg (therapeutic dose) 30 mg Supra-therapeutic dose evaluated in TQT study Target Cmax ~ 1.3 µg/mL **Dose suggested by FDA
  8. 8. Randomization and Study treatments A: Ondansetron B: Quinine C: Dolasetron D: Moxifloxacin E: Dofetilide F: Levocetirizine (negative) P: Placebo P1, P2, P3: Period 1, 2 and 3 Randomization scheme 2 cohorts; placebo pooled from both. 9 subjects on active and 6 on placebo Cohort Subject Period 1 Period 2 Period 3 1 1 A B C 1 2 B C A 1 3 C A B 1 4 C B A 1 5 B A C 1 6 A C B 1 7 P C B 1 8 C P A 1 9 B A P 1 10 A B C 2 11 D E F 2 12 E F D 2 13 F D E 2 14 F E D 2 15 E D F 2 16 D F E 2 17 P F E 2 18 F P D 2 19 E D P 2 20 D E F
  9. 9. Objectives and Endpoints Primary Objective: • To study the effect of 6 marketed drugs on the QTc interval using concentration effect modeling. Secondary Objectives: • To evaluate the safety of the two single doses of 6 marketed drugs in healthy subjects. • 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. • To evaluate the pharmacokinetics of the 6 marketed drugs in healthy subjects 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.
  10. 10. Criteria for QT Assessment Positive QT assessment (for the positive drugs in this study): 1. The QT effect is detected: The upper bound of the 2-sided 90% confidence interval (CI) of the projected placebo-corrected ∆QTcF is above 10 ms at the observed geometric mean Cmax of the drug. 2. The slope of the ER relationship is statistically significant: The lower bound of the 90% confidence interval for the slope of ∆∆QTcF vs. concentration is above zero. Negative QT assessment (to claim that a drug is negative, e.g. levocetirizine): • The upper bound of the confidence interval of the predicted placebo-corrected ∆QTcF at the observed geometric mean Cmax of the drug is below 10 ms. 0 2000 4000 6000 8000 10000 -10-50510 Concentration (ng/mL) QTCF(ms) Median concentration quantiles Mean (90% CI) predicted QTcF prolongation
  11. 11. Results, evaluable subjects Number of evaluable subjects Day 1 Day 2 Ondansetron 9 9 Quinine 8-9 6 Dolasetron 9 9 Moxifloxacin 9 9 Dofetilide 9 9 Levocetirizine 8 8 Placebo 6 6 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.
  12. 12. Top Line Results • All 5 positive drugs met the prespecified criteria , i.e. the study was able to demonstrate a drug-induced QT effect at the dose identified by FDA • The negative drug, levocetirizine, also met the criterion, i.e. a QT effect above 10 ms could be excluded
  13. 13. Results - Number of evaluable subjects Day 1 Day 2 Ondansetron 9 9 Quinine 9 6 Dolasetron 9 9 Moxifloxacin 9 9 Dofetilide 9 9 Levocetirizine 8 8 Placebo 6 6
  14. 14. Prespecified criteria for model selection • Criteria for the absence of hysteresis met for all drugs • Test for nonlinearity non significant for all drugs except dofetilide  For dofetilide, an Emax model provided a better fit to the data based on AIC
  15. 15. Moxifloxacin – by timepoint analysis Day Largest mean ∆∆QTc* (ms) 1 11.9 2 33.4
  16. 16. Moxifloxacin – Exposure response analysis Slope, mean ms per ng/mL LB 90% CI UB 90% CI Treatment effect (intercept) ms Cmax Day 1, ng/mL Predicted QTc effect mean, ms LB 90% CI UB 90% CI Criteria 0.0065 0.0059* 0.0072 2.3 1862 14.4 10.6 17.9** Met *: The positive slope is statistically significant **: QTc effect above 10 ms at the Cmax of Day 1 cannot be excluded Red bars denote observed median (IQR) ∆∆QTcF within each concentration decile
  17. 17. Levocetirizine – Exposure response analysis Slope, mean ms per ng/mL LB 90% CI UB 90% CI Treatment effect (intercept) ms Cmax Day 2, ng/mL Predicted QTc effect mean, ms LB 90% CI UB 90% CI Criterion 0.0014 -0.0013 0.0041 0.7 1005 2.1 -2.3 6.1* Met *: QTc effect above 10 ms can be excluded at the geometric mean Cmax on Day 2
  18. 18. Results – primary and robustness Drug Slope, mean ms per ng/mL LB 90% CI UB 90% CI Treat- ment effect ms Cmax Day 1, ng/mL Projected QTc effect mean, ms LB 90% CI* UB 90% CI* Positive drugs (Day 1) Ondansetron 0.033 0.025 0.042 0.2 284 9.7 6.2 12.8 Day 1 only 0.032 0.022 0.043 0.3 9.5 7.2 13.5 Quinine 0.004 0.0034 0.0047 -3.0 3623 11.6 6.8 17.1 Day 1 only 0.004 0.0031 0.0051 -4.9 9.8 6.7 17.3 Dolasetron 0.021 0.013 0.028 3.1 211 7.4 3.0 11.0 Day 1 only 0.016 0.0008 0.032 3.3 6.8 3.4 11.6 Moxifloxacin 0.0065 0.0059 0.0072 2.3 1862 14.5 10.5 17.7 Day 1 only 0.0045 0.0024 0.0065 3.4 11.7 10.6 17.9 Dofetilide* 22.2 18.9 25.6 1.1 0.42 10.5 6.3 14.9 Day 1 only 28.7 20.6 36.7 -0.9 11.3 6.1 14.6 Negative drug (Day 2) Levocetirizine 0.0014 -0.0013 0.0041 0.7 1005 2.1 -2.3 6.1 Day 2 only 0.00042 -0.0032 0.0041 1.6 2.0 -2.6 6.0 *: Slope from linear model for comparison. Predicted effect for dofetilide using Emax model: 11.6 ms; 90% CI 7.0 to 16.0
  19. 19. We propose using the same criteria as in the ICH E14 for QT assessment adapted to exposure response analysis: Criteria for negative QT assessment: The upper bound of the 2-sided 90% confidence interval (CI) of the predicted placebo-adjusted ∆QTcF is below 10 ms at clinically relevant plasma levels of the drug. The definition of clinically relevant plasma levels must be based on observations in patients, including high plasma levels seen in the 'worst-case scenario' and considerations are the same as when discussing the choice of the supratherapeutic dose in a TQT study. An advantage of QT assessment if performed in FIH studies is that often high exposure to the drug is achieved, in many cases reaching maximum tolerated levels and often higher than in any subsequent clinical trial. Our proposal for QT assessment in early phase clinical studies
  20. 20. Our proposal for QT assessment in early phase clinical studies
  21. 21. We believe that a successful outcome of the study (as defined below for positive QT assessment) would provide evidence in support of a TQT waiver for drugs with a negative outcome in future phase 1 studies conducted in the same robust fashion (e.g. SAD or MAD studies with exposure response analysis)? Do you agree? FDA: Yes (with caveats and provisions) Question asked at our previous FTF meeting with FDA (September/2013)
  22. 22. • Meeting with all key stakeholders at FDA held October 8 to discuss results and FDA’s independent analysis • Results presented to ICH E14 Discussion group • Results will be discussed on December 12 at a public meeting at FDA’s White Oak campus  Participation from regulators from all regions Regulatory Activities
  23. 23. Accepted for publication in Clinical Pharmacology & Therapeutics
  24. 24. MY CONCLUSION - EXPECT CHANGE
  25. 25. Publications to-date stemming from the IQ-CSRC initiative 1. Darpo, B., Garnett, C. Early QT assessment - how can our confidence in the data be improved? Br J Clin Pharmacol 76, 642-648 (2012) 2. Darpo, B. et al. Cardiac Safety Research Consortium: Can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward. Am. Heart J 168, 262-272 (2014) 3. Darpo, B. et al. The IQ-CSRC prospective clinical Phase 1 study: "Can early QT assessment using exposure response analysis replace the thorough QT study?“ Ann. Noninvasive Electrocardiol. 19, 70-81 (2014) 4. Ferber, Zhou, Darpo. Detection of QTc effects in small studies - Implications for replacing the thorough QT study ANE 2014; Nov 4. doi: 10.1111/anec.12227. [Epub ahead of print] 5. Darpo, B et al. Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase . Accepted for publication in CPT December, 2014

×