The pharmacological positive control can be replaced by a meal.

Transcription

1 The pharmacological positive control can be replaced by a meal. Wednesday, April 6th, 2016 CSRC/FDA Workshop: The Pro-arrhythmic Assessment of New Chemical Entities ACC Heart House Washington, D.C. Jorg Taubel- MD (15 min) CSRC

2 A meal sets into motion a physiological response which results in a change in cardiac repolarisation. Therefore it is a true effect and not a measurement error.

3 Provisions should be made to prevent meal effects of becoming a confounding factor. At the same time, if handled appropriately, it provides means of quality control for ECG sub-studies in various types of Phase I clinical trials.

4 EGC Signature

5 Food intake: profound effect on the ECG M J Taubel, A Naseem, G Ferber, AJ Camm Shortening of the QT Interval After Food Can Be Used to Demonstrate Assay Sensitivity in Thorough QT Studies. J Clin Pharmacol Nov 8. TQT Study in 32 Volunteers Comparison of a fasted baseline vs. a fed baseline Day

6 Food intake: profound effect on the ECG Notes: M 1. The pronounced heart rate increase (+10bpm) call for an appropriate heart rate correction formula. 2. Data shown for QTcF, QTcI and QTcB only 3. Our findings are consistent with literature (Nagi et al.) describing QTc prolongation after a meal. 4. However, Nagi (and others) assessed the immediate postprandial period only (1-2 hours) 5. They all used QTcB as the only heart rate correction method. 6. Our data shows a similar result utilising QTcB hours from meal start

7 Continuous 24 hour 12-lead Holter from a baseline day (Day -1) of a 4-way cross over TQT study; by Period with identical experimental set-up. Group mean QTcF (90% two sided CI). J Taubel, G Ferber, G Fox, S Fernandes, U Lorch, AJ Camm Thorough QT study of the effect of intravenous APD421 (amisulpride) on QTc interval in Caucasian and Japanese healthy subjects British Journal of Clinical Pharmacology (under review)

8 1) by period, based on baseline data 2) day 1 mean and 90 % CI of placebo group 3) day 1 based on the CE-model time effects. Continuous 24 hour 12-lead Holter placebo baseline day (Day -1) hours 6 hours

9 Notes: Continuous 24 hour 12-lead Holter placebo baseline day (Day -1) 1. Meal followed by a placebo injection 2. QT shortening immediate 3. ECG not affected by injection 4. Return to baseline 7 hours after a meal 5. NO difference between breakfast and lunch 6. But a reduced effect during night hours; possibly? sleep i.e. autonomic effects? circadian reduction of insulin and C-Peptide release

10 Underlying Mechanisms Notes: 1. We conducted a TQT study to investigate claims that insulin may prolong QTc (Gastadelli et al.) 2. We found no plasma concentration relationship between insulin and QTcX

11 What we & others have published GLUC PK-PD C-PEPT PK-PD Glucose = QTc Prolongation Clinical: Gordin et al Marfella et al Non-Clinical: Tang et al D Amico et al C-peptide = QTc Shortening Clinical: Wahren et al Dufayet et al Non-clinical: Galuska et al Vague et al. 2004

12 How to do it

13 Controlling meal effects is simple 1. Standardise meals on assessment days 2. Strictly supervise meal intake (time and amount) No sugary drinks (unless component of the meal) No snacking 3. Is there a different response to different types of meals? NB: Exclude c-peptide deficient subjects (diabetics) 13

14 Carbohydrate rich vs. high fat meal Breakfast Serving Cals (kcal) Proteins Carbohydrates Fat Fibre (g) kcal (g) kcal (g) kcal (g) kcal Breakfast Cereal, Kellogg's Cornflakes 30g Semi-skimmed milk 150ml Sugar 10g Wholemeal hoagie 98g Jam 20g Butter 7.9g Apple Juice 200ml Total % 81% 16% 0% Breakfast Serving Cals (kcal) Proteins Carbohydrates Fat Fibre (g) kcal (g) kcal (g) kcal (g) kcal Fried egg in butter 1 egg Grilled bacon 1 slice Hash browns 54g White toast 1 slice Whole milk 85ml Butter 7.9g Total % 29% 55% 0%

15 Insulin, C-Peptide and Glucose Concentrations C-peptide has the longest t 1/2 Taubel et al. 2012

16 Carbohydrate rich versus fatty

17 FDA breakfast shows a similar response Baseline day (-1) Day 1 N = hours 3-5 hours Breakfast Serving Cals (kcal) Proteins Carbohydrates Fat Fibre (g) kcal (g) kcal (g) kcal (g) kcal 1 egg fried in butter 100g slice of bacon 8g hash brown 50g slice of white toast 27g Milk 85ml Butter 10g Total % 23% 58% 0% Täubel J, Lorch U, Rossignol JF, Ferber G, John Camm A. Analyzing the relationship of QT interval and exposure to Nitazoxanide, a prospective candidate for influenza antiviral therapy J Clin Pharmacol Sep;54(9):

18 Design/Analysis

19 Design / Analysis A separate baseline day is not needed The effect is calculated from pre-dose baseline More than one time-point pre dose is desirable Suggested time window 3-5 hours from the start of the meal (which usually takes 20 min) Analysis of time effects based on the CE model Analysis of the placebo group (consider)

20 Data from a TQT study with QTc effects hours 3-5 hours Day 1: QTcF mean and 90 % CI of placebo pooled from all four periods Day 1: QTcF mean and 90 % CI based on the CE model time effects = time of start of the meal; one hour pre-dose

21 Reproducibility in comparison to Moxifloxacin

22 Moxifloxacin: Variability of ECG Response Δ2.9 ms

23 Moxifloxacin: Variability of ECG Response Δ4.1 ms If Moxifloxacin is given repeatedly to the same subjects within the same trial the variation of mean ddqtcf is >4ms between periods

24 Variation of the mean Effect Size Time Period Mean SE 90% CI Mean SE 90% CI Mean SE 90% CI 1h from start of meal 3h from start of meal Δ3.1 ms Δ3.9 ms Δ2.5 ms Study 1 (SAD) Study 2 TQT (C+) Study 3 TQT (F+) P P P P P P P P J Täubel, G Ferber, U Lorch, D Wang, M Sust, AJ Camm Single doses up to 800 mg of E do not prolong the QTc Interval A retrospective validation by pharmacokineticpharmacodynamic modelling of electrocardiography data utilising the effects of a meal on QTc to demonstrate ECG assay sensitivity PLOSONE 2015, DOI: /journal.pone J Taubel, G Ferber, G Fox, S Fernandes, U Lorch, AJ Camm Thorough QT study of the effect of intravenous APD421 (amisulpride) on QTc interval in Caucasian and Japanese healthy subjects British Journal of Clinical Pharmacology (under review) Täubel J, Lorch U, Rossignol JF, Ferber G, John Camm A. Analyzing the relationship of QT interval and exposure to Nitazoxanide, a prospective candidate for influenza antiviral therapy J Clin Pharmacol Sep;54(9): Note the SE of TQT versus SAD

25 SAD, MAD and similar

26 Does it work in SAD/MAD studies? FTIM TQT Small study populations SAD/MAD studies are not dedicated ECG studies (Noise and Bias)

27 Before you even measure a QT interval Noise (random): Lead Changes etc. Poorly defined end of T Heart rate/qt-hysteresis Clinical Site the site of manufacture ECG Core Lab and Statistics ECG Bias (if controlled): Food Drugs (e.g. DDI) Sleep/wake 1. The challenge presents itself in the clinical study site; meal effects cannot be eliminated later 2. Data needs to be free of random effects to show a QT effect in a smaller sample with more background bias/noise

28 Food effect as study bias hours from meal start Figure 4: Change in QTc from baseline on account of treatment (moxifloxacin vs. placebo using pre-dose baseline values). Figure 2: Placebo-adjusted moxifloxacin QTcF CFB comparing the use of time-matched vs. predose baseline values. CFB, change from baseline. The Effect of Moxifloxacin on QTc and Implications for the Design of Thorough QT Studies Article November 2008 Clinical Pharmacology & Therapeutics D M Bloomfield,, JA Wagner

29 N = 27 SAD/MAD TQT TD x4 TD x10

30 Retrospective use in SAD (finding MTD) Treatment (Day 1) Day -1 Baseline (placebo) (only top three doses are shown) Fig 5. Estimates of the time course of change from average baseline corrected for the concentration of each of the six analytes. The panel represents the estimated time course of the six best fitting models for QTcI during the first 12 h after drug administration. Each line represents the estimates based on the model including random slope for dqtci and one of the six analytes. The two sided 90% Cl is illustrated for each time point. The models show a good consistency regarding the estimate of time effect. Note the good agreement on the estimators based on active moiety and the five metabolites.

31 Benchmark against Gold Standard Moxifloxacin Meal effect Duration/max Effect >8 Hours/1-4 hours >6 hours/3-5 hours Effect size on ECG 8-14 ms 6-10 ms Typical time course profile yes yes Direction of effect Prolongation Shortening Mean variability within study Mean effect ~4 ms Mean effect ~4 ms Protocol In-Exclusion Hypersensitivity Diabetes Standardisation of dose 400 mg single oral dose (fed or fasted) Diet control required required ~500 kcal over 20 min (Carbo-hydrate rich) Power/Sample Size Sub-Group only Employs all subjects Acceptance criteria Point estimate 8-14 ms 90% LCI >5 ms Point estimate 5-10 ms 90% UCI <0 ms

32 Acknowledgements Ulrike Lorch MD FRCA FFPM Brian Prichard CBE FRCP FACC FESC FFPM John Camm QHP MD FRCP FESC FACC Georg Ferber

33 Thank you!