A Randomized, Double-Blind, Parallel-Group, 24-Week, Chronic-Dosing, Multi-Center Study to Assess the Efficacy and Safety of PT010, PT003, and PT009 Compared With Symbicort® Turbuhaler® (Kronos)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02497001

Acronym

KRONOS

Enrollment

1902

Registered

2015-07-14

Start date

2015-08-10

Completion date

2018-01-05

Last updated

2020-12-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

COPD

Brief summary

Study to Assess the Efficacy and Safety of PT010, PT003, and PT009 Compared With Symbicort® Turbuhaler® in Subjects with Moderate to Very Severe Chronic Obstructive Pulmonary Disease.

Detailed description

A Randomized, Double-Blind, Parallel-Group, 24-Week, Chronic-Dosing, Multi-Center Study to Assess the Efficacy and Safety of PT010, PT003, and PT009 Compared With Symbicort® Turbuhaler® as an Active Control in Subjects with Moderate to Very Severe Chronic Obstructive Pulmonary Disease This study includes the following 3 sub-studies: 12-hour Pulmonary Function Test (PFT), Pharmacokinetic (PK) Profile, and Hypothalamic-pituitary-adrenal Axis.

Interventions

DRUGBGF MDI 320/14.4/9.6 μg

Budesonide, Glycopyrronium, and Formoterol Fumarate Inhalation Aerosol (PT010, BGF metered dose inhaler \[MDI\])

DRUGGFF MDI (PT003) 14.4/9.6 μg

Glycopyrronium and Formoterol Fumarate Inhalation Aerosol (PT003, GFF MDI)

DRUGBFF MDI (PT009) 320/9.6 μg

Budesonide and Formoterol Fumarate Inhalation Aerosol (PT009, BFF MDI)

DRUGSymbicort® Turbuhaler® (TBH) Inhalation Powder

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

40 Years to 80 Years

Healthy volunteers

Inclusion criteria

* Given their signed written informed consent to participate. * Non-child bearing potential (ie, physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal); or Child bearing potential, has a negative serum pregnancy test at Visit 1, and agrees to acceptable contraceptive methods used consistently and correctly for the duration of the study. * Subjects with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS), or other local applicable guidelines. * Current or former smokers with a history of at least 10 pack-years of cigarette smoking. * Forced expiratory volume in 1 second (FEV1)/Forced vital capacity (FVC) ratio must be \<0.70 and FEV1 must be \<80% predicted normal value calculated using NHANES III reference equations (or reference norms applicable to other regions). * Required COPD maintenance therapy: * All Subjects must have been on two or more inhaled maintenance therapies for the management of their COPD for at least 6 weeks prior to Screening. Scheduled SABA and/or scheduled SAMA are considered inhaled maintenance therapies Please refer to the study protocol for the complete inclusion criteria list.

Exclusion criteria

* Significant diseases or conditions other than COPD, which, in the opinion of the Investigator, may put the subject at risk because of participation in the study or may influence either the results of the study or the subject's ability to participate in the study. * Women who are pregnant or lactating, or are planning to become pregnant during the course of the study, or women of childbearing potential who are not using an acceptable method of contraception. * Subjects, who in the opinion of the Investigator, have a current diagnosis of asthma. * Subjects who have been hospitalized due to poorly controlled COPD within 3 months prior to Visit 1 (Screening) or during the Screening Period * Subjects who have poorly controlled COPD, defined as acute worsening of COPD that requires treatment with oral corticosteroids or antibiotics within 6 weeks prior to Visit 1 (Screening) or during the Screening Period * Immune suppression or severe neurological disorders affecting control of the upper airway or other risk factors that in the opinion of the Investigator would put the subject at substantial risk of pneumonia. * Subjects with a diagnosis of narrow angle glaucoma, who, in the opinion of the Investigator, have not been adequately treated. * Subjects who have a history of hypersensitivity to β2-agonists, budesonide or any other corticosteroid components, glycopyrronium or other muscarinic anticholinergics, or any other component of the IMPs. Please refer to the study protocol for the complete inclusion criteria list.

Design outcomes

Primary

Measure	Time frame	Description
FEV1 AUC0-4	at Week 24	FEV1 AUC0-4 (L) for The Efficacy Estimand (Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4) AUC was normalized for length of follow up (e.g. typically 4 hours)).
Change From Baseline in Morning Pre-dose Trough FEV1	at Week 24	Morning Pre-Dose Trough FEV1 (L) for The Efficacy Estimand

Secondary

Measure	Time frame	Description
Change From Baseline in Morning Pre-dose Trough FEV1	over 24 Weeks	Morning Pre-Dose Trough FEV1 (L) for The Efficacy Estimand
Peak Change From Baseline in FEV1 Within 4 Hours Post-dosing	at Week 24	Peak Change from Baseline in FEV1 (L) Within 4 Hours Post-Dose for The Efficacy Estimand
Rate of Moderate or Severe COPD Exacerbations	over 24 weeks	Rate of Moderate or Severe COPD Exacerbations for the Efficacy Estimand
Percentage of Subjects Achieving a Minimal Clinically Important Difference (MCID) of 4 Units or More in SGRQ Total Score (SGRQ Responders)	at Week 24	Change from BGF
Change From Baseline in Average Daily Rescue Ventolin HFA Use	over 24 Weeks	Change from Baseline in Mean Daily Number of Puffs of Rescue Ventolin HFA for The Efficacy Estimand
Time to Onset of Action on Day 1, 5 Minutes Post Dose	Day 1	FEV1 (L) by Post-Dose Timepoint on Day 1 for The Efficacy Estimand
Time to Onset of Action on Day 1, 15 Minutes Post Dose	Day 1	FEV1 (L) by Post-Dose Timepoint on Day 1 for The Efficacy Estimand
Time to Onset of Action on Day 1, 30 Minutes Post Dose	Day 1	FEV1 (L) by Post-Dose Timepoint on Day 1 for The Efficacy Estimand
Time to Onset of Action on Day 1, 1 Hour Post Dose	Day 1	FEV1 (L) by Post-Dose Timepoint on Day 1 for The Efficacy Estimand
Time to Onset of Action on Day 1, 2 Hours Post Dose	Day 1	FEV1 (L) by Post-Dose Timepoint on Day 1 for The Efficacy Estimand
Time to Onset of Action on Day 1, 4 Hours Post Dose	Day 1	FEV1 (L) by Post-Dose Timepoint on Day 1 for The Efficacy Estimand

Countries

Canada, China, Japan, United States

Participant flow

Recruitment details

This study was conducted at 208 sites in four countries, from August 2015 until January 2018. The entire study period could take up to a maximum of 30 weeks.

Pre-assignment details

Subjects were randomized in a 2:2:1:1 scheme.

Participants by arm

Arm	Count
BGF MDI 320/14.4/9.6 ug Budesonide Glycopyrronium Formoterol Fumarate Metered Dose Inhalation 320/14.4/9.6 ug	639
GFF MDI 14.4/9.6 ug Glycopyrronium Formoterol Fumarate Metered Dose Inhalation 14.4/9.6 ug	625
BFF MDI 320/9.6 ug Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 ug	314
Symbicort TBH 400/12 ug Symbicort Turbuhaler 400/12 ug	318
Total	1,896

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	28	30	11	11
Overall Study	Lack of Efficacy	10	16	6	6
Overall Study	Lost to Follow-up	10	2	0	2
Overall Study	Major Protocol Deviation	3	4	4	4
Overall Study	Physician Decision	5	11	5	1
Overall Study	Protocol Violation	3	1	3	1
Overall Study	subjects that were not treated	1	2	2	1
Overall Study	Withdrawal by Subject	14	37	19	15

Baseline characteristics

Characteristic	BGF MDI 320/14.4/9.6 ug	GFF MDI 14.4/9.6 ug	BFF MDI 320/9.6 ug	Symbicort TBH 400/12 ug	Total
Age, Continuous	64.9 Years STANDARD_DEVIATION 7.8	65.1 Years STANDARD_DEVIATION 7.7	65.2 Years STANDARD_DEVIATION 7.2	65.9 Years STANDARD_DEVIATION 7.7	65.2 Years STANDARD_DEVIATION 7.7
Ethnicity (NIH/OMB) Hispanic or Latino	16 Participants	14 Participants	7 Participants	4 Participants	41 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	623 Participants	611 Participants	305 Participants	312 Participants	1851 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	2 Participants	2 Participants	4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	284 Participants	285 Participants	142 Participants	141 Participants	852 Participants
Race (NIH/OMB) Black or African American	23 Participants	38 Participants	15 Participants	14 Participants	90 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants	0 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) White	329 Participants	301 Participants	157 Participants	163 Participants	950 Participants
Sex: Female, Male Female	179 Participants	195 Participants	90 Participants	82 Participants	546 Participants
Sex: Female, Male Male	460 Participants	430 Participants	224 Participants	236 Participants	1350 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	6 / 639	3 / 625	2 / 314	1 / 318
other Total, other adverse events	126 / 639	84 / 625	59 / 314	55 / 318
serious Total, serious adverse events	55 / 639	68 / 625	21 / 314	29 / 318

Outcome results

Primary

Change From Baseline in Morning Pre-dose Trough FEV1

Morning Pre-Dose Trough FEV1 (L) for The Efficacy Estimand

Time frame: at Week 24

Population: mITT

Arm	Measure	Value (LEAST_SQUARES_MEAN)
BGF MDI 320/14.4/9.6 μg	Change From Baseline in Morning Pre-dose Trough FEV1	0.124 Liters
GFF MDI (PT003) 14.4/9.6 μg	Change From Baseline in Morning Pre-dose Trough FEV1	0.111 Liters
BFF MDI (PT009) 320/9.6 μg	Change From Baseline in Morning Pre-dose Trough FEV1	0.050 Liters
Symbicort®	Change From Baseline in Morning Pre-dose Trough FEV1	0.062 Liters

Primary

FEV1 AUC0-4

FEV1 AUC0-4 (L) for The Efficacy Estimand (Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4) AUC was normalized for length of follow up (e.g. typically 4 hours)).

Time frame: at Week 24

Population: mITT population total numbers may vary based on predefined subject exclusions prior to study unblinding

Arm	Measure	Value (LEAST_SQUARES_MEAN)
BGF MDI 320/14.4/9.6 μg	FEV1 AUC0-4	0.292 Liters
GFF MDI (PT003) 14.4/9.6 μg	FEV1 AUC0-4	0.288 Liters
BFF MDI (PT009) 320/9.6 μg	FEV1 AUC0-4	0.177 Liters
Symbicort®	FEV1 AUC0-4	0.189 Liters

Secondary

Change From Baseline in Average Daily Rescue Ventolin HFA Use

Change from Baseline in Mean Daily Number of Puffs of Rescue Ventolin HFA for The Efficacy Estimand

Time frame: over 24 Weeks

Population: mITT

Arm	Measure	Value (LEAST_SQUARES_MEAN)
BGF MDI 320/14.4/9.6 μg	Change From Baseline in Average Daily Rescue Ventolin HFA Use	-1.3 Puffs
GFF MDI (PT003) 14.4/9.6 μg	Change From Baseline in Average Daily Rescue Ventolin HFA Use	-1.1 Puffs
BFF MDI (PT009) 320/9.6 μg	Change From Baseline in Average Daily Rescue Ventolin HFA Use	-1.1 Puffs
Symbicort®	Change From Baseline in Average Daily Rescue Ventolin HFA Use	-1.6 Puffs

Secondary

Change From Baseline in Morning Pre-dose Trough FEV1

Morning Pre-Dose Trough FEV1 (L) for The Efficacy Estimand

Time frame: over 24 Weeks

Population: mITT

Arm	Measure	Value (LEAST_SQUARES_MEAN)
BGF MDI 320/14.4/9.6 μg	Change From Baseline in Morning Pre-dose Trough FEV1	0.147 Liters
GFF MDI (PT003) 14.4/9.6 μg	Change From Baseline in Morning Pre-dose Trough FEV1	0.125 Liters
BFF MDI (PT009) 320/9.6 μg	Change From Baseline in Morning Pre-dose Trough FEV1	0.073 Liters
Symbicort®	Change From Baseline in Morning Pre-dose Trough FEV1	0.088 Liters

Secondary

Peak Change From Baseline in FEV1 Within 4 Hours Post-dosing

Peak Change from Baseline in FEV1 (L) Within 4 Hours Post-Dose for The Efficacy Estimand

Time frame: at Week 24

Population: mITT

Arm	Measure	Value (LEAST_SQUARES_MEAN)
BGF MDI 320/14.4/9.6 μg	Peak Change From Baseline in FEV1 Within 4 Hours Post-dosing	0.370 Liters
GFF MDI (PT003) 14.4/9.6 μg	Peak Change From Baseline in FEV1 Within 4 Hours Post-dosing	0.361 Liters
BFF MDI (PT009) 320/9.6 μg	Peak Change From Baseline in FEV1 Within 4 Hours Post-dosing	0.253 Liters
Symbicort®	Peak Change From Baseline in FEV1 Within 4 Hours Post-dosing	0.264 Liters

Secondary

Percentage of Subjects Achieving a Minimal Clinically Important Difference (MCID) of 4 Units or More in SGRQ Total Score (SGRQ Responders)

Change from BGF

Time frame: at Week 24

Population: mITT

Arm	Measure	Value (LEAST_SQUARES_MEAN)
BGF MDI 320/14.4/9.6 μg	Percentage of Subjects Achieving a Minimal Clinically Important Difference (MCID) of 4 Units or More in SGRQ Total Score (SGRQ Responders)	6.06 Percentage
GFF MDI (PT003) 14.4/9.6 μg	Percentage of Subjects Achieving a Minimal Clinically Important Difference (MCID) of 4 Units or More in SGRQ Total Score (SGRQ Responders)	6.43 Percentage
BFF MDI (PT009) 320/9.6 μg	Percentage of Subjects Achieving a Minimal Clinically Important Difference (MCID) of 4 Units or More in SGRQ Total Score (SGRQ Responders)	8.23 Percentage

Secondary

Rate of Moderate or Severe COPD Exacerbations

Rate of Moderate or Severe COPD Exacerbations for the Efficacy Estimand

Time frame: over 24 weeks

Population: mITT

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
BGF MDI 320/14.4/9.6 μg	Rate of Moderate or Severe COPD Exacerbations	0.46 Exacerbations	Standard Error 0.05
GFF MDI (PT003) 14.4/9.6 μg	Rate of Moderate or Severe COPD Exacerbations	0.95 Exacerbations	Standard Error 0.09
BFF MDI (PT009) 320/9.6 μg	Rate of Moderate or Severe COPD Exacerbations	0.56 Exacerbations	Standard Error 0.08
Symbicort®	Rate of Moderate or Severe COPD Exacerbations	0.55 Exacerbations	Standard Error 0.08

Secondary