To Assess the Effects of Single Oral Dose of Selumetinib [AZD6244; ARRY-142886] [Hyd-Sulfate]), on QTc Interval in Healthy Male Volunteers

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02056392
• Collaborator: (none)
• Enrollment: 54
• Location: 1
• Arms: 3
• Duration (Months): 5
• Patients Per Site Per Month: 10.7

Study Details

Study Description

Brief Summary

Study to assess the effect of Selumetinib [AZD6244; ARRY-142886] [Hyd-Sulfate]), on QTc interval in healthy male volunteers.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumours	Drug: Selumetinib; Drug: Moxifloxacin; Drug: selumetinib placebo	Phase 1

Detailed Description

A double-blind (Selumetinib [AZD6244; ARRY-142886] [Hyd-Sulfate]), Placebo-controlled, Open-Label (Moxifloxacin) Positive-controlled, Randomized, Three-period Crossover Study to Assess the Effects of Single Oral Dose of Selumetinib (75 mg) on QTc Interval Compared to Placebo, using AVELOX (Moxifloxacin) as a Positive Control, in Healthy Male Volunteers

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: A Phase I, Double-blind (Selumetinib [AZD6244; ARRY-142886] [Hyd-Sulfate]), Placebo-controlled, Open-Label (Moxifloxacin) Positive-controlled, Randomized, Three-period Crossover Study to Assess the Effects of Single Oral Dose of Selumetinib (75 mg) on QTc Interval Compared to Placebo, Using AVELOX (Moxifloxacin) as a Positive Control, in Healthy Male Volunteers Aged 18 to 45 Years
• Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Selumetinib 75mg Volunteers will receive selumetinib 75mg administered by mouth, as a capsule	Drug: Selumetinib; Volunteers will receive 75 mg selumetinib oral dose (Treatment A); Other Names: AZD6244
Active Comparator: Moxifloxacin 400 mg Volunteers will receive moxifloxacin 400mg administered by mouth, as a capsule	Drug: Moxifloxacin; Volunteers will receive 400 mg Moxifloxacin oral dose (Treatment B); Other Names: Avelox®
Placebo Comparator: Selumetinib 75mg placebo Volunteers will receive selumetinib 75mg placebo, administered by mouth, as a capsule.	Drug: selumetinib placebo; Volunteers will receive selumetinib placebo oral dose (Treatment C); Other Names: AZD6244 placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in QTcF [30 min]

   Change from baseline in QTcF at 30 minutes (msec)

2. Change From Baseline in QTcF [1 hour]

   Change from baseline in QTcF at 1 hour (msec)

3. Change From Baseline in QTcF [1 hour 30 min]

   Change from baseline in QTcF at 1 hour 30 min (msec)

4. Change From Baseline in QTcF [2 hours]

   Change from baseline in QTcF at 2 hours (msec)

5. Change From Baseline in QTcF [3 hours]

   Change from baseline in QTcF at 3 hours (msec)

6. Change From Baseline in QTcF [4 hours]

   Change from baseline in QTcF at 4 hours (msec)

7. Change From Baseline in QTcF [6 hours]

   Change from baseline in QTcF at 6 hours (msec)

8. Change From Baseline in QTcF [8 hours]

   Change from baseline in QTcF at 8 hours (msec)

9. Change From Baseline in QTcF [12 hours]

   Change from baseline in QTcF at 12 hours (msec)

10. Change From Baseline in QTcF [24 hours]

    Change from baseline in QTcF at 24 hours (msec)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria: 1. Have a body mass index (BMI) between 18 and 30 kg/m2 and weigh at least 50 kg and no more than 100 kg (inclusive). 2. Must have not smoked in the last 30 days prior to screening for this study. 3. Have a calculated creatinine clearance (CrCL) greater than 50 mL/min using the Cockcroft-Gault formula.

Exclusion Criteria: 1. Subjects of Japanese or non-Japanese Asian ethnicity. 2. Subjects where any one parent or grandparent (maternal or paternal) is Japanese or non-Japanese Asian (e.g. China, Taiwan, Korea, Philippines, Thailand, Vietnam, and Malaysia). Asian Indians are acceptable. 3. Past history of central serous retinopathy or retinal vein thrombosis,intraocular pressure greater than 21 mmHg or uncontrolled glaucoma. 4. Any clinically relevant abnormal findings in physical examination, hematology, clinical chemistry, urinalysis, vital signs or ECG at baseline in the opinion of the investigator. 5. History or presence of any clinically significant disease or disorder in the opinion of the investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Overland Park	Kansas	United States

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Scott Rasmussen, MD, Quintiles 6700 W 115th Street, Kansas, US

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02056392
• Other Study ID Numbers: D1532C00071
• First Posted: Feb 6, 2014
• Last Update Posted: Nov 9, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by AstraZeneca: Phase I, healthy, pharmacokinetics
• Additional relevant MeSH terms: Moxifloxacin

Study Results

Participant Flow

Arm/Group Title	Selumetinib/Moxifloxacin/Selumetinib Placebo	Moxifloxacin/Selumetinib/Selumetinib Placebo	Moxifloxacin/Selumetinib Placebo/Selumetinib	Selumetinib Placebo/Moxifloxacin/Selumetinib	Selumetinib Placebo/Selumetinib/Moxifloxacin	Selumetinib/Selumetinib Placebo/Moxifloxacin
Arm/Group Description
Period Title: Overall Study
STARTED	10	9	9	9	8	9
COMPLETED	8	8	6	9	7	9
NOT COMPLETED	2	1	3	0	1	0

Baseline Characteristics

Arm/Group Title	Selumetinib/Moxifloxacin/Selumetinib Placebo	Moxifloxacin/Selumetinib/Selumetinib Placebo	Moxifloxacin/Selumetinib Placebo/Selumetinib	Selumetinib Placebo/Moxifloxacin/Selumetinib	Selumetinib Placebo/Selumetinib/Moxifloxacin	Selumetinib/Selumetinib Placebo/Moxifloxacin	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	10	9	9	9	8	9	54
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	26 (7)	25 (5)	25 (4)	31 (8)	28 (8)	30 (9)	27 (7)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	10 100%	9 100%	9 100%	9 100%	8 100%	9 100%	54 100%
Race/Ethnicity, Customized (Number) [Number]
White	7 70%	5 55.6%	4 44.4%	4 44.4%	5 62.5%	4 44.4%	29 53.7%
Black or African American	3 30%	4 44.4%	5 55.6%	5 55.6%	3 37.5%	5 55.6%	25 46.3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 30 minutes (msec)
Time Frame	30 min

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	2.0	-4.1	-4.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 90%; -1.8 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin, Placebo
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.1
	Confidence Interval	(2-Sided) 90%; 4.4 to 7.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 1 hour (msec)
Time Frame	1 hour

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	7.9	-1.4	-1.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 90%; -2.0 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin, Placebo
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.2
	Confidence Interval	(2-Sided) 90%; 7.6 to 10.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 1 hour 30 min (msec)
Time Frame	1 hour 30 min

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	8.1	-1.8	-0.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 90%; -0.7 to 2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin, Placebo
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.9
	Confidence Interval	(2-Sided) 90%; 8.3 to 11.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 2 hours (msec)
Time Frame	2 hours

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	7.9	-2.3	-1.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 90%; -1.2 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.1
	Confidence Interval	(2-Sided) 90%; 8.5 to 11.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 3 hours (msec)
Time Frame	3 hours

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	8.8	-3.2	-3.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 90%; -1.8 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin, Placebo
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	11.9
	Confidence Interval	() 90%; 10.3 to 13.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 4 hours (msec)
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	8.6	-2.2	-3.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 90%; -3.1 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin, Placebo
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.8
	Confidence Interval	(2-Sided) 90%; 9.2 to 12.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 6 hours (msec)
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	4.7	-4.1	-5.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 90%; -3.4 to -0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin, Placebo
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.8
	Confidence Interval	(2-Sided) 90%; 7.1 to 10.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 8 hours (msec)
Time Frame	8 hours

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	3.6	-5.3	-6.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 90%; -2.9 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin, Placebo
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.9
	Confidence Interval	(2-Sided) 90%; 7.2 to 10.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 12 hours (msec)
Time Frame	12 hours

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	4.2	-3.4	-8.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.7
	Confidence Interval	(2-Sided) 90%; -6.4 to -3.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin, Placebo
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.6
	Confidence Interval	(2-Sided) 90%; 6.0 to 9.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Primary Outcome

Title	Change From Baseline in QTcF
Description	Change from baseline in QTcF at 24 hours (msec)
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

All patients who had evaluable pharmacodynamic data available for at least one treatment group were included in the PD analysis set

Arm/Group Title	Moxifloxacin	Placebo	Selumetinib
Arm/Group Description	Moxiflxacin 400 mg (open label)	Selumetinib placebo (3 capsules)	Selumetinib 75mg bs (3x25mg capsules)
Measure Participants	50	49	50
Measure change from baseline	50	49	50
Least Squares Mean (95% Confidence Interval) [msec]	2.4	-1.6	-4.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Selumetinib
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 90%; -4.1 to -0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin, Placebo
	Comments	47 evaluable volunteers gives 90% power to show non-inferiority of selumetinib versus placebo across all 10 post-dose time points, using paired T-test, 1-sided alpha=0.05 and assuming a true difference of 3 msec.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	All one-sided 95% confidence intervals at each time point for the selumetinib difference versus placebo (2-sided 90% CIs) should be less than 10ms.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.0
	Confidence Interval	(2-Sided) 90%; 2.4 to 5.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	AEs were collected for up to 5 weeks, this was from the day before the first randomised treatment period (Day -1, Visit 2) until the follow-up visit.
Adverse Event Reporting Description	Of the 54 participants in the study, 3 did not receive Selumetinib, 3 did not receive Moxifloxacin and 4 did not receive Selumetinib Placebo (due to discontinuing the study).
Arm/Group Title	Selumetinib		Moxifloxacin		Placebo
Arm/Group Description	Selumetinib 75mg bs (3x25mg capsules)		Moxiflxacin 400 mg (open label)		Selumetinib placebo (3 capsules)
All Cause Mortality
	Selumetinib		Moxifloxacin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Selumetinib		Moxifloxacin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/51 (0%)		0/51 (0%)		1/50 (2%)
Gastrointestinal disorders
Hemorrhoids	0/51 (0%)		0/51 (0%)		1/50 (2%)
Other (Not Including Serious) Adverse Events
	Selumetinib		Moxifloxacin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/51 (9.8%)		5/51 (9.8%)		4/50 (8%)
Gastrointestinal disorders
Abdominal pain	0/51 (0%)		1/51 (2%)		0/50 (0%)
Dyspepsia	0/51 (0%)		1/51 (2%)		0/50 (0%)
Rectal hemorrhage	0/51 (0%)		1/51 (2%)		0/50 (0%)
Immune system disorders
Hypersensitivity	0/51 (0%)		0/51 (0%)		1/50 (2%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/51 (0%)		0/51 (0%)		1/50 (2%)
Musculoskeletal pain	0/51 (0%)		0/51 (0%)		1/50 (2%)
Pain in extremity	0/51 (0%)		1/51 (2%)		0/50 (0%)
Nervous system disorders
Headache	3/51 (5.9%)		1/51 (2%)		0/50 (0%)
Disturbance in attention	0/51 (0%)		1/51 (2%)		0/50 (0%)
Psychiatric disorders
Insomnia	1/51 (2%)		0/51 (0%)		0/50 (0%)
Skin and subcutaneous tissue disorders
Blister	1/51 (2%)		0/51 (0%)		0/50 (0%)
Skin irritation	0/51 (0%)		0/51 (0%)		1/50 (2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.