ELIXIR: Evaluation of Lung Clearance Index in Cystic Fibrosis (CF) Patients, Infected With P.Aeruginosa

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02248922
• Collaborator: (none)
• Enrollment: 17
• Locations: 6
• Arm: 1
• Actual Duration (Months): 26.4
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study was to evaluate lung clearance index (LCI) by a standardized procedure in a well characterized study setting and to assess feasibility of LCI as a more sensitive method than forced expiratory volume at 1 second (FEV1) to measure effectiveness of antibiotic therapy in patients with CF aged 6 years and older with mild to moderate lung disease.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lung Infection With Pseudomonas Aeruginosa in Cystic Fibrosis	Drug: TIS or TIP	Phase 4

Detailed Description

This study was terminated prematurely. The reason for trial termination was challenge with enrollment and patient recruitment. A significant decrease in the eligible patient population had been identified as main driver.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: An 8 Week Open-label Interventional Multicenter Study to Evaluate the Lung Clearance Index as Endpoint for Clinical Trials in Cystic Fibrosis Patients ≥ 6 Years of Age, Chronically Infected With Pseudomonas Aeruginosa
• Actual Study Start Date: Jan 27, 2015
• Actual Primary Completion Date: Apr 10, 2017
• Actual Study Completion Date: Apr 10, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tobramycin ALL 300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off	Drug: TIS or TIP; 300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Lung Clearance Index (LCI) After 4 Weeks Following Onset of Study [Baseline, week 4]

   The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal.

Secondary Outcome Measures

1. Change From Baseline of Forced Expiratory Volume at 1 Second (FEV1) After 4 Weeks Following Onset of Study [Baseline, week 4]

   Change of FEV1 (Forced expiry volume in the first second) measured by Spirometry

2. Change From Baseline of Colony-forming Units (CFU) After 4 Weeks Following Onset of Study [Baseline, week 4]

   Microbacterial density of Pseudomonas aeruginosa in Sputum-Samples in CFU (Colony Forming Units) per gram sputum.

3. Change From Baseline in Lung Clearance Index (LCI) After 1 Week [Baseline, week 1]

   The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal.

4. Change of Lung Clearance Index (LCI) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) [week 4, week 8]

   The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal.

5. Change of Forced Expiratory Volume at 1 Second(FEV1) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) [week 4, week 8]

   Change of FEV1 (Forced expiry volume in the first second) measured by Spirometry

6. Change of Colony-forming Units (CFU) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle) [week 4, week 8]

   Microbacterial density of Pseudomonas aeruginosa in Sputum-Samples in CFU (Colony Forming Units) per gram sputum.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of CF

• Patients with elevated LCI of ≥ 7.5 at screening

• Patients with FEV1 of ≥ 50% predicted at screening

• Use of inhaled Tobramycin in a 28 days on / off regimen in the past 3 months before screening

• chronic lung Infection with Pseudomonas aeruginosa

Exclusion Criteria:

• Patients who are regularly receiving more than one class of inhaled anti-pseudomonal antibiotic

• Patients who have used oral or intravenous anti-pseudomonal antibiotics within 28 days prior to on-phase of study drug

• Pregnant or nursing (lactating) women

• Change in dose, formulation or strength of the study drug in the past treatment cycle before screening

• History of hearing loss or chronic tinnitus

• Infection with Burkholderia cenocepacia complex

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Dresden		Germany	01307
2	Novartis Investigative Site	Erlangen		Germany	91054
3	Novartis Investigative Site	Essen		Germany	45147
4	Novartis Investigative Site	Frankfurt		Germany	60590
5	Novartis Investigative Site	Germering		Germany	82110
6	Novartis Investigative Site	Jena		Germany	07740

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Jörg Ziegler, PhD, Novartis Pharma GmbH, Nürnberg, Germany

Study Documents (Full-Text)

• Study Protocol - Aug 3, 2015
• Statistical Analysis Plan - Feb 10, 2017

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02248922
• Other Study ID Numbers: CTBM100CDE02
• First Posted: Sep 25, 2014
• Last Update Posted: Oct 9, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Cystic Fibrosis, Pseudomonas aeruginosa, Lung Clearance Index, Multiple Breath Washout, Inhaled Tobramycin, Inhaled Antibiotics.
• Additional relevant MeSH terms: Pseudomonas Infections; Cystic Fibrosis; Fibrosis

Study Results

Participant Flow

Recruitment Details	At least 35 patients were planned to be recruited in the study. However, in total, 17 patients entered into the study and completed. Reason for termination was challenge with enrollment and recruitment. A significant decrease in the eligible patient population was main driver.

Arm/Group Title	Tobramycin Inhalation Solution(TIS)	Tobramycin Inhalation Powder (TIP)
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) twice a day (BID) 28days on / 28 days off	TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
Period Title: Overall Study
STARTED	5	12
COMPLETED	5	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Tobramycin Inhalation Solution(TIS)	Tobramycin Inhalation Powder (TIP)	Total
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) twice a day (BID) 28days on / 28 days off	TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off	Total of all reporting groups
Overall Participants	5	12	17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	20.2 (8.26)	28.9 (9.79)	26.4 (9.99)
Sex: Female, Male (Count of Participants)
Female	3 60%	3 25%	6 35.3%
Male	2 40%	9 75%	11 64.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	5 100%	12 100%	17 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Lung Clearance Index (LCI) After 4 Weeks Following Onset of Study
Description	The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal.
Time Frame	Baseline, week 4

Outcome Measure Data

Analysis Population Description

Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.

Arm/Group Title	Tobramycin ALL
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
Measure Participants	17
Baseline	17.985 (1.1494)
Week 4	17.101 (0.8409)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobramycin ALL
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4099
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Change From Baseline of Forced Expiratory Volume at 1 Second (FEV1) After 4 Weeks Following Onset of Study
Description	Change of FEV1 (Forced expiry volume in the first second) measured by Spirometry
Time Frame	Baseline, week 4

Outcome Measure Data

Analysis Population Description

Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.

Arm/Group Title	Tobramycin ALL
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
Measure Participants	17
Baseline	76.964 (4.5121)
Week 4	77.481 (4.9877)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobramycin ALL
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6961
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Change From Baseline of Colony-forming Units (CFU) After 4 Weeks Following Onset of Study
Description	Microbacterial density of Pseudomonas aeruginosa in Sputum-Samples in CFU (Colony Forming Units) per gram sputum.
Time Frame	Baseline, week 4

Outcome Measure Data

Analysis Population Description

Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm. n is the number of patients of safety set with a non-missing value at the specific time point.

Arm/Group Title	Tobramycin ALL
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
Measure Participants	17
Baseline	56594.3 (28018.89)
Week 4	26113.0 (27280.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobramycin ALL
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3540
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Change From Baseline in Lung Clearance Index (LCI) After 1 Week
Description	The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal.
Time Frame	Baseline, week 1

Outcome Measure Data

Analysis Population Description

Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.

Arm/Group Title	Tobramycin ALL
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
Measure Participants	17
Baseline	17.985 (1.1494)
Week 1	17.506 (1.0002)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobramycin ALL
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5910
	Comments
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Change of Lung Clearance Index (LCI) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle)
Description	The Lung Clearance Index (LCI), measured by Multiple Breath Washout of a tracer gas reflects the obstruction of airways in the lung. Wash-out was completed by definition at the time point when the inhaled gas concentration declined to 2.5% of its concentration at baseline. Washout took longer in patients with more severe disease as gas was trapped in narrowed airways (leading to a higher LCI). A LCI of 7.5 and below is normal.
Time Frame	week 4, week 8

Outcome Measure Data

Analysis Population Description

Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.

Arm/Group Title	Tobramycin ALL
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
Measure Participants	17
Week 4	17.101 (0.8409)
Week 8	16.489 (1.1473)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobramycin ALL
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4249
	Comments
	Method	ANOVA
	Comments

6. Secondary Outcome

Title	Change of Forced Expiratory Volume at 1 Second(FEV1) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle)
Description	Change of FEV1 (Forced expiry volume in the first second) measured by Spirometry
Time Frame	week 4, week 8

Outcome Measure Data

Analysis Population Description

Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study (provided informed consent) and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm.

Arm/Group Title	Tobramycin ALL
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
Measure Participants	17
Week 4	77.481 (4.9877)
Week 8	78.705 (5.4782)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobramycin ALL
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3963
	Comments
	Method	ANOVA
	Comments

7. Secondary Outcome

Title	Change of Colony-forming Units (CFU) Between Week 4 (End of Study Drug Inhalation in the Current Treatment Cycle) and Week 8 (Prior to Start of Study Drug Inhalation in the Following Treatment Cycle)
Description	Microbacterial density of Pseudomonas aeruginosa in Sputum-Samples in CFU (Colony Forming Units) per gram sputum.
Time Frame	week 4, week 8

Outcome Measure Data

Analysis Population Description

Safety Set consisted of All 17 patients (in both arms: TIS and TIP) that entered the study and had been exposed to at least one dose of study drug. The efficacy analysis was based on safety set of Tobramycin ALL and not for each separate dosage form arm. n is the number of patients of safety set with a non-missing value at the specific time point.

Arm/Group Title	Tobramycin ALL
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) or TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
Measure Participants	17
Week 4	26113.0 (27280.98)
Week 8	56285.0 (28022.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobramycin ALL
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3502
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment through study completion, an average of 11 weeks.
Adverse Event Reporting Description	AE additional description
Arm/Group Title	Tobramycin Inhalation Solution(TIS)		Tobramycin Inhalation Powder (TIP)
Arm/Group Description	300mg nebulized Tobramycin (Tobramycin inhalation solution(TIS)) twice a day (BID) 28days on / 28 days off		TOBI Podhaler (Tobramycin inhalation powder(TIP), equivalent dry powder)twice a day (BID) 28days on / 28 days off
All Cause Mortality
	Tobramycin Inhalation Solution(TIS)		Tobramycin Inhalation Powder (TIP)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/12 (0%)
Serious Adverse Events
	Tobramycin Inhalation Solution(TIS)		Tobramycin Inhalation Powder (TIP)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Tobramycin Inhalation Solution(TIS)		Tobramycin Inhalation Powder (TIP)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		3/12 (25%)
Gastrointestinal disorders
Abdominal pain upper	0/5 (0%)		1/12 (8.3%)
Injury, poisoning and procedural complications
Sunburn	1/5 (20%)		0/12 (0%)
Investigations
Forced expiratory volume decreased	0/5 (0%)		1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Cough	0/5 (0%)		1/12 (8.3%)
Haemoptysis	1/5 (20%)		0/12 (0%)
Obstructive airways disorder	0/5 (0%)		1/12 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single- site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.