ANZCTR - Registration

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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

18/11/2021

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]

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)

Idiopathic Pulmonary Fibrosis (IPF)

Condition category

Condition code

Respiratory

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 52 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]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

To examine the safety and tolerability of the test doses of ACT001 with Progressing Fibrosing Interstitial Lung Disease (PF-ILD) patients

Timepoint [1]

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, 24, 28, 34, 40, 46 and 52 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]

To evaluate the change in pulmonary function via spirometry testing for PF-ILD participants from baseline to end of treatment.

Timepoint [2]

Compare the change in Forced Vital Capacity (FVC) measurement weekly from weeks 2-52 for participants treated with ACT001 alone or in combination with anti-fibrotic therapy from baseline to end of treatment

Primary outcome [3]

To evaluate the change in pulmonary function via spirometry testing for IPF participants from baseline to end of treatment.

Timepoint [3]

Compare the change in Forced Vital Capacity (FVC) measurement weekly from weeks 2-52for participants treated with ACT001 alone or in combination with anti-fibrotic therapy from baseline to end of treatment

Secondary outcome [1]

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]

Frequency of adverse events considered as related to ACT001

Secondary outcome [2]

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]

Time of withdrawal of patients from study and return to standard therapy assessed weekly for up to 12 months post-enrolment

Secondary outcome [3]

Evaluate change in Forced Vital Capacity (FVC) via spirometry testing from baseline to end of treatment

Timepoint [3]

Forced Vital Capacity (FVC) at 12 months post intervention commencement

Secondary outcome [4]

Assess any change in 6-minute walk test (6MWT) from baseline to end of treatment

Timepoint [4]

Distance measured in 6MWT, assessed weekly from weeks 2-52 post intervention commencement

Secondary outcome [5]

Participant assessment of change in dyspnoea from baseline to 6 months

Timepoint [5]

Change in dyspnoea associated with ADL from baseline to 12 months using the University of California, San Diego Shortness of Breath Questionnaire (SOBQ) measured at weeks 2, 8, 20, 28 and 34 post intervention commencement.

Secondary outcome [6]

Assess the change a patient well-being from baseline to 12 months

Timepoint [6]

Absolute change in K-BILD (King’s Brief Interstitial Lung Disease) and SOBQ from baseline to 12 months, both assessments are measured at weeks 8, 20, 28 and 34 post intervention commencement.

Eligibility

Key inclusion criteria

1. Adult patients aged = 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 over 10%, performed within 12 months of Visit 1. If the HRCT is
outside of the 12 months window, a scan needs to be performed during Screening and
prior to Visit 2 to confirm the diagnosis.
3. For participants with underlying Connective Tissue Disease (CTD): stable CTD not
requiring initiation of new therapy. If the patient has a pulmonary fibrosis component
as part of the CTD and is progressing, this patient can be included.
4. Pulmonary function at baseline reporting FVC of greater than 45% and DLCO of greater than 30%
5. Able to complete home based spirometry reading as determined by investigator
6. Female participants are eligible if they are of. Non-childbearing potential, defined as
i. Previous hysterectomy or bilateral oophorectomy
ii. Previous bilateral tubal ligation
iii. Post-menopausal (total cessation of menses for greater than or equal to 1 year)
d. Childbearing potential with a negative urine pregnancy test at screening, prior
to investigational product administration, and uses highly effective
contraception 28 days prior to commencement of study drug and throughout
the study until 3 months after the last investigational product administration.
Highly effective contraception, when used consistently and in accordance with
both the product label and the instructions of the physician, are defined as
follows:
i. Vasectomized partner who is sterile prior to the female patient’s
enrolment and is her sole sexual partner
ii. An intrauterine device (IUD) with a documented failure rate of less
than 1% per year (i.e. Copper or hormone-releasing IUD)
iii. Double barrier contraception defined as condom with a female
diaphragm
iv. Combined (estrogen and progestogen containing) hormonal
contraception associated with inhibition of ovulation and a barrier
method
v. Progestogen-only hormonal contraception associated with inhibition of
ovulation and a barrier method
vi. Sexual abstinence or in same sex relationship
For men and women, acceptable methods of contraception include use of a condom
with spermicide or use of oral, implantable or injectable contraceptives, or IUD or a
diaphragm with spermicide or diaphragm with condom.
7. Male participants with a potentially fertile partner are eligible if they have had a
vasectomy or are willing to 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. Female partners of male
participants are advised to also use contraception as noted above.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. History of chronic pulmonary obstructive disease that requires treatment, severe
pulmonary hypertension, drug-induced pulmonary toxicity, other forms of
idiopathic pneumonia, or interstitial lung diseases associated with environmental
exposure medication or systemic disease. Should the Investigator feel that a patient
would be suitable for inclusion into the study, but have components of their disease that fit into the above description, they should discuss this with the study Medical
Monitor for consideration.
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 calculated per the Cockcroft-gault equation
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 that result in a low failure rate of less than 1% per year when used
consistently and correctly, as well as one barrier method for 28 days prior to and 3
months after 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 anti-fibrotic dosing within
3 months of screening. If a patient requires a short course of steroids that is NOT
for the purpose of immune suppression, this should be discussed with the study
Medical Monitor as it may be appropriate to still include the patient.

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 40 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

Recruiting

Date of first participant enrolment

Anticipated

9/12/2019

Actual

29/07/2020

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)

QLD,VIC

Recruitment postcode(s) [1]

3011 - Footscray

Recruitment postcode(s) [2]

4032 - Chermside

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Accendatech Au Pty Ltd

Address [1]

Suite 2903, 201 Elizabeth Street Sydney NSW 2000

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Vincent's Hospital Melbourne Human Research Ethics Committee

Ethics committee address [1]

41 Victoria Parade, Fitzroy VIC 3065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

14/05/2019

Approval date [1]

18/09/2019

Ethics approval number [1]

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 12 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

A/Prof Ian Glaspole

Address

Respiratory Department The Alfred Hospital 55 Commercial Road Melbourne Victoria 3004 Australia

Country

Australia

Phone

+6103 9509 1999

Fax

[email protected]

Contact person for public queries

Name

Dr Steven Su

Address

Accendatech
Suite 2903, 201 Elizabeth Street
Sydney, NSW 2000

Country

Australia

Phone

+61 0434 103 986

Fax

[email protected]

Contact person for scientific queries

Name

Dr Steven Su

Address

Accendatech
Suite 2903, 201 Elizabeth Street
Sydney, NSW 2000

Country

Australia

Phone

+61 0434 103 986

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
5567	Clinical study report				Upon request from Principal Investigator (email: i... [More Details]

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	ACT001 suppressing M1 polarization against inflammation via NF-kappaB and STAT1 signaling pathways alleviates acute lung injury in mice.	2022	https://dx.doi.org/10.1016/j.intimp.2022.108944

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically