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Trial registered on ANZCTR


Registration number
ACTRN12619001643167
Ethics application status
Approved
Date submitted
11/11/2019
Date registered
25/11/2019
Date last updated
25/11/2019
Date data sharing statement initially provided
25/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 2 study to evaluate the safety and tolerability of ACT001 in treating adults with Progressing Fibrosing Interstitial Lung Disease (PF-ILD), including Idiopathic Pulmonary Fibrosis (IPF)
Scientific title
A Phase 2 prospective multi-centre, parallel group study to evaluate the safety, tolerability, and activity of ACT001 in Adult participants with Progressing Fibrosing Interstitial Lung Disease (PF-ILD), including Idiopathic Pulmonary Fibrosis (IPF) when used alone or in combination with standard of care therapy.
Secondary ID [1] 299728 0
ACT001-AU-003
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Progressing Fibrosing Interstitial Lung Disease (PF-ILD) 315075 0
Idiopathic Pulmonary Fibrosis (IPF) 315210 0
Condition category
Condition code
Respiratory 313415 313415 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The investigational product is ACT001, dimethylamino michael adduct of micheliolide (DMAMCL), the drug product is an immediate release capsule containing 100mg of DMAMCL and is yellow and grey in colour. Each size 0 capsule also contains gelatine starch, magnesium stearate and silicon dioxide. Using a three-step synthetic sequence, ACT001 was obtained from parthenolide, which can be isolated from western medical herb tanacetum parthenium (feverfew), or Chinese medical herb magnolia delavayi franch.

Cohort 1 will recruit participants that have been diagnosed with pulmonary fibrosing interstitial lung disease (PF-ILD), and are not receiving antifibrotic therapy.

Cohort 2 will recruit participants that have been diagnosed with PF-ILD, and are currently receiving antifibrotic therapy.

Patients will be assigned after consent to be administered either ACT001 orally (400mg/day) alone, or in combination with existing antifibrotic treatments. Each oral daily dose will be taken as two capsules in the morning and two in the evening after meal, with each dose recorded, for up to 24 weeks at investigator's discretion based on clinical assessment of safe use.

Participants will be required to return any unused doses of study drug and/or the original container to site. The number of capsules of study product returned to the site will be counted and recorded as a measure of compliance. The investigator must account for all used Investigational Product containers. The completed dispending and inventory record will be provided to the sponsor and copies filed in the Investigator Site File (ISF). At the completion or termination of the study, a final drug accountability review and reconciliation must be completed, and any discrepancies must be investigated, and their resolution documented.
Intervention code [1] 315992 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321889 0
To examine the safety and tolerability of the test doses of ACT001 with Progressing Fibrosing Interstitial Lung Disease (PF-ILD) patients
Timepoint [1] 321889 0
Any clinically significant change from baseline in vital signs, laboratory tests, ECGs, Physical examination and adverse events assessed at weeks 2, 4, 8, 12, 16, 20 and 24. Adverse Events will be assessed by clinical examination, participant self-report and via direct nonspecific questioning. Possible adverse events include gastrointestinal disturbances.
Primary outcome [2] 321890 0
To evaluate the change in pulmonary function via spirometry testing for PF-ILD participants from baseline to end of treatment.
Timepoint [2] 321890 0
Compare the change in Forced Vital Capacity (FVC) measurement weekly from weeks 2-24 for participants treated with ACT001 alone or in combination with anti-fibrotic therapy from baseline to end of treatment
Primary outcome [3] 322033 0
To evaluate the change in pulmonary function via spirometry testing for IPF participants from baseline to end of treatment.
Timepoint [3] 322033 0
Compare the change in Forced Vital Capacity (FVC) measurement weekly from weeks 2-24 for participants treated with ACT001 alone or in combination with anti-fibrotic therapy from baseline to end of treatment
Secondary outcome [1] 376600 0
Evaluate adverse event severity and frequency reported during study period.

Adverse Events will be assessed by clinical examination, participant self-report and via direct nonspecific questioning. Possible adverse events include gastrointestinal disturbances.
Timepoint [1] 376600 0
Frequency of adverse events considered as related to ACT001
Secondary outcome [2] 376601 0
Evaluate change in ILD status via incidence of rescue medication (assessed by data linkage to medical records) used for the management of IPF exacerbation during study period
Timepoint [2] 376601 0
Time of withdrawal of patients from study and return to standard therapy assessed weekly for up to 6 months post-enrolment
Secondary outcome [3] 376602 0
Evaluate change in Forced Vital Capacity (FVC) via spirometry testing from baseline to end of treatment
Timepoint [3] 376602 0
Forced Vital Capacity (FVC) at 6 months post intervention commencement
Secondary outcome [4] 376603 0
Assess any change in 6-minute walk test (6MWT) from baseline to end of treatment
Timepoint [4] 376603 0
Distance measured in 6MWT, assessed weekly from weeks 2-24 post intervention commencement
Secondary outcome [5] 376604 0
Participant assessment of change in dyspnoea from baseline to 6 months
Timepoint [5] 376604 0
Change in dyspnoea associated with ADL from baseline to 6 months using the University of California, San Diego Shortness of Breath Questionnaire (SOBQ) measured at weeks 8, 20 and 24 post intervention commencement.
Secondary outcome [6] 376605 0
Assess the change a patient well-being from baseline to 6 months
Timepoint [6] 376605 0
Absolute change in K-BILD (King’s Brief Interstitial Lung Disease) and SOBQ from baseline to 6 months, both assessments are measured at weeks 8, 20 and 24 post intervention commencement.

Eligibility
Key inclusion criteria
1. Male and Female adult patients aged over or equal to 18 years at Consent
2. Fibrosing lung disease on high resolution computerized tomography (HRCT), defined as reticular abnormality with traction bronchiectasis with or without honeycombing, with disease extent of >10%, performed within 12 months of Visit 1
3. For participants with underlying Connective Tissue Disease (CTD): stable CTD not requiring initiation of new therapy
4. Pulmonary function at baseline reporting FVC of >45% and DLCO of >30%
5. Able to complete home based spirometry reading as determined by investigator
6. Female participants are eligible if they are
a. Of non-childbearing potential,
b. Females of childbearing potential with a negative urine pregnancy test at screening (within 14 days of the first investigational product administration) and uses adequate contraception 28 days prior to commencement of study drug and throughout the study until 3 months after the last investigational product administration.
7. Male participants are eligible if they use adequate contraception 28 days prior to commencement of study drug administration and throughout the study until 3 months after the last investigational product administration.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History or presence of chronic pulmonary obstructive disease, severe pulmonary hypertension, drug-induced pulmonary toxicity, other forms of idiopathic pneumonia, or interstitial lung diseases associated with environmental exposure medication or systemic disease.
2. Pre-existing hypersensitivity to ACT001 or related compounds
3. Major extrapulmonary physiological restriction
4. Cardiovascular diseases as determined by the investigator to be sufficient to exclude from participation, such as severe hypertension, myocardial infarction within 6 months prior or unstable cardiac angina within 6 months
5. Creatinine clearance <30mL/min
6. Hepatic impairment as defined as AST or ALT >1.5 x upper limit of normal (ULN) with or without elevated bilirubin > 1.5 x ULN
7. History of thrombotic event (including stroke and transient ischemic attack) within 12 months
8. Other disease that may interfere with testing procedures or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this study
9. Women of childbearing potential not willing or able to use highly effective methods of birth control as well as one barrier method for 28 days prior to and 3 months after last ACT001 administration. Male participants are also required to use suitable contraception for 28 days prior to and 3 months after last ACT001 administration.
10. Current use of other investigational agents
11. Commencement or alteration of immune suppression or antifibrotic dosing with 3 months of screening

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Participants will be stratified into Cohort 1 or 2, based on pre-existing treatment with anti-fibrotic therapy.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The study will recruit up to 20 participants to be included in the evaluable population. This sample size has been assigned empirically.

The safety analysis set will consist of all Participants who received at least one dose of investigational product. Analysis of safety will be performed on the safety analysis set. The data collected will be presented in listings and summary tables to give an overview of the safety findings. No inferential statistical analysis of safety data is planned.

Baseline information will be summarized using descriptive statistics for the analysis sets.

All Adverse Events (AEs) will be captured from the first dose of Investigational Product (IP) until study completion. All AEs occurring between signing of the PICF and first dose of IP will be recorded as medical history.
The number and percentage of Participants, who experience non-serious AEs, as well as serious AEs, will be presented by System Organ Class (SOC) and by Preferred Term (PT) within SOC for each participant. Non-serious and serious AEs will be similarly presented by severity, by relationship to study drug, and by outcome of events. Moreover, the number of AEs will be presented (in addition to the number and percentage of Participants who experience AEs). Non-serious and serious AEs will be presented for each part of the study. The total number of non-serious or serious AEs, as well as the total number of Participants with a non-serious or serious AE, will also be presented.
A participant experiencing the same treatment-emergent AE multiple times will be counted only once for the corresponding PT. Similarly, if a participant experiences multiple AEs within the same SOC, the participant will be counted only once for that SOC. If a participant experiences more than one AE within different severity or relationship categories within the same SOC/PT, only the worst case (worst severity and related AE) will be reported. AEs will be sorted alphabetically by SOC and within each SOC the PT will be presented by decreasing order of total frequency. AEs will be coded to SOC and PT using the Medical Dictionary for Regulatory Activities (MedDRA).
A listing of SAEs and discontinuations due to AEs will be presented. Participant deaths will be listed separately. SAEs will be described by case narratives. All AEs will be presented by investigative site in a listing, which will include the participant identifier, PT, reported term, severity, seriousness, action taken, outcome, relationship, date of onset, duration, and end date.

Descriptive statistics (n, mean, standard deviation, median, and range) for each clinical laboratory test will be presented by study part and available visit. Change from baseline values will also be presented for each post-baseline measurement. Laboratory results will also be individually listed.

Descriptive statistics (n, mean, standard deviation, median, and range) will be presented for data related to vital signs (i.e. blood pressure, pulse rate, respiration rate and temperature). Change from baseline values will also be presented for each post-baseline measurement. Vital signs results will also be individually listed.

Physical Exam will be summarized by visit in terms of n (%) of patients with normal/abnormal results per body system and study part. Moreover, shift tables (from normal to abnormal and abnormal to normal) will be presented (when possible) for each postbaseline measurement. Physical examination results will also be individually listed.

The assessment of activity of ACT001, either alone or in combination with anti-fibrotic therapy, will be based on the change in clinical assessments from baseline to the end of treatment. These data will provide supportive long term use of ACT001 in maintaining pulmonary function. As the study population is not defined based on a statistical determination, assessment of significance in the change will not be completed. Rather descriptive statistics and clinical judgement will be used to evaluate the data obtained to identify the clinical effectiveness of the treatment.

As part of the study conduct, blood samples will be obtained from participants at pre-defined intervals during the study to allow an assessment of key biological indicators of activity of ACT001. Quantitative and qualitative evaluations of the various biomarkers are intended to aid in the evaluation of activity of ACT001 and therefore provide proof of concept for its use as a possible treatment of PF-ILD and IPF.

A review of the safety data obtained from the study will be conducted by a Data Safety Monitoring Board following the completion of Visit 6 for the first four (4) participants in accordance with an established charter.
This DSMB review will evaluate all safety data gathered including adverse events, SAE’s and the individual participants measurements for pulmonary function. The DSMB will confirm the continuation of the study or recommendations for any change to design or outcomes.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 15108 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 28403 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 304200 0
Commercial sector/Industry
Name [1] 304200 0
Accendatech Au Pty Ltd
Address [1] 304200 0
Suite 2903, 201 Elizabeth Street Sydney NSW 2000
Country [1] 304200 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Accendatech Au Pty Ltd
Address
Suite 2903, 201 Elizabeth Street Sydney NSW 2000
Country
Australia
Secondary sponsor category [1] 304436 0
None
Name [1] 304436 0
Address [1] 304436 0
Country [1] 304436 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304667 0
St Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 304667 0
41 Victoria Parade, Fitzroy VIC 3065
Ethics committee country [1] 304667 0
Australia
Date submitted for ethics approval [1] 304667 0
14/05/2019
Approval date [1] 304667 0
18/09/2019
Ethics approval number [1] 304667 0

Summary
Brief summary
The current treatment options for patients with progressing Fibrosing Interstitial Lung Disease (PF-ILD), including Idiopathic Pulmonary Fibrosis (IPF) is
limited and specific cohorts of patients cannot tolerate the approved treatments. Following the demonstration of activity in animal models for respiratory
fibrotic diseases, this study will evaluate the safety and biological activity of ACT001 in adult patients. The study design will utilise a daily dose of ACT001,
either alone or in combination with standard of care anti-fibrotic therapy, with evaluate safety, anti-inflammatory and anti-fibrotic activity in patients with
stable disease state and evaluate any change in their respiratory function of a 6 month treatment period. The outcomes of this study are intended to
support the biological activity of ACT001 so as to provide outcomes that can be translated into future research.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97786 0
A/Prof Ian Glaspole
Address 97786 0
Respiratory Department The Alfred Hospital 55 Commercial Road Melbourne Victoria 3004 Australia
Country 97786 0
Australia
Phone 97786 0
+6103 9509 1999
Fax 97786 0
Email 97786 0
i.glaspole@alfredhealth.com.au
Contact person for public queries
Name 97787 0
Dr Steven Su
Address 97787 0
Accendatech
Suite 2903, 201 Elizabeth Street
Sydney, NSW 2000
Country 97787 0
Australia
Phone 97787 0
+61 0434 103 986
Fax 97787 0
Email 97787 0
suychang@accendatech.com
Contact person for scientific queries
Name 97788 0
Dr Steven Su
Address 97788 0
Accendatech
Suite 2903, 201 Elizabeth Street
Sydney, NSW 2000
Country 97788 0
Australia
Phone 97788 0
+61 0434 103 986
Fax 97788 0
Email 97788 0
suychang@accendatech.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Study outcomes are reported as the total population, and not based on individual results.
What supporting documents are/will be available?
Clinical study report
How or where can supporting documents be obtained?
Type [1] 5567 0
Clinical study report
Citation [1] 5567 0
Link [1] 5567 0
Email [1] 5567 0
Other [1] 5567 0
Upon request from Principal Investigator (email: i.glaspole@alfredhealth.com.au)
Attachment [1] 5567 0
Summary results
No Results