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Clinical Trial Results:
A Phase 1, Open Label, Crossover Study to Evaluate Palatability and Relative Bioavailability of Two Pediatric Microsphere Formulations of Crizotinib in Healthy Participants

Summary
EudraCT number	2021-003805-23
Trial protocol	Outside EU/EEA
Global end of trial date	17 Oct 2019

Results information
Results version number	v1(current)
This version publication date	25 Sep 2021
First version publication date	25 Sep 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

A8081069

ISRCTN number

US NCT number

NCT03978143

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc

Sponsor organisation address

235 E 42nd Street, New York, United States, 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc, 001 1-800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc, 001 1-800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001493-PIP03-18

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 Mar 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

17 Oct 2019

Global end of trial reached?

Yes

Global end of trial date

17 Oct 2019

Was the trial ended prematurely?

Main objective of the trial

Pharmacokinetics: To estimate the relative bioavailability of 2 new crizotinib formulations (coated microsphere 1 [cMS1] and coated microsphere 2 [cMS2]) to the commercially available crizotinib formulated capsule (FC) at a 250 mg dose administered under fasted conditions in adult healthy participants. Taste: To evaluate the palatability of 2 new crizotinib formulations (cMS1 and cMS2) using a 250 mg dose in comparison with the crizotinib oral solution (OS) using a 250 mg dose by a taste questionnaire in adult healthy participants.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Jun 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 25

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Twenty-five subjects were randomised and all received at least 1 study treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Crizotinib cMS1 250 mg (Treatment A)

Arm description

Subjects received a single dose of crizotinib 250 mg as cMS1 under fasted condition on each Day 1 of Periods 1, 2, 3. The Taste Questionnaire then was administered at 1 (immediately after crizotinib dosing), 5, 10, and 20 minutes after the completion of crizotinib cMS1 dosing.

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

A single dose of crizotinib 250 mg as cMS1 was administered on each morning of Day 1 after an overnight fast of at least 10 hours in Periods 1, 2, 3.

Crizotinib cMS2 250 mg (Treatment B)

Arm description

Subjects received a single dose of crizotinib 250 mg as cMS2 under fasted condition on each Day 1 of Periods 1, 2, 3. The Taste Questionnaire then was administered at 1 (immediately after crizotinib dosing), 5, 10, and 20 minutes after the completion of crizotinib cMS2 dosing.

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

A single dose of crizotinib 250 mg as cMS2 was administered on each morning of Day 1 after an overnight fast of at least 10 hours in Periods 1, 2, 3.

Crizotinib FC 250 mg (Treatment C)

Arm description

Subjects received a single dose of crizotinib 250 mg as FC under fasted condition on each Day 1 of Periods 1, 2, 3.

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

A single dose of crizotinib 250 mg as FC was administered on each morning of Day 1 after an overnight fast of at least 10 hours in Periods 1, 2, 3.

Crizotinib OS 250 mg (Treatment D)

Arm description

Subjects received a single dose of crizotinib 250 mg as OS under fasted condition on Period 4 Day 1. The Taste Questionnaire then was administered at 1 (immediately after crizotinib dosing), 5, 10, and 20 minutes after the completion of crizotinib OS dosing.

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

A single dose of crizotinib 250 mg as OC was administered on the morning of Period 4 Day 1 after an overnight fast of at least 10 hours.

Crizotinib cMS1 250 mg + HF meal (Treatment E)

Arm description

Subjects received a single dose of crizotinib 250 mg as cMS1 with high-fat (HF) meal on Period 5 Day 1.

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

A single dose of crizotinib 250 mg as cMS1 was administered with high-fat, high-calorie meal after an overnight fast of at least 10 hours on Period 5 Day 1.

Crizotinib cMS2 250 mg + HF meal (Treatment F)

Arm description

Subjects received a single dose of crizotinib 250 mg as cMS2 with HF meal on Period 5 Day 1.

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

A single dose of crizotinib 250 mg as cMS2 was administered with high-fat, high-calorie meal after an overnight fast of at least 10 hours on Period 5 Day 1.

Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)

Arm description

Subjects received esomeprazole 40 mg 1 hour prior to dinner on Day -5 through Day -1; then a single dose of crizotinib 250 mg as cMS1 on Day 1 of Period 6.

Arm type

Experimental

Investigational medicinal product name

Esomeprazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

During Period 6, 40 mg delayed release esomeprazole was administered daily 1 hour prior to dinner on Day -5 through Day -1.

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

A single dose of crizotinib 250 mg as cMS1 was administered on the morning of Period 6 Day 1 after an overnight fast of at least 10 hours.

Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)

Arm description

Subjects received esomeprazole 40 mg 1 hour prior to dinner on Day -5 through Day -1; then a single dose of crizotinib 250 mg as cMS2 on Day 1 of Period 6.

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

PF-02341066

Other name

Pharmaceutical forms

Granules

Routes of administration

Oral use

Dosage and administration details

A single dose of crizotinib 250 mg as cMS2 was administered on the morning of Period 6 Day 1 after an overnight fast of at least 10 hours.

Investigational medicinal product name

Esomeprazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

During Period 6, 40 mg delayed release esomeprazole was administered daily 1 hour prior to dinner on Day -5 through Day -1.

Number of subjects in period 1	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)	Crizotinib OS 250 mg (Treatment D)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Started	25	25	25	25	12	13	12	13
Completed	22	23	23	22	11	11	11	11
Not completed	3	2	2	3	1	2	1	2
Physician decision	-	1	-	-	-	-	-	-
Adverse event, non-fatal	1	1	-	-	-	-	-	-
Not Treated	2	-	2	3	1	2	1	2

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

All subjects who were randomised and received at least 1 study treatment.

Reporting group values	Overall Study	Total
Number of subjects	25	25
Age Categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	25	25
From 65-84 years	0	0
85 years and over	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	41.28 ± 8.79	-
Gender Categorical
Units: Subjects
Female	2	2
Male	23	23
Race Categorical
Units: Subjects
White	11	11
Black or African American	13	13
Asian	1	1
Ethnicity
Units: Subjects
Hispanic or Latino	8	8
Not Hispanic or Latino	17	17
Height
Units: centimeter (cm)
arithmetic mean (standard deviation)	172.4 ± 7.02	-
Weight
Units: kilogram (kg)
arithmetic mean (standard deviation)	77.2 ± 11.67	-
Body Mass Index
Units: kilogram/metre^2 (kg/m^2)
arithmetic mean (standard deviation)	25.9 ± 3.04	-

End points

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Reporting group title

Crizotinib cMS1 250 mg (Treatment A)

Reporting group description

Reporting group title

Crizotinib cMS2 250 mg (Treatment B)

Reporting group description

Reporting group title

Crizotinib FC 250 mg (Treatment C)

Reporting group description

Subjects received a single dose of crizotinib 250 mg as FC under fasted condition on each Day 1 of Periods 1, 2, 3.

Reporting group title

Crizotinib OS 250 mg (Treatment D)

Reporting group description

Reporting group title

Crizotinib cMS1 250 mg + HF meal (Treatment E)

Reporting group description

Subjects received a single dose of crizotinib 250 mg as cMS1 with high-fat (HF) meal on Period 5 Day 1.

Reporting group title

Crizotinib cMS2 250 mg + HF meal (Treatment F)

Reporting group description

Subjects received a single dose of crizotinib 250 mg as cMS2 with HF meal on Period 5 Day 1.

Reporting group title

Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)

Reporting group description

Subjects received esomeprazole 40 mg 1 hour prior to dinner on Day -5 through Day -1; then a single dose of crizotinib 250 mg as cMS1 on Day 1 of Period 6.

Reporting group title

Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)

Reporting group description

Subjects received esomeprazole 40 mg 1 hour prior to dinner on Day -5 through Day -1; then a single dose of crizotinib 250 mg as cMS2 on Day 1 of Period 6.

Primary: Area under the plasma concentration-time profile from time 0 extrapolated to infinite time (AUCinf) for crizotinib - relative bioavailability

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End point title

Area under the plasma concentration-time profile from time 0 extrapolated to infinite time (AUCinf) for crizotinib - relative bioavailability ^[1]

End point description

AUCinf was defined as area under the plasma concentration-time profile from time 0 extrapolated to infinite time. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period. This endpoint is to estimate the relative bioavailability of 2 new crizotinib formulations (cMS1 and cMS2) to the commercially available crizotinib FC.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours post crizotinib dose in Periods 1 to 3 in Treatments A, B and C.

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)
Number of subjects analysed	23	25	23
Units: nanogram.hour per millilitre (ng.hr/mL)
geometric mean (geometric coefficient of variation)	2483 ± 39	2496 ± 45	2610 ± 44

Comparison for AUCinf

Statistical analysis description

Natural log transformed crizotinib AUCinf was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and subject within sequence as a random effect. Treatment C is the Reference Treatment while Treatments A is the Test Treatment.

Comparison groups

Crizotinib FC 250 mg (Treatment C) v Crizotinib cMS1 250 mg (Treatment A)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[2]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

96.11

Confidence interval

level

90%

sides

2-sided

lower limit

87.9

upper limit

105.09

Notes
[2] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 24 and not 46 as stated below.

Comparison for AUCinf

Statistical analysis description

Comparison groups

Crizotinib FC 250 mg (Treatment C) v Crizotinib cMS2 250 mg (Treatment B)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[3]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

98.49

Confidence interval

level

90%

sides

2-sided

lower limit

90.21

upper limit

107.54

Notes
[3] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 48 as stated below.

Primary: Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) for crizotinib - relative bioavailability

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End point title

Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) for crizotinib - relative bioavailability ^[4]

End point description

AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (Clast). PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period. This endpoint is to estimate the relative relative bioavailability of 2 new crizotinib formulations (cMS1 and cMS2) to the commercially available crizotinib FC.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours post crizotinib dose in Periods 1 to 3 in Treatments A, B and C.

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)
Number of subjects analysed	23	25	23
Units: ng.hr/mL
geometric mean (geometric coefficient of variation)	2312 ± 40	2311 ± 46	2428 ± 45

Comparison for AUClast

Statistical analysis description

Natural log transformed crizotinib AUClast was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and subject within sequence as a random effect. Treatment C is the Reference Treatment while Treatments B is the Test Treatment.

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib FC 250 mg (Treatment C)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[5]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

97.93

Confidence interval

level

90%

sides

2-sided

lower limit

89.31

upper limit

107.39

Notes
[5] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 48 as stated below.

Comparison for AUClast

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib FC 250 mg (Treatment C)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[6]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

95.94

Confidence interval

level

90%

sides

2-sided

lower limit

87.36

upper limit

105.36

Notes
[6] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 24 and not 46 as stated below.

Primary: Maximum observed concentration (Cmax) for crizotinib - relative bioavailability

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End point title

Maximum observed concentration (Cmax) for crizotinib - relative bioavailability ^[7]

End point description

Cmax was defined as maximum observed concentration. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period. This endpoint is to estimate the relative relative bioavailability of 2 new crizotinib formulations (cMS1 and cMS2) to the commercially available crizotinib FC.

End point type

Primary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours post crizotinib dose in Periods 1 to 3 in Treatments A, B and C.

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)
Number of subjects analysed	23	25	23
Units: nanogram per millilitre (ng/mL)
geometric mean (geometric coefficient of variation)	108.9 ± 38	101.2 ± 43	106.3 ± 29

Comparison for Cmax

Statistical analysis description

Natural log transformed crizotinib Cmax was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and subject within sequence as a random effect. Treatment C is the Reference Treatment while Treatments B is the Test Treatment.

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib FC 250 mg (Treatment C)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[8]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

97.12

Confidence interval

level

90%

sides

2-sided

lower limit

88.23

upper limit

106.9

Notes
[8] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 48 as stated below.

Comparison for Cmax

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib FC 250 mg (Treatment C)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[9]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

101.5

Confidence interval

level

90%

sides

2-sided

lower limit

92.06

upper limit

111.9

Notes
[9] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 24 and not 46 as stated below.

Primary: Taste questionnaire score of overall liking of drug formulation

Top of page

End point title

Taste questionnaire score of overall liking of drug formulation ^[10]

End point description

Analysis of taste sensory attributes (overall liking) using the Taste Questionnaire. Taste sensory attributes data from Periods 1-3, and 4 (Treatments A, B, and D) were analyzed to assess palatability of cMS1, cMS2, and OS. The data used in the analysis were transcribed and rescaled to a score from 0 to 100 from the raw measurements on the Taste Questionnaire. Overall liking of drug formulation was scored by asking subjects the question: "Please indicate how much you like or dislike the product you tasted."

End point type

Primary

End point timeframe

1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D.

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib OS 250 mg (Treatment D)
Number of subjects analysed	23	25	22
Units: Units on a scale
arithmetic mean (standard deviation)
1MIN	28.596 ± 24.689	23.245 ± 24.289	70.416 ± 29.768
5MIN	32.919 ± 27.577	24.228 ± 24.196	54.000 ± 31.093
10MIN	26.261 ± 20.578	23.246 ± 23.155	46.521 ± 29.487
20MIN	26.136 ± 20.727	19.566 ± 20.969	41.636 ± 28.956

Comparison for Overall Liking - Timepoint 1MIN

Statistical analysis description

Overall liking was analyzed using a mixed effect model with sequence, treatment, time and treatment by time interaction as fixed effects and subjects within sequence as a random effect. Treatment D is the Reference Treatment while Treatments A is the Test Treatment.

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-41.44

Confidence interval

level

90%

sides

2-sided

lower limit

-50.25

upper limit

-32.62

Notes
[11] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Overall Liking - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.0004

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-20.62

Confidence interval

level

90%

sides

2-sided

lower limit

-29.61

upper limit

-11.63

Notes
[12] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Overall Liking - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

= 0.0009

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-20.05

Confidence interval

level

90%

sides

2-sided

lower limit

-29.51

upper limit

-10.6

Notes
[13] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Overall Liking - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.0078

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-15.17

Confidence interval

level

90%

sides

2-sided

lower limit

-24.32

upper limit

-6.02

Notes
[14] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Overall Liking - Timepoint 1MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-45.63

Confidence interval

level

90%

sides

2-sided

lower limit

-54.37

upper limit

-36.89

Notes
[15] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Overall Liking - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-27.81

Confidence interval

level

90%

sides

2-sided

lower limit

-36.73

upper limit

-18.9

Notes
[16] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Overall Liking - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

= 0.0003

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-21.92

Confidence interval

level

90%

sides

2-sided

lower limit

-31.27

upper limit

-12.57

Notes
[17] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Overall Liking - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.0004

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-20.83

Confidence interval

level

90%

sides

2-sided

lower limit

-29.88

upper limit

-11.77

Notes
[18] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Primary: Taste questionnaire score of bitterness of drug formulation

Top of page

End point title

Taste questionnaire score of bitterness of drug formulation ^[19]

End point description

Analysis of taste sensory attributes (bitterness) using the Taste Questionnaire. Taste sensory attributes data from Periods 1-3, and 4 (Treatments A, B, and D) were analyzed to assess palatability of cMS1, cMS2, and OS. The data used in the analysis were transcribed and rescaled to a score from 0 to 100 from the raw measurements on the Taste Questionnaire. Bitterness of drug formulation was scored by asking subjects the question: "Please tell us about the degree of bitterness of the product you tasted."

End point type

Primary

End point timeframe

1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D.

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib OS 250 mg (Treatment D)
Number of subjects analysed	23	25	22
Units: Units on a scale
arithmetic mean (standard deviation)
1MIN	28.870 ± 25.642	24.525 ± 25.377	63.792 ± 28.018
5MIN	33.913 ± 27.184	26.537 ± 26.083	50.728 ± 26.601
10MIN	26.833 ± 21.178	21.898 ± 23.788	38.754 ± 27.664
20MIN	25.516 ± 22.293	15.771 ± 16.847	36.336 ± 26.011

Comparison for Bitterness - Timepoint 1MIN

Statistical analysis description

Bitterness was analyzed using a mixed effect model with sequence, treatment, time and treatment by time interaction as fixed effects and subjects within sequence as a random effect. Treatment D is the Reference Treatment while Treatments A is the Test Treatment.

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-34.39

Confidence interval

level

90%

sides

2-sided

lower limit

-43.25

upper limit

-25.53

Notes
[20] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Bitterness - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

= 0.0019

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-16.39

Confidence interval

level

90%

sides

2-sided

lower limit

-24.73

upper limit

-8.05

Notes
[21] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Bitterness - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

= 0.048

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-11.76

Confidence interval

level

90%

sides

2-sided

lower limit

-21.47

upper limit

-2.05

Notes
[22] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Bitterness - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.0274

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-10.44

Confidence interval

level

90%

sides

2-sided

lower limit

-18.12

upper limit

-2.75

Notes
[23] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Bitterness - Timepoint 1MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-37.68

Confidence interval

level

90%

sides

2-sided

lower limit

-46.47

upper limit

-28.89

Notes
[24] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Bitterness - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-22.45

Confidence interval

level

90%

sides

2-sided

lower limit

-30.72

upper limit

-14.19

Notes
[25] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Bitterness - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[26]

P-value

= 0.0081

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-15.82

Confidence interval

level

90%

sides

2-sided

lower limit

-25.41

upper limit

-6.23

Notes
[26] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Bitterness - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-19.53

Confidence interval

level

90%

sides

2-sided

lower limit

-27.15

upper limit

-11.91

Notes
[27] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Primary: Taste questionnaire score of mouth feel from drug formulation

Top of page

End point title

Taste questionnaire score of mouth feel from drug formulation ^[28]

End point description

Analysis of taste sensory attributes (mouth feel) using the Taste Questionnaire. Taste sensory attributes data from Periods 1-3, and 4 (Treatments A, B, and D) were analyzed to assess palatability of cMS1, cMS2, and OS. The data used in the analysis were transcribed and rescaled to a score from 0 to 100 from the raw measurements on the Taste Questionnaire. Mouth feel from drug formulation was scored by asking subjects the question: "Please tell us about the mouth feel (such as grittiness, stickiness, waxiness) of the product you tasted."

End point type

Primary

End point timeframe

1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D.

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib OS 250 mg (Treatment D)
Number of subjects analysed	23	25	22
Units: Units on a scale
arithmetic mean (standard deviation)
1MIN	28.447 ± 24.056	20.776 ± 21.025	58.338 ± 28.736
5MIN	24.198 ± 18.085	20.159 ± 20.840	47.326 ± 29.334
10MIN	19.055 ± 17.900	19.863 ± 21.053	38.727 ± 27.786
20MIN	17.192 ± 16.028	15.978 ± 16.439	32.804 ± 23.028

Comparison for Mouth Feel - Timepoint 1MIN

Statistical analysis description

Mouth feel was analyzed using a mixed effect model with sequence, treatment, time and treatment by time interaction as fixed effects and subjects within sequence as a random effect. Treatment D is the Reference Treatment while Treatments A is the Test Treatment.

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-29.48

Confidence interval

level

90%

sides

2-sided

lower limit

-38.37

upper limit

-20.58

Notes
[29] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Mouth Feel - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[30]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-22.81

Confidence interval

level

90%

sides

2-sided

lower limit

-31.44

upper limit

-14.18

Notes
[30] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Mouth Feel - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[31]

P-value

= 0.0022

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-19.67

Confidence interval

level

90%

sides

2-sided

lower limit

-29.84

upper limit

-9.49

Notes
[31] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Mouth Feel - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[32]

P-value

= 0.0007

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-15.37

Confidence interval

level

90%

sides

2-sided

lower limit

-22.47

upper limit

-8.27

Notes
[32] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Mouth Feel - Timepoint 1MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-36.32

Confidence interval

level

90%

sides

2-sided

lower limit

-45.13

upper limit

-27.51

Notes
[33] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Mouth Feel - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[34]

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-25.96

Confidence interval

level

90%

sides

2-sided

lower limit

-34.5

upper limit

-17.42

Notes
[34] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Mouth Feel - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.0039

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-18.16

Confidence interval

level

90%

sides

2-sided

lower limit

-28.18

upper limit

-8.15

Notes
[35] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Mouth Feel - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[36]

P-value

= 0.0004

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-16.06

Confidence interval

level

90%

sides

2-sided

lower limit

-23.09

upper limit

-9.02

Notes
[36] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Primary: Taste questionnaire score of tongue/mouth burn from drug formulation

Top of page

End point title

Taste questionnaire score of tongue/mouth burn from drug formulation ^[37]

End point description

Analysis of taste sensory attributes (tongue/mouth burn) using the Taste Questionnaire. Taste sensory attributes data from Periods 1-3, and 4 (Treatments A, B, and D) were analyzed to assess palatability of cMS1, cMS2, and OS. The data used in the analysis were transcribed and rescaled to a score from 0 to 100 from the raw measurements on the Taste Questionnaire. Tongue/mouth burn from drug formulation was scored by asking subjects the question: "Please tell us about the degree of tongue/mouth burn of the product you tasted."

End point type

Primary

End point timeframe

1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D.

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib OS 250 mg (Treatment D)
Number of subjects analysed	23	25	22
Units: Units on a scale
arithmetic mean (standard deviation)
1MIN	21.863 ± 23.830	21.394 ± 28.553	36.960 ± 29.910
5MIN	19.601 ± 23.969	15.062 ± 19.950	33.195 ± 30.228
10MIN	14.534 ± 17.706	15.428 ± 20.074	25.844 ± 27.356
20MIN	20.297 ± 26.175	12.480 ± 16.224	24.856 ± 26.188

Comparison for Tongue/Mouth Burn - Timepoint 1MIN

Statistical analysis description

Tongue/mouth burn was analyzed using a mixed effect model with sequence, treatment, time and treatment by time interaction as fixed effects and subjects within sequence as a random effect. Treatment D is the Reference Treatment while Treatments A is the Test Treatment.

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[38]

P-value

= 0.0113

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-14.48

Confidence interval

level

90%

sides

2-sided

lower limit

-23.68

upper limit

-5.27

Notes
[38] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Tongue/Mouth Burn - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

= 0.0051

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-13.05

Confidence interval

level

90%

sides

2-sided

lower limit

-20.5

upper limit

-5.61

Notes
[39] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Tongue/Mouth Burn - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[40]

P-value

= 0.0238

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-10.9

Confidence interval

level

90%

sides

2-sided

lower limit

-18.72

upper limit

-3.08

Notes
[40] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Tongue/Mouth Burn - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

= 0.4427

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-4.09

Confidence interval

level

90%

sides

2-sided

lower limit

-12.97

upper limit

4.79

Notes
[41] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Tongue/Mouth Burn - Timepoint 1MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[42]

P-value

= 0.013

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-14.06

Confidence interval

level

90%

sides

2-sided

lower limit

-23.19

upper limit

-4.92

Notes
[42] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Tongue/Mouth Burn - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[43]

P-value

= 0.0004

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-16.9

Confidence interval

level

90%

sides

2-sided

lower limit

-24.3

upper limit

-9.49

Notes
[43] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Tongue/Mouth Burn - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[44]

P-value

= 0.0487

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-9.36

Confidence interval

level

90%

sides

2-sided

lower limit

-17.12

upper limit

-1.6

Notes
[44] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Tongue/Mouth Burn - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[45]

P-value

= 0.0354

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-11.35

Confidence interval

level

90%

sides

2-sided

lower limit

-20.13

upper limit

-2.56

Notes
[45] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Primary: Taste questionnaire score of throat burn from drug formulation

Top of page

End point title

Taste questionnaire score of throat burn from drug formulation ^[46]

End point description

Analysis of taste sensory attributes (throat burn) using the Taste Questionnaire. Taste sensory attributes data from Periods 1-3, and 4 (Treatments A, B, and D) were analyzed to assess palatability of cMS1, cMS2, and OS. The data used in the analysis were transcribed and rescaled to a score from 0 to 100 from the raw measurements on the Taste Questionnaire. Throat burn from drug formulation was scored by asking subjects the question: "Please tell us about the degree of throat burn of the product you tasted."

End point type

Primary

End point timeframe

1 (immediately after dosing), 5, 10, and 20 minutes after crizotinib administration in Treatments A, B and D.

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib OS 250 mg (Treatment D)
Number of subjects analysed	23	25	22
Units: Units on a scale
arithmetic mean (standard deviation)
1MIN	19.900 ± 22.287	23.977 ± 29.753	38.493 ± 31.383
5MIN	19.379 ± 18.710	17.187 ± 22.791	36.469 ± 30.695
10MIN	20.968 ± 24.354	14.079 ± 18.150	32.234 ± 29.027
20MIN	20.198 ± 25.583	13.098 ± 16.455	27.999 ± 26.550

Comparison for Throat Burn - Timepoint 1MIN

Statistical analysis description

Throat burn was analyzed using a mixed effect model with sequence, treatment, time and treatment by time interaction as fixed effects and subjects within sequence as a random effect. Treatment D is the Reference Treatment while Treatments A is the Test Treatment.

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[47]

P-value

= 0.0033

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-18.05

Confidence interval

level

90%

sides

2-sided

lower limit

-27.8

upper limit

-8.31

Notes
[47] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Throat Burn - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[48]

P-value

= 0.0686

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-10.99

Confidence interval

level

90%

sides

2-sided

lower limit

-20.89

upper limit

-1.1

Notes
[48] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Throat Burn - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

= 0.0018

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-16.69

Confidence interval

level

90%

sides

2-sided

lower limit

-25.13

upper limit

-8.26

Notes
[49] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Throat Burn - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[50]

P-value

= 0.202

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-7.54

Confidence interval

level

90%

sides

2-sided

lower limit

-17.33

upper limit

2.24

Notes
[50] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 45 as stated below.

Comparison for Throat Burn - Timepoint 1MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[51]

P-value

= 0.0288

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-13.01

Confidence interval

level

90%

sides

2-sided

lower limit

-22.68

upper limit

-3.34

Notes
[51] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Throat Burn - Timepoint 5MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[52]

P-value

= 0.0008

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-18

Confidence interval

level

90%

sides

2-sided

lower limit

-26.37

upper limit

-9.64

Notes
[52] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Throat Burn - Timepoint 10MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[53]

P-value

= 0.005

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-17.17

Confidence interval

level

90%

sides

2-sided

lower limit

-26.94

upper limit

-7.4

Notes
[53] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Comparison for Throat Burn - Timepoint 20MIN

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib OS 250 mg (Treatment D)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[54]

P-value

= 0.0184

Method

ANOVA

Parameter type

Adjusted Mean Differences

Point estimate

-14.05

Confidence interval

level

90%

sides

2-sided

lower limit

-23.7

upper limit

-4.4

Notes
[54] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 47 as stated below.

Secondary: Number of subjects with laboratory test abnormalities (without regard to baseline abnormality) meeting pre-specified criteria

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End point title

Number of subjects with laboratory test abnormalities (without regard to baseline abnormality) meeting pre-specified criteria

End point description

Pre-specified criteria were established for each laboratory test to define the values that would be identified as of potential clinical importance, including hematology, chemistry and urinalysis. Laboratory data were listed in accordance with the sponsor reporting standards.

End point type

Secondary

End point timeframe

From screening through completion of Period 6 (appropriately 88 days) and/or early withdrawal if necessary.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)	Crizotinib OS 250 mg (Treatment D)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	25	23	22	11	11	11	11
Units: Subjects
Lymphocytes/Leukocytes (%) <0.8 x LLN	3	0	0	0	0	1	0	0
Lymphocytes/Leukocytes (%) >1.2 x ULN	1	0	0	0	0	0	0	0
Eosinophils/Leukocytes (%) >1.2 x ULN	0	1	1	0	0	0	0	0
Monocytes/Leukocytes (%) >1.2 x ULN	2	2	2	1	0	1	2	1
Bilirubin (mg/dL) >1.5 x ULN	0	1	0	0	0	0	1	0
Aspartate Aminotransferase (U/L) >3.0 x ULN	1	0	0	0	0	0	0	0
Alanine Aminotransferase (U/L) >3.0 x ULN	2	0	0	1	0	0	0	0
Creatinine (mg/dL) >1.3 x ULN	0	0	0	1	0	0	0	0
Urate (mg/dL) >1.2 x ULN	0	1	0	1	1	0	2	0
Indirect Bilirubin (mg/dL) >1.5 x ULN	0	1	0	0	0	0	0	0
Gamma Glutamyl Transferase(U/L) >3.0 x ULN	1	0	0	0	0	0	0	0
Creatine Kinase (U/L) >2.0 x ULN	0	1	0	0	0	1	0	1

No statistical analyses for this end point

Secondary: Number of subjects with electrocardiogram (ECG) data meeting pre-specified criteria

Top of page

End point title

Number of subjects with electrocardiogram (ECG) data meeting pre-specified criteria

End point description

Pre-specified criteria were established for ECG values of potential clinical concern, including PR interval (value>280 msec, %Chg>=25%, %Chg>=50%); QRS duration (value>120 msec, %Chg>=50%); QT interval (value>500 msec); QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett's formula (QTcB) interval (450<value<=480, 480<value<=500, value>500 msec); QTcF and QTcB interval (30<=Chg<60, Chg>=60).

End point type

Secondary

End point timeframe

From screening through completion of Period 6 (appropriately 88 days) and/or early withdrawal if necessary.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)	Crizotinib OS 250 mg (Treatment D)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	24	23	22	11	11	11	11
Units: Subjects
QTCB INTERVAL, AGGREGATE (MSEC) 30<=Chg<60	0	0	0	0	0	0	1	1

No statistical analyses for this end point

Secondary: Number of subjects with treatment-emergent adverse events (TEAEs)

Top of page

End point title

Number of subjects with treatment-emergent adverse events (TEAEs)

End point description

An adverse event (AE) was any untoward medical occurrence in a subjects. TEAEs were AEs related to the investigational product. A serious AE was any untoward medical occurrence at any dose that resulted in death; was life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect or that was considered to be an important medical event. A severe AE was an event that prevented normal everyday activities. The focus of AE summaries was on treatment-emergent AE.

End point type

Secondary

End point timeframe

From screening through completion of follow-up period of 28-35 days after the last dose of investigational product (approximately 130 days).

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)	Crizotinib OS 250 mg (Treatment D)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	25	23	22	11	11	11	11
Units: Subjects
All-causality TEAEs	12	9	11	6	4	4	4	1
Treatment-related TEAEs	11	9	9	6	3	4	2	1
All-causality serious AEs	0	0	0	0	0	0	0	0
Treatment-related serious AEs	0	0	0	0	0	0	0	0
All-causality severe AEs	0	0	0	0	0	0	0	0
Treatment-related severe AEs	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: AUCinf for crizotinib - food effect

Top of page

End point title

AUCinf for crizotinib - food effect ^[55]

End point description

AUCinf was defined as area under the plasma concentration-time profile from time 0 extrapolated to infinite time. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period. This endpoint is to explore the effect of food on the PK of cMS1 and cMS2.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Periods 1 to 3 in Treatments A, B and in Period 5 in Treatments E, F.

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)
Number of subjects analysed	23	25	11	11
Units: ng.hr/mL
geometric mean (geometric coefficient of variation)	2483 ± 39	2496 ± 45	1944 ± 38	1957 ± 39

Comparison for AUCinf – Food Effect

Statistical analysis description

Natural log transformed crizotinib AUCinf was analyzed using ANOVA with treatment and sequence as a fixed effect and subject within sequence as a random effect. Treatment B is the Reference Treatment while Treatment F is the Test Treatment.

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib cMS2 250 mg + HF meal (Treatment F)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[56]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

71.81

Confidence interval

level

90%

sides

2-sided

lower limit

61.75

upper limit

83.51

Notes
[56] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 36 as stated below.

Comparison for AUCinf – Food Effect

Statistical analysis description

Natural log transformed crizotinib AUCinf was analyzed using Analysis of Variance (ANOVA) with treatment and sequence as a fixed effect and subject within sequence as a random effect. Treatment A is the Reference Treatment while Treatment E is the Test Treatment.

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib cMS1 250 mg + HF meal (Treatment E)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[57]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

85.23

Confidence interval

level

90%

sides

2-sided

lower limit

73.25

upper limit

99.16

Notes
[57] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 34 as stated below.

Secondary: AUClast for crizotinib - food effect

Top of page

End point title

AUClast for crizotinib - food effect ^[58]

End point description

AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (Clast). PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period. This endpoint is to explore the effect of food on the PK of cMS1 and cMS2.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Periods 1 to 3 in Treatments A, B and in Period 5 in Treatments E, F.

Notes
[58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)
Number of subjects analysed	23	25	11	11
Units: ng.hr/mL
geometric mean (geometric coefficient of variation)	2312 ± 40	2311 ± 46	1757 ± 41	1780 ± 42

Comparison for AUClast – Food Effect

Statistical analysis description

Natural log transformed crizotinib AUClast was analyzed using ANOVA with treatment and sequence as a fixed effect and subject within sequence as a random effect. Treatment A is the Reference Treatment while Treatment E is the Test Treatment.

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib cMS1 250 mg + HF meal (Treatment E)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[59]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

82.9

Confidence interval

level

90%

sides

2-sided

lower limit

70.63

upper limit

97.3

Notes
[59] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 34 as stated below.

Comparison for AUClast – Food Effect

Statistical analysis description

Natural log transformed crizotinib AUClast was analyzed using ANOVA with treatment and sequence as a fixed effect and subject within sequence as a random effect. Treatment B is the Reference Treatment while Treatment F is the Test Treatment.

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib cMS2 250 mg + HF meal (Treatment F)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[60]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

70.44

Confidence interval

level

90%

sides

2-sided

lower limit

60.05

upper limit

82.62

Notes
[60] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 36 as stated below.

Secondary: Cmax for crizotinib - food effect

Top of page

End point title

Cmax for crizotinib - food effect ^[61]

End point description

Cmax was defined as maximum observed concentration. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period. This endpoint is to explore the effect of food on the PK of cMS1 and cMS2.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Periods 1 to 3 in Treatments A, B and in Period 5 in Treatments E, F.

Notes
[61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)
Number of subjects analysed	23	25	11	11
Units: ng/mL
geometric mean (geometric coefficient of variation)	108.9 ± 38	101.2 ± 43	82.96 ± 42	78.02 ± 32

Comparison for Cmax – Food Effect

Statistical analysis description

Natural log transformed crizotinib Cmax was analyzed using ANOVA with treatment and sequence as a fixed effect and subject within sequence as a random effect. Treatment B is the Reference Treatment while Treatment F is the Test Treatment.

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib cMS2 250 mg + HF meal (Treatment F)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[62]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

75.76

Confidence interval

level

90%

sides

2-sided

lower limit

63.63

upper limit

90.2

Notes
[62] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 36 as stated below.

Comparison for Cmax – Food Effect

Statistical analysis description

Natural log transformed crizotinib Cmax was analyzed using ANOVA with treatment and sequence as a fixed effect and subject within sequence as a random effect. Treatment A is the Reference Treatment while Treatment E is the Test Treatment.

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib cMS1 250 mg + HF meal (Treatment E)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[63]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

77.24

Confidence interval

level

90%

sides

2-sided

lower limit

64.81

upper limit

92.05

Notes
[63] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 34 as stated below.

Secondary: AUCinf for crizotinib - proton pump inhibitor (PPI) effect

Top of page

End point title

AUCinf for crizotinib - proton pump inhibitor (PPI) effect ^[64]

End point description

AUCinf was defined as area under the plasma concentration-time profile from time 0 extrapolated to infinite time. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period. This endpoint is to explore the effect of esomeprazole on the PK of cMS1 and cMS2.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Periods 1 to 3 in Treatments A, B and in Period 6 in Treatments G, H.

Notes
[64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	25	11	11
Units: ng.hr/mL
geometric mean (geometric coefficient of variation)	2483 ± 39	2496 ± 45	1854 ± 34	1697 ± 45

Comparison for AUCinf – PPI Effect

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[65]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

62.27

Confidence interval

level

90%

sides

2-sided

lower limit

53.55

upper limit

72.41

Notes
[65] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 36 as stated below.

Comparison for AUCinf – PPI Effect

Statistical analysis description

Natural log transformed crizotinib AUCinf was analyzed using ANOVA with treatment and sequence as a fixed effect and subject within sequence as a random effect. Treatment A is the Reference Treatment while Treatment G is the Test Treatment.

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[66]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

81.28

Confidence interval

level

90%

sides

2-sided

lower limit

69.85

upper limit

94.57

Notes
[66] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 34 as stated below.

Secondary: AUClast for crizotinib - PPI effect

Top of page

End point title

AUClast for crizotinib - PPI effect ^[67]

End point description

AUClast was defined as area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (Clast). PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period. This endpoint is to explore the effect of esomeprazole on the PK of cMS1 and cMS2.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Periods 1 to 3 in Treatments A, B and in Period 6 in Treatments G, H.

Notes
[67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	25	11	11
Units: ng.hr/mL
geometric mean (geometric coefficient of variation)	2312 ± 40	2311 ± 46	1677 ± 37	1532 ± 49

Comparison for AUClast – PPI Effect

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[68]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

79.11

Confidence interval

level

90%

sides

2-sided

lower limit

67.4

upper limit

92.85

Notes
[68] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 34 as stated below.

Comparison for AUClast – PPI Effect

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[69]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

60.63

Confidence interval

level

90%

sides

2-sided

lower limit

51.69

upper limit

71.12

Notes
[69] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 36 as stated below.

Secondary: Cmax for crizotinib - PPI effect

Top of page

End point title

Cmax for crizotinib - PPI effect ^[70]

End point description

Cmax was defined as maximum observed concentration. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period. This endpoint is to explore the effect of esomeprazole on the PK of cMS1 and cMS2.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Periods 1 to 3 in Treatments A, B and in Period 6 in Treatments G, H.

Notes
[70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	25	11	11
Units: ng/mL
geometric mean (geometric coefficient of variation)	108.9 ± 38	101.2 ± 43	82.36 ± 35	70.42 ± 47

Comparison for Cmax – PPI Effect

Statistical analysis description

Comparison groups

Crizotinib cMS2 250 mg (Treatment B) v Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[71]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

68.38

Confidence interval

level

90%

sides

2-sided

lower limit

57.43

upper limit

81.41

Notes
[71] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 25 and not 36 as stated below.

Comparison for Cmax – PPI Effect

Statistical analysis description

Comparison groups

Crizotinib cMS1 250 mg (Treatment A) v Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[72]

Method

Parameter type

Ratio of Adjusted Geometric Means

Point estimate

76.68

Confidence interval

level

90%

sides

2-sided

lower limit

64.34

upper limit

91.39

Notes
[72] - As this was a crossover, 6-period, 6-sequence study, the same subjects received different study treatments in separate study periods. Due to limitations in system functionality which cannot be corrected currently, the total number of subjects included in the analysis is 23 and not 34 as stated below.

Secondary: Time for Cmax (Tmax) for crizotinib

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End point title

Time for Cmax (Tmax) for crizotinib ^[73]

End point description

Tmax was defined as time for Cmax of crizotinib. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Treatments A, B, C, E, F, G, and H.

Notes
[73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	25	23	11	11	11	11
Units: Hour
median (full range (min-max))	4.00 (1.00 to 6.00)	6.00 (2.00 to 6.25)	4.03 (1.00 to 8.00)	6.00 (4.00 to 8.00)	6.00 (4.00 to 10.0)	6.00 (4.00 to 6.03)	6.00 (4.00 to 6.03)

No statistical analyses for this end point

Secondary: Terminal half-life (t1/2) for crizotinib

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End point title

Terminal half-life (t1/2) for crizotinib ^[74]

End point description

t1/2 was defined as terminal half-life of crizotinib. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Treatments A, B, C, E, F, G, and H.

Notes
[74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	25	23	11	11	11	11
Units: Hour
arithmetic mean (standard deviation)	25.72 ± 3.2139	26.33 ± 3.9059	25.36 ± 3.4036	29.25 ± 7.2854	28.52 ± 7.4028	29.44 ± 6.4993	28.45 ± 4.9589

No statistical analyses for this end point

Secondary: Apparent oral clearance (CL/F) for crizotinib

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End point title

Apparent oral clearance (CL/F) for crizotinib ^[75]

End point description

CL/F was defined as apparent oral clearance of crizotinib. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Treatments A, B, C, E, F, G, and H.

Notes
[75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	25	23	11	11	11	11
Units: Litre per hour (L/hr)
geometric mean (geometric coefficient of variation)	100.8 ± 39	100.2 ± 45	95.78 ± 44	128.4 ± 38	127.7 ± 39	134.8 ± 34	147.5 ± 45

No statistical analyses for this end point

Secondary: Apparent volume of distribution (Vz/F) for crizotinib

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End point title

Apparent volume of distribution (Vz/F) for crizotinib ^[76]

End point description

Vz/F was defined as apparent volume of distribution of crizotinib. PK parameter evaluable analysis set was used to analyze this endpoint, including all subjects randomised and treated who had at least 1 of the PK crizotinib parameters of primary interest in at least 1 period.

End point type

Secondary

End point timeframe

0 (pre-dose), 1, 2, 4, 6, 8, 10, 12, 24, 48, and 96 hours after crizotinib administration in Treatments A, B, C, E, F, G, and H.

Notes
[76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis was planned only for the arms specified.

End point values	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib FC 250 mg (Treatment C)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)
Number of subjects analysed	23	25	23	11	11	11	11
Units: Litre (L)
geometric mean (geometric coefficient of variation)	3710 ± 49	3770 ± 56	3476 ± 54	5295 ± 57	5131 ± 59	5618 ± 54	5970 ± 63

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Screening (within 28 days prior to Day 1) up to 35 days after last dose of investigational product, the total duration of the study is approximately 130 days including screening.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Crizotinib cMS1 250 mg (Treatment A)

Reporting group description

Reporting group title

Crizotinib FC 250 mg (Treatment C)

Reporting group description

Subjects received a single dose of crizotinib 250 mg as FC under fasted condition on each Day 1 of Periods 1, 2, 3.

Reporting group title

Crizotinib cMS2 250 mg (Treatment B)

Reporting group description

Reporting group title

Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)

Reporting group description

Subjects received esomeprazole 40 mg 1 hour prior to dinner on Day -5 through Day -1; then a single dose of crizotinib 250 mg as cMS1 on Day 1 of Period 6.

Reporting group title

Crizotinib cMS2 250 mg + HF meal (Treatment F)

Reporting group description

Subjects received a single dose of crizotinib 250 mg as cMS2 with HF meal on Period 5 Day 1.

Reporting group title

Crizotinib cMS1 250 mg + HF meal (Treatment E)

Reporting group description

Subjects received a single dose of crizotinib 250 mg as cMS1 with HF meal on Period 5 Day 1.

Reporting group title

Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)

Reporting group description

Subjects received esomeprazole 40 mg 1 hour prior to dinner on Day -5 through Day -1; then a single dose of crizotinib 250 mg as cMS2 on Day 1 of Period 6.

Reporting group title

Crizotinib OS 250 mg (Treatment D)

Reporting group description

Serious adverse events	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib FC 250 mg (Treatment C)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)	Crizotinib OS 250 mg (Treatment D)
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 23 (0.00%)	0 / 23 (0.00%)	0 / 25 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Crizotinib cMS1 250 mg (Treatment A)	Crizotinib FC 250 mg (Treatment C)	Crizotinib cMS2 250 mg (Treatment B)	Crizotinib cMS1 250 mg + Esomeprazole (Treatment G)	Crizotinib cMS2 250 mg + HF meal (Treatment F)	Crizotinib cMS1 250 mg + HF meal (Treatment E)	Crizotinib cMS2 250 mg + Esomeprazole (Treatment H)	Crizotinib OS 250 mg (Treatment D)
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 23 (47.83%)	11 / 23 (47.83%)	9 / 25 (36.00%)	4 / 11 (36.36%)	4 / 11 (36.36%)	4 / 11 (36.36%)	1 / 11 (9.09%)	6 / 22 (27.27%)
Injury, poisoning and procedural complications
Skin abrasion
subjects affected / exposed	1 / 23 (4.35%)	1 / 23 (4.35%)	1 / 25 (4.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	1	1	0	0	1	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 23 (13.04%)	2 / 23 (8.70%)	2 / 25 (8.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)
occurrences all number	3	2	2	0	0	0	0	0
Headache
subjects affected / exposed	2 / 23 (8.70%)	1 / 23 (4.35%)	1 / 25 (4.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	1 / 11 (9.09%)	1 / 11 (9.09%)	1 / 22 (4.55%)
occurrences all number	2	1	1	1	0	1	1	1
Lethargy
subjects affected / exposed	2 / 23 (8.70%)	3 / 23 (13.04%)	0 / 25 (0.00%)	0 / 11 (0.00%)	2 / 11 (18.18%)	0 / 11 (0.00%)	1 / 11 (9.09%)	1 / 22 (4.55%)
occurrences all number	2	4	0	0	2	0	1	1
Eye disorders
Ocular hyperaemia
subjects affected / exposed	0 / 23 (0.00%)	0 / 23 (0.00%)	0 / 25 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 23 (13.04%)	4 / 23 (17.39%)	3 / 25 (12.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	2 / 22 (9.09%)
occurrences all number	3	4	3	2	0	1	0	2
Abdominal pain upper
subjects affected / exposed	0 / 23 (0.00%)	0 / 23 (0.00%)	1 / 25 (4.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Constipation
subjects affected / exposed	1 / 23 (4.35%)	1 / 23 (4.35%)	0 / 25 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	1 / 11 (9.09%)	2 / 22 (9.09%)
occurrences all number	1	1	0	0	1	0	3	2
Diarrhoea
subjects affected / exposed	7 / 23 (30.43%)	5 / 23 (21.74%)	6 / 25 (24.00%)	1 / 11 (9.09%)	2 / 11 (18.18%)	2 / 11 (18.18%)	0 / 11 (0.00%)	3 / 22 (13.64%)
occurrences all number	8	8	6	2	3	2	0	3
Nausea
subjects affected / exposed	2 / 23 (8.70%)	1 / 23 (4.35%)	2 / 25 (8.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	2 / 22 (9.09%)
occurrences all number	2	1	2	1	0	1	0	2
Renal and urinary disorders
Urine odour abnormal
subjects affected / exposed	0 / 23 (0.00%)	0 / 23 (0.00%)	0 / 25 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 23 (0.00%)	0 / 23 (0.00%)	0 / 25 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1, Open Label, Crossover Study to Evaluate Palatability and Relative Bioavailability of Two Pediatric Microsphere Formulations of Crizotinib in Healthy Participants

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Area under the plasma concentration-time profile from time 0 extrapolated to infinite time (AUCinf) for crizotinib - relative bioavailability

Primary: Area under the plasma concentration-time profile from time 0 extrapolated to infinite time (AUCinf) for crizotinib - relative bioavailability

Primary: Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) for crizotinib - relative bioavailability

Primary: Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) for crizotinib - relative bioavailability

Primary: Maximum observed concentration (Cmax) for crizotinib - relative bioavailability

Primary: Maximum observed concentration (Cmax) for crizotinib - relative bioavailability

Primary: Taste questionnaire score of overall liking of drug formulation

Primary: Taste questionnaire score of overall liking of drug formulation

Primary: Taste questionnaire score of bitterness of drug formulation

Primary: Taste questionnaire score of bitterness of drug formulation

Primary: Taste questionnaire score of mouth feel from drug formulation

Primary: Taste questionnaire score of mouth feel from drug formulation

Primary: Taste questionnaire score of tongue/mouth burn from drug formulation

Primary: Taste questionnaire score of tongue/mouth burn from drug formulation

Primary: Taste questionnaire score of throat burn from drug formulation

Primary: Taste questionnaire score of throat burn from drug formulation

Secondary: Number of subjects with laboratory test abnormalities (without regard to baseline abnormality) meeting pre-specified criteria

Secondary: Number of subjects with laboratory test abnormalities (without regard to baseline abnormality) meeting pre-specified criteria

Secondary: Number of subjects with electrocardiogram (ECG) data meeting pre-specified criteria

Secondary: Number of subjects with electrocardiogram (ECG) data meeting pre-specified criteria

Secondary: Number of subjects with treatment-emergent adverse events (TEAEs)

Secondary: Number of subjects with treatment-emergent adverse events (TEAEs)

Secondary: AUCinf for crizotinib - food effect

Secondary: AUCinf for crizotinib - food effect

Secondary: AUClast for crizotinib - food effect

Secondary: AUClast for crizotinib - food effect

Secondary: Cmax for crizotinib - food effect

Secondary: Cmax for crizotinib - food effect

Secondary: AUCinf for crizotinib - proton pump inhibitor (PPI) effect

Secondary: AUCinf for crizotinib - proton pump inhibitor (PPI) effect

Secondary: AUClast for crizotinib - PPI effect

Secondary: AUClast for crizotinib - PPI effect

Secondary: Cmax for crizotinib - PPI effect

Secondary: Cmax for crizotinib - PPI effect

Secondary: Time for Cmax (Tmax) for crizotinib

Secondary: Time for Cmax (Tmax) for crizotinib

Secondary: Terminal half-life (t1/2) for crizotinib

Secondary: Terminal half-life (t1/2) for crizotinib

Secondary: Apparent oral clearance (CL/F) for crizotinib

Secondary: Apparent oral clearance (CL/F) for crizotinib

Secondary: Apparent volume of distribution (Vz/F) for crizotinib

Secondary: Apparent volume of distribution (Vz/F) for crizotinib

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1, Open Label, Crossover Study to Evaluate Palatability and Relative Bioavailability of Two Pediatric Microsphere Formulations of Crizotinib in Healthy Participants