Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000854336
Ethics application status
Approved
Date submitted
31/05/2017
Date registered
9/06/2017
Date last updated
27/05/2019
Date data sharing statement initially provided
18/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Open-Label, Multiple Ascending Dose (MAD) Study of SM04646 Inhalation Solution in Subjects with Mild to Moderate Idiopathic Pulmonary Fibrosis (IPF)
Scientific title
A Phase 1, Open-Label Study, to Evaluate the Safety and Tolerability of multiple inhalation of SM04646 Inhalation Solution in Subjects with Mild to Moderate Idiopathic Pulmonary Fibrosis (IPF)
Secondary ID [1] 291394 0
Nil
Universal Trial Number (UTN)
There is no UTN number for this study.
Trial acronym
None
Linked study record
ACTRN12615001349538

Health condition
Health condition(s) or problem(s) studied:
Idiopathic pulmonary fibrosis (IPF) 302481 0
Condition category
Condition code
Respiratory 302041 302041 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase 1 Open-Label Study in Subjects with Mild to Moderate Idiopathic Pulmonary Fibrosis (IPF), using a Multiple Ascending Dose (MAD) inhalation of nebulised SM04646.

A previous study has been conducted using single doses of SM04646 in healthy volunteers. This is the first study in humans where multiple doses of SM04646 will be given. It is also the first study where SM04646 will be given to subjects with the health condition of IPF.

SM04646 will be supplied as a single-use nebulized Inhalation Solution in vehicle containing mannitol and tyloxapol. Subjects will be treated with 28 consecutive daily doses of nebulized SM04646 Inhalation Solution and will be followed for approximately 30 days after last treatment. At a minimum, study medication administration on Days 1, 2, 7, 14, 21, and 28 will be performed by qualified and designated study staff at the study centre; on all other dosing days, study medication administration will be performed either at the study site or at the subject’s home with support from a medically qualified staff member.

Dose escalation levels will be 2.0 mg, 7.0 mg, and 20.0 mg. Enrollment of subsequent dose level cohorts will occur only after the safety data from the previous dose level cohort are reviewed and approval for dose-escalation is granted by the Safety Review Committee (SRC). Upon review and approval of escalation to a subsequent dose level, no further subjects will be enrolled at the current dose level. The exception to this, however, is if there is a Dose Limiting Toxicity (DLT). A DLT is defined as any of the following occurring within the 28-day dosing period or within follow-up and determined to be at least possibly related to the study medication by the Principal Investigator:

* A Grade 3 or higher adverse event (AE) per the Common Terminology Criteria for Adverse Events (CTCAE) v4.03

* A serious adverse event (SAE)

The SRC will convene after each DLT and following the completion of the dosing period for each dose level cohort (after Day 28) to determine if further enrolment may continue for a given cohort or if all further enrolment is to cease.

If 3 or more unique subjects experience DLTs following the first dose of study medication administration in a given cohort, the Maximum Tolerated Dose (MTD) will be considered exceeded and dosing for the study will cease. If all cohorts are enrolled without exceeding the MTD, the Maximum Recommended Dose (MRD) will be the highest dose cohort enrolled.
Intervention code [1] 297497 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 301468 0
Incidence and severity of adverse events (AEs). AEs are assessed by the physical examination, clinical interview, ECGs, and clinical laboratory abnormality assessments.
Timepoint [1] 301468 0
Every day from Day 1 post study drug administration to end of study Day 60.
Primary outcome [2] 301485 0
Incidence and severity of clinical laboratory abnormalities (non-fasting). These are assessed by blood and urine samples.
At a minimum, the following tests will be conducted:
Chemistry panel - Albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), bicarbonate, calcium corrected, chloride, creatinine, glucose, lactate dehydrogenase, potassium, sodium, and bilirubin
Hematology - Hemoglobin, hematocrit, erythrocytes (RBC), leukocytes (WBC) with differential, and platelet count
Urinalysis - Colour, clarity, specific gravity, pH, protein, glucose, ketones, nitrite, leukocytes, and occult blood
Urine microscopy - if applicable
Timepoint [2] 301485 0
Samples taken on:
Screening Visit
Days 1, 2, 7, 14, 21, 28 (prior to study drug administration)
Days 29, 45 and 60 after intervention commencement
or early termination
Primary outcome [3] 301486 0
Change from baseline in vital sign measurements (blood pressure, temperature, respiratory rate, and pulse rate). This is a composite primary outcome.
Timepoint [3] 301486 0
Measurements taken on:
Screening Visit
Days 1 and 28 (pre and post study drug administration apart from temperature which is only recorded at pre study drug administration)
Days 2, 7, 14, 21, 29, 45 and 60 after intervention commencement
or early termination
Secondary outcome [1] 332797 0
THIS IS A PRIMARY OUTCOME
Change from baseline of FVC, FEV1, and DLCO assessments (safety). These are assessed by spirometry. This is a composite primary outcome.
Timepoint [1] 332797 0
Measurements taken on:
Screening Visit:
Days 1 and 28 (pre and post study drug administration)
Days 2, 7, 14, 21, 29, 45 and 60 after intervention commencement
or early termination
Secondary outcome [2] 332811 0
THIS IS A PRIMARY OUTCOME
Change from baseline of oxygen saturation measurements. This outcome is assessed for safety by spirometry.
Timepoint [2] 332811 0
Measurements taken on:
Screening Visit
Days 1 and 28 (continuous from prior to study medication administration through to post 4 hours study medication administration).
Days 2, 7, 14, 21, 29, 45 and 60 after intervention commencement
or early termination
Secondary outcome [3] 332812 0
THIS IS A PRIMARY OUTCOME
Incidence of DLTs
Timepoint [3] 332812 0
Every day from Day 1 post study drug administration to end of study Day 60.

A DLT is defined as any of the following occurring within the 28-day dosing period or within follow-up and determined to be at least possibly related to the study medication by the Principal Investigator:

* A Grade 3 or higher adverse event (AE) per the Common Terminology Criteria for Adverse Events (CTCAE) v4.0

* A serious adverse event (SAE)
Secondary outcome [4] 332813 0
Change from baseline in 12-lead electrocardiogram (ECG) parameters and categorical summaries of both absolute ECG parameters and ECG changes compared to baseline
Timepoint [4] 332813 0
ECGs measurements taken on:
Screening Visit:
Days 1 and 28 (pre and post study drug administration)
Days 2, 7, 14, 21, 29, 45 and 60 after intervention commencement
or early termination
Secondary outcome [5] 332814 0
Plasma concentrations of SM04646 on Days 1, 2, 28, and 29
Timepoint [5] 332814 0
PK samples taken on:
Days 1 and and 28 (pre and post study drug administration)
Days 2 and 29 (post 24 hour study drug administration)
Secondary outcome [6] 332819 0
Plasma PK parameter estimates of SM04646 on Days 1 and 28, as appropriate. PK parameters such as maximum observed plasma concentration (Cmax), time of maximum observed plasma concentration (tmax), area under the plasma concentration
time curve (AUC), accumulation, dose proportionality, and terminal elimination half-life (t1/2) will be assessed, as appropriate.
Timepoint [6] 332819 0
PK samples taken on:
Days 1 and 28 (pre and post study drug administration)

Eligibility
Key inclusion criteria
- Diagnosis of Idiopathic pulmonary fibrosis (IPF)
- Forced vital capacity (FVC) greater than or equal to 50%
- Lung diffusing capacity (DLCO) greater than or equal to 35%
- FEV1/FVC greater than or equal to 0.70 after administration of a bronchodilator
- Resting O2 saturation greater than or equal to 90% after 10 minutes at rest on room air
- Full understanding of the requirements of the study and willingness and ability to comply with all study visits and procedures
- Able to comprehend and willing to sign an informed consent form (ICF)
- Able to tolerate and complete placebo (vehicle) inhalation
Minimum age
40 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Women who are pregnant or lactating
- Women who are not post-menopausal who are sexually active and are not willing to use birth control
- Males who are sexually active and not willing to use a condom
- Males unwilling to refrain from sperm donation
- Subjects unwilling to refrain from blood and plasma donation
- A history of abuse of prescription or illicit drugs
- Positive urine drug screen
- Recent occurrence of serious illness requiring hospitalization
- Current smoker, or recent history of smoking
- Recent use of non-inhaled tobacco- or nicotine-containing products
- Regular alcohol abuse
- Known hypersensitivity to the active substance or any excipients
- Lung transplantation anticipated during the duration of the trial
- Receipt of any of the following medication or treatment:
a. Nintedanib or Pirfenidone within 7 days prior to screening
b. Previous therapeutic radiation treatment of the lungs, mediastinum, or chest wall
c. Participation in a clinical research trial that included the receipt of an investigational product or any experimental therapeutic procedure
d. Immunosuppressive medications
e. Use of any therapy targeted to treat IPF
f. Use of any cytokine modulator
g. Recent use of a bronchodilator
- History of any of the following conditions:
a. Pulmonary embolism or pulmonary hypertension
b. Poor creatinine clearance
c. Active TB infection or history of incompletely treated latent TB infection
d. History of malignancy within the last 5 years
e. Connective tissue disease
f. Congenital respiratory conditions
g. Chronic obstructive pulmonary disease (COPD) or asthma
h. Recent respiratory tract infection
i. Recent acute exacerbation of IPF
j. HIV, hepatitis C, or active hepatitis B infection
k. Hepatic cirrhosis
l. Recent symptomatic coronary artery disease or myocardial infarction (MI)
m. Hypertension
n. Hypotension
o. Any condition that is dependent on oxygen therapy
- Any condition that constitutes a risk or contraindication for participation
- Abnormal haematology values or blood chemistry values
- History of cardiac arrhythmia
- Subjects who are immediate family members of personnel directly affiliated with the study at the
investigative site, or are directly affiliated with the study at the investigative site
- Subjects employed by Samumed Pacific Pty Ltd, or any of its affiliates or development partners
(responsible for the conduct of the study)
- Subjects who are immediate family members of personnel directly affiliated with the study at the investigative site, or are directly affiliated with the study at the investigative site
- Subjects employed by Samumed Pacific Pty Ltd, or any of its affiliates or development partners responsible for the conduct of the study

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)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This study is a multiple-dose, dose-escalation safety study in subjects with mild to moderate IPF.

Eligible subjects will be treated with 28 consecutive daily doses of nebulized SM04646 Inhalation Solution. Subjects will be observed for ~30 additional days after treatment, for a total per subject study period of ~60 days.

Dose escalation will take place after the applicable cohort completes the dosing period and if dose escalation is approved by the Safety Review Committee (SRC). The SRC will review the safety and tolerability findings at each dose level after the dosing period is completed (Day 28) and after each Dose Limiting Toxicity (DLT). The SRC must agree that the data support continuation of the study and/or dose escalation.

The occurrence of clinical signs or symptoms, of abnormal laboratory, pulmonary function or ECG assessments, or of oxygen saturation levels suggesting toxicity may result in a decision to reduce the incremental increase of planned dose escalations or not to evaluate any additional dose(s) of SM04646 Inhalation Solution.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The sample size for this study was not based on statistical power calculations, but is consistent with typical sample sizes used for similar studies to assess preliminary safety and PK.

The general analytical approach for all endpoints will be descriptive in nature, providing a summary and estimate of the safety profile of SM04646 Inhalation Solution in subjects with IPF. No formal statistical hypothesis testing will be conducted in this study.

Demographic variables will include age, sex, race, ethnicity, height, and weight. For continuous variables, number of subjects in the analysis, mean, standard deviation (SD), median, minimum, and maximum will be reported. All categorical endpoints will be summarized using frequencies and percentages.

Safety analyses will be conducted on all subjects who received any study medication administration.

Plasma concentration and PK parameter summaries will include descriptive statistics, as appropriate. PK parameters will only be estimated if plasma concentrations are detectable at a sufficient number of timepoints.

PK analyses will be conducted on all subjects that missed 4 or less doses and received in-window dosing on Days 1, 27, and 28.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
12/06/2017
Actual
18/07/2017
Date of last participant enrolment
Anticipated
30/03/2019
Actual
28/02/2019
Date of last data collection
Anticipated
31/05/2019
Actual
30/04/2019
Sample size
Target
10
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 11257 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 23135 0
5011 - Woodville

Funding & Sponsors
Funding source category [1] 295865 0
Commercial sector/Industry
Name [1] 295865 0
Samumed Pacific Pty Ltd
Country [1] 295865 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Samumed Pacific Pty Ltd
Address
Level 15 Exchange Tower
2 The Esplanade
Perth WA 6000
Australia
Country
Australia
Secondary sponsor category [1] 294727 0
None
Name [1] 294727 0
Address [1] 294727 0
Country [1] 294727 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297148 0
Bellberry Limited
Ethics committee address [1] 297148 0
Ethics committee country [1] 297148 0
Australia
Date submitted for ethics approval [1] 297148 0
11/01/2017
Approval date [1] 297148 0
03/03/2017
Ethics approval number [1] 297148 0
2017-20-115
Ethics committee name [2] 300806 0
CALHN Human Research Ethics Committee
Ethics committee address [2] 300806 0
Ethics committee country [2] 300806 0
Australia
Date submitted for ethics approval [2] 300806 0
17/11/2017
Approval date [2] 300806 0
13/03/2018
Ethics approval number [2] 300806 0
Q20180107

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73134 0
Dr Antony VEALE
Address 73134 0
The Queen Elizabeth Hospital, Respiratory Medicine 4C, 28 Woodville Road, Woodville South SA 5011
Country 73134 0
Australia
Phone 73134 0
+61 8 8222 7053
Fax 73134 0
+61 7 3163 8519
Email 73134 0
[email protected]
Contact person for public queries
Name 73135 0
Yusuf YAZICI
Address 73135 0
Samumed, LLC
9381 Judicial Dr, Suite 160
San Diego, CA 92121
Country 73135 0
United States of America
Phone 73135 0
+1 858 926 2926
Fax 73135 0
+1 858 926 9315
Email 73135 0
[email protected]
Contact person for scientific queries
Name 73136 0
Yusuf YAZICI
Address 73136 0
Samumed, LLC
9381 Judicial Dr, Suite 160
San Diego, CA 92121
Country 73136 0
United States of America
Phone 73136 0
+1 858 926 2926
Fax 73136 0
+1 858 926 9315
Email 73136 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This trial studies a regulated drug product that was not approved, licensed or cleared by any regulator for any use before the Primary Completion Date of the trial, and the sponsor intends to continue with product development and may at a future date seek regulatory approval, licensure, or clearance of the drug product under study


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.