Clinical Trials Register

Summary
EudraCT Number:	2011-000126-30
Sponsor's Protocol Code Number:	ASM8-A-208
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-05-19
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

UK - MHRA

A.2

EudraCT number

2011-000126-30

A.3

Full title of the trial

A phase II, multi-centre, single blind study to evaluate the safety, tolerability and explore the efficacy of 8.0 mg ASM8 inhaled daily for 14 days in adult subjects with moderate to severe asthma

A.3.2

Name or abbreviated title of the trial where available

Safety & Tolerability of 8mg ASM8 in moderate to severe asthmatics

A.4.1

Sponsor's protocol code number

ASM8-A-208

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pharmaxis Ltd
B.1.3.4	Country	Australia
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	TPI ASM8
D.3.2	Product code	TPI ASM8
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	TOP004
D.3.9.1	CAS number	none
D.3.9.2	Current sponsor code	TOP004
D.3.9.3	Other descriptive name	Deoxyribonucleic acid, d(P-thio)(GGGTCTGCDGCGGGDTGGT), sodium salt
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	2
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOP005
D.3.9.2	Current sponsor code	TOP005
D.3.9.3	Other descriptive name	Deoxyribonucleic acid, d(P-thio)(GTTDCTDCTTCCDCCTGCCTG), sodium salt
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	2
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	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	Inhalation vapour, 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

moderate to severe asthma

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10003638
E.1.2	Term	Atopic asthma
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10001705
E.1.2	Term	Allergic asthma
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

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 determine the safety and tolerability of 8.0 mg of ASM8 when given daily for 14 days by the Aeroneb® Go nebulizer to moderate to severe asthmatics.

E.2.2

Secondary objectives of the trial

To evaluate the effects of treatment on:
• Sputum eosinophil counts (% and total) measured at the end of each treatment and the final visit;
• Spirometry (FEV1, FEF 25-75, FVC and PEF) measured at the end of each treatment and the final visit;
• peak expiratory flow measurements (PEF) (at waking and bedtime) throughout the study;
• airway responsiveness to Osmohale™ at the end of each treatment and the final visit;
• exhaled nitric oxide (NO) at the end of each treatment and the final visit;
• sputum eosinophilic cationic protein and mRNA for the CCR3 receptor and the Beta sub-unit of the IL-3, IL-5 and GM-CSF receptors the end of each treatment and the final visit;
• the asthma control questionnaire (ACQ) at the end of each treatment and the final visit;
• the Asthma QOL score and subscale scores at the end of each treatment and the final visit; and
• the use of daily rescue medication (salbutamol) throughout the study.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The subject must:
1. Be a non-smoker or ex-smoker (who has stopped for at least 6 months and who had less than a 10 pack year history);
2. Be 18 or older and less than 75 years old;
3. Be willing to use adequate and effective contraception as defined in section 5.4 (male and female subjects - female subjects at risk of pregnancy only). Women of childbearing potential must demonstrate a negative test result of serum ß-hCG at screening and must have a negative urine pregnancy at each visit to remain in the study;
4. Be diagnosed with asthma for ≥3 months and otherwise in good health as assessed by the investigator;
5. Have moderate to severe asthma as defined by ATS criteria [8];
6. Be currently receiving inhaled short-acting bronchodilator and at least a moderate dose inhaled corticosteroid (defined as total daily dose of 500 ug or more of fluticasone or equivalent) with a long acting bronchodilator (LABA) treatment for asthma;
7. Have used inhaled corticosteroids for at least the last 3 consecutive months prior to screening. The dose of inhaled corticosteroids and LABA should be stable over the last 30 days prior to screening;
8. Be on a stable dose if using inhaled anticholinergic agents, antileukotrienes and xanthenes (theophyllines) for the preceding 30 days and the dose will not change during the study;
9. Have an FEV1 % predicted greater than or equal to 50 % (at least 6 hours after last use of salbutamol) and lower or equal to 100%, where the FEV1 recorded is the best of three reproducible values (within a maximum change of 5% on the 2 best values);
10. Have a positive skin-prick test to at least one of common aeroallergens (including cat fur and dander, house dust mite (HDM), mixed grass pollen, etc.) in the previous 12-months. Allergen skin prick tests will be performed to at least 10 common aeroallergens with a positive and negative control. Historical data signed and dated up to 12 months prior to screening date showing at least one positive reaction, can be used in replacement, if the record can be verified by the monitoring CRA. Short-acting antihistamines should not be used within 4 days prior to skin tests and long-acting antihistamines must be avoided at all times during the study.
11. Have a positive response to inhaled mannitol (equal to or less than 200 mg) and be capable of repetitively producing adequate sputum during sputum induction. Adequate sputum is defined as a load of at least 75 mg with a viability factor of not less than 40%; (if sputum contains more than 12 million cells or more than 20 % epithelial cells acceptability will need to be approved by the sponsor); and
12. Be able to understand and provide written informed consent.
For entry into the therapeutic portion of the study (Visit 2), the subject MUST have:
13. A minimum level of daytime symptoms requiring inhaled Beta-agonist on an as-needed-basis with an asthma control questionnaire (ACQ) greater than 1.5 points and less than 5 points,
14. Employed the Aeroneb® Go nebuliser at least 75% of the time within 2 hours of the specified times as reviewed. If this criterion is not fully met, the Run-In phase can be extended for two additional days.

E.4

Principal exclusion criteria

The subject must NOT:
1. Have a pulmonary or other health condition (including, but not limited to, cancer, medication dependency or abuse, or psychiatric disease) for which the Investigator considers that participation in this protocol represents a risk for the subject;
2. Have a history of classic chronic obstructive pulmonary disease (COPD, including a 20 pack/year of smoking), vocal cord dysfunction, uncontrolled acid reflux or any chronic active lung disease other than asthma;
3. Have a respiratory tract infection within 4 weeks preceding study entry or an unresolved sinus infection;
4. Have a history of clinically significant hypotensive episodes or symptoms of fainting, dizziness, or light-headedness when performing pulmonary function tests or blood drawing or bronchospasm with inhaled saline solution or mannitol;
5. Have a history or symptoms of cardiovascular disease, particularly coronary artery disease, arrhythmias, hypertension, or congestive heart failure that are judged clinically significant by the investigator;
6. Have a history or symptoms of significant diabetes, renal insufficiency, autoimmune, hematological or neurological disease, including transient ischemic attack (TIA), stroke, seizure disorder, or behavioural disturbances which in the Investigator’s opinion may put the subject at significant risk, may confound results or may interfere significantly with the patient’s participation in the study;
7. Have a history of serious adverse reaction or hypersensitivity to corticosteroids;
8. Have a known coagulopathy;
9. Have an abnormal recent (less than 12 months) chest X-ray or electrocardiogram that is judged clinically significant;
10. Be pregnant or lactating or have positive plasma pregnancy test;
11. Had an exacerbation of asthma in the last 6 weeks;
12. Have used cromones within 2 weeks of screening;
13. Have used omalizumab (xolair) within 5 months of screening;
14. Been receiving more than 20 mg of prednisolone or equivalent, or the dose of oral/systemic corticosteroids modified over the last 6 weeks;
15. Have used tricyclic antidepressants, benzodiazepines, immunosuppressives, anticoagulants (warfarin, heparin, or other long-acting synthetic anticoagulants), for more than one day of the last 60 days of screening;
16. Have used long-acting antihistamine drugs within 2 weeks of screening;
17. Have a history of endotracheal intubation for asthma-related exacerbation within 3 years of screening;
18. Have participated in any other investigational medication treatment protocol within the preceding 30 days, or a longer and more appropriate time as determined by the Investigator (e.g., approximately five half-lives of the previous investigational medication);
19. Have a documented worsening of asthma due to allergies in the period of year where the study will be performed;
20. Have a concomitant disease or lung condition which could interfere with the conduct of the study or for which the treatment might interfere with the conduct of the study;
21. Have a malignancy (other than resected basal and squamous cell carcinoma and in situ cervical cancer) within 5 years of screening visit or if malignancy occurred  5 years before, documentation of the absence of recurrence since then;
22. Have had a vaccination within 4 weeks of screening or planned vaccination during the study other than the influenza vaccine;
23. Have a recent (less than 1 year) history of alcohol dependency;
24. Be unable to comply with the study requirements or unable to attend all clinic visits during the protocol period or for any other reason (i.e. unwillingness to comply with study procedures);
25. Be a participating investigator, study co-ordinator, employee of an investigator or family member of any of the aforementioned.
26. Need to increase inhaled corticosteroids or add any other medication for asthma because of uncontrolled asthma.
In addition, for enrolment into the therapeutic portion of the study (Visit 2) the subject must NOT:
27. Have a respiratory status that is deemed too unstable to safely continue into this study or for which the evaluation suggests additional therapy (e.g. increased ICS or addition of oral steroids) is necessary;
28. Have developed important bronchospasm during the Run-in phase while using the placebo saline solution with the Aeroneb® Go or during Osmohale ™ / Aridol ™ (Mannitol Challenge Test – MCT) challenge that in the investigator's opinion would put the subject at risk of complications;
29. Have clinically significant abnormalities in laboratory test results (including but not limited to haematology, chemistry panel and urinalysis);
30. Have been non-compliant with the completion of the DRC (i.e. less than 85% of data of each item during the Run-in phase);
31. Have an asthma control questionnaire less than 1.5 or 5.0 and higher at the end of the run-in phase or
32. Have an FEV1 less than 50% predicted.

E.5 End points

E.5.1

Primary end point(s)

The safety and tolerability of ASM8 will be assessed by comparing the response where subjects have taken Placebo and the response where subjects have taken ASM8 to the baseline measurements.

As this is a broad outcome, it will be assessed by tabulating:
Incidence, severity and relationship to study drug of AEs/SAEs throughout the study.

Routine laboratory chemistry, haematology and urinalysis results and blood levels of IL-1 and TNF-α at the end of each treatment and at the final visit.

Absolute values and change in percentage when compared to placebo in lung carbon monoxide diffusion capacity & pulse oximetry at the end of each treatment and the final visit.

Absolute values and change from baseline in systolic blood pressure, diastolic blood pressure, heart rate and respiratory rate at the end of each treatment and at the final visit.

Use of concomitant medications.

Physical examintation findings at the end of each treatment and at the final visit.

Absolute Counts and Percentages of Sputum total cells, differential cells and sputum levels of IL-1 and TNF-α at the end of each treatment and the final visit. Change in % from baselines will be presented.

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)

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

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.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

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

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 end of the trial will be considered last subject last visit

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1