Clinical Trials Register

Summary
EudraCT Number:	2015-000398-11
Sponsor's Protocol Code Number:	GS-US-205-0170
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2015-02-03
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2015-000398-11

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Aztreonam for Inhalation Solution (AZLI) in a Continuous Alternating Therapy (CAT) Regimen of Inhaled Antibiotics for the Treatment of Chronic Pulmonary Pseudomonas aeruginosa Infection in Subjects with Cystic Fibrosis

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Clinical Trial to Assess the Safety and Efficacy of an Alternating Therapy of Antibiotics with the Drug Aztreonam for Inhalation Solution (AZLI) for the Treatment of Lung Infection by the bacteria Pseudomonas aeruginosa in Patients with Cystic Fibrosis.

A.4.1

Sponsor's protocol code number

GS-US-205-0170

A.5.4

Other Identifiers

Name:	IND No	Number:	064402
Name:	Clinical Trials.gov	Number:	NCT01641822

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Gilead Sciences, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Gilead Sciences, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gilead Sciences International Ltd
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Flowers Building, Granta Park
B.5.3.2	Town/ city	Abington, Cambridge
B.5.3.3	Post code	CB21 6GT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441223897496
B.5.5	Fax number	+441223897284
B.5.6	E-mail	clinical.trials@gilead.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Cayston Aztreonam 75 mg powder and solvent for nebuliser solution
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences International
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/204
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder and solvent for nebuliser solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AZTREONAM
D.3.9.1	CAS number	78110-38-0
D.3.9.2	Current sponsor code	AZLI
D.3.9.4	EV Substance Code	SUB05664MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	75
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	TOBI® 300 mg/5 mL Nebuliser Solution
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharmaceuticals UK Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Nebuliser solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOBRAMYCIN
D.3.9.3	Other descriptive name	TOBRAMYCIN
D.3.9.4	EV Substance Code	SUB11134MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Powder and solvent for nebuliser solution
D.8.4	Route of administration of the placebo	Inhalation use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Cystic fibrosis and chronic infection of lower respiratory tract with Pseudomonas aeruginosa

E.1.1.1

Medical condition in easily understood language

Cystic fibrosis and chronic lung infection with a bacterium (germ) called Pseudomonas aeruginosa

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	PT
E.1.2	Classification code	10011762
E.1.2	Term	Cystic fibrosis
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate the safety and efficacy of a CAT regimen with AZLI and TIS in adult and pediatric subjects with CF and pulmonary PA infection.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males or females ≥ 6 years of age
2. Diagnosis of CF as determined by the 1997 CF Consensus Conference criteria: At least 1 or more accompanying clinical features consistent with CF AND
— Documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test
OR
— Abnormal nasal transepithelial potential difference (NPD) test
OR
— Two well-characterized, disease-causing genetic mutations in the CF transmembrane conductance regulator (CFTR) gene
3. Documented presence of PA in 2 lower respiratory tract cultures (eg, sputum, throat swab) within the 12 months prior to or at Screening (Visit 1). Cultures must be a minimum of 3 months apart, with the most recent PA-positive culture within 3 months prior to Screening Visit 1. A PA-positive sputum or throat swab culture at Screening (Visit 1) can qualify as the most recent PA-positive culture.
4. Subject must be able to perform reproducible pulmonary function tests (PFTs)
5. FEV1 ≥ 25% and ≤ 75% predicted at Screening (Visit 1)
6. History of at least 1 hospitalization or 1 course of IV antibiotics for an acute respiratory exacerbation within the previous 12 months from Screening
7. Clinically stable with no evidence of significant respiratory symptoms or, if obtained for clinical evaluation, no acute chest radiograph findings at Screening (Visit 1) or Enrollment (Visit 2) that would require administration of IV antibiotics, oxygen supplementation, or hospitalization
8. Chest radiograph without significant acute findings (eg, infiltrates [lobar or diffuse interstitial], pleural effusion, pneumothorax); or chest radiograph, CT, or MRI obtained and interpreted within the 90 days prior to enrollment, without acute findings and no significant intercurrent illness; chronic, stable findings (eg, chronic scarring or atelectasis) are allowed
9. Subjects must be able to provide written informed consent (or assent if applicable) prior to any study related procedures; parent/guardian must be able to give written informed consent prior to any study related procedure
10. A negative urine pregnancy test is required for female subjects of childbearing potential (see Section 1)
11. All sexually active female subjects who are not postmenopausal, or surgically sterile, or who do not have medically documented ovarian failure and are of childbearing potential must agree to use highly effective contraception (per Section 7.8.2) during heterosexual intercourse throughout the study and for 30 days after the last dose of TIS or study drug;
females utilizing hormonal contraceptives as a birth control method must have used the same method for at least 3 months prior to start of TIS treatment
12. Male subjects who are sexually active are required to use barrier contraception (condom with spermicide) during heterosexual intercourse and refrain from sperm donation from screening through to study completion and for 90 days from the last dose of TIS or study drug

E.4

Principal exclusion criteria

1. Concurrent use of oral, IV, or inhaled antibiotics at Enrollment (Visit 2)
2. Concurrent hospitalization at Enrollment (Visit 2)
3. History of sputum or throat swab culture yielding Burkholderia spp. or any rapid growing mycobacterial infection (eg, M. abscessus) within 2 years of Enrollment (Visit 2)
4. Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone per day or 20 mg prednisone every other day
5. Current requirement for daily continuous oxygen supplementation or requirement (medically necessary) of more than 2 L/minute at night (subject would not meet this exclusion criterion if supplemental oxygen is used for comfort only)
6. Administration of any investigational drug or device within 28 days of Enrollment (Visit 2) or within 6 half-lives of the investigational drug (whichever is longer)
7. History of local or systemic hypersensitivity to monobactam or aminoglycoside antibiotics (inhaled or systemically administered) or history of aminoglycoside antibiotic-associated toxicity (oto-, renal, or neuromuscular toxicity)
8. History of allergies/intolerance to inhaled short-acting β2 agonists
9. History of lung transplantation
10. Changes in chronic azithromycin use, bronchodilator (BD), dornase alfa, physiotherapy technique or regimen, hypertonic saline, or corticosteroid medications within 28 days prior to Enrollment (Visit 2)
11. Pregnant or lactating females; a negative serum or urine pregnancy test is required for female subjects of childbearing potential (see Section 7.8.2)
12. Abnormal renal or hepatic function results at most recent test within the previous 90 days, defined as
— AST, ALT > 3 times upper limit of normal range (ULN)
— Creatinine >1.5 time ULN
13. Presence of any condition or abnormality that would compromise subject safety or the quality of data, or any serious or active medical or psychiatric illness, which in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance with the protocol

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the rate of protocol-defined exacerbations from Day 1 through Week 24.

E.5.1.1

Timepoint(s) of evaluation of this end point

Study visits from from Day 1 through Week 24.

E.5.2

Secondary end point(s)

• Average actual change from baseline in FEV1 % predicted at the end of each course of study drug (Weeks 4, 12, and 20)
• Percent of subjects who use non-study IV or inhaled antibiotics for protocol-defined pulmonary exacerbations, Day 1 to Week 24
• Time to first protocol-defined pulmonary exacerbation
• Rate of hospitalizations for a respiratory event
• Average change from baseline in the CFQ-R Respiratory Symptom Scale (RSS) score at the end of each course of study drug (Weeks 4, 12, and 20)

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 1 to Week 24

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

200

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

250

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After the end of the trial patients will revert to their respective standard of care.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Cystic Fibrosis Foundation Therapeutics, Therapeutics Development Network
G.4.3.4	Network Country	United States

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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