Clinical Trials Register

Summary
EudraCT Number:	2014-002479-28
Sponsor's Protocol Code Number:	MOL-ARDS-002
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:	2015-04-15
Trial 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

2014-002479-28

A.3

Full title of the trial

GM-CSF Inhalation to improve HOst defense and Pulmonary barrier rEstoration

GM-CSF Inhalation zur Verbesserung der Wirtsabwehr und der Wiederherstellung der alveolären Barrierefunktion

A.3.1

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

GM-CSF Inhalation to improve HOst defense and Pulmonary barrier rEstoration

GM-CSF Inhalation zur Verbesserung der Wirtsabwehr und der Wiederherstellung der alveolären Barrierefunktion

A.3.2

Name or abbreviated title of the trial where available

GI-HOPE

A.4.1

Sponsor's protocol code number

MOL-ARDS-002

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	Justus-Liebig University
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DZL (Deutsche Zentrum für Lungenforschung)
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Savara ApS
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Koordinierungszentrum für Klinische Studien der Philipps-Universität Marburg (KKS Marburg)
B.5.2	Functional name of contact point	Project manager
B.5.3	Address:
B.5.3.1	Street Address	Karl von Frisch Str.50
B.5.3.2	Town/ city	Marburg
B.5.3.3	Post code	35043
B.5.3.4	Country	Germany
B.5.4	Telephone number	0049064212826503
B.5.5	Fax number	0049064212866517
B.5.6	E-mail	katarzyna.piskulak@kks.uni-marburg.de

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	Molgradex 300 mcg nebuliser solution
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	MOLGRAMOSTIM
D.3.9.1	CAS number	99283-10-0
D.3.9.3	Other descriptive name	Recombinant human Granulocyte Macrophage Colony Stimulating Factor (rhGM-CSF)
D.3.9.4	EV Substance Code	SUB09040MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
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	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	Yes
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

Pneumonia associated Acute Respiratory Distress Syndrome (ARDS)

E.1.1.1

Medical condition in easily understood language

Patients with pneumonia-associated lung injury on pulmonary inflammation and barrier restoration.

Patienten mit Pneumonie-assoziiertem Lungenversagen hinsichtlich pulmonaler Inflammation und Wiederherstellung der Barrierefunktion

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10000036
E.1.2	Term	A.R.D.S.
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

To assess the efficacy of two different doses of inhaled molgramostim (150µg and 450µg) compared to placebo when administered to patients with pneumonia-associated ARDS, as measured by HOst defense and Pulmonary barrier rEstoration (GI-HOPE) Score.

E.2.2

Secondary objectives of the trial

• To assess safety and tolerability of two different doses of inhaled molgramostim (150µg and 450µg) when administered to patients with pneumonia-associated ARDS.
• To assess levels of GM-CSF (in serum) after 150µg and 450µg of inhaled molgramostim compared to placebo when administered to patients with pneumonia-associated ARDS.
• To assess pulmonary barrier function, systemic inflammation and improvement in morbidity in patients with pneumonia-associated ARDS treated with inhaled molgramostim.

Exploratory objective:
• To investigate the composition of different leucocyte subpopulations in BALF

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All of the following inclusion criteria must be met before the patient can enter into the trial:
1. Signed informed consent form by the patient or a legal representative according to local regulations
2. Man or woman 18 to 75 years of age, inclusive
3. Women who have been post-menopausal for more than 1 year or women of childbearing potential using a highly efficient method of contraception (i.e. a method with less than 1% failure rate such as combined hormonal contraception, progesterone-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tube occlusion, vasectomized partner, sexual abstinence) during dosing and hospitalisation. Women must have a negative serum or urine pregnancy test before the first dose of study medication and must not be lactating.
4. Diagnosis of pneumonia-associated ARDS where the underlying condition is Community-Acquired Pneumonia (CAP) or Hospital-Acquired Pneumonia (HAP) in patients not on invasive ventilation upon diagnosis of HAP
5. Diagnosis of ARDS according to the Berlin ARDS definition (The ARDS definition task force) as evidenced by:
a. onset within 1 week of a known clinical insult or new or worsening respiratory symptoms
b. bilateral opacities on chest imaging, in the investigator’s opinion not fully explained by
effusions, lobar/lung collapse, or nodules,
c. respiratory failure in the investigator’s opinion not fully explained by cardiac failure or fluid
overload
d. PaO2/FIO2 ≤300 mmHg with PEEP ≥5 cm H2O
6. Requirement for positive pressure ventilation (non-invasive or via endotracheal tube) for more than 72 hours in total with FiO2 ≥ 50% (or less when on additional ECMO) not longer than 14 days

E.4

Principal exclusion criteria

1. Receiving vasopressors of >100 µg/min
2. History of liver cirrhosis Child Pugh C, chronic hemodialysis (before severe pneumonia/ARDS), lung cancer
3. Malignancy with expected survival time of less than 6 months
4. History of, or listing for lung transplantation
5. Highly immunosuppressive therapy or anti-malignant combination chemotherapy within 3 weeks prior to first dose of study drug
6. Any anti-malignant chemotherapy within 24 hours prior to first dose of study drug
7. AIDS or known history of HIV infection
8. Pregnancy
9. Autoimmune thrombocytopenia, myelodysplastic syndromes with > 20% marrow blast cells
10. History or presence of hypersensitivity or idiosyncratic reaction to molgramostim or to related compounds (i.e., Growgen®, Leucomax®, Leukine™, Topleucon™)
11. Participation in another clinical trial within 90 days prior to the first dose of study drug

E.5 End points

E.5.1

Primary end point(s)

GI-HOPE score representing changes at Day 4/5 with respect to Baseline (Day -1)

The GI-HOPE score assesses change in bronchoalveolar lavage fluid (BALF) mononuclear phagocyte activation/polarization by flow cytometry (mean fluorescence intensities of parameters CD80, CD86, CD206, HLA-DR) with respect to baseline. Each parameter is given as log10 of the fold induction comparing the parameter of Day 4/5 to Day -1 and all 4 parameters are added up to a score (the value for CD206 is multiplied by (-1)). The GI-HOPE score is a surrogate marker assessing the change in BALF from Day -1 to Day 4/5.

E.5.1.1

Timepoint(s) of evaluation of this end point

The GIHOPE score is a surrogate marker assessing the change in
BALF from day -1 to day 4/5

E.5.2

Secondary end point(s)

Secondary endpoints:
· Safety of dose levels/treatments
· Oxygenation according to Horowitz index
· Acute Physiology and Chronic Health Evaluation
(APACHE) II
· Sequential Organ Failure Assessment (SOFA)
· Extravascular Lung Water Index (ELWI)
· C-reactive protein test
· Days on vaso-active drugs in a 28-day period
· Days alive in a 28-day period
· All-cause mortality
· GM-CSF levels in serum

Exploratory endpoint: Composition of different leucocyte subpopulations in BALF

E.5.2.1

Timepoint(s) of evaluation of this end point

28 days follow up

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

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

This is a randomized, double-blind, parallel group, multicenter phase II study in two parts. Part 1 is a Dose Escalation/Safety run-in part to generate safety data on two different doses of inhaled molgramostim for assessment by an IDMB. The IDMB will make recommendations whether the dose can be increased from the 150µg to 450µg dose in Part 1, and if the study can proceed to Part 2, which is a Parallel Group comparison of two different doses of inhaled molgramostim (150 and 450µg) vs placebo.

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

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

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

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

End of the study is defined as “Last Patient Out" and database closure.

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

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Consent by a legal representative according to local regulations is possible

Unterschriebene Einwilligung eines Betreuers/Vorsorgebevollmächtigten ist möglich

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.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

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

2015-09-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-24

P. End of Trial
P.	End of Trial Status	Completed

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