EMPIRE CF: A Phase 2 Study to Evaluate the Efficacy, Safety, and Tolerability of CTX-4430 in Adult Cystic Fibrosis (CF) Patients

• ClinicalTrials.gov Identifier: NCT02443688
• Recruitment Status: Completed
• First Posted: May 14, 2015
• Results First Posted: July 25, 2019
• Last Update Posted: September 4, 2019
• Sponsor: Celtaxsys, Inc.
• Information provided by (Responsible Party): Celtaxsys, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Cystic Fibrosis
• Interventions: Drug: CTX-4430; Drug: Placebo
• Enrollment: 200

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Matching Placebo
Arm/Group Description	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks Placebo
Period Title: Overall Study
Started	66	67	67
Completed	54	58	55
Not Completed	12	9	12
Reason Not Completed
Adverse Event	2	3	2
Lost to Follow-up	1	0	0
Physician Decision	3	0	1
Pregnancy	0	0	1
Withdrawal by Subject	3	3	4
Non-compliance with study drug	1	2	4
Sponsor Request	2	1	0

Baseline Characteristics

Arm/Group Title		100 mg CTX-4430	50 mg CTX-4430	Matching Placebo	Total
Arm/Group Description		Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks Placebo	Total of all reporting groups
Overall Number of Baseline Participants		66	67	66	199
Baseline Analysis Population Description		One subject in the matching placebo cohort was randomized but did not take any study drug. Therefore, the matching placebo group has 66 subjects listed instead of 67 subjects making it a total of 199 subjects who received study drug.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	66 participants	67 participants	66 participants	199 participants
	<=18 years	2 3.0%	6 9.0%	4 6.1%	12 6.0%
	Between 18 and 65 years	64 97.0%	61 91.0%	62 93.9%	187 94.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	66 participants	67 participants	66 participants	199 participants
		24.3 (3.24)	23.7 (3.64)	23.2 (3.38)	23.7 (3.43)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	66 participants	67 participants	66 participants	199 participants
	Female	30 45.5%	38 56.7%	33 50.0%	101 50.8%
	Male	36 54.5%	29 43.3%	33 50.0%	98 49.2%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	66 participants	67 participants	66 participants	199 participants
	Hispanic or Latino	5 7.6%	2 3.0%	0 0.0%	7 3.5%
	Not Hispanic or Latino	61 92.4%	65 97.0%	66 100.0%	192 96.5%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	66 participants	67 participants	66 participants	199 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 1.5%	3 4.5%	0 0.0%	4 2.0%
	White	62 93.9%	62 92.5%	66 100.0%	190 95.5%
	More than one race	3 4.5%	2 3.0%	0 0.0%	5 2.5%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
On cystic fibrosis transmembrane conductance regulator (CFTR) Modulator Therapy: Yes; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	66 participants	67 participants	66 participants	199 participants
		21 31.8%	22 32.8%	19 28.8%	62 31.2%
On CFTR Modulator Therapy: No; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	66 participants	67 participants	66 participants	199 participants
		45 68.2%	45 67.2%	47 71.2%	137 68.8%
Number of Pulmonary Exacerbations in the year prior to Screening; Mean (Standard Deviation); Unit of measure: Pulmonary Exacerbations/year
	Number Analyzed	66 participants	67 participants	66 participants	199 participants
		2.32 (1.947)	2.13 (1.466)	1.94 (1.357)	2.13 (1.609)

Outcome Measures

1. Primary Outcome

Title	Difference From Placebo in Absolute Change From Baseline in Forced Expiratory Volume in 1 Second Percent Predicted (ppFEV1)
Description	Difference from Placebo in absolute change from Baseline at Week 48 was assessed for FEV1 percent predicted.
Time Frame	Baseline, Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Population - All subjects randomized to and receiving at least 1 dose of assigned treatment. The primary analysis was based upon the pooled results of the 100mg and 50mg doses.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	The average of the Week 48 absolute change from Baseline in FEV1 percent predicted for the two CTX-4430 doses.	Once daily oral capsule for 48 weeks
Overall Number of Participants Analyzed	66	67	133	66
Mean (95% Confidence Interval); Unit of Measure: FEV1 percent predicted
	-1.30; (-3.22 to 0.62)	-3.76; (-5.65 to -1.86)	-2.53; (-3.88 to -1.18)	-2.69; (-4.63 to -0.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	100 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Single Group Difference from Placebo Mean Change from Baseline with 95% confidence interval (CI)
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.39
	Confidence Interval	(2-Sided) 95%; -1.34 to 4.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.38
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	50 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Single Group Difference from Placebo Mean Change from Baseline with 95% CI
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.07
	Confidence Interval	(2-Sided) 95%; -3.78 to 1.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.37
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pooled CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Difference from placebo of pooled arms (100mg CTX-4430 and 50mg CTX-4430) in change from baseline in ppFEV1 at Week 48.
Statistical Test of Hypothesis	P-Value	0.45
	Comments	0.1 alpha level (2-sided) prespecified
	Method	ANOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -2.20 to 2.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.2
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Number of Pulmonary Exacerbations Through 48 Weeks
Description	Rate of protocol-defined pulmonary exacerbations reported through the Week 48/Early Termination visit will be annualized where a year is defined by 52 weeks and will be analyzed using a negative binomial regression.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Population - All subjects randomized to and receiving at least 1 dose of assigned treatment. The statistical analysis plans states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed	66	67	133	66
Mean (95% Confidence Interval); Unit of Measure: pulmonary exacerbations per year
	1.57; (1.22 to 2.02)	1.46; (1.13 to 1.89)	1.51; (1.26 to 1.81)	1.56; (1.21 to 2.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	100 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Single Group Rate with 95% CI
Method of Estimation	Estimation Parameter	see Estimation Comment below
	Estimated Value	1.57
	Confidence Interval	(2-Sided) 95%; 1.22 to 2.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments	Estimated using negative binomial distribution by treatment group unadjusted for multiple comparisons.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	50 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Single Group Rate with 95% CI
Method of Estimation	Estimation Parameter	see Estimation Comment below
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; 1.13 to 1.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments	Estimated using negative binomial distribution by treatment group unadjusted for multiple comparisons.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Matching Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Single Group Rate with 95% CI
Method of Estimation	Estimation Parameter	see Estimation Comment below
	Estimated Value	1.56
	Confidence Interval	(2-Sided) 95%; 1.21 to 2.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments	Estimated using negative binomial distribution by treatment group unadjusted for multiple comparisons.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pooled CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Pooled Group Rate with 95% CI
Method of Estimation	Estimation Parameter	see Estimation Comment below
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95%; 1.26 to 1.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments	Estimated using negative binomial distribution unadjusted for multiple comparisons.

3. Secondary Outcome

Title	Hazard Ratio Pulmonary Exacerbation While in the Study
Description	Hazard Ratio of pulmonary exacerbation versus placebo for all subjects. Pulmonary exacerbations are defined as treatment with oral, inhaled, or intravenous antibiotic(s) for ≥4 of symptoms/signs per the modified Fuchs criteria.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Population - All subjects randomized to and receiving at least 1 dose of assigned treatment. The statistical analysis plans states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results
Overall Number of Participants Analyzed	66	67	133
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: hazard ratio
	0.88; (0.576 to 1.339)	0.86; (0.563 to 1.308)	0.87; (0.605 to 1.246)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	100 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	95% 2-sided confidence interval for the Hazard Ratio relative to Placebo unadjusted for multiple comparisons
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	50 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	95% 2-sided confidence interval for the Hazard Ratio relative to Placebo unadjusted for multiple comparisons
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	100 mg CTX-4430, 50 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	95% 2-sided confidence interval for the Hazard Ratio Relative to Placebo unadjusted for multiple comparisons
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Subjects Without a Pulmonary Exacerbation While in the Study
Description	Subjects who did not experience a protocol-defined pulmonary exacerbation during the study
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Population - All subjects randomized to and receiving at least 1 dose of assigned treatment.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed	66	67	133	66
Measure Type: Count of Participants; Unit of Measure: Participants
	25 37.9%	26 38.8%	51 38.3%	20 30.3%

5. Secondary Outcome

Title	Relative Change (Percent Change) From Baseline in ppFEV1
Description	Percent change from Baseline for ppFEV1 at 48 weeks was assessed.
Time Frame	Baseline, Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Population - All subjects randomized to and receiving at least 1 dose of assigned treatment. (Observed Data). The statistical analysis plans states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed	59	59	118	57
Mean (95% Confidence Interval); Unit of Measure: percent change from baseline
	-2.38; (-5.37 to 0.60)	-4.81; (-7.84 to -1.79)	-3.60; (-5.72 to -1.47)	-3.40; (-6.59 to -0.22)

6. Secondary Outcome

Title	Change From Baseline at 48 Weeks for Forced Vital Capacity Percent Predicted (FVC) and FEF25-75% (Forced Expiratory Flow During the Middle Half of the Forced Vital Capacity) Percent Predicted
Description	[Not Specified]
Time Frame	Baseline, Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Population - All subjects randomized to and receiving at least 1 dose of assigned treatment. (Observed Data). The statistical analysis plans states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed	59	59	118	57
Mean (95% Confidence Interval); Unit of Measure: absolute change of percent predicted
Forced vital capacity (FVC) percent predicted	-1.57; (-3.37 to 0.23)	-2.06; (-3.88 to -0.25)	-1.82; (-3.10 to -0.54)	-1.41; (-3.32 to 0.51)
Forced expiratory flow(FEF25-75%)percent predicted	-1.61; (-4.26 to 1.03)	-4.79; (-7.46 to -2.11)	-3.20; (-5.08 to -1.32)	-4.38; (-7.20 to -1.57)

7. Secondary Outcome

Title	Change From Baseline for Specified Biomarkers
Description	Results were only calculated in subjects who had a verifiable result at the Baseline and Week 48 visits.
Time Frame	Baseline, Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Population - All subjects randomized to and receiving at least 1 dose of assigned treatment and who had results at Baseline and Week 48. The statistical analysis plans states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title		100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:		Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed		66	67	133	66
Mean (95% Confidence Interval); Unit of Measure: log10(mcg/mL)
Sputum DNA	Number Analyzed	33 participants	42 participants	75 participants	42 participants
		0.06; (-0.13 to 0.25)	0.17; (0.01 to 0.34)	0.12; (-0.01 to 0.24)	-0.05; (-0.22 to 0.12)
Sputum Elastase	Number Analyzed	33 participants	43 participants	76 participants	41 participants
		-0.02; (-0.20 to 0.16)	0.17; (0.02 to 0.33)	0.08; (-0.04 to 0.20)	-0.08; (-0.25 to 0.08)

8. Secondary Outcome

Title	Change From Baseline for C-reactive Protein (Hs-CRP)
Description	Results were only calculated in subjects who had a verifiable result at the Baseline and Week 48 visits.
Time Frame	Baseline, Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Population - All subjects randomized to and receiving at least 1 dose of assigned treatment and who had results at Baseline and Week 48. The statistical analysis plans states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed	51	55	106	51
Mean (95% Confidence Interval); Unit of Measure: mg/dL
	2.16; (-1.84 to 6.16)	-0.33; (-4.21 to 3.56)	0.92; (-1.87 to 3.70)	-1.87; (-5.91 to 2.17)

9. Other Pre-specified Outcome

Title	Number of Pulmonary Exacerbation Per Year for Participants With ppFEV1 >75 at Baseline
Description	Rate of protocol-defined pulmonary exacerbations reported through the Week 48/Early Termination visit will be annualized where a year is defined by 52 weeks and will be analyzed using a negative binomial regression.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Population of subjects with Baseline ppFEV1 >75. The statistical analysis plans states the two active doses will be compared to placebo individually as well as combined. The statistical analysis plans states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed	22	25	47	24
Mean (95% Confidence Interval); Unit of Measure: pulmonary exacerbations per year
	0.84; (0.49 to 1.44)	1.28; (0.84 to 1.96)	1.04; (0.74 to 1.46)	1.61; (1.07 to 2.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	100 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Single Group Rate with 95% CI
Method of Estimation	Estimation Parameter	see Estimation Comment below
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.23
	Estimation Comments	Estimated using negative binomial distribution by treatment group unadjusted for multiple comparisons.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	50 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Single Group Rate with 95% CI
Method of Estimation	Estimation Parameter	see Estimation Comment below
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.28
	Estimation Comments	Estimated using negative binomial distribution by treatment group unadjusted for multiple comparisons.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Matching Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Single Group Rate with 95% CI
Method of Estimation	Estimation Parameter	see Estimation Comment below
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 1.07 to 2.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.34
	Estimation Comments	Estimated using negative binomial distribution by treatment group unadjusted for multiple comparisons.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Pooled CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Group Rate with 95% CI
Method of Estimation	Estimation Parameter	see Estimation Comment below
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments	Estimated using negative binomial distribution by treatment group unadjusted for multiple comparisons.

10. Other Pre-specified Outcome

Title	Hazard Ratio Pulmonary Exacerbation for Participants With ppFEV1 >75 at Baseline
Description	Hazard ratio of pulmonary exacerbation versus placebo for all subjects
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Population of subjects with Baseline ppFEV1 >75. The statistical analysis plan states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results.
Overall Number of Participants Analyzed	22	25	47
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: hazard ratio
	0.52; (0.245 to 1.101)	0.62; (0.304 to 1.274)	0.57; (0.307 to 1.051)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	100 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	95% 2-sided confidence interval for the Hazard Ratio Relative to Placebo unadjusted for multiple comparisons
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.25 to 1.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	50 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	95% 2-sided confidence interval for the Hazard Ratio Relative to Placebo unadjusted for multiple comparisons
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.30 to 1.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	100 mg CTX-4430, 50 mg CTX-4430
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	95% 2-sided confidence interval for the Hazard Ratio Relative to Placebo unadjusted for multiple comparisons
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.31 to 1.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments	[Not Specified]

11. Other Pre-specified Outcome

Title	Subjects Without a Pulmonary Exacerbation by Participants With ppFEV1 >75 at Baseline
Description	Subjects who did not experience a protocol-defined pulmonary exacerbation during the study.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Population of subjects with Baseline ppFEV1 >75.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results.	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed	22	25	47	24
Measure Type: Count of Participants; Unit of Measure: Participants
	11 50.0%	12 48.0%	23 48.9%	6 25.0%

12. Other Pre-specified Outcome

Title	Number of Pulmonary Exacerbation by Subjects if Taking CFTR-Modulator Therapy at Baseline
Description	Rate of protocol-defined pulmonary exacerbations reported through the Week 48/Early Termination visit will be annualized where a year is defined by 52 weeks and will be analyzed using a negative binomial regression.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Population of subjects taking CFTR modulating therapy at Baseline. The statistical analysis plans states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results.	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed	21	22	43	19
Mean (95% Confidence Interval); Unit of Measure: pulmonary exacerbations per year
	1.24; (0.78 to 1.96)	1.08; (0.67 to 1.74)	1.16; (0.83 to 1.61)	1.45; (0.91 to 2.31)

13. Other Pre-specified Outcome

Title	Hazard Ratio Pulmonary Exacerbation by Subjects if Taking CFTR-Modulator Therapy at Baseline
Description	Hazard Ratio pulmonary exacerbation versus placebo for all subjects taking CFTR-modulating therapy at Baseline
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Population of subjects taking CFTR modulating therapy at Baseline. The statistical analysis plans states the two active doses will be compared to placebo individually as well as pooled.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results
Overall Number of Participants Analyzed	21	22	43
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: hazard ratio
	0.73; (0.328 to 1.641)	0.69; (0.313 to 1.514)	0.71; (0.359 to 1.408)

14. Other Pre-specified Outcome

Title	Subjects Without a Pulmonary Exacerbation by Subjects if Taking CFTR-Modulator Therapy at Baseline
Description	Subjects who did not experience a protocol-defined pulmonary exacerbation during the study.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Population of subjects taking CFTR modulating therapy at Baseline.

Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed	21	22	43	19
Measure Type: Count of Participants; Unit of Measure: Participants
	10 47.6%	10 45.5%	20 46.5%	6 31.6%

15. Post-Hoc Outcome

Title	Number of Pulmonary Exacerbation by Baseline FEV1 Percent Predicted at Week 48
Description	Rate of protocol-defined pulmonary exacerbations reported through the Week 48/Early Termination visit will be annualized where a year is defined by 52 weeks and will be analyzed using a negative binomial regression.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Subject's FEV1 percent predicted at screening are presented below.

Arm/Group Title		100 mg CTX-4430	50 mg CTX-4430	Pooled CTX-4430	Matching Placebo
Arm/Group Description:		Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral 100mg and 50mg pooled results	Once daily oral capsule for 48 weeks Placebo
Overall Number of Participants Analyzed		66	67	133	66
Mean (95% Confidence Interval); Unit of Measure: pulmonary exacerbations per year
Baseline FEV1>50%	Number Analyzed	62 participants	65 participants	127 participants	63 participants
		1.5094; (1.1549 to 1.9727)	1.4376; (1.0991 to 1.8803)	1.4731; (1.2187 to 1.7806)	1.5297; (1.1708 to 1.9986)
Baseline FEV1>55%	Number Analyzed	53 participants	60 participants	113 participants	55 participants
		1.5006; (1.1265 to 1.9989)	1.4159; (1.0760 to 1.8633)	1.4576; (1.1952 to 1.7777)	1.5425; (1.1643 to 2.0435)
Baseline FEV1>60%	Number Analyzed	43 participants	52 participants	95 participants	43 participants
		1.2698; (0.9181 to 1.7561)	1.4446; (1.0907 to 1.9133)	1.3544; (1.0928 to 1.6785)	1.4728; (1.0795 to 2.0094)
Baseline FEV1>65%	Number Analyzed	35 participants	40 participants	75 participants	39 participants
		1.0473; (0.7170 to 1.5298)	1.2523; (0.9018 to 1.7390)	1.1452; (0.8912 to 1.4716)	1.4489; (1.0540 to 1.9918)
Baseline FEV1>70%	Number Analyzed	29 participants	31 participants	60 participants	32 participants
		0.9198; (0.5930 to 1.4269)	1.1995; (0.8250 to 1.7440)	1.0504; (0.7871 to 1.4018)	1.5365; (1.0912 to 2.1636)
Baseline FEV1>75%	Number Analyzed	22 participants	25 participants	47 participants	24 participants
		0.8417; (0.4913 to 1.4418)	1.2786; (0.8358 to 1.9560)	1.0374; (0.7361 to 1.4619)	1.6125; (1.0728 to 2.4237)

Adverse Events

Time Frame	Baseline up to 28 days after the subject's last dose of study medication where the last dose is 48 weeks or early discontinuation of study drug.
Adverse Event Reporting Description	An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and does not necessarily have a causal relationship with this product. For purposes of this trial, AEs will be reported from the signing of the study informed consent (ICF) through study completion or early termination. A Treatment-Emergent AE is an AE that occurs after the first dose of study medication.
Arm/Group Title	100 mg CTX-4430	50 mg CTX-4430	Matching Placebo
Arm/Group Description	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks CTX-4430	Once daily oral capsule for 48 weeks Placebo
All-Cause Mortality
	100 mg CTX-4430	50 mg CTX-4430	Matching Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/66 (0.00%)	0/67 (0.00%)	0/66 (0.00%)
Serious Adverse Events
	100 mg CTX-4430	50 mg CTX-4430	Matching Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	27/66 (40.91%)	26/67 (38.81%)	21/66 (31.82%)
Blood and lymphatic system disorders
Haemolytic Anaemia * 1	0/66 (0.00%)	0/67 (0.00%)	1/66 (1.52%)
Gastrointestinal disorders
Distal intestinal obstruction syndrome * 1	1/66 (1.52%)	1/67 (1.49%)	0/66 (0.00%)
Vomiting * 1	0/66 (0.00%)	1/67 (1.49%)	0/66 (0.00%)
Infections and infestations
Appendicitis * 1	1/66 (1.52%)	0/67 (0.00%)	0/66 (0.00%)
Cellulitis * 1	1/66 (1.52%)	0/67 (0.00%)	0/66 (0.00%)
Chronic Sinusitis * 1	0/66 (0.00%)	1/67 (1.49%)	0/66 (0.00%)
Infective pulmonary exacerbation of cystic fibrosis * 1	21/66 (31.82%)	23/67 (34.33%)	19/66 (28.79%)
Lower respiratory tract infection fungal * 1	1/66 (1.52%)	0/67 (0.00%)	0/66 (0.00%)
Nocardiosis * 1	0/66 (0.00%)	0/67 (0.00%)	1/66 (1.52%)
Pneumonia mycoplasmal * 1	0/66 (0.00%)	1/67 (1.49%)	0/66 (0.00%)
Pyelonephritis * 1	0/66 (0.00%)	1/67 (1.49%)	0/66 (0.00%)
Rhinovirus infection * 1	0/66 (0.00%)	0/67 (0.00%)	1/66 (1.52%)
Scedosporium infection * 1	0/66 (0.00%)	0/67 (0.00%)	1/66 (1.52%)
Sepsis * 1	1/66 (1.52%)	0/67 (0.00%)	0/66 (0.00%)
Sinusitis * 1	1/66 (1.52%)	0/67 (0.00%)	0/66 (0.00%)
Injury, poisoning and procedural complications
Lower limb fracture * 1	0/66 (0.00%)	1/67 (1.49%)	0/66 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Borderline serous tumour of ovary * 1	0/66 (0.00%)	1/67 (1.49%)	0/66 (0.00%)
Renal and urinary disorders
Calculus ureteric * 1	0/66 (0.00%)	0/67 (0.00%)	1/66 (1.52%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure * 1	0/66 (0.00%)	1/67 (1.49%)	0/66 (0.00%)
Cough * 1	0/66 (0.00%)	0/67 (0.00%)	1/66 (1.52%)
Haemoptysis * 1	1/66 (1.52%)	1/67 (1.49%)	2/66 (3.03%)
Nasal septum deviation * 1	1/66 (1.52%)	0/67 (0.00%)	0/66 (0.00%)
Surgical and medical procedures
Antibiotic therapy * 1	2/66 (3.03%)	0/67 (0.00%)	0/66 (0.00%)
Therapeutic embolisation * 1	0/66 (0.00%)	0/67 (0.00%)	1/66 (1.52%)
Therapy Change * 1	1/66 (1.52%)	0/67 (0.00%)	0/66 (0.00%)
1 Term from vocabulary, MedDRA (18.0); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	100 mg CTX-4430	50 mg CTX-4430	Matching Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	66/66 (100.00%)	67/67 (100.00%)	65/66 (98.48%)
Gastrointestinal disorders
Diarrhoea * 1	5/66 (7.58%)	9/67 (13.43%)	4/66 (6.06%)
Nausea * 1	8/66 (12.12%)	5/67 (7.46%)	5/66 (7.58%)
Abdominal pain upper * 1	3/66 (4.55%)	7/67 (10.45%)	5/66 (7.58%)
Vomiting * 1	3/66 (4.55%)	1/67 (1.49%)	4/66 (6.06%)
Abdominal pain * 1	4/66 (6.06%)	3/67 (4.48%)	4/66 (6.06%)
Constipation * 1	1/66 (1.52%)	4/67 (5.97%)	3/66 (4.55%)
General disorders
Fatigue * 1	9/66 (13.64%)	9/67 (13.43%)	7/66 (10.61%)
Pyrexia * 1	8/66 (12.12%)	6/67 (8.96%)	7/66 (10.61%)
Chest discomfort * 1	8/66 (12.12%)	3/67 (4.48%)	7/66 (10.61%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis * 1	43/66 (65.15%)	45/67 (67.16%)	49/66 (74.24%)
Nasopharyngitis * 1	14/66 (21.21%)	11/67 (16.42%)	13/66 (19.70%)
Sinusitis * 1	6/66 (9.09%)	3/67 (4.48%)	5/66 (7.58%)
Gastroenteritis * 1	4/66 (6.06%)	1/67 (1.49%)	2/66 (3.03%)
Influenza * 1	5/66 (7.58%)	3/67 (4.48%)	4/66 (6.06%)
Rhinitis * 1	3/66 (4.55%)	4/67 (5.97%)	2/66 (3.03%)
Upper respiratory tract infection * 1	4/66 (6.06%)	4/67 (5.97%)	5/66 (7.58%)
Investigations
Alanine aminotransferase increased * 1	4/66 (6.06%)	0/67 (0.00%)	2/66 (3.03%)
Forced expiratory volume decreased * 1	5/66 (7.58%)	4/67 (5.97%)	4/66 (6.06%)
Sputum Abnormal * 1	0/66 (0.00%)	4/67 (5.97%)	1/66 (1.52%)
Weight decreased * 1	1/66 (1.52%)	4/67 (5.97%)	4/66 (6.06%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	5/66 (7.58%)	3/67 (4.48%)	1/66 (1.52%)
Back pain * 1	1/66 (1.52%)	4/67 (5.97%)	1/66 (1.52%)
Nervous system disorders
Headache * 1	9/66 (13.64%)	16/67 (23.88%)	7/66 (10.61%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	29/66 (43.94%)	27/67 (40.30%)	21/66 (31.82%)
Haemoptysis * 1	12/66 (18.18%)	17/67 (25.37%)	11/66 (16.67%)
Sputum increased * 1	7/66 (10.61%)	13/67 (19.40%)	11/66 (16.67%)
Oropharyngeal pain * 1	9/66 (13.64%)	7/67 (10.45%)	4/66 (6.06%)
Nasal congestion * 1	8/66 (12.12%)	7/67 (10.45%)	9/66 (13.64%)
Dyspnoea * 1	5/66 (7.58%)	6/67 (8.96%)	5/66 (7.58%)
Epistaxis * 1	3/66 (4.55%)	4/67 (5.97%)	1/66 (1.52%)
Paranasal sinus hypersecretion * 1	0/66 (0.00%)	5/67 (7.46%)	1/66 (1.52%)
Rales * 1	4/66 (6.06%)	1/67 (1.49%)	1/66 (1.52%)
Rhinorrhoea * 1	5/66 (7.58%)	6/67 (8.96%)	2/66 (3.03%)
Sinus congestion * 1	2/66 (3.03%)	5/67 (7.46%)	5/66 (7.58%)
Skin and subcutaneous tissue disorders
Rash * 1	6/66 (9.09%)	3/67 (4.48%)	1/66 (1.52%)
1 Term from vocabulary, MedDRA (18.0); * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

PI is free to publish results of the study after (1) the first multi-center publication or (2) 24 months after close of the study, whichever occurs first.

Proposed publications are to be submitted to the sponsor for review and comment for a period of at least 90 days (which may be extended under certain circumstances related to protection of intellectual property as well as for deletion of any Confidential Information).

Results Point of Contact

• Name/Title: Director, Clincal Operations
• Organization: Celtaxsys, Inc.
• Phone: 4702060153 ext 123
• EMail: sbirnbaum@celtaxsys.com

• Responsible Party: Celtaxsys, Inc.
• ClinicalTrials.gov Identifier: NCT02443688
• Other Study ID Numbers: CTX-4430-CF-201
• First Submitted: May 8, 2015
• First Posted: May 14, 2015
• Results First Submitted: April 29, 2019
• Results First Posted: July 25, 2019
• Last Update Posted: September 4, 2019