Trial | NCT02544217

Trial | NCT02544217 Report issue

Title

A Dose-escalating Clinical Trial With KH176

A Phase I, Randomized, Double Blind, Placebo-controlled, Dose-escalating Clinical Trial With KH176

Phase
Phase 1

Lead Sponsor
Khondrion BV

Study Type
Interventional

Status
Completed Results Posted

Indication/Condition
Mitochondrial Disease Mitochondrial DNA tRNALeu(UUR) m.3243A<G Mutation MELAS LHON Leigh Syndrome

Intervention/Treatment
kh176 ...
KH176 placebo

Study Participants
32

Mitochondrial Diseases are rare progressive, multi-system, often early fatal disorders affecting both children and adults. KH176 is a novel chemical entity currently under development for the treatment of inherited mitochondrial diseases, including MELAS (Mitochondrial Encephalomyopathy, Lactic acidosis, and Stroke-like episodes), Leigh's Disease and Leber's Hereditary Optic Neuropathy (LHON). KH176 is a potent intracellular redox modulating agent targeting the reactive oxygen species which are important in the pathogenesis of disorders of mitochondrial oxidative phosphorylation. After demonstrating a favourable safety profile in the pre-clinical testing, the safety, tolerability and pharmacokinetic and pharmacodynamic characteristics of the compound will now be evaluated in healthy male subjects in this trial

Study Started

May 31

2015

Primary Completion

Sep 30

2015

Study Completion

Oct 31

2015

Results Posted

Nov 12

2020

Last Update

Oct 18

2021

Drug KH176

Drug placebo

Single Escalating Experimental

2 alternating groups receiving escalating single doses of active/placebo

Drug KH176
Drug placebo

Multiple Escalating Experimental

3 multiple escalating groups, receiving active/placebo

Drug KH176
Drug placebo

Criteria

Inclusion Criteria:

Healthy as assessed by medical history, physical examination, Vital Signs, Clinical Laboratory, ECG

Exclusion Criteria:

Allergies,
Concomitant medication,
concomitant disease,
relevant surgery,
recent blood donation

Summary

Group I Placebo

Group II Placebo

SAD Group I 10mg

SAD Group II 30mg

SAD Group I 100mg

SAD Group II 300mg

SAD Group I 800mg

SAD Group II 2000mg

Group I Placebo + Food

Group I 100mg + Food

MAD Group III 200mg

MAD Group IV 400mg

MAD Group V 800mg

Placebo

All Events

Event Type	Organ System	Event Term	Group I Placebo	Group II Placebo	SAD Group I 10mg	SAD Group II 30mg	SAD Group I 100mg	SAD Group II 300mg	SAD Group I 800mg	SAD Group II 2000mg	Group I Placebo + Food	Group I 100mg + Food	MAD Group III 200mg	MAD Group IV 400mg	MAD Group V 800mg	Placebo

Relationship to Study Drug and Severity of Treatment-emergent Adverse Events

Group I Placebo

Not related TEAE

4.0

TEAE

Possibly related

1.0

SAD Group I 10mg

Not related TEAE

Possibly related

Serious TEAE

TEAE

2.0

TEAE

Unlikely related

2.0

Serious TEAE

TEAE

7.0

TEAE

Unlikely related

SAD Group II 300mg

Not related TEAE

Possibly related

1.0

TEAE

Serious TEAE

TEAE

1.0

TEAE

Unlikely related

SAD Group I 800mg

Not related TEAE

Possibly related

Serious TEAE

TEAE

Unlikely related

SAD Group II 2000mg

Not related TEAE

Possibly related

3.0

Unlikely related

1.0

TEAE

SAD: Change From Baseline in ECG Results by Timepoint: Corrected QT Interval According to Fridericia's Formula (QTcF)

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation of the corrected QT intervals the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing. QTcF is calculated as the quotient between the QT interval in milliseconds and the cube root of the RR interval in seconds, according to Fridericia's formula.

msec (Mean)

Standard Deviation: 4.0

Change from BL at FU

2.8

Change from BL at FU

6.5

msec (Mean)

Standard Deviation: 13.0

Pharmacodynamics of KH176

Change from baseline in biochemistry related to Oxidative Phosphorylation (OXPHOS) (glutathione, lactate); MAD group

Standard Deviation: 532

MAD Group IV

GSH/GSSG Day 7-0h

1694.0

ratio GSH/GSSG (Mean)

Standard Deviation: 572

GSH/GSSG Day 7-12h

1680.0

ratio GSH/GSSG (Mean)

Standard Deviation: 657

GSH/GSSG Day 7-3h

1712.0

ratio GSH/GSSG (Mean)

Standard Deviation: 465

GSH/GSSG Day 7-6h

1718.0

ratio GSH/GSSG (Mean)

Standard Deviation: 542

Ox glutathione (GSH)/Red Glutathati(GSSG) Day 1-0h

1584.0

ratio GSH/GSSG (Mean)

Standard Deviation: 491

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Red Blood Cell Count. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Erythrocyte Sedimentation Rate (SAD Group)

Standard Deviation: 1.2

Group II Placebo

Baseline

2.8

mm/hr (Mean)

Standard Deviation: 2.1

Change from BL at 24h

0.3

mm/hr (Mean)

Standard Deviation: 1.0

Baseline

2.0

mm/hr (Mean)

Standard Deviation: 1.4

Change from BL at 24h

Change from BL at FU

0.5

Standard Deviation: 6.8

SAD Group II 2000mg

Baseline

4.0

mm/hr (Mean)

Standard Deviation: 3.2

Change from BL at 24h

3.0

mm/hr (Mean)

Standard Deviation: 3.6

Change from BL at FU

0.5

Group I 100mg + Food

Baseline

2.5

mm/hr (Mean)

Standard Deviation: 3.0

Change from BL at 24h

1.0

mm/hr (Mean)

Standard Deviation: 2.0

Change from BL at FU

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Erythrocyte Sedimentation Rate MAD Group

Standard Deviation: 3.5

MAD Group III

Baseline (pre-dose Day 1)

4.0

mm/hr (Mean)

Standard Deviation: 2.4

Change from BL at Day 3

2.0

mm/hr (Mean)

Standard Deviation: 3.5

Change from BL at Day 8

4.8

mm/hr (Mean)

Standard Deviation: 5.7

Change from BL at FU

5.0

Baseline (pre-dose Day 1)

2.0

mm/hr (Mean)

Standard Deviation: 1.4

Change from BL at Day 3

0.5

mm/hr (Mean)

Standard Deviation: 0.6

Change from BL at Day 8

2.5

mm/hr (Mean)

Standard Deviation: 1.7

Change from BL at FU

1.0

mm/hr (Mean)

Standard Deviation: 0.8

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Hematocrit SAD Group

Hematocrit is a measure of the ratio of red blood cells (RBCs) in the blood by volume. Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Haemoglobin. SAD

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Hemoglobin Concentration - SAD

Erythrocyte mean corpuscular hemoglobin concentration (MCHC) is a measure of the average concentration of hemoglobin per red blood cell. Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.62

Group II Placebo

Baseline (pre-dose Day 1)

33.98

g/dL RBC (Mean)

Standard Deviation: 1.01

Change from BL at 24h - Day 1

0.43

g/dL RBC (Mean)

Standard Deviation: 0.42

Change from BL at FU

0.47

g/dL RBC (Mean)

Standard Deviation: 0.42

SAD Group I 10mg

Baseline (pre-dose Day 1)

34.18

0.45

g/dL RBC (Mean)

Standard Deviation: 0.68

Change from BL at FU

-0.2

g/dL RBC (Mean)

Standard Deviation: 0.42

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Volume - SAD

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 1.85

Group II Placebo

Baseline (pre-dose Day 1)

87.52

fL (Mean)

Standard Deviation: 3.71

Change from BL at 24h

-0.38

fL (Mean)

Standard Deviation: 1.09

Change from BL at FU

-1.03

Baseline (pre-dose Day 1)

88.35

fL (Mean)

Standard Deviation: 2.88

Change from BL at 24h

0.48

fL (Mean)

Standard Deviation: 0.41

Change from BL at FU

-0.92

fL (Mean)

Standard Deviation: 1.28

SAD Group I 100mg

Baseline (pre-dose Day 1)

86.93

-0.55

fL (Mean)

Standard Deviation: 0.79

Change from BL at FU

0.2

fL (Mean)

Standard Deviation: 0.81

MAD: Change From Baseline in ECG Results by Time Point: QTcF

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation of the corrected QT intervals the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing, or around the expected Cmax on Day 1 or 7 for the multiple-dose part. QTcF is calculated as the quotient between the QT interval in milliseconds and the cube root of the RR interval in seconds, according to Fridericia's formula.

Change From Baseline in Hematology Laboratory Test Results by Timepoint: White Blood Cell Count. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Lymphocytes. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Neutrophils. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Hematocrit MAD Group

Hematocrit is a measure of the ratio of red blood cells (RBCs) in the blood by volume. Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value

MAD Group III

Baseline

39.93

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 1.20

Change from BL at Day 3

2.67

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 1.94

Change from BL at Day 8

3.3

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 1.24

Change from BL at FU

0.92

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 1.06

MAD Group IV

Baseline

43.4

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 3.51

Change from BL at Day 3

1.17

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 1.69

Change from BL at Day 8

1.22

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 3.26

Change from BL at FU

-0.1

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 3.26

MAD Group V

Baseline

45.1

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 1.33

Change from BL at Day 3

0.13

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 0.45

Change from BL at Day 8

0.1

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 1.22

Change from BL at FU

-1.05

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 0.64

Placebo

Baseline

43.3

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 1.95

Change from BL at Day 3

1.7

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 1.91

Change from BL at Day 8

1.93

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 2.69

Change from BL at FU

-0.75

% of red cells to volume of whole blood. (Mean)

Standard Deviation: 2.32

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Eosinophils. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Thrombocytes. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Group I Placebo

Baseline (pre-dose Day 1)

209.5

0.3

cells 10^3/µL (Mean)

Standard Deviation: 9.0

Change from BL at FU

16.3

cells 10^3/µL (Mean)

Standard Deviation: 12.5

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Basophils. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value ateach timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Group I Placebo

Baseline (pre-dose Day 1)

23.3

cells/µL (Mean)

Standard Deviation: 5.2

Change from BL at 24h

-5.0

Baseline (pre-dose Day 1)

30.0

cells/µL (Mean)

Standard Deviation: 18.3

Change from BL at 24h

-7.5

cells/µL (Mean)

Standard Deviation: 9.6

Baseline (pre-dose Day 1)

20.0

cells/µL (Mean)

Standard Deviation: 11.5

Change from BL at 24h

2.5

cells/µL (Mean)

Standard Deviation: 5.0

Change from BL at FU

20.0

Standard Deviation: 21.2

Group I 100mg + Food

Baseline (pre-dose Day 1)

25.0

cells/µL (Mean)

Standard Deviation: 17.3

Change from BL at 24h

-2.5

cells/µL (Mean)

Standard Deviation: 9.6

Change from BL at FU

-2.5

cells/µL (Mean)

Standard Deviation: 5.0

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Monocytes. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

SAD Group I 800mg

Baseline (pre-dose Day 1)

462.5

cells/µL (Mean)

Standard Deviation: 147.1

Change from BL at 24h

-25.0

cells/µL (Mean)

Standard Deviation: 112.4

Change from BL at FU

Standard Deviation: 63.4

Group I Placebo + Food

Baseline (pre-dose Day 1)

550.0

cells/µL (Mean)

Standard Deviation: 70.7

Change from BL at 24h

-45.0

cells/µL (Mean)

Standard Deviation: 21.2

Change from BL at FU

-20.0

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.74

MAD Group IV

Baseline (pre-dose Day 1)

89.32

fL (Mean)

Standard Deviation: 2.73

Change from BL at Day 3

0.52

fL (Mean)

Standard Deviation: 1.15

Change from BL at Day 8

-0.43

fL (Mean)

Standard Deviation: 0.28

Change from BL at FU

-0.55

Baseline (pre-dose Day 1)

89.02

fL (Mean)

Standard Deviation: 2.93

Change from BL at Day 3

0.4

fL (Mean)

Standard Deviation: 1.08

Change from BL at Day 8

0.28

fL (Mean)

Standard Deviation: 0.95

Change from BL at FU

0.65

fL (Mean)

Standard Deviation: 0.77

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Hemoglobin. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.49

MAD Group IV

Baseline (pre-dose Day 1)

15.23

g/dL (Mean)

Standard Deviation: 1.38

Change from BL at Day 3

0.42

g/dL (Mean)

Standard Deviation: 0.74

Change from BL at Day 8

0.55

g/dL (Mean)

Standard Deviation: 1.22

Change from BL at FU

-0.05

Baseline (pre-dose Day 1)

14.82

g/dL (Mean)

Standard Deviation: 0.67

Change from BL at Day 3

0.62

g/dL (Mean)

Standard Deviation: 0.50

Change from BL at Day 8

0.75

g/dL (Mean)

Standard Deviation: 0.83

Change from BL at FU

-0.35

g/dL (Mean)

Standard Deviation: 0.63

Change From Baseline in Hematology Laboratory Test Results by Timepoint: White Blood Cell Count. MAD

Blood samples were collected from participants at the indicated time points for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each time point are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 2.519

MAD Group IV

Baseline (pre-dose Day 1)

4.753

cells 10^3/µL (Mean)

Standard Deviation: 0.410

Change from BL at Day 3

0.48

cells 10^3/µL (Mean)

Standard Deviation: 0.787

Change from BL at Day 8

0.48

cells 10^3/µL (Mean)

Standard Deviation: 0.252

Change from BL at FU

0.23

Baseline (pre-dose Day 1)

4.583

cells 10^3/µL (Mean)

Standard Deviation: 0.487

Change from BL at Day 3

0.277

cells 10^3/µL (Mean)

Standard Deviation: 0.932

Change from BL at Day 8

0.563

cells 10^3/µL (Mean)

Standard Deviation: 0.983

Change from BL at FU

-0.14

cells 10^3/µL (Mean)

Standard Deviation: 0.930

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Neutrophils. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 2317.4

MAD Group IV

Baseline (pre-dose Day 1)

2602.5

cells/µL (Mean)

Standard Deviation: 582.4

Change from BL at Day 3

350.0

cells/µL (Mean)

Standard Deviation: 602.4

Change from BL at Day 8

312.5

cells/µL (Mean)

Standard Deviation: 355.1

Change from BL at FU

177.5

Baseline (pre-dose Day 1)

2483.3

cells/µL (Mean)

Standard Deviation: 583.6

Change from BL at Day 3

81.7

cells/µL (Mean)

Standard Deviation: 540.7

Change from BL at Day 8

261.0

cells/µL (Mean)

Standard Deviation: 634.9

Change from BL at FU

-75.0

cells/µL (Mean)

Standard Deviation: 532.1

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Haemoglobin Concentration. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.44

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Lymphocytes. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 257.5

MAD Group IV

Baseline (pre-dose Day 1)

1498.5

cells/µL (Mean)

Standard Deviation: 125.1

Change from BL at Day 3

159.0

cells/µL (Mean)

Standard Deviation: 188.6

Change from BL at Day 8

124.0

cells/µL (Mean)

Standard Deviation: 148.8

Change from BL at FU

39.0

Baseline (pre-dose Day 1)

1508.3

cells/µL (Mean)

Standard Deviation: 317.1

Change from BL at Day 3

215.0

cells/µL (Mean)

Standard Deviation: 372.3

Change from BL at Day 8

283.3

cells/µL (Mean)

Standard Deviation: 402.6

Change from BL at FU

5.0

cells/µL (Mean)

Standard Deviation: 465.9

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Mean Corpuscular Hemoglobin. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.47

MAD Group IV

Baseline (pre-dose Day 1)

31.33

pg/cell (Mean)

Standard Deviation: 1.24

Change from BL at Day 3

0.23

pg/cell (Mean)

Standard Deviation: 0.39

Change from BL at Day 8

0.12

pg/cell (Mean)

Standard Deviation: 0.22

Change from BL at FU

-0.2

Baseline (pre-dose Day 1)

30.47

pg/cell (Mean)

Standard Deviation: 0.97

Change from BL at Day 3

0.2

pg/cell (Mean)

Standard Deviation: 0.25

Change from BL at Day 8

0.25

pg/cell (Mean)

Standard Deviation: 0.33

Change from BL at FU

0.02

pg/cell (Mean)

Standard Deviation: 0.25

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Red Blood Cell Count. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.099

MAD Group IV

Baseline (pre-dose Day 1)

4.858

cells 10^6/µL (Mean)

Standard Deviation: 0.380

Change from BL at Day 3

0.1

cells 10^6/µL (Mean)

Standard Deviation: 0.193

Change from BL at Day 8

0.16

cells 10^6/µL (Mean)

Standard Deviation: 0.362

Change from BL at FU

0.02

Baseline (pre-dose Day 1)

4.873

cells 10^6/µL (Mean)

Standard Deviation: 0.360

Change from BL at Day 3

0.167

cells 10^6/µL (Mean)

Standard Deviation: 0.196

Change from BL at Day 8

0.198

cells 10^6/µL (Mean)

Standard Deviation: 0.249

Change from BL at FU

-0.12

cells 10^6/µL (Mean)

Standard Deviation: 0.237

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Eosinophils. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 131.8

MAD Group IV

Baseline (pre-dose Day 1)

183.5

cells/µL (Mean)

Standard Deviation: 84.6

Change from BL at Day 3

-31.0

cells/µL (Mean)

Standard Deviation: 53.2

Change from BL at Day 8

-28.5

cells/µL (Mean)

Standard Deviation: 66.0

Change from BL at FU

31.5

Baseline (pre-dose Day 1)

141.7

cells/µL (Mean)

Standard Deviation: 96.2

Change from BL at Day 3

-28.3

cells/µL (Mean)

Standard Deviation: 43.6

Change from BL at Day 8

-22.7

cells/µL (Mean)

Standard Deviation: 56.4

Change from BL at FU

-45.0

cells/µL (Mean)

Standard Deviation: 76.4

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Monocytes. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 176.7

MAD Group IV

Baseline (pre-dose Day 1)

424.0

cells/µL (Mean)

Standard Deviation: 140.9

Change from BL at Day 3

-11.5

cells/µL (Mean)

Standard Deviation: 142.6

Change from BL at Day 8

76.0

cells/µL (Mean)

Standard Deviation: 95.3

Change from BL at FU

-21.5

Baseline (pre-dose Day 1)

418.3

cells/µL (Mean)

Standard Deviation: 61.5

Change from BL at Day 3

1.7

cells/µL (Mean)

Standard Deviation: 64.3

Change from BL at Day 8

24.3

cells/µL (Mean)

Standard Deviation: 53.1

Change from BL at FU

-43.3

cells/µL (Mean)

Standard Deviation: 85.0

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Thrombocytes. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 41.3

MAD Group IV

Baseline (pre-dose Day 1)

211.5

cells 10^3/µL (Mean)

Standard Deviation: 41.2

Change from BL at Day 3

17.5

cells 10^3/µL (Mean)

Standard Deviation: 9.5

Change from BL at Day 8

4.8

cells 10^3/µL (Mean)

Standard Deviation: 22.3

Change from BL at FU

5.5

Baseline (pre-dose Day 1)

206.7

cells 10^3/µL (Mean)

Standard Deviation: 48.1

Change from BL at Day 3

17.3

cells 10^3/µL (Mean)

Standard Deviation: 15.1

Change from BL at Day 8

29.5

cells 10^3/µL (Mean)

Standard Deviation: 12.5

Change from BL at FU

21.7

cells 10^3/µL (Mean)

Standard Deviation: 10.7

Change From Baseline in Hematology Laboratory Test Results by Timepoint: Basophils. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 15.0

MAD Group IV

Baseline (pre-dose Day 1)

34.0

cells/µL (Mean)

Standard Deviation: 10.8

Change from BL at Day 3

8.5

cells/µL (Mean)

Standard Deviation: 17.4

Change from BL at Day 8

-6.5

cells/µL (Mean)

Standard Deviation: 17.0

Change from BL at FU

1.0

Baseline (pre-dose Day 1)

23.3

cells/µL (Mean)

Standard Deviation: 10.3

Change from BL at Day 3

3.3

cells/µL (Mean)

Standard Deviation: 8.2

Change from BL at Day 8

4.0

cells/µL (Mean)

Standard Deviation: 14.7

Change from BL at FU

5.0

cells/µL (Mean)

Standard Deviation: 18.7

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Aspartate Aminotransferase. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Group I 100mg + Food

Baseline (pre-dose Day 1)

18.5

U/L (Mean)

Standard Deviation: 4.8

Change from BL at 24h

-1.0

U/L (Mean)

Standard Deviation: 2.2

Change from BL at FU

Standard Deviation: 1.0

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Total Protein. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

SAD Group I 800mg

Baseline (pre-dose Day 1)

66.3

g/L (Mean)

Standard Deviation: 3.5

Change from BL at 24h

3.0

g/L (Mean)

Standard Deviation: 5.0

Change from BL at FU

Standard Deviation: 3.3

Group I Placebo + Food

Baseline (pre-dose Day 1)

66.5

g/L (Mean)

Standard Deviation: 2.1

Change from BL at 24h

2.5

g/L (Mean)

Standard Deviation: 4.9

Change from BL at FU

1.0

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value

Standard Deviation: 13.8

Group II Placebo

Baseline (pre-dose Day 1)

19.0

U/L (Mean)

Standard Deviation: 14.1

Change from BL at 24h

1.2

U/L (Mean)

Standard Deviation: 2.1

Change from BL at FU

10.0

U/L (Mean)

Standard Deviation: 16.1

SAD Group I 10mg

Baseline (pre-dose Day 1)

24.0

Change from BL at FU

3.5

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Creatinine. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Chloride. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 3.5

Group II Placebo

Baseline (pre-dose Day 1)

104.0

mmol/L (Mean)

Standard Deviation: 1.7

Change from BL at 24h

-2.5

mmol/L (Mean)

Standard Deviation: 1.4

Change from BL at FU

-3.2

Baseline (pre-dose Day 1)

104.0

mmol/L (Mean)

Standard Deviation: 0.8

Change from BL at 24h

-3.5

mmol/L (Mean)

Standard Deviation: 0.6

Change from BL at FU

-3.5

mmol/L (Mean)

Standard Deviation: 1.3

SAD Group I 100mg

Baseline (pre-dose Day 1)

102.3

-0.5

mmol/L (Mean)

Standard Deviation: 1.3

Change from BL at FU

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Total Bilirubin. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.42

Group II Placebo

Baseline (pre-dose Day 1)

0.75

mg/dL (Mean)

Standard Deviation: 0.60

Change from BL at 24h

0.12

mg/dL (Mean)

Standard Deviation: 0.08

Change from BL at FU

-0.02

Baseline (pre-dose Day 1)

0.68

mg/dL (Mean)

Standard Deviation: 0.33

Change from BL at 24h

0.38

mg/dL (Mean)

Standard Deviation: 0.13

Baseline (pre-dose Day 1)

0.63

mg/dL (Mean)

Standard Deviation: 0.22

Change from BL at 24h

-0.03

mg/dL (Mean)

Standard Deviation: 0.15

Change from BL at FU

Standard Deviation: 0.10

Group I Placebo + Food

Baseline (pre-dose Day 1)

0.45

mg/dL (Mean)

Standard Deviation: 0.21

Change from BL at 24h

0.15

mg/dL (Mean)

Standard Deviation: 0.07

Change from BL at FU

0.1

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Creatinine Kinase. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Urea. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Group I Placebo

Baseline (pre-dose Day 1)

27.5

mg/dL (Mean)

Standard Deviation: 9.3

Change from BL at 24h

Change from BL at FU

1.2

Baseline (pre-dose Day 1)

30.0

mg/dL (Mean)

Standard Deviation: 8.4

Change from BL at 24h

-2.5

mg/dL (Mean)

Standard Deviation: 5.0

Change from BL at FU

-0.8

Baseline (pre-dose Day 1)

24.0

-0.5

mg/dL (Mean)

Standard Deviation: 3.3

Change from BL at FU

-1.5

mg/dL (Mean)

Standard Deviation: 4.7

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Sodium. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 2.4

Group II Placebo

Baseline (pre-dose Day 1)

142.5

mmol/L (Mean)

Standard Deviation: 1.2

Change from BL at 24h

-0.7

mmol/L (Mean)

Standard Deviation: 0.8

Change from BL at FU

-1.8

1.8

mmol/L (Mean)

Standard Deviation: 0.5

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Potassium. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Phosphate. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Calcium (Corrected for Albumin). SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Uric Acid. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Triiodothyronine (T3). SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Lipase. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: (Fasting) Glucose. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Human Serum Albumin. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

SAD Group I 800mg

Baseline (pre-dose Day 1)

44.0

g/L (Mean)

Standard Deviation: 1.2

Change from BL at 24h

1.5

g/L (Mean)

Standard Deviation: 3.1

Change from BL at FU

Standard Deviation: 1.7

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Cholesterol. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: High Density Lipoproteins. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Triglycerides. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Low Density Lipoproteins. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Bicarbonate. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Thyroid-stimulating Hormone. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Thyroxine (T4). SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Timepoint: Lactate. SAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of clinical chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Total Protein. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of hematology parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 3.4

MAD Group IV

Baseline (pre-dose Day 1)

67.3

g/L (Mean)

Standard Deviation: 4.6

Change from BL at Day 3

2.3

g/L (Mean)

Standard Deviation: 1.7

Change from BL at Day 8

4.3

g/L (Mean)

Standard Deviation: 4.3

Change from BL at FU

4.8

Baseline (pre-dose Day 1)

66.0

g/L (Mean)

Standard Deviation: 2.1

Change from BL at Day 3

1.7

g/L (Mean)

Standard Deviation: 2.3

Change from BL at Day 8

4.8

g/L (Mean)

Standard Deviation: 1.7

Change from BL at FU

1.8

g/L (Mean)

Standard Deviation: 2.0

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Alkaline Phosphatase. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 13.3

MAD Group IV

Baseline (pre-dose Day 1)

67.3

U/L (Mean)

Standard Deviation: 10.7

Change from BL at Day 3

2.0

U/L (Mean)

Standard Deviation: 1.4

Change from BL at Day 8

5.0

U/L (Mean)

Standard Deviation: 4.2

Change from BL at FU

10.8

Baseline (pre-dose Day 1)

52.3

U/L (Mean)

Standard Deviation: 9.5

Change from BL at Day 3

1.8

U/L (Mean)

Standard Deviation: 1.8

Change from BL at Day 8

3.3

U/L (Mean)

Standard Deviation: 1.9

Change from BL at FU

3.3

U/L (Mean)

Standard Deviation: 4.0

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Aspartate Aminotransferase. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 3.9

MAD Group IV

Baseline (pre-dose Day 1)

21.5

U/L (Mean)

Standard Deviation: 5.7

Change from BL at Day 3

-5.0

U/L (Mean)

Standard Deviation: 1.4

Change from BL at Day 8

-2.8

U/L (Mean)

Standard Deviation: 1.9

Change from BL at FU

1.3

Baseline (pre-dose Day 1)

23.0

U/L (Mean)

Standard Deviation: 6.6

Change from BL at Day 3

-1.7

U/L (Mean)

Standard Deviation: 3.6

Change from BL at Day 8

-1.5

U/L (Mean)

Standard Deviation: 4.8

Change from BL at FU

2.8

U/L (Mean)

Standard Deviation: 8.2

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Creatine Kinase. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 23.1

MAD Group IV

Baseline (pre-dose Day 1)

192.3

U/L (Mean)

Standard Deviation: 149.4

Change from BL at Day 3

-68.8

U/L (Mean)

Standard Deviation: 57.3

Change from BL at Day 8

-83.8

U/L (Mean)

Standard Deviation: 91.7

Change from BL at FU

-7.5

Baseline (pre-dose Day 1)

229.8

U/L (Mean)

Standard Deviation: 156.0

Change from BL at Day 3

-106.5

U/L (Mean)

Standard Deviation: 115.2

Change from BL at Day 8

-123.5

U/L (Mean)

Standard Deviation: 144.9

Change from BL at FU

42.2

U/L (Mean)

Standard Deviation: 153.5

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Gamma GT. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 1.3

MAD Group IV

Baseline (pre-dose Day 1)

18.3

U/L (Mean)

Standard Deviation: 9.2

Change from BL at Day 3

0.3

U/L (Mean)

Standard Deviation: 1.3

Change from BL at Day 8

0.3

U/L (Mean)

Standard Deviation: 3.0

Change from BL at FU

-0.5

Baseline (pre-dose Day 1)

21.5

U/L (Mean)

Standard Deviation: 11.3

Change from BL at Day 3

0.7

U/L (Mean)

Standard Deviation: 1.2

Change from BL at Day 8

Change from BL at FU

-0.8

U/L (Mean)

Standard Deviation: 2.5

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Total Bilirubin. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.32

MAD Group IV

Baseline (pre-dose Day 1)

0.55

mg/dL (Mean)

Standard Deviation: 0.13

Change from BL at Day 3

0.05

mg/dL (Mean)

Standard Deviation: 0.13

Change from BL at Day 8

0.03

mg/dL (Mean)

Standard Deviation: 0.21

Change from BL at FU

-0.08

Baseline (pre-dose Day 1)

0.65

mg/dL (Mean)

Standard Deviation: 0.29

Change from BL at Day 3

0.13

mg/dL (Mean)

Standard Deviation: 0.08

Change from BL at Day 8

0.08

mg/dL (Mean)

Standard Deviation: 0.08

Change from BL at FU

-0.05

mg/dL (Mean)

Standard Deviation: 0.19

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Urea. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 8.4

MAD Group IV

Baseline (pre-dose Day 1)

28.0

mg/dL (Mean)

Standard Deviation: 5.5

Change from BL at Day 3

2.8

mg/dL (Mean)

Standard Deviation: 2.4

Change from BL at Day 8

-0.5

mg/dL (Mean)

Standard Deviation: 3.1

Change from BL at FU

-0.5

Baseline (pre-dose Day 1)

30.2

mg/dL (Mean)

Standard Deviation: 3.5

Change from BL at Day 3

2.5

mg/dL (Mean)

Standard Deviation: 3.0

Change from BL at Day 8

-1.0

mg/dL (Mean)

Standard Deviation: 4.5

Change from BL at FU

-0.3

mg/dL (Mean)

Standard Deviation: 6.7

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Creatinine. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.130

MAD Group IV

Baseline (pre-dose Day 1)

0.96

mg/dL (Mean)

Standard Deviation: 0.079

Change from BL at Day 3

0.122

mg/dL (Mean)

Standard Deviation: 0.033

Change from BL at Day 8

0.122

mg/dL (Mean)

Standard Deviation: 0.069

Change from BL at FU

-0.02

Baseline (pre-dose Day 1)

0.897

mg/dL (Mean)

Standard Deviation: 0.110

Change from BL at Day 3

0.057

mg/dL (Mean)

Standard Deviation: 0.050

Change from BL at Day 8

0.053

mg/dL (Mean)

Standard Deviation: 0.056

Change from BL at FU

0.007

mg/dL (Mean)

Standard Deviation: 0.039

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Sodium. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 1.0

MAD Group IV

Baseline (pre-dose Day 1)

141.3

mmol/L (Mean)

Standard Deviation: 0.5

Change from BL at Day 3

-1.5

mmol/L (Mean)

Standard Deviation: 0.6

Change from BL at Day 8

0.8

mmol/L (Mean)

Standard Deviation: 0.5

Change from BL at FU

-0.3

Baseline (pre-dose Day 1)

142.0

mmol/L (Mean)

Standard Deviation: 0.9

Change from BL at Day 3

-1.0

mmol/L (Mean)

Standard Deviation: 0.6

Change from BL at Day 8

-0.5

mmol/L (Mean)

Standard Deviation: 1.4

Change from BL at FU

0.2

mmol/L (Mean)

Standard Deviation: 2.1

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Potassium. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.39

MAD Group IV

Baseline (pre-dose Day 1)

4.35

mmol/L (Mean)

Standard Deviation: 0.19

Change from BL at Day 3

0.33

mmol/L (Mean)

Standard Deviation: 0.37

Change from BL at Day 8

0.15

mmol/L (Mean)

Standard Deviation: 0.39

Change from BL at FU

0.45

Baseline (pre-dose Day 1)

4.32

mmol/L (Mean)

Standard Deviation: 0.17

Change from BL at Day 3

0.52

mmol/L (Mean)

Standard Deviation: 0.49

Change from BL at Day 8

0.15

mmol/L (Mean)

Standard Deviation: 0.41

Change from BL at FU

0.3

mmol/L (Mean)

Standard Deviation: 0.26

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Chloride. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.0

MAD Group IV

Baseline (pre-dose Day 1)

101.5

mmol/L (Mean)

Standard Deviation: 0.6

Change from BL at Day 3

-2.0

mmol/L (Mean)

Standard Deviation: 1.8

Change from BL at Day 8

-2.0

mmol/L (Mean)

Standard Deviation: 1.4

Change from BL at FU

-2.3

Baseline (pre-dose Day 1)

102.2

mmol/L (Mean)

Standard Deviation: 1.5

Change from BL at Day 3

-1.5

mmol/L (Mean)

Standard Deviation: 0.8

Change from BL at Day 8

-2.2

mmol/L (Mean)

Standard Deviation: 2.1

Change from BL at FU

-1.3

mmol/L (Mean)

Standard Deviation: 1.5

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Calcium (Corrected for Albumin). MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.088

MAD Group IV

Baseline (pre-dose Day 1)

2.31

mmol/L (Mean)

Standard Deviation: 0.058

Change from BL at Day 3

0.083

mmol/L (Mean)

Standard Deviation: 0.067

Change from BL at Day 8

0.083

mmol/L (Mean)

Standard Deviation: 0.063

Change from BL at FU

0.083

Baseline (pre-dose Day 1)

2.323

mmol/L (Mean)

Standard Deviation: 0.039

Change from BL at Day 3

0.068

mmol/L (Mean)

Standard Deviation: 0.046

Change from BL at Day 8

0.088

mmol/L (Mean)

Standard Deviation: 0.037

Change from BL at FU

0.055

mmol/L (Mean)

Standard Deviation: 0.037

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Uric Acid. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.92

MAD Group IV

Baseline (pre-dose Day 1)

4.93

mg/dL (Mean)

Standard Deviation: 0.91

Change from BL at Day 3

0.58

mg/dL (Mean)

Standard Deviation: 0.39

Change from BL at Day 8

-0.02

mg/dL (Mean)

Standard Deviation: 0.43

Change from BL at FU

0.55

Baseline (pre-dose Day 1)

5.25

mg/dL (Mean)

Standard Deviation: 1.14

Change from BL at Day 3

-0.07

mg/dL (Mean)

Standard Deviation: 0.31

Change from BL at Day 8

-0.63

mg/dL (Mean)

Standard Deviation: 0.52

Change from BL at FU

-0.05

mg/dL (Mean)

Standard Deviation: 0.42

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Lipase. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 3.3

MAD Group IV

Baseline (pre-dose Day 1)

26.5

Baseline (pre-dose Day 1)

32.8

U/L (Mean)

Standard Deviation: 12.1

Change from BL at Day 3

26.0

U/L (Mean)

Standard Deviation: 55.4

Change from BL at Day 8

50.5

U/L (Mean)

Standard Deviation: 106.4

Change from BL at FU

-2.8

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

MAD Group III

Baseline (pre-dose Day 1)

25.3

Baseline (pre-dose Day 1)

21.3

U/L (Mean)

Standard Deviation: 17.4

Change from BL at Day 3

-0.3

U/L (Mean)

Standard Deviation: 2.2

Change from BL at Day 8

2.3

U/L (Mean)

Standard Deviation: 2.6

Change from BL at FU

6.3

Baseline (pre-dose Day 1)

22.3

U/L (Mean)

Standard Deviation: 5.2

Change from BL at Day 3

2.0

U/L (Mean)

Standard Deviation: 4.2

Change from BL at Day 8

2.8

U/L (Mean)

Standard Deviation: 5.9

Change from BL at FU

2.3

U/L (Mean)

Standard Deviation: 6.9

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Phosphate. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.131

MAD Group IV

Baseline (pre-dose Day 1)

1.033

mmol/L (Mean)

Standard Deviation: 0.164

Change from BL at Day 3

0.003

mmol/L (Mean)

Standard Deviation: 0.074

Change from BL at Day 8

Change from BL at FU

-0.01

Baseline (pre-dose Day 1)

1.0

mmol/L (Mean)

Standard Deviation: 0.162

Change from BL at Day 3

-0.005

mmol/L (Mean)

Standard Deviation: 0.111

Change from BL at Day 8

-0.002

mmol/L (Mean)

Standard Deviation: 0.113

Change from BL at FU

-0.002

mmol/L (Mean)

Standard Deviation: 0.190

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Human Serum Albumin. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 2.1

MAD Group IV

Baseline (pre-dose Day 1)

45.5

g/L (Mean)

Standard Deviation: 3.1

Change from BL at Day 3

3.8

g/L (Mean)

Standard Deviation: 1.3

Change from BL at Day 8

3.5

g/L (Mean)

Standard Deviation: 3.0

Change from BL at FU

3.0

Baseline (pre-dose Day 1)

44.7

g/L (Mean)

Standard Deviation: 1.5

Change from BL at Day 3

1.5

g/L (Mean)

Standard Deviation: 2.1

Change from BL at Day 8

3.8

g/L (Mean)

Standard Deviation: 1.8

Change from BL at FU

1.7

g/L (Mean)

Standard Deviation: 1.4

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Fasting Glucose. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 1.4

MAD Group IV

Baseline (pre-dose Day 1)

85.5

mg/dL (Mean)

Standard Deviation: 13.8

Change from BL at Day 3

2.8

mg/dL (Mean)

Standard Deviation: 6.3

Change from BL at Day 8

-9.5

mg/dL (Mean)

Standard Deviation: 5.5

Change from BL at FU

2.0

Baseline (pre-dose Day 1)

87.2

mg/dL (Mean)

Standard Deviation: 10.0

Change from BL at Day 3

1.5

mg/dL (Mean)

Standard Deviation: 2.5

Change from BL at Day 8

-3.5

mg/dL (Mean)

Standard Deviation: 7.7

Change from BL at FU

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Cholesterol. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 14.2

MAD Group IV

Baseline (pre-dose Day 1)

191.0

mg/dL (Mean)

Standard Deviation: 11.3

Change from BL at Day 3

8.8

mg/dL (Mean)

Standard Deviation: 9.7

Change from BL at Day 8

2.5

mg/dL (Mean)

Standard Deviation: 20.5

Change from BL at FU

8.0

Baseline (pre-dose Day 1)

177.8

mg/dL (Mean)

Standard Deviation: 30.7

Change from BL at Day 3

19.7

mg/dL (Mean)

Standard Deviation: 15.3

Change from BL at Day 8

24.3

mg/dL (Mean)

Standard Deviation: 24.4

Change from BL at FU

-5.5

mg/dL (Mean)

Standard Deviation: 8.6

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Triglycerides. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 52.1

MAD Group IV

Baseline (pre-dose Day 1)

83.5

mg/dL (Mean)

Standard Deviation: 26.3

Change from BL at Day 3

35.5

mg/dL (Mean)

Standard Deviation: 32.7

Change from BL at Day 8

46.8

mg/dL (Mean)

Standard Deviation: 26.9

Change from BL at FU

0.5

Baseline (pre-dose Day 1)

90.2

mg/dL (Mean)

Standard Deviation: 67.5

Change from BL at Day 3

14.8

mg/dL (Mean)

Standard Deviation: 29.3

Change from BL at Day 8

28.3

mg/dL (Mean)

Standard Deviation: 18.2

Change from BL at FU

-8.0

mg/dL (Mean)

Standard Deviation: 39.0

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Low Density Lipoproteins. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 11.0

MAD Group IV

Baseline (pre-dose Day 1)

112.9

mg/dL (Mean)

Standard Deviation: 19.0

Change from BL at Day 3

4.9

mg/dL (Mean)

Standard Deviation: 5.2

Change from BL at Day 8

1.4

mg/dL (Mean)

Standard Deviation: 13.8

Change from BL at FU

6.9

Baseline (pre-dose Day 1)

93.3

mg/dL (Mean)

Standard Deviation: 23.7

Change from BL at Day 3

18.8

mg/dL (Mean)

Standard Deviation: 13.6

Change from BL at Day 8

25.6

mg/dL (Mean)

Standard Deviation: 25.7

Change from BL at FU

-1.9

mg/dL (Mean)

Standard Deviation: 9.7

Phospholipidosis

Change from Day 1 to Day 7 in di-docosahexaenoyl (22:6)-bis(monoacylglycerol) phosphate (di-22:6-BMP) and normalized di-22:6-BMP (urine) - MAD

MAD Group III

di-22:6-BMP: Change from Day 1 to Day 7

-1.473

ng/mL (Mean)

Standard Deviation: 4.520

Normalized di-22:6-BMP: Change from Day 1 to Day 7

1.298

di-22:6-BMP: Change from Day 1 to Day 7

-2.63

ng/mL (Mean)

Standard Deviation: 2.633

Normalized di-22:6-BMP: Change from Day 1 to Day 7

0.337

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 2.1

MAD Group IV

Baseline (pre-dose Day 1)

61.0

mg/dL (Mean)

Standard Deviation: 20.1

Change from BL at Day 3

-3.0

mg/dL (Mean)

Standard Deviation: 4.8

Change from BL at Day 8

-7.8

mg/dL (Mean)

Standard Deviation: 8.6

Change from BL at FU

1.3

Baseline (pre-dose Day 1)

66.8

mg/dL (Mean)

Standard Deviation: 17.7

Change from BL at Day 3

-2.5

mg/dL (Mean)

Standard Deviation: 6.2

Change from BL at Day 8

-7.0

mg/dL (Mean)

Standard Deviation: 6.6

Change from BL at FU

-2.2

mg/dL (Mean)

Standard Deviation: 8.9

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Thyroid-stimulating Hormone. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.50

MAD Group IV

Baseline (pre-dose Day 1)

1.48

mU/L (Mean)

Standard Deviation: 0.45

Change from BL at Day 3

0.09

mU/L (Mean)

Standard Deviation: 0.21

Change from BL at Day 8

0.45

mU/L (Mean)

Standard Deviation: 0.23

Change from BL at FU

-0.15

Baseline (pre-dose Day 1)

1.58

mU/L (Mean)

Standard Deviation: 0.41

Change from BL at Day 3

0.25

mU/L (Mean)

Standard Deviation: 0.39

Change from BL at Day 8

0.85

mU/L (Mean)

Standard Deviation: 0.54

Change from BL at FU

0.05

mU/L (Mean)

Standard Deviation: 0.39

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Trilodothyronine (T3). MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.26

MAD Group IV

Baseline (pre-dose Day 1)

3.35

pg/mL (Mean)

Standard Deviation: 0.26

Change from BL at Day 3

-0.28

pg/mL (Mean)

Standard Deviation: 0.29

Change from BL at Day 8

0.1

pg/mL (Mean)

Standard Deviation: 0.27

Change from BL at FU

-0.05

Baseline (pre-dose Day 1)

3.08

pg/mL (Mean)

Standard Deviation: 0.35

Change from BL at Day 3

-0.15

pg/mL (Mean)

Standard Deviation: 0.34

Change from BL at Day 8

-0.05

pg/mL (Mean)

Standard Deviation: 0.33

Change from BL at FU

0.18

pg/mL (Mean)

Standard Deviation: 0.08

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Thyroxine (T4). MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.05

MAD Group IV

Baseline (pre-dose Day 1)

1.25

ng/dL (Mean)

Standard Deviation: 0.06

Change from BL at Day 3

0.02

ng/dL (Mean)

Standard Deviation: 0.05

Change from BL at Day 8

0.07

ng/dL (Mean)

Standard Deviation: 0.10

Change from BL at FU

0.03

Baseline (pre-dose Day 1)

1.07

ng/dL (Mean)

Standard Deviation: 0.14

Change from BL at Day 3

0.03

ng/dL (Mean)

Standard Deviation: 0.08

Change from BL at Day 8

0.17

ng/dL (Mean)

Standard Deviation: 0.10

Change from BL at FU

0.1

ng/dL (Mean)

Standard Deviation: 0.06

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Bicarbonate. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 0.69

MAD Group IV

Baseline (pre-dose Day 1)

25.53

mmol/L (Mean)

Standard Deviation: 0.92

Change from BL at Day 3

2.2

mmol/L (Mean)

Standard Deviation: 1.51

Change from BL at Day 8

1.42

mmol/L (Mean)

Standard Deviation: 1.59

Change from BL at FU

1.68

Baseline (pre-dose Day 1)

27.23

mmol/L (Mean)

Standard Deviation: 0.87

Change from BL at Day 3

0.03

mmol/L (Mean)

Standard Deviation: 1.40

Change from BL at Day 8

0.47

mmol/L (Mean)

Standard Deviation: 1.69

Change from BL at FU

-0.27

mmol/L (Mean)

Standard Deviation: 1.87

Change From Baseline in Chemistry Laboratory Test Results by Time Point: Lactate. MAD Group

Blood samples were collected from participants at the indicated timepoints for evaluation of chemistry parameters. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.

Standard Deviation: 3.30

MAD Group IV

Baseline (pre-dose Day 1)

7.0

mg/dL (Mean)

Standard Deviation: 1.82

Change from BL at Day 3

2.23

mg/dL (Mean)

Standard Deviation: 4.01

Change from BL at Day 8

2.3

mg/dL (Mean)

Standard Deviation: 2.08

Change from BL at FU

1.08

Baseline (pre-dose Day 1)

9.12

mg/dL (Mean)

Standard Deviation: 1.94

Change from BL at Day 3

5.93

mg/dL (Mean)

Standard Deviation: 6.62

Change from BL at Day 8

1.23

mg/dL (Mean)

Standard Deviation: 3.66

Change from BL at FU

-0.12

mg/dL (Mean)

Standard Deviation: 4.07

MAD: Change From Baseline in ECG Results by Time Point: Corrected QT Interval According to Barret's Formaula (QTcB)

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing, or around the expected Cmax on Day 1 or 7 for the multiple- dose part.

msec (Mean)

Standard Deviation: 7.2

Change from pre-dose Day 7 BL at 6h - Day 7

-1.8

Change from pre-dose Day 7 BL at 6h - Day 7

5.3

msec (Mean)

Standard Deviation: 9.8

MAD: Change From Baseline in ECG Results by Time Point: P Wave-Q Wave Interval (PQ Interval)

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation of the PQ interval the average of the 3 recordings will be taken as baseline.

msec (Mean)

Standard Deviation: 3.4

Change from pre-dose Day 7 at 4h

-1.0

msec (Mean)

Standard Deviation: 3.8

Change from pre-dose Day 7 at 8h - Day 7

Change from pre-dose Day 7 BL at 6h - Day 7

-3.5

Change from pre-dose Day 7 BL at 6h - Day 7

-6.7

msec (Mean)

Standard Deviation: 5.2

MAD: Change From Baseline in ECG Results by Time Point: the Interval That Denotes Depolarization of the Ventricles, Between the Beginning of the Q Wave and the End of the S Wave (QRS Interval)

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing, or around the expected Cmax on Day 1 or 7 for the multiple- dose part.

MAD Group III

Standard Deviation: 1.9

Change from BL Day 7 BL at 6h - Day 7

0.5

Change from BL Day 7 at 2h - Day 7

1.0

msec (Mean)

Standard Deviation: 1.2

Change from BL Day 7 at 4h

-0.5

msec (Mean)

Standard Deviation: 1.0

Change from BL Day 7 at 8h - Day 7

-0.5

msec (Mean)

Standard Deviation: 1.9

Change from BL Day 7 BL at 6h - Day 7

-2.5

Change from BL Day 7 BL at 6h - Day 7

0.7

msec (Mean)

Standard Deviation: 2.4

MAD: Change From Baseline in ECG Results by Time Point: QT Interval

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline. Other ECG recordings will be singlet (one recording of at least 3 complexes) prior to dosing, or around the expected Cmax on Day 1 or 7 for the multiple- dose part.

Standard Deviation: 12.4

Change from pre-dose Day 7 at 2h - Day 7

Change from pre-dose Day 7 at 4h

-7.0

msec (Mean)

Standard Deviation: 1.2

Change from pre-dose Day 7 at 8h - Day 7

-18.5

msec (Mean)

Standard Deviation: 13.7

Change from pre-dose Day 7 BL at 6h - Day 7

-15.5

Change from pre-dose Day 7 BL at 6h - Day 7

-14.3

msec (Mean)

Standard Deviation: 26.8

SAD: Change From Baseline in ECG Results by Time Point: PQ Interval

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline.

msec (Mean)

Standard Deviation: 6.2

Change from BL at FU

-1.3

Baseline (Pre-dose Day 1)

177.0

msec (Mean)

Standard Deviation: 26.9

Change from baseline at 1h

-9.0

msec (Mean)

Standard Deviation: 9.9

Change from BLat 12h post dose

-9.0

Change from BL at FU

-3.5

msec (Mean)

Standard Deviation: 5.0

SAD: Change From Baseline in ECG Results by Time Point: QRS Interval

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline.

msec (Mean)

Standard Deviation: 1.3

Change from BL at FU

-0.7

Change from BL at FU

Standard Deviation: 3.0

Change from BL at 24h post dose

Change from BL at 2h post dose

2.5

msec (Mean)

Standard Deviation: 7.2

Change from BL at 4h post dose

2.5

msec (Mean)

Standard Deviation: 3.0

Change from BL at 6h post dose

1.5

msec (Mean)

Standard Deviation: 2.5

Change from BL at 8h post dose

Change from BL at FU

-3.0

Baseline (Pre-dose Day 1)

95.0

msec (Mean)

Standard Deviation: 7.1

Change from baseline at 1h

1.0

msec (Mean)

Standard Deviation: 1.4

Change from BL at 12h post dose

Change from BL at 24h post dose

-3.0

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline.

msec (Mean)

Standard Deviation: 9.9

Change from BL at FU

-18.3

Change from BL at FU

-1.0

msec (Mean)

Standard Deviation: 8.9

SAD: Change From Baseline in ECG Results by Time Point: QTcB Interval

The baseline ECG recording consists of a triplicate recording (3 recordings of a least 3 complexes within a 5 minute window) prior to dosing on Day 1. For the evaluation the average of the 3 recordings will be taken as baseline.

Standard Deviation: 17.6

SAD Group II Placebo

Baseline (Pre-dose Day 1)

385.5

msec (Mean)

Standard Deviation: 9.8

Change from BL at 12h post dose

3.8

msec (Mean)

Standard Deviation: 8.9

Change from BL at 1h

-0.7

Baseline (Pre-dose Day 1)

382.0

msec (Mean)

Standard Deviation: 21.4

Change from BL at 12h post dose

-1.0

msec (Mean)

Standard Deviation: 2.2

Change from BL at 1h

-1.0

Change from BL at 8h post dose

8.5

msec (Mean)

Standard Deviation: 18.7

Change from BL at FU

8.3

Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.

Geometric Coefficient of Variation: 3.83

Terminal Elimination Half-life (T1/2) of KH183: SAD

Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.

Group I 100mg + Food

14.9

hours (Geometric Mean)

Geometric Coefficient of Variation: 7.86

Maximum Concentration (Cmax) of KH176: SAD Group

Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.

Group I 100mg + Food

165.0

ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 7.40

Maximum Concentration (Cmax) of KH183 Over 24 Hours: SAD

Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.

Group I 100mg + Food

117.0

ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 20.0

Maximum Concentration (Cmax) of KH183 (Active Metabolite of KH176): MAD Group

Plasma concentrations of KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.: Cmax was obtained directly from the concentration-time data.

Cmax Dose 100mg

Day 1

99.4

ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 20.9

Day 7

152.0

Day 1

550.0

ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 14.1

Day 7

450.0

ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 28.3

Maximum Concentration (Cmax) of KH176: MAD

Plasma concentrations of KH176 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.

Cmax Dose 100mg

Day 1

184.0

ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 57.0

Day 7

353.0

Day 1

1330.0

ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 27.3

Day 7

2100.0

ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 27.2

Time to Maximum Concentration (Tmax) of KH176 Over 24 Hours: SAD

Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.

Group I 100mg + Food

2.45

hours (Geometric Mean)

Geometric Coefficient of Variation: 23.7

Time to Reach Peak Plasma Concentration (Tmax) of KH183: SAD

Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.

SAD Group I 10mg

1.32

ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 34.8

Time to Maximum Concentration (Tmax) of KH176 at Day 1, Day 7: MAD Group

Plasma concentrations of KH176 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.

Tmax Dose 100mg

Day 1

1.57

hours (Geometric Mean)

Geometric Coefficient of Variation: 173

Day 7

0.931

Day 1

0.866

hours (Geometric Mean)

Geometric Coefficient of Variation: 70.4

Day 7

1.36

hours (Geometric Mean)

Geometric Coefficient of Variation: 85.5

Area Under the Plasma Concentration Versus Time Curve (AUClast) of KH176: SAD Group

Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food), 300mg, 800mg, 2000mg b.i.d.

Group I 100mg + Food

1650.0

h*ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 1.67

Time to Maximum Concentration (Tmax) of KH183 (Active Metabolite of KH176): MAD Group

Plasma concentrations of KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.. tmax was obtained directly from the concentration-time data.

Tmax Dose 100mg

Day 1

2.06

hours (Geometric Mean)

Geometric Coefficient of Variation: 116

Day 7

1.19

Day 1

1.22

hours (Geometric Mean)

Geometric Coefficient of Variation: 23.7

Day 7

1.61

hours (Geometric Mean)

Geometric Coefficient of Variation: 48.1

Accumulation Factor (Racc) of KH176 Over 7 Days: MAD Group

Plasma concentrations of KH176 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.. Racc was calculated as follows: AUCtau day 7/ AUCtau day 1.

Racc Dose 100mg

2.52

ratio (Geometric Mean)

Geometric Coefficient of Variation: 31.2

Racc- Dose 200mg

2.65

ratio (Geometric Mean)

Geometric Coefficient of Variation: 2.5

Racc - Dose 400mg

2.17

ratio (Geometric Mean)

Geometric Coefficient of Variation: 14.4

Accumulation Factor (Racc) of KH183 (Active Metabolite of KH176): MAD Group

Plasma concentrations of KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.: Accumulation factor was calculated as follows: AUCtau day 7/ AUCtau day 1.

Racc Dose 100mg

1.86

ratio (Geometric Mean)

Geometric Coefficient of Variation: 46.7

Racc- Dose 200mg

1.32

ratio (Geometric Mean)

Geometric Coefficient of Variation: 13.1

Racc - Dose 400mg

1.19

ratio (Geometric Mean)

Geometric Coefficient of Variation: 24.7

Area Under the Plasma Concentration Versus Time Curve (AUClast) of KH183: SAD Group

Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.

Group I 100mg + Food

1590.0

h*ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 26.1

Area Under the Plasma Concentration-time Curve (AUCtau) of KH176: MAD Group:

Plasma concentrations of KH176 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.

AUCtau Dose 100mg

Day 1

1090.0

h*ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 49.3

Day 7

2760.0

Day 1

6890.0

h*ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 19.2

Day 7

14900.0

h*ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 28.2

Area Under the Plasma Concentration-time Curve During a Dose Interval (AUCtau) of KH183 (Active Metabolite of KH176): MAD Group

Plasma concentrations of KH183 were analysed after multiple-dose administration of doses of 100, 200 and 400 mg b.i.d.

AUCtau Dose 100mg

Day 1

702.0

h*ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 29.2

Day 7

1310.0

Day 1

3600.0

h*ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 11.1

Day 7

4270.0

h*ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 30.5

Area Under the Plasma Concentration-time Curve From Time Zero Until Infinity (AUCl0-inf) of KH183: SAD

Plasma concentrations of KH183 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.

Group I 100mg + Food

2410.0

h*ng/mL (Geometric Mean)

Geometric Coefficient of Variation: 29.1

Area Under the Plasma Concentration-time Curve From Time Zero Until Infinity (AUCl0-inf) of KH176: SAD

Plasma concentrations of KH176 were analysed after single dose administration of doses 10mg, 30mg, 100mg (with and without food) , 300mg, 800mg, 2000mg b.i.d.

Geometric Coefficient of Variation: 1.04