Title

Safety and Tolerability Study of KNS-760704 in Amyotrophic Lateral Sclerosis (ALS)
A 2-Part, Randomized, Double-Blind, Safety and Tolerability Study Evaluating KNS-760704 in Patients With Amyotrophic Lateral Sclerosis (ALS)
  • Phase

    Phase 2
  • Study Type

    Interventional
  • Intervention/Treatment

    pramipexole ...
  • Study Participants

    194
This was a 2-part study of dexpramipexole in patients with ALS.

Part 1 was a randomized, placebo-controlled, multi-center study to evaluate the safety, tolerability, and clinical effects of oral administration of 3 dosage levels of dexpramipexole vs. placebo for 12 weeks.

Part 2 was a randomized, double-blind, 2-arm, parallel group, extension study evaluating the safety, tolerability, and clinical effects of oral administration of 2 dosage levels of dexpramipexole for up to 72 weeks.
This study was a two-part, multicenter, double-blind study in subjects with ALS to evaluate the safety and tolerability of dexpramipexole treatment, as well as the preliminary effects on measures of clinical function and mortality of dexpramipexole treatment.

In part 1, 102 subjects with ALS were randomized at 20 US sites to receive placebo, dexpramipexole at 50 mg/day; dexpramipexole at 150 mg/day; or dexpramipexole at 300 mg/day for 12 weeks. Participants who completed Part 1 were eligible to enroll into Part 2.

Part 2 was a randomized, double-blind, 2-arm, parallel-group, extension study evaluating the longer-term safety, tolerability, and clinical effects of oral administration of 2 dosage levels of dexpramipexole. In part 2, following a 4-week, placebo washout, continuing subjects received dexpramipexole at 50 mg/day or 300 mg/day as double-blind treatment for up to 72 additional weeks (Part 2 duration was up to a total of 76 weeks, including the 4 week placebo portion).
Study Started
Apr 09
2008
Primary Completion
Jul 31
2009
Study Completion
Sep 04
2009
Results Posted
Jul 08
2021
Last Update
Jul 08
2021

Drug Placebo

Placebo: 2 tablets taken orally twice daily

Drug Dexpramipexole 50 mg/day

Dexpramipexole: 2 x 12.5 mg tablets taken orally twice daily

  • Other names: KNS-760704, BIIB050

Drug Dexpramipexole 150 mg/day

Dexpramipexole: 2 x 37.5 mg tablets taken orally twice daily

  • Other names: KNS-760704, BIIB050

Drug Dexpramipexole 300 mg/day

Dexpramipexole: 2 x 75 mg tablets taken orally twice daily

  • Other names: BIIB050, KNS-760704

Part 1: Placebo or Dexpramipexole Placebo Comparator

During Part 1, subjects received twice daily doses of dexpramipexole (50 mg/day, 150 mg/day, or 300 mg/day) or matching placebo for approximately 12 weeks.

Part 2: Placebo washout Experimental

At the beginning of Part 2, subjects received twice daily doses of placebo for approximately 4 weeks.

Part 2: Dexpramipexole Experimental

Following the Part 2 placebo washout, subjects received dexpramipexole (50 mg/day or 300 mg/day), subjects received twice daily doses of placebo for up to 18 months.

Criteria

Inclusion Criteria:

Patients with diagnosis of familial or sporadic ALS, defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology El Escorial criteria
Patients with ALS symptom onset < 24 months from randomization
Patients with upright vital capacity (VC) > 65% of predicted for age, height, and gender

Exclusion Criteria:

Patients in whom causes of neuromuscular weakness other than ALS have not been excluded
Patients without clinical evidence of upper motor neuron dysfunction
Patients with clinically suspected ALS according to the World Federation of Neurology El Escorial criteria
Patients with prior exposure to KNS-760704 or the R(+) enantiomer of pramipexole (i.e., R(+)-pramipexole)
Patients taking other investigational agents (including lithium) within 30 days of randomization or during the study

Summary

Part 1: Placebo

Part 1: Dexpramipexole (50 mg/Day)

Part 1: Dexpramipexole (150 mg/Day)

Part 1: Dexpramipexole (300 mg/Day)

Part 2: Placebo Washout

Part 2: Dexpramipexole (50 mg/Day)

Part 2: Dexpramipexole (300 mg/Day)

All Events

Event Type Organ System Event Term Part 1: Placebo Part 1: Dexpramipexole (50 mg/Day) Part 1: Dexpramipexole (150 mg/Day) Part 1: Dexpramipexole (300 mg/Day) Part 2: Placebo Washout Part 2: Dexpramipexole (50 mg/Day) Part 2: Dexpramipexole (300 mg/Day)

Part 1: Number of Participants With Potentially Clinically Significant Hematology Results by Treatment Group

Number of Participants with Potentially Clinically Significant Hematology Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test.

Placebo

Eosinophils (x10^3/uL) > 5000/uL

Hemoglobin (g/dL) < 8 g/dL

Neutrophils (x10^3/uL) < 1000/uL

Platelets (x10^3/uL) < 50,000/uL

White Blood Cell Count (x10^3/uL) < 2000/uL

50 mg/Day

Eosinophils (x10^3/uL) > 5000/uL

Hemoglobin (g/dL) < 8 g/dL

Neutrophils (x10^3/uL) < 1000/uL

Platelets (x10^3/uL) < 50,000/uL

White Blood Cell Count (x10^3/uL) < 2000/uL

150 mg/Day

Eosinophils (x10^3/uL) > 5000/uL

Hemoglobin (g/dL) < 8 g/dL

Neutrophils (x10^3/uL) < 1000/uL

Platelets (x10^3/uL) < 50,000/uL

White Blood Cell Count (x10^3/uL) < 2000/uL

300 mg/Day

Eosinophils (x10^3/uL) > 5000/uL

Hemoglobin (g/dL) < 8 g/dL

Neutrophils (x10^3/uL) < 1000/uL

Platelets (x10^3/uL) < 50,000/uL

White Blood Cell Count (x10^3/uL) < 2000/uL

Part 1: Number of Participants With Potentially Clinically Significant Blood Chemistry Results by Treatment Group

Number of Participants with Potentially Clinically Significant Blood Chemistry Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test.

Placebo

Alkaline Phosphatase (U/L) > 1.5xULN

ALT (SGPT) (U/L) > 3xULN

AST (SGOT) (U/L) > 3xULN

BUN (mg/dL) > 5xULN

Calcium (mg/dL) High > 12.5 mg/dL

Calcium (mg/dL) Low < 7 mg/dL

Creatine Kinase (U/L) >= 10xULN

Creatinine (mg/dL) > 3xULN

Glucose (mg/dL) High > 250 mg/dL

Glucose (mg/dL) Low < 40 mg/dL

Potassium (mEq/L) High > 6.5 mEq/L

Potassium (mEq/L) Low < 2.5 mEq/L

Sodium (mEq/L) high > 157 mEq/L

Sodium (mEq/L) low < 123 mEq/L

Total Bilirubin (mg/dL) > 1.5xULN

50 mg/Day

Alkaline Phosphatase (U/L) > 1.5xULN

ALT (SGPT) (U/L) > 3xULN

AST (SGOT) (U/L) > 3xULN

BUN (mg/dL) > 5xULN

Calcium (mg/dL) High > 12.5 mg/dL

Calcium (mg/dL) Low < 7 mg/dL

Creatine Kinase (U/L) >= 10xULN

Creatinine (mg/dL) > 3xULN

Glucose (mg/dL) High > 250 mg/dL

Glucose (mg/dL) Low < 40 mg/dL

Potassium (mEq/L) High > 6.5 mEq/L

Potassium (mEq/L) Low < 2.5 mEq/L

Sodium (mEq/L) high > 157 mEq/L

Sodium (mEq/L) low < 123 mEq/L

Total Bilirubin (mg/dL) > 1.5xULN

150 mg/Day

Alkaline Phosphatase (U/L) > 1.5xULN

ALT (SGPT) (U/L) > 3xULN

AST (SGOT) (U/L) > 3xULN

BUN (mg/dL) > 5xULN

Calcium (mg/dL) High > 12.5 mg/dL

Calcium (mg/dL) Low < 7 mg/dL

Creatine Kinase (U/L) >= 10xULN

Creatinine (mg/dL) > 3xULN

Glucose (mg/dL) High > 250 mg/dL

Glucose (mg/dL) Low < 40 mg/dL

Potassium (mEq/L) High > 6.5 mEq/L

Potassium (mEq/L) Low < 2.5 mEq/L

Sodium (mEq/L) high > 157 mEq/L

Sodium (mEq/L) low < 123 mEq/L

Total Bilirubin (mg/dL) > 1.5xULN

300 mg/Day

Alkaline Phosphatase (U/L) > 1.5xULN

ALT (SGPT) (U/L) > 3xULN

AST (SGOT) (U/L) > 3xULN

BUN (mg/dL) > 5xULN

Calcium (mg/dL) High > 12.5 mg/dL

Calcium (mg/dL) Low < 7 mg/dL

Creatine Kinase (U/L) >= 10xULN

Creatinine (mg/dL) > 3xULN

Glucose (mg/dL) High > 250 mg/dL

Glucose (mg/dL) Low < 40 mg/dL

Potassium (mEq/L) High > 6.5 mEq/L

Potassium (mEq/L) Low < 2.5 mEq/L

Sodium (mEq/L) high > 157 mEq/L

Sodium (mEq/L) low < 123 mEq/L

Total Bilirubin (mg/dL) > 1.5xULN

Part 1: Number of Participants With Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group

Number of Participants with Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group. Percentages are based on the number of patients with at least one non-missing post-baseline value in each treatment group.

Placebo

Conduction 1st Degree A-V Block

Conduction 2nd Degree A-V Block

Conduction 3rd Degree A-V Block

Conduction Left Bundle Branch Block

Conduction Pre-excitation (PR < 120 msec)

Conduction Prolonged QTcB

Conduction Prolonged QTcF

Conduction Right Bundle Branch Block

Myocardial Ischemia/Infarction Acute or Subacute Myocardial Infarction

Myocardial Ischemia/Infarction Myocardial Ischemia

Myocardial Ischemia/Infarction Old Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Ischemia

Rhythm Atrial Fibrillation

Rhythm Atrial Flutter

Rhythm Junctional Rhythm

Rhythm Other Ventricular Rhythm

Rhythm Sinus Block/Sinus Arrest

Rhythm Sinus Bradycardia < 40 bpm

Rhythm Sinus Tachycardia > 120 bpm

Rhythm Supraventricular

Rhythm Tachycardia > 100 bpm

Rhythm Torsades de Pointes

U Wave Abnormal U wave present

50 mg/Day

Conduction 1st Degree A-V Block

Conduction 2nd Degree A-V Block

Conduction 3rd Degree A-V Block

Conduction Left Bundle Branch Block

Conduction Pre-excitation (PR < 120 msec)

Conduction Prolonged QTcB

Conduction Prolonged QTcF

Conduction Right Bundle Branch Block

Myocardial Ischemia/Infarction Acute or Subacute Myocardial Infarction

Myocardial Ischemia/Infarction Myocardial Ischemia

Myocardial Ischemia/Infarction Old Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Ischemia

Rhythm Atrial Fibrillation

Rhythm Atrial Flutter

Rhythm Junctional Rhythm

Rhythm Other Ventricular Rhythm

Rhythm Sinus Block/Sinus Arrest

Rhythm Sinus Bradycardia < 40 bpm

Rhythm Sinus Tachycardia > 120 bpm

Rhythm Supraventricular

Rhythm Tachycardia > 100 bpm

Rhythm Torsades de Pointes

U Wave Abnormal U wave present

150 mg/Day

Conduction 1st Degree A-V Block

Conduction 2nd Degree A-V Block

Conduction 3rd Degree A-V Block

Conduction Left Bundle Branch Block

Conduction Pre-excitation (PR < 120 msec)

Conduction Prolonged QTcB

Conduction Prolonged QTcF

Conduction Right Bundle Branch Block

Myocardial Ischemia/Infarction Acute or Subacute Myocardial Infarction

Myocardial Ischemia/Infarction Myocardial Ischemia

Myocardial Ischemia/Infarction Old Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Ischemia

Rhythm Atrial Fibrillation

Rhythm Atrial Flutter

Rhythm Junctional Rhythm

Rhythm Other Ventricular Rhythm

Rhythm Sinus Block/Sinus Arrest

Rhythm Sinus Bradycardia < 40 bpm

Rhythm Sinus Tachycardia > 120 bpm

Rhythm Supraventricular

Rhythm Tachycardia > 100 bpm

Rhythm Torsades de Pointes

U Wave Abnormal U wave present

300 mg/Day

Conduction 1st Degree A-V Block

Conduction 2nd Degree A-V Block

Conduction 3rd Degree A-V Block

Conduction Left Bundle Branch Block

Conduction Pre-excitation (PR < 120 msec)

Conduction Prolonged QTcB

Conduction Prolonged QTcF

Conduction Right Bundle Branch Block

Myocardial Ischemia/Infarction Acute or Subacute Myocardial Infarction

Myocardial Ischemia/Infarction Myocardial Ischemia

Myocardial Ischemia/Infarction Old Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Ischemia

Rhythm Atrial Fibrillation

Rhythm Atrial Flutter

Rhythm Junctional Rhythm

Rhythm Other Ventricular Rhythm

Rhythm Sinus Block/Sinus Arrest

Rhythm Sinus Bradycardia < 40 bpm

Rhythm Sinus Tachycardia > 120 bpm

Rhythm Supraventricular

Rhythm Tachycardia > 100 bpm

Rhythm Torsades de Pointes

U Wave Abnormal U wave present

Part 1: Number of Participants With Potentially Clinically Significant Vital Sign Measurements by Treatment Group

Number of Participants with Potentially Clinically Significant Vital Sign Measurements by Treatment Group. Percentages are based on the number of patients with at least one non-missing post-baseline value in each treatment group.

Placebo

Body Weight Decrease of < -7% lbs from baseline

Body Weight Increase of > 7% lbs from baseline

Diastolic Blood Pressure Decrease of < -15 mmHg from baseline and <= 50 mmHg

Diastolic Blood Pressure Increase of > 15 mmHg from baseline and >= 105 mmHg

Pulse Decrease of < -15 bpm from baseline and <= 50

Pulse Increase of > 15 bpm from baseline and >= 120

Systolic Blood Pressure Decrease of < -20 mmHg from baseline and <= 90 mmHg

Systolic Blood Pressure Increase of > 20 mmHg from baseline and >= 180mmHg

50 mg/Day

Body Weight Decrease of < -7% lbs from baseline

Body Weight Increase of > 7% lbs from baseline

Diastolic Blood Pressure Decrease of < -15 mmHg from baseline and <= 50 mmHg

Diastolic Blood Pressure Increase of > 15 mmHg from baseline and >= 105 mmHg

Pulse Decrease of < -15 bpm from baseline and <= 50

Pulse Increase of > 15 bpm from baseline and >= 120

Systolic Blood Pressure Decrease of < -20 mmHg from baseline and <= 90 mmHg

Systolic Blood Pressure Increase of > 20 mmHg from baseline and >= 180mmHg

150 mg/Day

Body Weight Decrease of < -7% lbs from baseline

Body Weight Increase of > 7% lbs from baseline

Diastolic Blood Pressure Decrease of < -15 mmHg from baseline and <= 50 mmHg

Diastolic Blood Pressure Increase of > 15 mmHg from baseline and >= 105 mmHg

Pulse Decrease of < -15 bpm from baseline and <= 50

Pulse Increase of > 15 bpm from baseline and >= 120

Systolic Blood Pressure Decrease of < -20 mmHg from baseline and <= 90 mmHg

Systolic Blood Pressure Increase of > 20 mmHg from baseline and >= 180mmHg

300 mg/Day

Body Weight Decrease of < -7% lbs from baseline

Body Weight Increase of > 7% lbs from baseline

Diastolic Blood Pressure Decrease of < -15 mmHg from baseline and <= 50 mmHg

Diastolic Blood Pressure Increase of > 15 mmHg from baseline and >= 105 mmHg

Pulse Decrease of < -15 bpm from baseline and <= 50

Pulse Increase of > 15 bpm from baseline and >= 120

Systolic Blood Pressure Decrease of < -20 mmHg from baseline and <= 90 mmHg

Systolic Blood Pressure Increase of > 20 mmHg from baseline and >= 180mmHg

Part 1: Slope of ALSFRS-R (ALS Functional Rating Scale With Respiratory Component) From Baseline to Week 12 by Treatment Group

The ALSFRS-R (ALS functional rating scale with respiratory component) is a validated scale which measures 4 functional domains, comprising respiratory function, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48, with higher scores representing better function. Slope is calculated using a linear mixed effects model with x-axis time in months and y-axis ALSFRS-R score. Units for slope are change per month in units on the ALSFRS-R scale.

Placebo

-1.278
slope (Least Squares Mean)
95% Confidence Interval: -1.82 to -0.74

Dexpramipexole (50 mg/Day)

-1.885
slope (Least Squares Mean)
95% Confidence Interval: -2.48 to -1.29

Dexpramipexole (150 mg/Day)

-1.165
slope (Least Squares Mean)
95% Confidence Interval: -1.71 to -0.62

Dexpramipexole (300 mg/Day)

-0.878
slope (Least Squares Mean)
95% Confidence Interval: -1.44 to -0.31

Part 1: Slope of Upright Vital Capacity From Baseline to Week 12 by Treatment Group

Slope of change in Upright Vital Capacity (percent predicted upright vital capacity) from Baseline to Week 12. A negative change/slope indicates clinical worsening. Slope is calculated using a linear mixed effects model with x-axis time in months and y-axis as percent predicted upright vital capacity. Units for slope are change per month in percent predicted upright vital capacity.

Placebo

-4.398
slope (Least Squares Mean)
95% Confidence Interval: -6.42 to -2.38

Dexpramipexole (50 mg/Day)

-4.003
slope (Least Squares Mean)
95% Confidence Interval: -6.23 to -1.77

Dexpramipexole (150 mg/Day)

-2.389
slope (Least Squares Mean)
95% Confidence Interval: -4.44 to -0.34

Dexpramipexole (300 mg/Day)

-3.947
slope (Least Squares Mean)
95% Confidence Interval: -6.07 to -1.82

Part 2 Placebo Washout: Number of Participants With Potentially Clinically Significant Hematology

Number of Participants with Potentially Clinically Significant Hematology Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test.

Placebo

Eosinophils (x10^3/uL) > 5000/uL

Hemoglobin (g/dL) < 8 g/dL

Neutrophils (x10^3/uL) < 1000/uL

Platelets (x10^3/uL) < 50,000/uL

White Blood Cell Count (x10^3/uL) < 2000/uL

Part 2 Placebo Washout: Number of Participants With Potentially Clinically Significant Blood Chemistry Results

Number of Participants with Potentially Clinically Significant Blood Chemistry Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per laboratory test.

Placebo

Alkaline Phosphatase (U/L) > 1.5xULN

ALT (SGPT) (U/L) > 3xULN

AST (SGOT) (U/L) > 3xULN

BUN (mg/dL) > 5xULN

Calcium (mg/dL) High > 12.5 mg/dL

Calcium (mg/dL) Low < 7 mg/dL

Creatine Kinase (U/L) >= 10xULN

Creatinine (mg/dL) > 3xULN

Glucose (mg/dL) High > 250 mg/dL

Glucose (mg/dL) Low < 40 mg/dL

Potassium (mEq/L) High > 6.5 mEq/L

Potassium (mEq/L) Low < 2.5 mEq/L

Sodium (mEq/L) high > 157 mEq/L

Sodium (mEq/L) low < 123 mEq/L

Total Bilirubin (mg/dL) > 1.5xULN

Part 2 Placebo Washout: Number of Participants With Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings

Number of Participants with Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group. Percentages are based on the number of patients with at least one non-missing post-baseline value in each treatment group.

Placebo

Conduction 1st Degree A-V Block

Conduction 2nd Degree A-V Block

Conduction 3rd Degree A-V Block

Conduction Left Bundle Branch Block

Conduction Pre-excitation (PR < 120 msec)

Conduction Prolonged QTcB

Conduction Prolonged QTcF

Conduction Right Bundle Branch Block

Myocardial Ischemia/Infarction Acute or Subacute Myocardial Infarction

Myocardial Ischemia/Infarction Myocardial Ischemia

Myocardial Ischemia/Infarction Old Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Ischemia

Rhythm Atrial Fibrillation

Rhythm Atrial Flutter

Rhythm Junctional Rhythm

Rhythm Other Ventricular Rhythm

Rhythm Sinus Block/Sinus Arrest

Rhythm Sinus Bradycardia < 40 bpm

Rhythm Sinus Tachycardia > 120 bpm

Rhythm Supraventricular

Rhythm Tachycardia > 100 bpm

Rhythm Torsades de Pointes

U Wave Abnormal U wave present

Part 2 Placebo Washout: Number of Participants With Potentially Clinically Significant Vital Sign Measurements

Number of Participants with Potentially Clinically Significant Vital Sign Measurements by Treatment Group. Percentages are based on the number of patients with at least one non-missing post-baseline value in each treatment group.

Placebo

Body Weight Decrease of < -7% lbs from baseline

Body Weight Increase of > 7% lbs from baseline

Diastolic Blood Pressure Decrease of < -15 mmHg from baseline and <= 50 mmHg

Diastolic Blood Pressure Increase of > 15 mmHg from baseline and >= 105 mmHg

Pulse Decrease of < -15 bpm from baseline and <= 50

Pulse Increase of > 15 bpm from baseline and >= 120

Systolic Blood Pressure Decrease of < -20 mmHg from baseline and <= 90 mmHg

Systolic Blood Pressure Increase of > 20 mmHg from baseline and >= 180mmHg

Part 2 Placebo Washout: Absolute Change in ALSFRS-R Total Score

The ALSFRS-R (ALS functional rating scale with respiratory component) is a validated scale which measures 4 functional domains, comprising respiratory function, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48, with higher scores representing better function. Units are points on the ALSFRS-R score as an absolute change from the baseline of the placebo washout to week 4 of the placebo washout.

Placebo

-1.2
units on a scale (Mean)
Standard Error: 0.27

Part 2 Placebo Washout: Absolute Change in Upright Vital Capacity (Percent Predicted) From Baseline to End of Placebo Washout (Week 4)

Absolute change in Upright Vital Capacity From Baseline to Week 4. Units are percent of predicted Upright Vital Capacity. A negative change indicates clinical worsening.

Placebo

-3.1
units on a scale (Mean)
Standard Error: 0.95

Part 2 Double-Blind Treatment: Number of Participants With Potentially Clinically Significant Hematology Results by Treatment Group

Number of Participants with Potentially Clinically Significant Hematology Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per parameter.

50 mg/Day

Eosinophils (x10^3/uL) > 5000/uL

Hemoglobin (g/dL) < 8 g/dL

Neutrophils (x10^3/uL) < 1000/uL

Platelets (x10^3/uL) < 50,000/uL

White Blood Cell Count (x10^3/uL) < 2000/uL

300 mg/Day

Eosinophils (x10^3/uL) > 5000/uL

Hemoglobin (g/dL) < 8 g/dL

Neutrophils (x10^3/uL) < 1000/uL

Platelets (x10^3/uL) < 50,000/uL

White Blood Cell Count (x10^3/uL) < 2000/uL

Part 2 Double-Blind Treatment: Number of Participants With Potentially Clinically Significant Blood Chemistry Results by Treatment Group

Number of Participants with Potentially Clinically Significant Blood Chemistry Results by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per parameter.

50 mg/Day

Alkaline Phosphatase (U/L) > 1.5xULN

ALT (SGPT) (U/L) > 3xULN

AST (SGOT) (U/L) > 3xULN

BUN (mg/dL) > 5xULN

Calcium (mg/dL) High > 12.5 mg/dL

Calcium (mg/dL) Low < 7 mg/dL

Creatine Kinase (U/L) >= 10xULN

Creatinine (mg/dL) > 3xULN

Glucose (mg/dL) High > 250 mg/dL

Glucose (mg/dL) Low < 40 mg/dL

Potassium (mEq/L) High > 6.5 mEq/L

Potassium (mEq/L) Low < 2.5 mEq/L

Sodium (mEq/L) high > 157 mEq/L

Sodium (mEq/L) low < 123 mEq/L

Total Bilirubin (mg/dL) > 1.5xULN

300 mg/Day

Alkaline Phosphatase (U/L) > 1.5xULN

ALT (SGPT) (U/L) > 3xULN

AST (SGOT) (U/L) > 3xULN

BUN (mg/dL) > 5xULN

Calcium (mg/dL) High > 12.5 mg/dL

Calcium (mg/dL) Low < 7 mg/dL

Creatine Kinase (U/L) >= 10xULN

Creatinine (mg/dL) > 3xULN

Glucose (mg/dL) High > 250 mg/dL

Glucose (mg/dL) Low < 40 mg/dL

Potassium (mEq/L) High > 6.5 mEq/L

Potassium (mEq/L) Low < 2.5 mEq/L

Sodium (mEq/L) high > 157 mEq/L

Sodium (mEq/L) low < 123 mEq/L

Total Bilirubin (mg/dL) > 1.5xULN

Part 2 Double-Blind Treatment: Number of Participants With Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group

Number of Participants with Treatment Emergent Potentially Clinically Significant Electrocardiogram (ECG) Findings by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per parameter.

50 mg/Day

Conduction 1st Degree A-V Block

Conduction 2nd Degree A-V Block

Conduction 3rd Degree A-V Block

Conduction Left Bundle Branch Block

Conduction Pre-excitation (PR < 120 msec)

Conduction Prolonged QTcB

Conduction Prolonged QTcF

Conduction Right Bundle Branch Block

Myocardial Ischemia/Infarction Acute or Subacute Myocardial Infarction

Myocardial Ischemia/Infarction Myocardial Ischemia

Myocardial Ischemia/Infarction Old Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Ischemia

Rhythm Atrial Fibrillation

Rhythm Atrial Flutter

Rhythm Junctional Rhythm

Rhythm Other Ventricular Rhythm

Rhythm Sinus Block/Sinus Arrest

Rhythm Sinus Bradycardia < 40 bpm

Rhythm Sinus Tachycardia > 120 bpm

Rhythm Supraventricular

Rhythm Tachycardia > 100 bpm

Rhythm Torsades de Pointes

U Wave Abnormal U wave present

300 mg/Day

Conduction 1st Degree A-V Block

Conduction 2nd Degree A-V Block

Conduction 3rd Degree A-V Block

Conduction Left Bundle Branch Block

Conduction Pre-excitation (PR < 120 msec)

Conduction Prolonged QTcB

Conduction Prolonged QTcF

Conduction Right Bundle Branch Block

Myocardial Ischemia/Infarction Acute or Subacute Myocardial Infarction

Myocardial Ischemia/Infarction Myocardial Ischemia

Myocardial Ischemia/Infarction Old Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Infarction

Myocardial Ischemia/Infarction Possible Myocardial Ischemia

Rhythm Atrial Fibrillation

Rhythm Atrial Flutter

Rhythm Junctional Rhythm

Rhythm Other Ventricular Rhythm

Rhythm Sinus Block/Sinus Arrest

Rhythm Sinus Bradycardia < 40 bpm

Rhythm Sinus Tachycardia > 120 bpm

Rhythm Supraventricular

Rhythm Tachycardia > 100 bpm

Rhythm Torsades de Pointes

U Wave Abnormal U wave present

Part 2 Double-Blind Treatment: Number of Participants With Potentially Clinically Significant Vital Sign Measurements by Treatment Group

Number of Participants with Potentially Clinically Significant Vital Sign Measurements by Treatment Group. Percentages based on number of patients with at least one non-missing post-baseline value in each treatment group. Patients are only counted once per criterion per parameter.

50 mg/Day

Body Weight Decrease of < -7% lbs from baseline

Body Weight Increase of > 7% lbs from baseline

Diastolic Blood Pressure Decrease of < -15 mmHg from baseline and <= 50 mmHg

Diastolic Blood Pressure Increase of > 15 mmHg from baseline and >= 105 mmHg

Pulse Decrease of < -15 bpm from baseline and <= 50

Pulse Increase of > 15 bpm from baseline and >= 12