Clinical Trials Register

Summary
EudraCT Number:	2013-005348-28
Sponsor's Protocol Code Number:	ARD-3150-1201
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-09-11
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
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Ireland - HPRA

A.2

EudraCT number

2013-005348-28

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Pulmaquin® in the Management of Chronic Lung Infections with Pseudomonas aeruginosa in Subjects with Non-Cystic Fibrosis Bronchiectasis, including 28 Day Open-Label Extension and Pharmacokinetic Substudy (ORBIT-3)

A.3.1

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

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Pulmaquin® (ARD-3150, Dual Release Ciprofloxacin for Inhalation) in subjects who have a lung infection that includes the bacteria Pseudomonas aeruginosa due to non-cystic fibrosis bronchiectasis. This study includes a 28-day open-label extension (all patients will receive study drug for the last 28 days of the study).

A.3.2

Name or abbreviated title of the trial where available

Pulmaquin® with Non-Cystic Fibrosis Bronchiectasis (ORBIT 3)

A.4.1

Sponsor's protocol code number

ARD-3150-1201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01515007

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	Aradigm Corporation
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	Aradigm Corporation
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	Aradigm Corporation
B.5.2	Functional name of contact point	Chief Medical Officer
B.5.3	Address:
B.5.3.1	Street Address	3929 Point Eden Way
B.5.3.2	Town/ city	Hayward, California
B.5.3.3	Post code	CA 94545
B.5.3.4	Country	United States
B.5.4	Telephone number	0015102658838
B.5.5	Fax number	0015102658878
B.5.6	E-mail	froehlichj@aradigm.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	No
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.3.1	Product name	Pulmaquin®
D.3.2	Product code	ARD-3150
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	Ciprofloxacin Hydrochloride
D.3.9.1	CAS number	86483-48-9
D.3.9.2	Current sponsor code	Ciprofloxacin for Inhalation (CFI)
D.3.9.3	Other descriptive name	CIPROFLOXACIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	AS1
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	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ciprofloxacin Hydrochloride
D.3.9.1	CAS number	86483-48-9
D.3.9.2	Current sponsor code	Free Ciprofloxacin for Inhalation (FCI)
D.3.9.3	Other descriptive name	CIPROFLOXACIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	AS2
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	20
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	No
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	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

Chronic lung infections with Pseudomonas aeruginosa in subjects with non-cystic fibrosis bronchiectasis.

E.1.1.1

Medical condition in easily understood language

Lung infection that includes the bacteria Pseudomonas aeruginosa due to non-cystic fibrosis bronchiectasis.

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10057582
E.1.2	Term	Lung infection pseudomonal
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10006446
E.1.2	Term	Bronchiectasis NOS
E.1.2	System Organ Class	100000004855

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of this study is to evaluate the efficacy of Pulmaquin compared to placebo in the management of chronic lung infections with P. aeruginosa in subjects with non-cystic fibrosis (non-CF) bronchiectasis by evaluating the time to first pulmonary exacerbation in the Double-Blind Phase.

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are to evaluate the following:
• Efficacy of Pulmaquin compared to placebo as assessed by clinical outcomes (including pulmonary exacerbations), pulmonary function, patient-reported outcomes, and exercise testing in the Double-Blind Phase.
• Microbiological response in the Double-Blind Phase and the Open-Label Extension.
• Safety and tolerability of Pulmaquin compared to placebo in the Double-Blind Phase.
• Safety and tolerability of Pulmaquin in the Open-Label Extension.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

A pharmacokinetic substudy to be conducted as part of study ARD-3150-1201 (ORBIT 3) open label extension.
Objective: to assess the PK of Pulmaquin in blood and sputum in subjects with non-CF bronchiectasis.

E.3

Principal inclusion criteria

Subjects will be entered into this study only if they meet all of the following criteria:
1. Are willing and able to provide written informed consent.
2. Are males or females who are 18 year of age or older and are able to walk.
3. Have had a confirmed diagnosis of non-CF bronchiectasis per computerized tomography (or high resolution computerized tomography) showing bronchial wall dilatation (internal bronchial lumen diameter greater than accompanying pulmonary artery or lack of tapering) with or without bronchial wall thickening.
4. Have a documented history of at least 2 pulmonary exacerbations treated with courses of antibiotics within the last 12 months.
5. Have forced expiratory volume in 1 second (FEV1) ≥ 25% of predicted values at the Screening Visit (Visit 0).
6. Have positive documented P. aeruginosa in a sputum/deep-throat swab culture (or bronchoalveolar lavage [BAL] or bronchoscopic specimen) prior to the Screening Visit (Visit 0). Subjects without documented P. aeruginosa prior to Screening who meet all other eligibility criteria must have at
least two sputum samples or deep-throat swabs collected 3-4 or more weeks apart from each other during the 42- day Screening Phase. Two of the samples collected must test positive for P. aeruginosa. These two positive tests must be from samples taken a minimum of 3-4 or more weeks
apart.
7. Have positive P. aeruginosa in the sputum/deep-throat swab culture collected at the Screening Visit (Visit 0) and at least one P. aeruginosa isolate non-resistant to ciprofloxacin. If the sputum sample is negative for P. aeruginosa, or only shows resistant P. aeruginosa isolates, the sputum/swab culture can be repeated multiple times during Screening to document the presence of P. aeruginosa. In subjects without documented P. aeruginosa prior to Screening who meet all other eligibility criteria and who had two or more sputum cultures or deep- throat swab cultures obtained 3-4 or more weeks apart from each other during Screening, at least one P. aeruginosa isolate taken after 3-4 or more weeks must be non-resistant to ciprofloxacin for the subject to be considered eligible for randomization. The qualifying sputum culture results must be available within the 42-day Screening Phase.
8. Are clinically stable and capable of performing the 6mwt without supplemental oxygen.
9. Are willing and able to comply with the requirements for participation in the study.
10. Female subjects of childbearing potential must have a negative pregnancy test at the Screening Visit and must use an acceptable method of contraception for at least 3 months prior to the first dose of study drug and for 28 days after the last dose of study drug. Acceptable methods of contraception for women are
-combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
o oral
o intravaginal
o transferral
-progestogen-only hormonal contraception associated with inhibition of ovulation:
o oral
o injectable hormonal contraception
o implantable hormonal contraception
-placement of an intrauterine device (IUD)
-placement of an intrauterine hormone-releasing system ( IUS)
-bilateral tubal occlusion
-vasectomised partner
-sexual abstinence (when this is the preferred and usual lifestyle of the subject)
To be considered "not of childbearing potential", female subjects must be postmenopausal for at least 1 year as confirmed by an elevated follicle-stimulating hormone (FSH) level (≥ 30 mIU/mL) at Screening and 1 year of amenorrhea, or have been irreversibly surgically sterilized by hysterectomy, oophorectomy, or bilateral tubal ligation for at least 3 months prior to the first dose of study drug.
Male subjects whose female partners are of childbearing potential (definition as above) must agree to use an acceptable method of birth control for the duration of study treatment and for 28 days after the last dose of study drug.

E.4

Principal exclusion criteria

Subjects will be randomized into this study only if they meet none of the following criteria:
1. Have a pulmonary exacerbation during the Screening Phase (between signing the ICF and randomization), defined as requiring acute treatment with treatment with inhaled, oral, or intravenous antibiotics.
2. Have a clinical diagnosis of CF.
3. Have primary diagnosis of Chronic Obstructive Pulmonary Disease (COPD) related to smoking history of greater than 10 pack years.
4. Have a current diagnosis of active allergic bronchopulmonary aspergillosis.
5. Have received any intravenous, oral, or inhaled anti-pseudomonal antibiotic (except chronic macrolides erythromycin, clarithromycin or
azithromycin with a stable dose) within 28 days prior to Visit 1.
6. Have an allergy to ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, or norfloxacin.
7. Have a known allergy to soy products.
8. Have used tizanidine within 28 days prior to Visit 1 and would need to use tizanidine during the study (because tizanidine is contraindicated
due to a PK interaction with ciprofloxacin).
9. Have initiated supplemental oxygen within 28 days prior to Visit 1.
10. Have used any intravenous or intramuscular corticosteroid or have used oral corticosteroid > 10 mg/day or > 20 mg every other day
(prednisone or prednisolone equivalents) within 28 days of Visit 1.
11. Have had changes in either the treatment regimen or initiation of treatment with any of the following medications within 28 days prior to
Visit 1:
a. Macrolides, e.g., azithromycin, clarithromycin or erythromycin
b. Inhaled hypertonic saline or inhaled mannitol
c. Mucolytics
d. Bronchodilator medications
e. Oral corticosteroid
12. Have had changes in pulmonary rehabilitation, chest physiotherapy technique or frequency within 28 days prior to Visit 1.
13. Have a history of solid organ (e.g., lung) transplantation.
14. Have a non-tuberculosis mycobacterial infection and are currently receiving antibiotic treatment or are anticipated to require initiation of
antibiotic treatment during the study.
15. Have active tuberculosis.
16. Have serum creatinine levels ≥ 2.0x upper limit of normal (ULN) at the Screening Visit (Visit 0).
17. Have serum transaminase levels > 3x ULN at the Screening Visit (Visit 0).
18. Have a febrile illness within 1 week prior to Visit 1.
19. Have had massive hemoptysis (greater than or equal to 300 mL or requiring blood transfusion) within 6 months prior to Visit 1.
20. Have received an investigational drug or device within 42 days prior to Visit 1.
21. Have a malignancy or any other serious or active medical illness with a life expectancy of less than 12 months.
22. Have any serious or active medical or psychiatric illness, which in the opinion of the Investigator, would interfere with subjects' treatment,
assessment, or compliance with the protocol.
23. Have a history or suspicion of unreliability, poor cooperation, or noncompliance with medical treatment.
24. Are unable to use nebulizers during the course of the study.
25. Are unable either to understand the instruction for use of the study drug or to complete the Quality of Life Questionnaire-Bronchiectasis
(QoL-B) at Visit 1.
26. Have previously been randomized in this study.
27. Are pregnant, plan to become pregnant during this study, are nursing mothers or are unwilling to use an acceptable method of contraception
for the duration of the study.
28. Have any other condition that, in the opinion of the Investigator, would prohibit the subject from participating in the study.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint of this study is the time to first pulmonary exacerbation from baseline (Day 1) to Week 48.

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline (Day 1) to Week 48.

E.5.2

Secondary end point(s)

- Number of pulmonary exacerbations from baseline (Day 1) to Week 48.
- Number of severe pulmonary exacerbations from baseline (Day 1) to
Week 48.
- Change in Respiratory Symptoms Domain score of Qol-B from baseline (Day 1) to Week 48.

E.5.2.1

Timepoint(s) of evaluation of this end point

From baseline (Day 1) to Week 48.

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

Yes

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

Yes

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

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

France

Germany

Hungary

Ireland

Israel

Italy

Latvia

Poland

Romania

South Africa

Spain

United Kingdom

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

The study will close when all subjects have completed the follow-up telephone call at Day 394(+- 4 days), which will take place 30 days after the subject receives the last dose of open-label study drug at Visit 15 (Day 364).
Therefore End of Study is defined as when the last patient completes Visit 16 (Study Day 394) – or the last early withdrawal visit, whichever is later.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1