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Clinical Trial Results:
Proof of concept study in male and female intensive care patients to investigate the clinical effect of repetitive orally inhaled doses of AP301 on alveolar liquid clearance in acute lung injury

Summary
EudraCT number	2012-001863-64
Trial protocol	AT
Global end of trial date	11 Aug 2014

Results information
Results version number	v2(current)
This version publication date	26 Mar 2016
First version publication date	09 Aug 2015
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set according to EudraCT requirement, study results have been reviewed again, no corrections needed.

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AP301-II-001

ISRCTN number

US NCT number

NCT01627613

WHO universal trial number (UTN)

Sponsor organisation name

Apeptico GmbH

Sponsor organisation address

Mariahilfer Straße 136, Top 1.15, Vienna, Austria, 1060

Public contact

Doz. Dr. Bernhard Fischer, Apeptico Forschung und Entwicklung GmbH, 0043 6641432919, b.fischer@apeptico.com

Scientific contact

Doz. Dr. Bernhard Fischer, Apeptico Forschung und Entwicklung GmbH, 0043 6641432919, b.fischer@apeptico.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

11 Jul 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Aug 2014

Global end of trial reached?

Yes

Global end of trial date

11 Aug 2014

Was the trial ended prematurely?

Main objective of the trial

To assess the effect of orally inhaled AP301 on alveolar liquid clearance in ALI patients with the purpose to assess the treatment associated changes of extravascular lung water (EVLW) within 7 days of treatment.

Protection of trial subjects

Patients have been treated according to standard of care to minimize any pain and suffering in connection to their initial disease/condition leading to ICU admission and development of ALI.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Jul 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 40

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

To be eligible, subjects had to be mechanically ventilated adult male and female patients at AKH, Vienna, Austria, with an onset of the ALI within the last 48 hours, present with a paO2/FiO2 ratio ≤300 mmHg, bilateral pulmonary infiltrates in the frontal chest X-ray, have absence of cardiac failure, and an EVLWI ≥8ml/kg PBW.

Screening details

Demographic data , vital signs the medical history as well as concomitant medication has been documented. Blood gases, clinical chemistry and hematology were determined. The following scores were obtained: GOCA, SOFA, EVLW and lung injury scores were measured. Hemodyn. parameters were analyzed. For childbearing women, pregnancy test was performed

Period 1 title

Overall study participation (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

Treatment

Arm description

In this arm, patientes received the IMP.

Arm type

Experimental

Investigational medicinal product name

AP-301

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for nebuliser solution

Routes of administration

Inhalation use

Dosage and administration details

After patients met inclusion criteria, in study group I orally delivered doses of 87.6 mg AP301 (dose per subject, 5 ml nebuliser filling dose) were inhaled every 12 hours (± 30 min), for a total of 7 days. 87,6 mg AP301 are based on 125 mg nebuliser filling dose. This dose level is well below the highest dose level used in the phase I study. It represents a dose level corresponding to the most effective dose levels used in pharmacologic studies. To enable oral inhalation, reconstituted AP301 in WFI wasconverted into an inhalable aerosol by the Aeroneb Solo medicinal device. The Aeroneb Solo medicinal device is a product of Aerogen, Galway, Ireland and is a commercially available liquid nebuliser.

Placebo

Arm description

in this arm, patients received Placebo treatment without active substance

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

After patients meet inclusion criteria, in study group II Placebo solution (0.9% physiologic NaCl, / 5 ml nebuliser filling dose) was inhaled every 12 hours (± 30 min), for a total of 7 days. To enable oral inhalation, reconstituted AP301 in WFI was converted into an inhalable aerosol by the Aeroneb Solo medicinal device. The Aeroneb Solo medicinal device is a product of Aerogen, Galway, Ireland and is a commercially available liquid nebuliser.

Number of subjects in period 1	Treatment	Placebo
Started	20	20
Completed	14	16
Not completed	6	4
Adverse event, serious fatal	6	4

Baseline characteristics

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Reporting group title

Overall study participation

Reporting group description

Reporting group values	Overall study participation	Total
Number of subjects	40	40
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	33	33
From 65-84 years	7	7
85 years and over	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	48.88 ( 16.04 )	-
Gender categorical
Units: Subjects
Female	14	14
Male	26	26

Subject analysis set title

AP-301

Subject analysis set type

Full analysis

Subject analysis set description

Here, all patients received the IMP, AP-301

Subject analysis set title

Placebo

Subject analysis set type

Full analysis

Subject analysis set description

In this arm, patients received Placebo treatment

Subject analysis sets values	AP-301	Placebo
Number of subjects	19	20
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	14	18
From 65-84 years	5	2
85 years and over	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	47.55 ( 17.39 )	50.2 ( 14.91 )
Gender categorical
Units: Subjects
Female	5	8
Male	14	12

End points

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Reporting group title

Treatment

Reporting group description

In this arm, patientes received the IMP.

Reporting group title

Placebo

Reporting group description

in this arm, patients received Placebo treatment without active substance

Subject analysis set title

AP-301

Subject analysis set type

Full analysis

Subject analysis set description

Here, all patients received the IMP, AP-301

Subject analysis set title

Placebo

Subject analysis set type

Full analysis

Subject analysis set description

In this arm, patients received Placebo treatment

Primary: EVLWI

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End point title

EVLWI

End point description

EVLW stands for extravascular lung water, and upon damage of the alveolar capillary barrier the infiltration of water into the lung can happen (Hypermeability Oedema).

End point type

Primary

End point timeframe

Within the treatment period of seven days

End point values	Treatment	Placebo	AP-301	Placebo
Number of subjects analysed	20	20	19	20
Units: ml/PBW
number (not applicable)	1.94	0.65	1.94	0.65

Statistical Analysis of AP-301-II

Comparison groups

AP-301 v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

> 0.05

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[1] - This has been a pilot study to evaluate the effect of AP-301 on the reduction of EVLW in ICU patients

Adverse events

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Timeframe for reporting adverse events

Twenty eight days after inclusion of study subjects

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Treatment

Reporting group description

In this arm, patients received the IMP.

Reporting group title

Placebo

Reporting group description

in this arm, patients received Placebo treatment without active substance

Serious adverse events	Treatment	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 20 (30.00%)	5 / 20 (25.00%)
number of deaths (all causes)	6	4
number of deaths resulting from adverse events	0	0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	5 / 20 (25.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 5	0 / 1
Nervous system disorders
Intracranial bleeding
subjects affected / exposed	1 / 20 (5.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastrointestinal disorders
Acute abdomen
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Acute respiratory insufficiency
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pulmonary embolism
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypoxaemia/hypoxia
subjects affected / exposed	0 / 20 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Treatment	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 20 (60.00%)	12 / 20 (60.00%)
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 20 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	4
Surgical and medical procedures
Tracheostomy
subjects affected / exposed	4 / 20 (20.00%)	6 / 20 (30.00%)
occurrences all number	5	8
Blood and lymphatic system disorders
Anemia
subjects affected / exposed	6 / 20 (30.00%)	7 / 20 (35.00%)
occurrences all number	11	9
General disorders and administration site conditions
Fever
subjects affected / exposed	0 / 20 (0.00%)	3 / 20 (15.00%)
occurrences all number	0	4

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
Proof of concept study in male and female intensive care patients to investigate the clinical effect of repetitive orally inhaled doses of AP301 on alveolar liquid clearance in acute lung injury

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: EVLWI

Primary: EVLWI

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: Proof of concept study in male and female intensive care patients to investigate the clinical effect of repetitive orally inhaled doses of AP301 on alveolar liquid clearance in acute lung injury

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: EVLWI

Primary: EVLWI

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Proof of concept study in male and female intensive care patients to investigate the clinical effect of repetitive orally inhaled doses of AP301 on alveolar liquid clearance in acute lung injury