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Trial registered on ANZCTR


Registration number
ACTRN12619000610134
Ethics application status
Approved
Date submitted
28/03/2019
Date registered
23/04/2019
Date last updated
4/06/2019
Date data sharing statement initially provided
23/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effectiveness and safety of LM011 in treating subjects diagnosed with non-alcoholic steatohepatitis (NASH).
Scientific title
An open-label study to assess the efficacy and safety of LM011 in subjects diagnosed with Non-Alcoholic Steatohepatitis (NASH)
Secondary ID [1] 297818 0
LM011-18-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-Alcoholic Steatohepatitis (NASH) 312185 0
Condition category
Condition code
Metabolic and Endocrine 310735 310735 0 0
Metabolic disorders
Oral and Gastrointestinal 310822 310822 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
LM-011-18-01 is a single arm open label study to test the safety and effectiveness of LM-011 in patients diagnosed with “nonalcoholic steatohepatitis’ (NASH).

20 NASH patients will be enrolled and receive orally LM011 once a day for a duration of 16 weeks. All patients will undergo dose adjustment to reach a desirable target dose following the guidance in the protocol.

Subjects will receive 4 loading doses on Day 1, and one daily maintenance dose starting on Day 2. The loading doses range from 12.5 mL/day to 25 mL/day based on the participant's lean body weight. The initial maintenance dose ranges from 2.5 mL/day to 5 mL/day, also based on the participant's lean body weight.

The therapeutic window of LM011 is narrow with a desired target range of 0.7-1 ng/mL, as such, plasma concentration will be monitored on an ongoing basis. Blood samples will be collected starting at Visits 2, 3, 4, 5 and 6 or at Early Termination. If LM011 plasma concentration is determined to be outside the target range of 0.7 – 1 ng/mL or if clinically significant adverse events related to study drug are reported or significant lean body weight change compared to baseline, the investigator will adjusts the dose according to the guidance of the protocol.

Adherence to the intervention will be monitored in two ways:
1. A primary compliance measurement will be calculated based on the volumes provided in Participants’ Dosing Diary. This will be manually entered into the Viedoc EDC system on the Drug Compliance eCRF by the site staff at each visit upon return of the dosing diary by the participant, and will be verified by the CRA during each monitoring visit.

Compliance (%) = [Volume of LM011 Used (mL) ÷ Expected Volume of LM011 Expected (mL)] x 100

Volume of LM011 Used (mL) will be determined by the Actual Dose Administered (mL) from the participants’ diaries.

Volume of LM011 Expected (mL) will be determined by number of doses expected for the duration between scheduled visits.

2. A secondary check of compliance will be performed through weighing of LM011 bottles prior to dispensing to participants and upon return of LM011 bottles from participants at the next scheduled visit. The weight of the IP bottles before dispensing and upon return of unused and partially used bottles will be entered into the Viedoc EDC system on the Drug Accountability eCRF. The compliance will be programmatically calculated outside of the EDC system and a report will be generated on a weekly basis for CRA review. The CRA will reconcile the primary and secondary compliance values, and follow up with sites where any discrepancies are noted. Participant retraining will be required if inconsistencies are apparent, and further escalation to the CRO and Sponsor will be necessary where inconsistencies are noted more than once. If necessary, such patients will be dropped from the study.

Calculations of Amount of LM011 Taken by Patients

Volume LMO11 Used (mL) = Mass of LM011 (g) Used ÷ Density (g/cm3)

Where the Density of LM011 = 1.11 g/cm3

Calculations of Compliance

Compliance (%) = [(Volume LM011 Used ÷ Volume LMO11 Prescribed)] X 100

In addition to the monitoring described above, site staff will also reinforce the importance of drug compliance with the patient during scheduled visits as well as during telephone calls with the patients, e.g. when the LM011 concentration results become available, or during general telephone contact calls with the patient as applicable.
Intervention code [1] 314062 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 319585 0
Percent change from Screening in liver fat fraction (%), measured by Magnetic Resonance Imaging-derived proton density fat fraction (MRI-PDFF).

MRI-PDFF data will be collected at screening visit and at end-of-study visit (Week 16) for all individual subjects. If there are subjects with missing Week-16 MRI-PDFF data due to drop out, regardless of reasons, two types of analyses will be performed. The first type of analysis will exclude the subject(s) who drop out, while the second type will include the drop-out subject(s) but will assume LM011 has no effect on “liver fat fraction” on these subject(s).
Timepoint [1] 319585 0
16 weeks
Primary outcome [2] 319586 0
Proportion of subjects with at least a 25% decrease in % steatosis

The percentage change is calculated by taking the difference between the baseline and Week 16 measurements and divide the difference by the baseline value . Similar to that described above for the analysis of the first Primary Endpoint, two types of analysis will also be performed. For subjects drop out early, the first type of analysis will exclude the subject(s) who drop out, while the second type of analysis will include all subject(s) and will assume LM011 had no effect on liver fat fraction on the subjects who drop out early.

At Screening and Week 16, MRI-PDFF over 9 regions of interest will provide estimates of liver fat fractions, measured in %. Based on this biomarker, % steatosis of the liver can be estimated.
The percentage change is calculated by taking the difference between the Screening and Week 16 measurements in % steatosis and divide the difference by the Screening % steatosis.
Proportion of subjects with at least 25% decrease will be summarized.
Timepoint [2] 319586 0
16 weeks
Secondary outcome [1] 368790 0
Change in liver fat fraction by MRI-PDFF
Timepoint [1] 368790 0
16 weeks or 11 weeks if the subjects early terminated from the study.
Secondary outcome [2] 368791 0
Change in aspartate aminotransferase (AST) based on chemistry laboratory test results.
AST will be analyzed with a serum assay.
Timepoint [2] 368791 0
16 weeks or 11 weeks if the subjects early terminated from the study.
Secondary outcome [3] 368792 0
Change in alanine aminotransferase (ALT) based on chemistry laboratory test results.
ALT will be analyzed with a serum assay.
Timepoint [3] 368792 0
16 weeks or 11 weeks if the subjects early terminated from the study.
Secondary outcome [4] 368793 0
Change in enhanced Liver Fibrosis (ELF) Score
Timepoint [4] 368793 0
16 weeks or 11 weeks if the subjects early terminated from the study.
Secondary outcome [5] 368794 0
Percentage of subjects with at least 15% reduction in liver steatosis

The percentage change is calculated by taking the difference between the baseline and Week 16 measurements and divide the difference by the baseline value. Thus, for conditions with some subjects drop out of study early (hence no measurement on “liver fat fraction” was collected for Week 16), two types of analyses will be conducted: the first analysis will exclude subject(s) who did not complete the study, while the second analysis will include subject(s) who drop out of study early, but will assume LM011 had no effect on liver fat fraction .


At Screening and Week 16, MRI-PDFF over 9 regions of interest will provide estimates of liver fat fractions, measured in %. Based on this biomarker, % steatosis of the liver can be estimated.
The percentage change is calculated by taking the difference between the Screening and Week 16 measurements in % steatosis and divide the difference by the Screening % steatosis. Proportion of subjects with at least 15% decrease will be summarized.
The calculation is the same as the primary outcome. The only difference is that 15% cutoff is to be used.
Timepoint [5] 368794 0
16 weeks or 11 weeks if the subjects early terminated from the study.

Eligibility
Key inclusion criteria
1. Males or females between 18 and 75 years old with a documented diagnosis of NASH by a licensed medical practitioner within the last 12 months prior to Screening Visit
2. BMI between 28 and 40 kg/m2
3. Negative urine drugs-of-abuse screen
4. MRI-PDFF at least 15.7%
5. Fibroscan score not more than 12 kPa
6. Able and willing to comply with the protocol and availability for all scheduled clinic visits and telephone calls
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known cardiovascular disease
2. History of cirrhosis based on imaging or clinical criteria and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding.
3. History of liver transplantation
4. History of hepatocellular carcinoma (HCC)
5. History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, or resected noninvasive cutaneous squamous carcinoma at the time of Screening visit
6. Females who are pregnant or breastfeeding.
7. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents and immunomodulating agents (such as systemic corticosteroids, interleukins, interferons).
8. Use of any experimental medications within the last 6 months of Screening Visit or during participation of the trial.
9. Weight loss of >5% from the time of diagnosis of NASH, based on subject’s reporting
10. Currently or participated in a weight loss program within the last 6 months.
11. Any history of bariatric surgery.
12. Diabetes mellitus Type I
13. Daily alcohol intake (on average) >20 ml (2 units)/day for women and 30 ml (3 units)/day for men within the last 12 months prior to Screening Visit and plan to consume the same alcohol amount referenced above during the trial.
14. Any severe, acute, or chronic medical or psychiatric condition that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of study results and, in the investigator’s opinion, would make the subject inappropriate for entry into this 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)
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
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
29/04/2019
Actual
Date of last participant enrolment
Anticipated
30/08/2019
Actual
Date of last data collection
Anticipated
30/12/2019
Actual
Sample size
Target
20
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 13511 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 13512 0
Nepean Hospital - Kingswood
Recruitment hospital [3] 13513 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [4] 13518 0
St George Hospital - Kogarah
Recruitment hospital [5] 13557 0
The Alfred - Prahran
Recruitment hospital [6] 13558 0
Gallipoli Medical Research Foundation - Greenslopes
Recruitment postcode(s) [1] 26130 0
2050 - Camperdown
Recruitment postcode(s) [2] 26131 0
2747 - Kingswood
Recruitment postcode(s) [3] 26132 0
6009 - Nedlands
Recruitment postcode(s) [4] 26137 0
2217 - Kogarah
Recruitment postcode(s) [5] 26201 0
3004 - Prahran
Recruitment postcode(s) [6] 26202 0
4120 - Greenslopes

Funding & Sponsors
Funding source category [1] 302342 0
Commercial sector/Industry
Name [1] 302342 0
Lifemax Laboratories (Australia) Pty Ltd
Country [1] 302342 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Lifemax Laboratories (Australia) Pty Ltd
Address
58 Gipps Street,
Collingwood, VIC 3066
Country
Australia
Secondary sponsor category [1] 302230 0
Commercial sector/Industry
Name [1] 302230 0
Novotech (CRO)
Address [1] 302230 0
235 Pyrmont St.
Pyrmont NSW 2009
Country [1] 302230 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303017 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 303017 0
Ethics committee country [1] 303017 0
Australia
Date submitted for ethics approval [1] 303017 0
30/11/2018
Approval date [1] 303017 0
11/02/2019
Ethics approval number [1] 303017 0
X18-0477 & HREC/18/RPAH/68

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

Contacts
Principal investigator
Name 92178 0
A/Prof Simone Strasser
Address 92178 0
A.W Morrow GE/Liver Center, Level 9, West, Missenden Road
CAMPERDOWN, NSW 2050
Country 92178 0
Australia
Phone 92178 0
+61295157606
Fax 92178 0
Email 92178 0
simone.strasser@health.nsw.gov.au
Contact person for public queries
Name 92179 0
Tatiana Tsoutsman
Address 92179 0
A.W Morrow GE/Liver Center, Level 9, West, Missenden Road
CAMPERDOWN, NSW 2050
Country 92179 0
Australia
Phone 92179 0
+61295157383
Fax 92179 0
Email 92179 0
tatiana.tsoutsman@sswahs.nsw.gov.au
Contact person for scientific queries
Name 92180 0
Simone Strasser
Address 92180 0
A.W Morrow GE/Liver Center, Level 9, West, Missenden Road
CAMPERDOWN, NSW 2050
Country 92180 0
Australia
Phone 92180 0
+61295157606
Fax 92180 0
Email 92180 0
simone.strasser@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.