# Presentation: 816940

## Questions from the Committee Victor Raczkowski, MD, MS

**Vice President, US Regulatory Affairs**
**Solvay Pharmaceuticals**

## BACKUP SLIDES

## Serious Adverse Events: Time of Onset Females

|  | 
Day 0-1 |  | 
Day 2-7 |  | 
8-28 day |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Tedi | Plac | Tedi | Plac | Tedi | Plac |
| Deaths | 1 (0.2%) | 0 | 2 (0.4%) | 0 | 2 (0.4%) | 1 (0.4%) |
| Hypotension | 2 (0.5%) | 1 (0.4%) | 0 | 1 (0.4%) | 0 | 0 |
| Myocardial Infarction | 0 | 0 | 2 (0.5%) | 1 (0.4%) | 1 (0.2%) | 0 |
| Ventricular Tachycardia | 2 (0.5%) | 0 | 0 | 0 | 0 | 0 |
| Thrombo-embolic Events | 1 (0.2%) | 0 | 3 (0.7%) | 3 (1.3%) | 2 (0.5%) | 0 |
| TdP | 1 (0.2%) | 0 | 0 | 0 | 0 | 0 |
| Bradycardia | 1 (0.2%) | 1 (0.4%) | 1 | 1 (0.4%) | 0 | 0 |

## Serious Adverse Events: Time of Onset Males

|  | 
0-1 Day |  | 
2-7 Days |  | 
8-28 Days |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Tedi | Plac | Tedi | Plac | Tedi | Plac |
| Deaths | 0 | 0 | 0 | 0 | 2 (0.4%) | 1 (0.4%) |
| Hypotension | 0 | 0 | 0 | 1 (0.4%) | 0 | 0 |
| Myocardial Infarction | 0 | 0 | 3 (0.6%) | 1 (0.4%) | 1 (0.2%) | 0 |
| Ventricular Tachycardia | 4 ( 0.8%) | 0 | 0 | 3 (1.2%) | 1 (0.2%) | 0 |
| Thromboembolic Events | 0 | 0 | 3 (0.6%) | 0 | 1 (0.2%) | 0 |
| TdP | 0 | 0 | 0 | 0 | 0 | 0 |
| Bradycardia | 0 | 0 | 2 (0.4%) | 0 | 1 (0.2%) | 0 |

## Serious Adverse Events: Time of Onset Females

|  | 
Day 0-1 |  | 
Day 2-7 |  | 
8-28 day |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Tedi | Plac | Tedi | Plac | Tedi | Plac |
| Deaths | 1 (0.2%) | 0 | 2 (0.5%) | 0 | 2 (0.5%) | 1 (0.4%) |
| Hypotension | 2 (0.5%) | 1 (0.4%) | 0 | 1 (0.4%) |  |  |
| Myocardial Infarction | 0 | 0 | 2 (0.5%) | 1 (0.4%) | 1 (0.2%) | 0 |
| Pulmonary Oedema | 0 | 0 | 1 (0.2%) | 0 |  |  |
| Thrombo-embolic Events | 1 (0.2%) | 0 | 3 (0.7%) | 2 (%) | 2 (0.5%) | 0 |
| TdP | 1 (0.2%) | 0 | 0 | 0 | 0 | 0 |
| Bradycardia | 1 (0.2%) | 1 (0.4%) | 1 (0.2%) | 1 (0.4%) | 0 | 0 |

## Serious Adverse Events: Time of Onset Males

|  | 
0-1 Day |  | 
2-7 Days |  | 
8-28 Days |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Tedi | Plac | Tedi | Plac | Tedi | Plac |
| Deaths | 0 | 0 | 0 | 0 | 1 (0.2%) | 2 (0.5%) |
| Hypotension | 0 | 0 | 0 | 1 (0.4%) | 0 | 0 |
| Myocardial Infarction | 0 | 0 | 3 (0.6%) | 1 (0.4%) | 1 (0.2%) | 0 |
| Pulmonary Oedema | 0 | 0 | 1 (0.2%) | 0 | 0 | 0 |
| Thromboembolic Events | 0 | 0 | 3 (0.6%) | 0 | 1 (0.4%) | 0 |
| Bradycardia | 0 | 0 | 2 (0.5%) | 0 | 0 | 0 |

## Medical History: Females

|  | Tedisamil
(N = 476) 
n    (%) | Placebo
N = 211
n    (%) |
| --- | --- | --- |
|  |  |  |
| Coronary Artery Disorder NEC | 74 ( 19.3%) | 50 ( 22.0%) |
| Heart Failure NEC | 73 ( 19.1%) | 37 ( 16.3%) |
| Myocardial Infarction | 19 ( 5.0%) | 12 ( 5.3%) |
| Acute Myocardial Infarction | 3 ( 0.8%) | 4 ( 1.8%) |
| Mitral Valvular Disorders | 22 ( 5.7%) | 17 ( 7.5%) |
| Central Nervous System Haemorrhages and Cerebrovascular Accidents | 18 ( 4.7%) | 13 ( 5.7%) |
| Vascular Hypotensive Disorders | 2 ( 0.5%) | 1 ( 0.4%) |
|  |  |  |

## Medical History: Males

|  | Tedisamil
(N = 476) 
n    (%) | Placebo
N = 211
n    (%) |
| --- | --- | --- |
|  |  |  |
| Coronary Artery Disorder NEC | 116 ( 24.4%) | 53 ( 25.1%) |
| Cardiac Valve Disorders NEC | 1 ( 0.2%) | 1 ( 0.5%) |
| Heart Failure NEC | 91 ( 19.1%) | 39 ( 18.5%) |
| Myocardial Infarction | 43 ( 9.0%) | 20 ( 9.5%) |
| Age Indeterminate Myocardial Infarction | 3 ( 0.6%) | 1 ( 0.5%) |
| Acute Myocardial Infarction | 5 ( 1.1%) | 4 ( 1.9%) |
| Mitral Valvular Disorders | 19 ( 4.0%) | 11 ( 5.2%) |
| Central Nervous System Haemorrhages and Cerebrovascular Accidents | 14 ( 2.9%)
 | 8 ( 3.8%) |
| Vascular Hypotensive Disorders | 0 | 2 ( 0.9%) |
|  |  |  |

## QTcB Change from Baseline (SD) in Normal Subjects and Subjects with Moderate Renal Impairment

| QTc prolongation (mean change from baseline) |  |  |  |  |
| --- | --- | --- | --- | --- |
|  | Combined Tedisamil |  | Placebo |  |
|  | CrCl <60 ml/min | CrCl ≥60 ml/min | CrCl <60 ml/min | CrCl ≥60 ml/min |
|  | N=161 | N=738 | N=90 | N=359 |
| QTc Bazett |  |  |  |  |
| Baseline | 428.6 ± 38.8 | 426.2 ± 33.7 | 433.8 ± 32.7 | 428.9 ± 34.5 |
| 30 min | 29.9 ± 40.0 | 31.6 ± 37.1 | -0.2 ± 22.7 | -1.2 ± 24.7 |
| 2.5 hrs | 7.0 ± 31.4 | 9.0 ± 28.8 | 2.9 ± 26.2 | -1.1 ± 25.5 |
| 4 hrs | -1.7 ± 35.4 | 3.3 ± 31.1 | -0.5 ± 32.6 | -5.9 ± 29.0 |
| 8 hrs | -0.9 ±34.1 | 2.5 ± 30.3 | -2.5 ± 28.8 | -7.2 ± 32.9 |
| 12 hrs | 3.0 ± 26.4 | 3.8 ± 27.3 | -3.3 ± 20.5 | -1.9 ± 25.7 |
| 24 hrs | -2.2 ± 31.5 | -3.6 ± 29.4 | -2.7 ± 27.9 | -7.6 ± 30.4 |

## Integrated Safety Database: TEAEs Converters vs Non-converters: Females

| System organ class
Preferred term | Subjects who Converted 
to NSR
0.48 mg/kg | Subjects who did not convert to NSR
0.48 mg/kg |
| --- | --- | --- |
| Subjects with at least 1 TEAE | 27 (61.4%)  | 119 (65.7%)  |
| Blood and lymphatic system disorders | - | 3 ( 1.7%)  |
| Cardiac disorders | 20 (45.5%)  | 71 (39.2%)  |
| Endocrine disorders | - | 8 ( 4.4%)  |
| Eye disorders | 1 ( 2.3%)  | 1 ( 0.6%)  |
| Gastrointestinal disorders | 5 (11.4%)  | 8 ( 4.4%) |
| Gen. disorders & admin. site conditions | 9 (20.5%)  | 17 ( 9.4%)  |
| Infection and infestations | 3 ( 6.8%)  | 10 ( 5.5%) |
| Injury, poisoning and procedural complications | 1 ( 2.3%)  | 2 ( 1.1%)  |
| Investigations | 2 ( 4.5%)  | 18 ( 9.9%)  |

## FDA Analysis – Sensitivity Analysis – ITT as in file: Conversion Within 2.5 hrs

| 3.112 | AFib males |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | FDA Analysis |  |  | Sensitivity Analysis |  |  |  | Dossier |  |
| mg/kg | Placebo-corrected | P-value |  | Placebo-corrected | P-value |  |  | Placebo-corrected | P-value |
| 0.32 | 17 | 0.014 |  | 17.2 | 0.014 |  |  | 17.6 | 0.0096 |
| 0.48 | 45 | <0.001 |  | 45.4 | <0.0001 |  |  | 47.3 | <0.0001 |
| 0.64 | 56 | <0.001 |  | 57.9 | <0.0001 |  |  | 61.8 | <0.0001 |

## Randomized but not TreatedReasons: AFib/AFl ITT Sample

|  | Total 
N=1169
n (%) |  | Tedisamil
N=775
n (%) |  | Placebo
N=394
n (%) |  |
| --- | --- | --- | --- | --- | --- | --- |
| Randomized but not treated  | 42 | (3.6) | 27 | (3.5) | 15 | (3.8) |
|  |  |  |  |  |  |  |
| Conversions | 28 | (2.4) | 15 | (1.9) | 13 | (3.3) |
|  |  |  |  |  |  |  |
| Non-conversions | 14 | (1.2) | 12 | (1.5) | 2 | (0.5) |
| QTc too high | 3 | (0.3) | 2 | (0.3) | 1 | (0.3) |
| AE | 2 | 0.2) | 2 | (0.3) | 0 | (0.0) |
| Other safety exclusion criteria | 3 | (0.3) | 2 | (0.3) | 1 | (0.3) |
| Withdrew consent | 3 | (0.3) | 3 | (0.4) | 0 | (0.0) |
| Unknown | 3 | (0.3) | 3 | (0.4) | 0 | (0.0) |

## Definition of Sensitivity Analysis 

- All randomized AFib subjects are included in the analysis
- Subjects who converted to NSR within 2.5 hours are counted as successes regardless of whether they also received electrical cardioversion or not
- Subjects who converted to NSR before the initiation of the study drug infusion are counted as successes

## Listing of Subjects with DC Cardioversion within 2.5 hrs after start of infusion

| SubjID | Study | Treatment | Gender |  |
| --- | --- | --- | --- | --- |
| 25825 | 3.112 | 0.64 mg/kg | M |  |
| 41021 | 3.114 | 0.32 mg/kg | M |  |
| 41420 | 3.114 | 0.48 mg/kg | M |  |
| 86405* | 3.118 | Placebo | F |  |
|  |  |  |  |  |
| 23405 | 3.112 | 0.48 mg/kg | F | Females in 3.112 not part of primary efficacy analysis |
| 25414 | 3.112 | 0.64 mg/kg | F | Females in 3.112 not part of primary efficacy analysis |
|  |  |  |  |  |
| 90136* | 2.107 | 0.32 mg/kg | F | 2.107 was not part of primary efficacy |

- *DC cardioversion was unsuccessful

## Reasons for Exclusions from AFib/AFl ITT sample - BB page 35

|  |  |  |  |  | tedisamil | placebo | Total |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| All randomized
3.112/.114/116/117/118; 
30-min; AFib/AFl |  |  |  |  | 775 | 394 | 1169 |  |  |
| Excluded: 
-  not treated |  |  |  |  | 
27 (3.5%) | 
15 (3.8%) | 
42 (3.6%) |  |  |
|  Conversion before infusion 
   (treated) |  |  |  |  | 3 (0.4%)  | 0 | 3 (0.3%) |  |  |
|   No post-baseline Holter/ECG
 |  |  |  |  | 1 (0.1%) | 0 | 1 (0.1%) |  |  |
|  AFib/AFl ITT sample |  |  |  |  | 744 | 379 | 1123 |  |  |
|  Excluded from analysis:
- DC cardioversion within 2,5 hrs |  |  |  |  | 
5 | 
1 | 
6 |  |  |
|  |  |  |  |  |  |  |  |  |  |
|  |  |  |  |  |  |  |  |  |  |

## Exclusions from AFib/AFl ITT Sample - Summary

- all exclusions of randomized subjects from ITT analyses were pre-specified
- all exclusions were done without knowledge of treatment assignment
- 4 categories
- number of exclusions were balanced between treatment groups, or very low
- no bias expected
- sensitivity analyses were performed
- including DC cardioversions as failures (dossier)
- including all randomized (additional analysis)
- no impact on efficacy findings

## Number of Randomized Subjects per Country

| Country | Study Number |  |  |  |  |  |  |  |  | Total per Country |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | 2.102 | 2.107 | 3.111 | 3.112 | 3.113 | 3.114 | 3.116 | 3.117 | 3.118 |  |
| Argentina |  |  |  |  |  | 10 | 9 |  |  | 19 |
| Bulgaria |  |  |  |  |  |  |  |  | 60 | 60 |
| Canada |  | 27 |  |  |  |  |  |  |  | 27 |
| Czech Republic |  |  |  | 5 |  |  | 25 | 23 |  | 53 |
| Germany |  | 59 | 2 |  |  | 15 | 4 |  | 1 | 81 |
| Greece |  | 2 |  |  |  |  |  |  |  | 2 |
| Hungary |  |  |  |  |  |  |  |  | 42 | 42 |
| India |  |  |  |  |  | 5 |  |  |  | 5 |
| Israel |  |  |  |  |  | 32 | 20 |  |  | 52 |
| Italy |  |  |  |  |  |  |  |  | 4 | 4 |
| Lithuania |  |  |  |  | 2 | 13 |  |  |  | 15 |
| Poland |  | 16 | 6 | 76 |  |  | 70 | 40 | 35 | 243 |
| Romania |  |  |  |  |  | 24 | 16 |  |  | 40 |
| Russian Federation         |  |  | 8 | 97 |  |  | 58 | 21 |  | 184 |
| Serbia and Montenegro         |  |  |  |  |  | 17 | 23 |  |  | 40 |
| Slovakia |  |  |  |  | 1 | 34 | 60 |  |  | 95 |
| South Africa |  |  |  |  |  | 6 | 2 |  |  | 8 |
| Sweden |  | 2 |  |  |  |  |  |  |  | 2 |
| Ukraine |  |  |  | 89 |  | 137 | 77 | 30 |  | 333 |
| United Kingdom |  |  |  |  |  | 2 | 2 |  |  | 4 |
| United States         | 26 | 94 | 1 | 16 |  |  | 1 | 9 | 13 | 160 |

## Number of Randomized Subjects by Country

| Argentina | 19 |
| --- | --- |
| Bulgaria | 60 |
| Canada | 27 |
| Czech Republic | 53 |
| Germany | 81 |
| Greece | 2 |
| Hungary | 42 |
| India | 5 |
| Israel | 52 |
| Italy | 4 |
| Lithuania | 15 |

| Poland | 243 |
| --- | --- |
| Romania | 40 |
| Russian Federation | 184 |
| Serbia and Montenegro | 40 |
| Slovakia | 95 |
| South Africa | 8 |
| Sweden | 2 |
| Ukraine | 333 |
| United Kingdom | 4 |
| USA | 160 |
|  |  |

## Pharmacokinetics in Obese Subjects

| Dose | Gender/BMI | N | Cmax
ng/ml | AUC
(ng*h/mL) |
| --- | --- | --- | --- | --- |
| 0.32 mg/kg | Female ≤ 28 kg/m2 | 92 | 984 | 3237 |
| 0.32 mg/kg | Female > 28 kg/m2 | 109 | 1014 | 3175 |
| 0.48 mg/kg | Male ≤ 28 kg/m2 | 92 | 1227 | 3593 |
| 0.48 mg/kg | Male > 28 kg/m2 | 77 | 1428 | 4052 |

## Effect of Bodyweight

- Tedisamil is a non-lipophilic drug
- Distribution over total body water only
-  basis for mg/kg dosing on BW
- For subjects BMI> 28 kg/m2:
- limit the dose to prevent high Cmax
- dosing based on BW associated with a fixed BMI of 28 kg/m2
- Meta-analysis: LBM: major effect on Volume of ditribution: supports for mg/kg dosing on BW

## Tedisamil CL Decreases up to 42% in Patients with Moderate Renal Impairment, with no Substantial Effect on Cmax following a Single Dose Short Infusion

- Time (hrs)

- Tedisamil (ng/mL)

- Tedisamil 0.32 mg/kg

## Reasons for Stopping the Infusion Prematurely Study 3.118 

|  |  | 0.32mg/kgN | PlaceboN |
| --- | --- | --- | --- |
| Safety sample (= treated) |  | 77 | 75 |
| Infusion prematurely stopped |  | 1 | 0
 |
| Reason |  |  |  |
| - | Adverse events | 1 | – |

## Reasons for Stopping the Infusion Prematurely Study 3.116 

|  |  | 0.24mg/kgN | 0.32 mg/kgN | 
PlaceboN |
| --- | --- | --- | --- | --- |
| Safety sample (= treated) |  | 120 | 120 | 118 |
| Infusion prematurely stopped |  | 2 | 3 | 2
 |
| Reason |  |  |  |  |
|  | Systolic BP < 90 mmHg | – | – | 1 |
|  | QRS duration increase > 30% | 1 | 3 | 1 |
|  | Conversion into NSR | 1 | – | – |

## Reasons for Stopping the Infusion Prematurely Study 3.117 

|  |  | 0.48 mg/kgN | 
PlaceboN |
| --- | --- | --- | --- |
| Safety sample (= treated) |  | 59 | 58 |
| Infusion prematurely stopped |  | 1 | 1
 |
| Reason |  |  |  |
| - | Patient converted to sinus rhythm | 1 | – |
| - | QRS duration increase > 30% | – | 1 |

## Reasons for Stopping the Infusion Prematurely Study 3.114 – 30-Minute Infusion

|  |  | 0.16 mg/kgN | 0.32 mg/kgN | 0.48 mg/kgN | 
PlaceboN |
| --- | --- | --- | --- | --- | --- |
| Safety sample (= treated) |  | 58 | 59 | 54 | 57 |
| Infusion prematurely stopped |  | 0 | 3 | 2 | 0 |
| Reason |  |  |  |  |  |
| - | QT interval > 550 ms and/or > 20 % increase from baseline, measured after conversion | – | – | 1 | – |
| - | Conversion to sinus rhythm | – | 1 | – | – |
| - | Conversion to sinus rhythm, bradycardia | – | – | 1 | – |
| - | Due to administrator reason protocol violation | – | 1 | – | – |
| – | Onset of ventricular tachycardia | – | 1 | – | – |

## Reasons for Stopping the Infusion PrematurelyStudy 3.112 – Females 

|  | 0.32 mg/kgN | 0.48 mg/kgN | 0.64 mg/kgN | 
PlaceboN |
| --- | --- | --- | --- | --- |
| Safety sample (= treated) | 6 | 11 | 10 | 9 |
| Infusion prematurely stopped | 1 | 1 | 1 | 0 |
| Reason	 |  |  |  |  |
| 	Systolic BP < 90 mmHg | – | – | 1 | 0 |
| 	Threatening change in rhythm or AV conduction | 1 | 1 | – | – |

## Reasons for Stopping the Infusion PrematurelyStudy 3.112 – Males

|  |  | 0.32 mg/kgN | 0.48 mg/kgN | 0.64 mg/kgN | 
PlaceboN |
| --- | --- | --- | --- | --- | --- |
| Safety sample (= treated) |  | 65 | 59 | 50 | 62 |
| Infusion prematurely stopped |  | 1 | 3 | 4 | 0
 |
| Reason |  |  |  |  |  |
| - | Threatening change in rhythm or AV conduction | – | 1 | 1 | – |
| - | QT interval > 550 ms and/or > 20 % increase from baseline, measured after conversion | 1 | 2 | 2 | – |
| - | Systolic BP < 90 mmHg, QT interval > 550 ms and/or > 20 % increase from baseline, measured after conversion | – | – | 1 | – |

## Primary Efficacy Parameter Study S219.3.118

| Dose
(mg/kg) | 3h-45d |  |  | ≤48h |  |  | >48h |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | n | %-conversion |  | n | %-conversion |  | n | %-conversion |
| 0.32 | 67 | 12 (17.9%)** |  | 19 | 8 (42.1%) |  | 16 | 4 (8.3%) |
| placebo | 67 | 3 (4.5%) |  | 48 | 2 (12.5%) |  | 52 | 1 (2.0%) |

- ** P < 0.01

## Primary Efficacy Parameter Study S219.3.117

| Dose
(mg/kg) | 3h-45d |  |  | ≤48h |  |  | >48h |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | n | %-conversion |  | n | %-conversion |  | n | %-conversion |
| 0.48 | 48 | 14 (29.2%)** |  | 23 | 13 (56.5%) |  | 25 | 1 (4.0%) |
| placebo | 48 | 3 (6.3%) |  | 32 | 3 (9.4%) |  | 16 | 0 |

- ** P < 0.01

## Primary Efficacy Parameter Study S219.3.116

| Dose
(mg/kg) |  | 3h-45d |  |  | ≤48h |  |  | >48h |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  |  | n | %-conversion |  | n | %-conversion |  | n | %-conversion |
| 0.24 | 106 |  | 10 (9.4%) |  | 32 | 13 (35.1%) |  | 74 | 2 (2.7%) |
| 0.32 | 107 |  | 23 (21.5%)*** |  | 37 | 8 (25.0%) |  | 70 | 10 (14.3%) |
| placebo | 105 |  | 3 (2.9%) |  | 32 | 1 (3.1%) |  | 73 | 2 (2.7%) |

- *** P < 0.001

## Primary Efficacy Parameter Study S219.3.114

| Dose
(mg/kg) | 3h-45d |  |  | ≤48h |  |  | >48h |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | n | %-conversion |  | n | %-conversion |  | n | %-conversion |
| 0.16 | 50  | 12 (24.0) |  | 26 | 11 (42.3%) |  | 24 | 1 (4.2%) |
| 0.32 | 51  | 15 (29.4)* |  | 18 | 11 (61.1%) |  | 33 | 4 (12.1%) |
| 0.48 | 45 | 14 (31.1)* |  | 20 | 10 (50.0%) |  | 24 | 4 (16.7%) |
| placebo | 51 | 5 (9.8) |  | 19 | 5 (26.3%) |  | 32 | 0 |

- * P < 0.05

## Primary Efficacy ParameterStudy S219.3.112

| Dose
(mg/kg) | 3h-45d |  |  | ≤48h |  |  | >48h |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | n | %-conversion |  | n | %-conversion |  | n | %-conversion |
| 0.32 | 56 | 13 (23.2%)**  |  | 26 | 9 (34.6%) |  | 30 | 4 (13.3%) |
| 0.48 | 51 | 27 (52.9%)*** |  | 28 | 18 (64.3%) |  | 23 | 9 (39.1%) |
| 0.64 | 44 | 29 (65.9%)*** |  | 27 | 19 (70.4%) |  | 17 | 10 (62.5%) |
| placebo | 53 | 3 (5.7%) |  | 28 | 3 (10.7%) |  | 25 | 0 |

- **   P < 0.01
- *** P < 0.001

## Concomitant Medications of Special Interest:Females ITT sample

|  | Subjects, n (%) |  |  |
| --- | --- | --- | --- |
|  | 0.32 mg/kg
N = 222 | Tedisamil
N = 383 | Placebo
N = 227 |
| Agents Acting on RAS  | 156 (70.3) | 271 (70.8) | 165 (72.7) |
| Antithrombotic Agents | 211 (95.0) | 361 (94.3) | 217 (95.6) |
| β-blocking Agents | 178 (80.2) | 297 (77.5) | 181 (79.7) |
| Calcium Channel Blockers | 53 (23.9) | 105 (27.4) | 69 (30.4) |
| Cardiac Therapy | 157 (70.7) | 266 (69.5) | 162 (71.4) |
| Diuretics | 98 (44.1) | 172 (44.9) | 122 (53.7) |
| Drugs used in Diabetes | 28 (12.6) | 55 (14.4) | 39 (17.2) |
| Lipid Lowering Agents | 52 (23.4) | 81 (21.1) | 51 (22.5) |

## Concomitant Medication Taken by ≥ 5% of Subjects (1) – ITT Sample

| ATC
Second Level Subgroup  | Combined Tedisamil
N = 859
n (%) | Placebo
N = 438
n (%) |
| --- | --- | --- |
| Agents acting on the Renin-Angiotensin System  | 546 (63.6) | 280 (63.9) |
| All other Therapeutic Products  | 43 (5.0) | < 5% |
| Analgesics  | 120 (14.0) | 52 (11.9) |
| Anesthetics  | 224 (26.1) | 133 (30.4) |
| Antibacterials for Systemic Use | 61 (7.1) | 37 (8.4) |
| Antihistamines for Systemic Use | < 5%  | < 5%  |
| Antihypertensives | < 5%  | 28 (6.4)  |
| Anti-inflammatory and Anti-rheumatic Products | < 5%  | < 5%  |
| Anti-thrombotic Agents | 815 (94.9) | 412 (94.1) |
| Beta-Blocking Agents | 637 (74.2) | 333 (76.0) |
| Blood Substitutes and Perfusion Solutions | 97 (11.3) | 68 (15.5) |
| Calcium Channel Blockers | 197 (22.9) | 117 (26.7)  |
| Cardiac Therapy | 574 (66.8) | 312 (71.2) |

## Baseline CharacteristicsHistory of AFib/AFl

|  | Males |  |  | Females |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil | Placebo |  | Tedisamil | Placebo |
|  | N = 476 | N = 211 |  | N = 383 | N = 227 |
| Subjects with first episode, n (%)  | 237 (49.8) | 95 (45.0) |  | 175 (45.7) | 106 (46.7) |
| Subjects with recurrent episode, n (%) | 239 (50.2) | 116 (55.0) |  | 208 (54.3) | 121 (53.3) |
| 	Atrial Fibrillation  | 190 (79.5) | 95 (81.9) |  | 178 (85.6) | 99 (81.8) |
| 	Atrial Flutter  | 19 (7.9) | 13 (11.2) |  | 10 (4.8) | 6 (5.0) |
| 	Both | 30 (12.6) | 8 (6.9) |  | 20 (9.6) | 15 (12.4)  |
| Mean duration of AFib/AFl in yrs ± SD | 5.0 ± 5.8 | 4.5 ± 5.4 |  | 3.3 ± 3.5 | 3.3 ± 3.4 |

## Baseline Characteristics Predominant Rhythm 

|  | Subjects, n (%) |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Males |  |  | Females |  |  |
|  | 0.48 mg/kg | Combined Tedisamil | Placebo | 0.32 mg/kg | Combined Tedisamil | Placebo |
|  AFib | 174 (84.1) | 449 (85.0) | 191 (82.7) | 199 (88.4) | 351 (87.1) | 217 (90.8) |
| AFl | 33 (15.9) | 79 (15.0) | 40 (17.3) | 26 (11.6) | 52 (12.9) | 22 (9.2) |

## Baseline CharacteristicsHistory of AFib/AFl

|  | Males |  |  | Females |  |
| --- | --- | --- | --- | --- | --- |
|  | Tedisamil | Placebo |  | Tedisamil | Placebo |
|  | N = 476 | N = 211 |  | N = 383 | N = 227 |
| Subjects with first episode, n (%)  | 237 (49.8)  | 95 (45.0)  |  | 175 (45.7)  | 106 (46.7)  |
| Subjects with recurrent episode, n (%) | 239 (50.2)  | 116 (55.0)  |  | 208 (54.3)  | 121 (53.3)  |
|  Mean Duration of AFib/AFl in yrs ± SD* | 5.0 ± 5.8  | 4.5 ± 5.4  |  | 3.3 ± 3.5  | 3.3 ± 3.4  |

*** for those with a recurrent episode**

## Primary Efficacy Parameter Conversion to NSR within 2.5 hrs – By History of AFIB/AFL

| Dose,
mg/kg | Male |  |  |  |  | Female |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | First
episode |  | Recurrent
episode |  |  | First
episode |  | Recurrent
episode |  |
|  | n | Converting, % | n | Converting, % |  | n | Converting, % | n | Converting, % |
| 0.16 | 34 | 6 (17.6) | 24 | 6 (25.0) |  | 0 | - | 0 | - |
| 0.24 | 0 | - | 0 | - |  | 63 | 7 (11.1) | 55 | 5 (9.1) |
| 0.32 | 53 | 9 (17.0) | 69 | 19 (27.5) |  | 90 | 15 (16.7) | 112 | 22 (19.6) |
| 0.48 | 99 | 29 (29.3) | 72 | 30 (41.7) |  | 2 | 1 (50.0) | 8 | 1 (12.5) |
| 0.64 | 24 | 17 (70.8) | 25 | 15 (60.0) |  | 3 | 1 (33.3) | 8 | 2 (33.3) |
| Placebo | 83 | 6 (7.2) | 94 | 5 (5.3) |  | 94 | 3 (3.2) | 107 | 6 (5.6)  |

## Primary Efficacy Parameter Conversion to NSR Within 2.5 hrs – By Predominant Rhythm

| Dose,
mg/kg | Male |  |  |  |  |  | Female |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | AFib |  |  | AFl |  |  | AFib |  |  | AFl |  |
|  | n | Converting, %  |  | n | Converting, %  |  | n | Converting, %  |  | n | Converting, % |
| 0.16 | 50 | 12 (24.0) |  | 8 | 0 |  | 0 | - |  | 0 |  |
| 0.24 | 0 | - |  | 0 | - |  | 106 | 10 (9.4) |  | 12 | 2 (16.7) |
| 0.32 | 107 | 28 (26.2) |  | 15 | 0 |  | 179 | 36 (20.1) |  | 23 | 1 (4.3) |
| 0.48 | 144 | 55 (38.2) |  | 27 | 4 (14.8) |  | 8 | 2 (25.0) |  | 2 | 0 |
| 0.64 | 43 | 29 (67.4) |  | 6 | 3 (50.0) |  | 2 | 2 (33.3) |  | 3 | 1 (33.3) |
| Placebo | 152 | 11 (7.2) |  | 25 | 0 |  | 180 | 6 (3.3) |  | 21 | 3 (14.3) |

## HemodynamicsK.219.5005

| Dosage group
(mg/kg) |  | PAP(mmHg) | PCWP(mmHg) | PAEDP(mmHg) | PRA(mmHg) | PRV(mmHg) |
| --- | --- | --- | --- | --- | --- | --- |
| 0.1 | Rest | -2.1 | -1.4 | -2.5 | -0.3 | 0.0 |
|  | Max workload | -0.6 | -0.9 | -3.1 |  |  |
| 0.2 | Rest | -1.6 | -0.9 | -1.3 | -0.3 | -0.4 |
|  | Max workload | +1.0 | -1.4 | +0.5 |  |  |
| 0.3 | Rest | +1.8 | +2.3* | +1.6 | +0.9 | +0.9 |
|  | Max workload | +2.6 | +4.8 | +4.3 |  |  |
| 0.4 | Rest | +3.3* | +2.8 | +2.6* | +1.5 | +1.5 |
|  | Max workload | -1.8 | -0.1 | -1.0 |  |  |
| Mean values       * p<0.05           ** p<0.01 |  |  |  |  |  |  |

***Table 6:  Effects of Tedisamil on Pulmonary and Cardiac Pressure Indices – differences post-drug and pre-drug***

## HemodynamicsK.219.5005

- Study K.219.5005
- Single, intravenous, rising dose, open study of tedisamil dihydrochloride (KC 8857) investigating hemodynamics in patients with documented ischemic heart disease.

## HemodynamicsS219.3.109

|  | Visit | Tedisamil(N = 24) | Placebo(N = 32) | p-value for difference |
| --- | --- | --- | --- | --- |
| RAP (mmHg) | Baseline | 7.4 ± 3.7 | 7.3 ± 3.7 |  |
|  | Visit 9 (Wk 12) | 5.2 ± 3.4 | 5.0 ± 5.5 |  |
|  | Change from baseline | -2.4 ± 3.5 | -2.9 ± 4.8 | 0.784 |
|  |  |  |  |  |
| ESRVP (mmHg) | Baseline | 39.7 ± 12.1 | 42.7 ± 15.8 |  |
|  | Visit 9 (Wk 12) | 38.4 ± 14.2 | 41.2 ± 19.2 |  |
|  | Change from baseline | -1.3 ± 10.3 | -1.1 ± 12.3 | 0.999 |
|  |  |  |  |  |
| EDRVP (mmHg) | Baseline | 3.6 ± 2.5 | 3.7 ± 2.6 |  |
|  | Visit 9 (Wk 12) | 3.0 ± 2.7 | 3.0 ± 4.0 |  |
|  | Change from baseline | -0.8 ± 2.6 | -0.6 ± 3.9 | 0.849 |
| RAP = right atrial pressure; ESRVP = endsystolic right ventricular pressure; EDRVP = enddiastolic right ventricular pressure. |  |  |  |  |

***Secondary Parameter:  Pulmonary Capillary Wedge Pressure (PCWP) at Rest Per-protocol patient sample (N = 56)***

## HemodynamicsS219.3.109

| PCWP at rest (mmHg) | Tedisamil
(N = 24) mean ± SD | Placebo 
(N = 32) mean ± SD | p-value for equivalence |
| --- | --- | --- | --- |
| Baseline | 18.1 ± 5.4 | 19.4 ± 6.2 |  |
| Visit 9 (wk 12) | 16.0 ± 6.2 | 16.2 ± 8.8 |  |
| Visit 9 - baseline | -2.0 ± 5.6 | -3.2 ± 7.5 | 0.070 |
|  |  |  |  |

***Primary Parameter: Pulmonary Capillary Wedge Pressure (PCWP) at Rest***
***Per-protocol patient sample (N = 56)***

## HemodynamicsS219.3.109

- Study  S219.3.109
- Double-blind randomized study comparing the hemodynamic effects of oral tedisamil and placebo in patients with symptomatic congestive heart failure

## In Normal Sinus Rhythm at 24 hrs

| Males |  |  |
| --- | --- | --- |
|  | 0.48 mg/kg Tedisamil | Placebo |
| NSR at 24 hrs | 88/172 (51%) | 84/177 (47%) |
| – no DC | 61/133 (46%) | 36/122 (30%) |
| – DC | 27/39 (69%) | 48/55 (87%) |
| Females |  |  |
|  | 0.32 mg/kg Tedisamil | Placebo |
| NSR at 24 hrs | 80/202 (40%) | 69/202 (34%) |
| – no DC | 49/163 (30%) | 27/152 (18%) |
| – DC | 31/39 (79%) | 42/50 (84%) |

## Conversion to NSR – Male

|  | 3 – 48 hrs | 48 hrs – 7 days | 8 – 45 days |
| --- | --- | --- | --- |
| tedisamil 0.48 mg/kg | 52.4% | 28.6% | 13.1% |
| Placebo | 12.4% | 0 | 0 |
| Change | 40.0% | 28.6% | 13.1% |

***AFib/AFl Duration***

## Conversion to NSR – Female

|  | 3 – 48 hrs | 48 hrs – 7 days | 8 – 45 days |
| --- | --- | --- | --- |
| tedisamil 0.32 mg/kg | 32.4% | 16.3 | 8.0% |
| Placebo | 10.0% | 0% | 3.3% |
| Change | 22.4% | 16.3% | 4.7% |

***AFib/AFl Duration***