©Dr Jorg Taubel MD

The pharmacological positive control can be

replaced by a meal. Jorg Taubel- MD

(15 min)

CSRC 20161

Wednesday, April 6th, 2016CSRC/FDA Workshop: The Pro-arrhythmic Assessment of New Chemical EntitiesACC Heart House | Washington, D.C.

©Dr Jorg Taubel MD

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.

©Dr Jorg Taubel MD

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.

©Dr Jorg Taubel MD

EGC Signature

©Dr Jorg Taubel MD

Food intake: profound effect on the ECG

TQT Study in 32 Volunteers

Comparison of a fasted baseline vs. a fed baseline Day

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. 2011 Nov 8.

M

©Dr Jorg Taubel MD

Food intake: profound effect on the ECGM

1 2 3 4 5 6 hours from meal start

Notes:1. The pronounced heart rate increase (+10bpm) call

for an appropriate heart rate correction formula.2. Data shown for QTcF, QTcI and QTcB only3. 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

©Dr Jorg Taubel MD

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)

©Dr Jorg Taubel MD

1) by period, based on baseline data2) day 1 mean and 90 % CI of placebo group3) day 1 based on the CE-model time effects.

7 hours 6 hours

07 14 20 02

1 2 3 4 6 7 1 2 4 5 6 1 3 4 5 6

06

Continuous 24 hour 12-lead Holter placebo baseline day (Day -1)

©Dr Jorg Taubel MD

Notes:

1. Meal followed by a placebo injection2. QT shortening immediate 3. ECG not affected by injection4. Return to baseline 7 hours after a meal5. NO difference between breakfast and lunch6. But a reduced effect during night hours; possibly

? sleep i.e. autonomic effects ? circadian reduction of insulin and C-Peptide release

Continuous 24 hour 12-lead Holter placebo baseline day (Day -1)

©Dr Jorg Taubel MD

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

©Dr Jorg Taubel MD

What we & others have published

Glucose = QTc ProlongationClinical:

Gordin et al. 2008

Marfella et al. 2000

Non-Clinical: Tang et al. 2010

D’Amico et al. 2001

C-peptide = QTc ShorteningClinical:

Wahren et al. 2012

Dufayet et al. 1998

Non-clinical: Galuska et al. 2011

Vague et al. 2004

GLUC PK-PD C-PEPT PK-PD

©Dr Jorg Taubel MD

How to do it

©Dr Jorg Taubel MD

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

©Dr Jorg Taubel MD

Carbohydrate rich vs. high fat meal

Breakfast 11.035 Serving Cals (kcal) Proteins Carbohydrates Fat Fibre

(g) kcal (g) kcal (g) kcal (g) kcal

Breakfast Cereal, Kellogg's Cornflakes 30g 112.0 2.1 8.4 25 100.0 0.2 1.8 0.9 0.0

Semi-skimmed milk 150ml 73.2 5.1 20.4 25 100.0 2.6 23.4 0 0.0

Sugar 10g 40.0 0 0.0 10 40.0 0 0.0 0 0.0

Wholemeal hoagie 98g 235.0 11 44.0 39.4 157.6 2.3 20.7 6.4 0.0

Jam 20g 55.6 0.1 0.4 13.8 55.2 0 0.0 0.2 0.0

Butter 7.9g 58.0 0 0.0 0 0.0 6.5 58.5 0 0.0

Apple Juice 200ml 88.0 0.2 0.8 20.7 82.8 0.2 1.8 0 0.0

Total 661.818.5 74.0 133.9 535.6 11.8 106.2 7.5 0.0

11% 81% 16% 0%

Breakfast 11.035 Serving Cals (kcal) Proteins Carbohydrates Fat Fibre

(g) kcal (g) kcal (g) kcal (g) kcal

Fried egg in butter 1 egg 90.0 6.3 25.2 0.4 1.6 6.8 61.2 0 0.0

Grilled bacon 1 slice 44.0 2.9 11.6 0.1 0.4 3.5 31.5 0 0.0

Hash browns 54g 95.0 1.2 4.8 13 52.0 3.9 35.1 1.4 0.0

White toast 1 slice 64.0 2 8.0 12 48.0 0.9 8.1 0.6 0.0

Whole milk 85ml 54.6 2.8 11.2 4.3 17.2 3.1 27.9 0 0.0

Butter 7.9g 58.0 0 0.0 0 0.0 6.5 58.5 0 0.0

Total 405.6

15.2 60.8 29.8 119.2 24.7 222.3 2.0 0.0

15% 29% 55% 0%

©Dr Jorg Taubel MD

Insulin, C-Peptide and Glucose Concentrations

C-peptide has the longest t1/2

Taubel et al. 2012

©Dr Jorg Taubel MD

Carbohydrate rich versus fatty

1 2 3 4 5 6

©Dr Jorg Taubel MD

FDA breakfast shows a similar response

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. 2014 Sep;54(9):987-94. 2014

3-5 hours

Breakfast 10.035 Serving Cals (kcal) Proteins Carbohydrates Fat Fibre

(g) kcal (g) kcal (g) kcal (g) kcal

1 egg fried in butter 100g 189.9 13.0 52.0 0.1 0.2 15.3 137.7 0.5 0.01 slice of bacon 8g 41.2 3.0 12.1 0.1 0.5 3.2 28.6 0.0 0.01 hash brown 50g 77.9 2.3 9.2 12.0 48.0 2.3 20.7 2.5 0.01 slice of white toast 27g 78.4 3.0 12.0 13.0 52.0 1.6 14.4 1.0 0.0Milk 85ml 55.4 3.0 12.0 4.1 16.4 3.0 27.0 0.0 0.0Butter 10g 72.9 0.0 0.0 0.0 0.0 8.1 72.9 0.0 0.0

Total 515.724.3 97.3 29.3 117.1 33.5 301.3 4.0 0.0

19% 23% 58% 0%

N = 49

Baseline day (-1)Day 1

3-5 hours

©Dr Jorg Taubel MD

Design/Analysis

©Dr Jorg Taubel MD

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)

©Dr Jorg Taubel MD

Data from a TQT study with QTc effects

= time of start of the meal; one hour pre-dose

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 modeltime effects

0

-5

-10

-153-5 hours3-5 hours

©Dr Jorg Taubel MD

Reproducibility

… in comparison to Moxifloxacin

©Dr Jorg Taubel MD

Moxifloxacin: Variability of ECG Response

Δ2.9 ms

©Dr Jorg Taubel MD

Moxifloxacin: Variability of ECG Response

If Moxifloxacin is given repeatedly to the same subjects within the same trialthe variation of mean ddQTcF is >4ms between periods

Δ4.1 ms

©Dr Jorg Taubel MD

Variation of the mean Effect Size

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. 2014 Sep;54(9):987-94. 2014

Time Period Mean SE 90% CI Mean SE 90% CI Mean SE 90% CI

Study 1 (SAD) Study 2 TQT (C+) Study 3 TQT (F+)

1h from start of

meal

P1 -5.1 1.7 -8.0 -2.2 -6.5 1.3 -8.6 -4.3 -10.5 1.3 -12.5 -8.4

P2 -7.8 1.8 -10.7 -4.8 -6.5 1.3 -8.6 -4.3 -9.4 1.3 -11.5 -7.2

P3 -5.1 1.7 -8.0 -2.2 -4.7 1.3 -6.9 -2.5 -8.5 1.4 -10.8 -6.3

P4 -7.6 1.7 -10.4 -4.7 -6.5 1.3 -8.7 -4.3 -7.9 1.4 -10.2 -5.7

3h from start of

meal

P1 -6.8 1.8 -9.7 -3.9 -8.4 1.3 -10.6 -6.3 -10.3 1.3 -12.4 -8.2

P2 -6.6 1.8 -9.6 -3.7 -8.2 1.3 -10.4 -6.0 -7.8 1.3 -10.0 -5.6

P3 -4.7 1.7 -7.5 -1.8 -10.4 1.3 -12.6 -8.2 -9.2 1.4 -11.4 -7.0

P4 -7.1 1.7 -10.0 -4.2 -12.1 1.3 -14.3 -9.9 -8.6 1.4 -10.8 -6.3

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)

J Täubel, G Ferber, U Lorch, D Wang, M Sust, AJ Camm

Single doses up to 800 mg ofE-52862 do not prolong the QTcInterval – A retrospective validation by pharmacokinetic-pharmacodynamic modelling of electrocardiography data utilising the effects of a meal on QTc to demonstrate ECG assay sensitivity

PLOSONE 2015, DOI: 10.1371/journal.pone.0136369

Δ3.1 ms Δ2.5 msΔ3.9 ms

Note the SE of TQT versus SAD

©Dr Jorg Taubel MD

SAD, MAD and similar

©Dr Jorg Taubel MD

Does it work in SAD/MAD studies?

Small study populations

SAD/MAD studies are not dedicated ECG studies (Noise and Bias)

TQTFTIM

©Dr Jorg Taubel MD

Before you even measure a QT interval

Noise (random):• Lead Changes etc.

• Poorly defined end of T

• Heart rate/QT-hysteresis

Bias (if controlled):• Food

• Drugs (e.g. DDI)

• Sleep/wake

ECG

ECG Core Lab and Statistics

Clinical Site“the site of manufacture”

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

©Dr Jorg Taubel MD

Food effect as study bias

The Effect of Moxifloxacin on QTc and Implications for the Design of Thorough QT StudiesArticle · November 2008 · Clinical Pharmacology & TherapeuticsD M Bloomfield, …, JA Wagner

Figure 2: Placebo-adjusted moxifloxacin QTcF CFB comparing the use of time-matched vs. predose baseline values. CFB, change from baseline.

Figure 4: Change in QTc from baseline on account of treatment (moxifloxacin vs. placebo using pre-dose baseline values).

1 2 3 4 9 hours from meal start

©Dr Jorg Taubel MD

SAD/MAD TQT

TD x4 TD x10

N = 27

©Dr Jorg Taubel MD

Retrospective use in SAD (finding MTD)

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 drugadministration. Each line represents the estimates based on the model including random slope for dQTcI and one of the sixanalytes. The two sided 90% Cl is illustrated for each time point. The models show a good consistency regarding the estimate oftime effect. Note the good agreement on the estimators based on active moiety and the five metabolites.

Day -1 Baseline (placebo)

Treatment (Day 1)

0

-5

-10

0

-5

-10

+5

(only top three doses are shown)

©Dr Jorg Taubel MD

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)

~500 kcal over 20 min

(Carbo-hydrate rich)

Diet control required required

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

©Dr Jorg Taubel MD

Acknowledgements

Ulrike LorchMD FRCA FFPM

Brian PrichardCBE FRCPFACC FESC FFPM

John CammQHP MD FRCPFESC FACC

Georg Ferber

©Dr Jorg Taubel MD

Thank you!