Clinical Trials Register

Summary
EudraCT Number:	2019-000718-13
Sponsor's Protocol Code Number:	BT–L-CsA–201–SCT
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-06-06
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

Germany - BfArM

A.2

EudraCT number

2019-000718-13

A.3

Full title of the trial

BOSTON-4: A Phase IIa Multi-Center, Randomized, Single-Blind Safety and
Tolerability Study of inhaled Liposomal Cyclosporine A in Bronchiolitis
Obliterans Syndrome Following Allogeneic Hematopoietic Stem Cell
Transplantation

A.3.1

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

A Clinical Research Study to Investigate the Safety and Tolerability of
inhaled Liposomal Cyclosporine A (L-CsA) in Patients with Bronchiolitis
Obliterans Syndrome after Allogeneic Hematopoietic Stem Cell
Transplantation.

A.3.2

Name or abbreviated title of the trial where available

BOSTON-4

A.4.1

Sponsor's protocol code number

BT–L-CsA–201–SCT

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	Zambon SpA
B.1.3.4	Country	Italy
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	Zambon SpA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Zambon SpA
B.5.2	Functional name of contact point	Paola Castellani
B.5.3	Address:
B.5.3.1	Street Address	Via Lillo del Duca 10
B.5.3.2	Town/ city	Bresso (MI)
B.5.3.3	Post code	20091
B.5.3.4	Country	Italy
B.5.4	Telephone number	+393428058450
B.5.6	E-mail	paola.castellani@zambongroup.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/210
D.3 Description of the IMP
D.3.1	Product name	Liposomal Cyclosporine A
D.3.2	Product code	L-CsA
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	Ciclosporin (Ciclosporinium)
D.3.9.1	CAS number	59865-13-3
D.3.9.3	Other descriptive name	CICLOSPORIN A
D.3.9.4	EV Substance Code	SUB129839
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	5
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.IMP: 2
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/210
D.3 Description of the IMP
D.3.1	Product name	Liposomal Cyclosporine A
D.3.2	Product code	L-CsA
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	Ciclosporin (Ciclosporinium)
D.3.9.1	CAS number	59865-13-3
D.3.9.3	Other descriptive name	CICLOSPORIN A
D.3.9.4	EV Substance Code	SUB129839
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	10
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	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

Bronchiolitis Obliterans Syndrome in Patients Following Allogeneic Hematopoietic Stem Cell Transplantation

E.1.1.1

Medical condition in easily understood language

Bronchiolitis Obliterans Syndrome in Patients Following Allogeneic Hematopoietic Stem Cell Transplantation

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

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 assess the tolerability and
safety, of two dose levels of aerosolized L-CsA vs placebo in addition to
SoC therapy for BOS in adult allo-HSCT recipients.

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are to assess PK and exploratory
efficacy and quality of life of two dose levels of aerosolized L-CsA vs
placebo in addition to SoC therapy for BOS in adult allo-HSCT recipients.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years
2. Patients must have undergone hematopoietic stem cell
transplantation and have documented diagnosis of chronic Graft versus
Host Disease (cGvHD) guided by the NIH consensus criteria.
3. Patients must have been diagnosed with BOS within >6 months and ≤
3 years at Screening visit.
4. Spirometry test carried out at Screening visit must show:
A FEV1 above 51% of predicted
AND
A ≥ 10% decline in FEV1 (L) within 2 years
5. Patient must be capable of understanding the purposes and risks of
the study, has given written informed consent, and agrees to comply
with the study requirements.
6. Women of childbearing potential must have a negative serum or urine
pregnancy test within 7 days prior to randomization and must agree to
use one of the methods of contraception listed in Appendix II of the
protocol through their End of Study Visit.

E.4

Principal exclusion criteria

1. Other acute or chronic restrictive or obstructive lung diseases,
including but not limited to: Patients with clinically active asthma
(variable and recurring symptoms of airflow obstruction and bronchial
hyper-responsiveness), chronic obstructive pulmonary disease,
interstitial lung disease, or cryptogenic organizing pneumonia or other
causes of restrictive lung disease such as neuromuscular weakness or
diaphragmatic paralysis.
2. Any acute pulmonary bacterial, viral (as confirmed by multiplex PCR)
or fungal infection not successfully resolved at least 4 weeks prior to the
Screening Visit.
3. Chronic renal dysfunction with serum creatinine ≥ 2.5 mg/dL.
4. Chronic hepatic dysfunction with serum total bilirubin > 5x upper limit
of normal (ULN), transaminases > 5x ULN, or alkaline phosphatase > 5x
ULN.
5. Evidence of clinical relapse of the primary malignancy, according to
investigator's judgement, which warranted allogeneic bone marrow
transplant.
6. Use of azithromycin within 4 weeks prior to Randomization (Visit 1).
7. Chronic oxygen use or use of non-invasive ventilation.
8. Active smokers (i.e. any kind of inhaled nicotine consumption).
9. Pregnant women or women who are unwilling to use appropriate birth
control to avoid pregnancy over the course of the clinical trial.
10. Women who are currently breastfeeding.
11. Known hypersensitivity to L-CsA or to cyclosporine A.
12. Patients with life-expectancy of less than 6 months.
13. Receipt of an investigational drug as part of a clinical trial within 4
weeks prior to the Screening Visit. Participation in registries is allowed
14. Psychiatric disorders or altered mental status precluding
understanding of the informed consent process and/or completion of the
necessary procedures.
15. Any co-existing medical condition that in the Investigator's judgment
will substantially increase the risk associated with the patient's
participation in the clinical trial.
16. Pre-scheduled hospitalizations, surgeries or interventions planned to
be performed after obtaining Informed Consent for this study.

E.5 End points

E.5.1

Primary end point(s)

IMP tolerability and safety during the first 4 weeks of treatment

IMP Tolerability Parameters:
• Local Tolerability:
o Cough
o Wheezing
o Bronchospasm
o Throat irritation
o Change in FEV1

•Overall Tolerability:
o Clinical Global Impressions (CGI) scale
o Investigator’s tolerability assessment at Visit 3 and Visit 5

Safety Parameters:
• Adverse events (AEs)
• Serious adverse events (SAEs)
• Clinical laboratory values
• Vital signs

E.5.1.1

Timepoint(s) of evaluation of this end point

IMP tolerability and safety during the first 4 weeks of treatment

Please refer to 'Schedule of Activities' in the Protocol

E.5.2

Secondary end point(s)

IMP tolerability and safety during the first 12 weeks of treatment;

IMP Tolerability Parameters:
• Local Tolerability:
o Cough
o Wheezing
o Bronchospasm
o Throat irritation
o Change in FEV1

•Overall Tolerability:
o Clinical Global Impressions (CGI) scale
o Investigator’s tolerability assessment at Visit 3 and Visit 5

Safety Parameters:
• Adverse events (AEs)
• Serious adverse events (SAEs)
• Clinical laboratory values
• Vital signs

CsA Pharmacokinetic Parameters:
o Cmax
o tmax
o AUC0-4h
• Whole blood trough levels

E.5.2.1

Timepoint(s) of evaluation of this end point

IMP tolerability and safety during the first 12 weeks of treatment;

Pharmacokinetic Parameters:
• PK: (Week 0) at pre-dose; directly after end of inhalation; 15, 30, and 45 minutes, and 1, 1.5, 2, and 4 hours after end of inhalation:
• Whole blood trough levels (at Weeks 2, 4, 8, and 12)

Please refer to 'Schedule of Activities' in the Protocol

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

E.6.4

Safety

Yes

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.4

Double blind

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

LSLV

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 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.1.1.1

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)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

None - Standard Treatment of Care.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-10-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-06-16

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