Trial Outcomes & Findings for Phase 3 Study of Aztreonam for Inhalation Solution (AZLI) in a Continuous Alternating Therapy Regimen for the Treatment of Chronic Pseudomonas Aeruginosa Infection in Patients With CF (NCT NCT01641822)

Last Updated: 2016-05-09

Results Overview

PDEs were characterized by a change or worsening from baseline of 1 or more documented signs or symptoms (decreased exercise tolerance, increased cough, increased sputum or chest congestion, decreased appetite, or other signs or symptoms) associated with the use of non-study IV or inhaled antibiotics and be verified by a blinded independent adjudication committee.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

107 participants

Primary outcome timeframe

Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)

Results posted on

2016-05-09

Participant Flow

Participants were enrolled at study sites in the United States. The first participant was screened on 13 December 2012. The last study visit occurred on 15 January 2015.

Following enrollment, participants received tobramycin inhalation solution (TIS) in the TIS Run-In Phase, and if still eligible were randomized 1 to 1 to receive aztreonam for inhalation solution (AZLI) or placebo to match AZLI alternating with TIS in the Comparative Phase.

Participant milestones

Participant milestones
Measure	TIS Run-In Treatment Group Enrolled participants received 28 days of TIS (300 mg 2 times daily) during the run-in phase.	AZLI Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Placebo Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days.
Run-in Phase STARTED	107	0	0
Run-in Phase COMPLETED	93	0	0
Run-in Phase NOT COMPLETED	14	0	0
Comparative Phase STARTED	0	43	47
Comparative Phase Received Randomized Study Drug Treatment	0	42	46
Comparative Phase COMPLETED	0	37	37
Comparative Phase NOT COMPLETED	0	6	10

Reasons for withdrawal

Reasons for withdrawal
Measure	TIS Run-In Treatment Group Enrolled participants received 28 days of TIS (300 mg 2 times daily) during the run-in phase.	AZLI Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Placebo Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days.
Run-in Phase Noncompliance with study drug	1	0	0
Run-in Phase Adverse Event	3	0	0
Run-in Phase Withdrew consent	1	0	0
Run-in Phase Protocol-specified criteria for withdraw	9	0	0
Comparative Phase Noncompliance with study drug	0	1	0
Comparative Phase Investigator's discretion	0	0	1
Comparative Phase Pregnancy	0	0	1
Comparative Phase Adverse event, serious fatal	0	1	0
Comparative Phase Withdrew consent	0	3	7
Comparative Phase Protocol-specified criteria for withdraw	0	1	1

Baseline Characteristics

Phase 3 Study of Aztreonam for Inhalation Solution (AZLI) in a Continuous Alternating Therapy Regimen for the Treatment of Chronic Pseudomonas Aeruginosa Infection in Patients With CF

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	AZLI n=43 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Placebo n=47 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Total n=90 Participants Total of all reporting groups
Age, Continuous	28.8 years STANDARD_DEVIATION 12.10 • n=5 Participants	28.0 years STANDARD_DEVIATION 10.88 • n=7 Participants	28.4 years STANDARD_DEVIATION 11.42 • n=5 Participants
Age, Customized 6 - 12 years	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants
Age, Customized 13 - 17 years	5 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants
Age, Customized ≥ 18 years	35 participants n=5 Participants	40 participants n=7 Participants	75 participants n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants	28 Participants n=7 Participants	52 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	19 Participants n=7 Participants	38 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	38 Participants n=5 Participants	43 Participants n=7 Participants	81 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Race/Ethnicity, Customized White	41 participants n=5 Participants	45 participants n=7 Participants	86 participants n=5 Participants
Race/Ethnicity, Customized Other	2 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment United States	43 participants n=5 Participants	47 participants n=7 Participants	90 participants n=5 Participants
FEV1 % predicted at Day 1	49.95 percentage of FEV1 % predicted STANDARD_DEVIATION 17.500 • n=5 Participants	50.25 percentage of FEV1 % predicted STANDARD_DEVIATION 15.131 • n=7 Participants	50.11 percentage of FEV1 % predicted STANDARD_DEVIATION 16.213 • n=5 Participants
CFQ-R Respiratory Score at Day 1	59.72 units on a scale STANDARD_DEVIATION 18.408 • n=5 Participants	64.24 units on a scale STANDARD_DEVIATION 15.044 • n=7 Participants	62.11 units on a scale STANDARD_DEVIATION 16.773 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)

Population: Intent-to-Treat (ITT) Analysis Set: all randomized participants

Outcome measures

Outcome measures
Measure	AZLI n=43 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Placebo n=47 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days.
Rate of Protocol-defined Exacerbations (PDE) From Baseline Through Week 24	1.309 PDEs per participant year	1.762 PDEs per participant year

SECONDARY outcome

Timeframe: Comparative Phase: Baseline and Weeks 4, 12 and 20

Population: Participants in the ITT Analysis Set with available data were analyzed.

FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex and body composition. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.

Outcome measures

Outcome measures
Measure	AZLI n=42 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Placebo n=45 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days.
Average Actual Change From Baseline in FEV1 % Predicted Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20)	1.37 percentage of FEV1 % predicted Standard Error 0.674	0.04 percentage of FEV1 % predicted Standard Error 0.658

SECONDARY outcome

Timeframe: Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)

Population: ITT Analysis Set

Outcome measures

Outcome measures
Measure	AZLI n=43 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Placebo n=47 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days.
Percentage of Participants Who Used Non-study IV or Inhaled Antibiotics for PDEs	48.8 percentage of participants	55.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)

Population: ITT Analysis Set

The time to first protocol-defined pulmonary exacerbation was calculated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	AZLI n=43 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Placebo n=47 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days.
Time to First Protocol-defined Pulmonary Exacerbation	175 days Interval 76.0 to Not reached due to an insufficient number of events	140.0 days Interval 90.0 to Not reached due to an insufficient number of events

SECONDARY outcome

Timeframe: Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)

Population: ITT Analysis Set

The rate of hospitalizations for a respiratory event per participant year was calculated using negative binomial regression analysis.

Outcome measures

Outcome measures
Measure	AZLI n=43 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Placebo n=47 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days.
Rate of Hospitalizations for a Respiratory Event	1.043 hospitalizations per participant year	1.624 hospitalizations per participant year

SECONDARY outcome

Timeframe: Comparative Phase: Baseline and Weeks 4, 12 and 20

Population: Participants in the ITT Analysis Set with available data were analyzed.

Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS). The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.

Outcome measures

Outcome measures
Measure	AZLI n=39 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI (75 mg 3 times daily) for 28 days followed by TIS (300 mg 2 times daily) for 28 days.	Placebo n=45 Participants Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS (300 mg 2 times daily) for 28 days.
Average Change From Baseline in the CFQ-R Respiratory Symptom Scale (RSS) Score Across All Courses of AZLI/Placebo Treatment (Weeks 4, 12 and 20)	1.00 units on a scale Standard Deviation 1.736	-2.06 units on a scale Standard Deviation 1.629

Adverse Events

TIS Run-In Treatment Group

Serious events: 4 serious events

Other events: 27 other events

Deaths: 0 deaths

AZLI

Serious events: 21 serious events

Other events: 38 other events

Deaths: 0 deaths

Placebo

Serious events: 24 serious events

Other events: 44 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Disclosures

Gilead Sciences

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: * The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or * The study has been completed at all study sites for at least 2 years
Publication restrictions are in place

Restriction type: OTHER