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Trial registered on ANZCTR


Registration number
ACTRN12619001324101
Ethics application status
Approved
Date submitted
20/09/2019
Date registered
27/09/2019
Date last updated
12/03/2020
Date data sharing statement initially provided
27/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to treat cancer related weight loss in patients with mesothelioma
Scientific title
A single centre phase II, randomised placebo controlled cross over study to examine the effect of anamorelin on cancer cachexia in patients with mesothelioma
Secondary ID [1] 299349 0
Nil known
Universal Trial Number (UTN)
U1111-1240-6828
Trial acronym
ANTHEM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mesothelioma 314501 0
Condition category
Condition code
Cancer 312846 312846 0 0
Lung - Mesothelioma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Anamorelin (100mg) 1 oral tablet once a day, one hour before food for 28 days
Placebo, 1 oral tablet once a day, one hour before food for 28 days
This is a cross over study, so all participants will receive either the study drug and the placebo for 28 days followed by a washout period of 3 days, then either the study drug or the placebo for another 28 days.
Adherence will be monitored by drug tablet return and review of patient compliance diary.
Intervention code [1] 315621 0
Treatment: Drugs
Comparator / control treatment
The placebo will contain, Microcrystalline cellulose, 272.65mg; Lactose monohydrate, 272.56mg; Magnesium stearate, 2.7mg; Opadry II Yellow 85F42233, 18.4mg. It will look exactly like the intervention treatment tablet.

Control group
Placebo

Outcomes
Primary outcome [1] 321459 0
Change in appendicular skeletal muscle mass as measured by Dual Energy X-Ray Absorptiometry
Timepoint [1] 321459 0
Pre-treatment, then at day 29-31 and at day 61
Secondary outcome [1] 375017 0
Weight change measured in kilograms on digital scales
Timepoint [1] 375017 0
Pre-treatment, then at day 29-31 and at day 61.
Secondary outcome [2] 375019 0
Change in body mass index calculated using the formula BMI=weight (kg)/height^2 (m^2).
Timepoint [2] 375019 0
Pre-treatment, then at day 29-31 and day 61
Secondary outcome [3] 375021 0
Change in health related quality of life, measured using the validated instruments; Functional Assessment of Cancer Therapy-Lung (FACT-L)-a 36 item questionnaire, and the Functional Assessment of Anorexia/Cachexia Treatment (FAACT)-a 12 item questionnaire.
Timepoint [3] 375021 0
Pre-treatment, then at day 29-31 and at day 61.
Secondary outcome [4] 375024 0
Change in objective physical activity. Measured by an accelerometer which will be worn by the participant on a belt around the waist 24 hours a day for three days.
Timepoint [4] 375024 0
Pre-treatment for three days, then for three days before face to face visit on day 29-31 and then for three days before face to face visit on day 61.
Secondary outcome [5] 375027 0
Dietary intake. This will be assessed via telephone interview using the 24 hour food recall method. Dietary intake data will be analysed using 'Foodworks 8' software (Xyris Software Pty Ltd, Australia)
Timepoint [5] 375027 0
Pre-treatment, then at day 29-31 and at day 61.
Secondary outcome [6] 375030 0
Blood samples for biomarkers of anorexia/cachexia and nutrition as an exploratory tertiary outcome. Measuring inflammation-associated factors in serum using the Human Inflammation Array QI (from RayBiotech Inc, Norcross GA). These include IFN-gamma, IL1 alpha, IL1 beta, IL-10, IL-13, IL-4, IL-6, IL-8, MCP-1 and TNF alpha. Serum albumin, plasma glycerol (as a measure of lipolysis), serum leptin, ghrelin, transthyretin and serum adiponectin will also be measured.
Timepoint [6] 375030 0
Pre-treatment, then at day 29-31 and at day 61.
Secondary outcome [7] 375037 0
Patient experience. Measured by a short questionnaire developed specifically for this project which will undergo a content analysis to determine similarities.
Timepoint [7] 375037 0
Measured at day 29 and day 61
Secondary outcome [8] 375039 0
Patient compliance. Measured by telephone conversation and review of patient compliance diary, and drug tablet return.
Timepoint [8] 375039 0
Phone call at day 14 and day 46. Review of physical diary at day 29 and day 61.
Secondary outcome [9] 375047 0
Change in electrical activity in the heart measured by an electrocardiogram (ECG). ECG changes are a possible adverse event associated with this drug.
Timepoint [9] 375047 0
Pre-treatment, then at day 29-31 and at day 61.
Secondary outcome [10] 375048 0
Changes to blood sugar levels. An inappropriate increase in blood sugar levels is a possible adverse effect of this drug.
Timepoint [10] 375048 0
Pre-treatment, then at day 14, day 29-31, day 46 and at day 61.
Secondary outcome [11] 375049 0
Changes in blood markers for liver function. Derangement of liver function is a possible adverse effect of this drug. Markers measured will be: Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and total bilirubin. This is a composite outcome looking at overall liver function.
Timepoint [11] 375049 0
Pre-treatment, then at day 14, day 29-31, day 46 and at day 61.
Secondary outcome [12] 375050 0
Overall survival.
Timepoint [12] 375050 0
Measure at 26 weeks from day zero, by audit of medical records

Eligibility
Key inclusion criteria
Adults (18 years and above)
Confirmed malignant pleural mesothelioma (histology or cytology);
Cachexia (defined as >5% weight loss in 6 months or < body mass index (BMI) 20 kg/m^2 with weight loss >2%);
Life expectancy >3 months at randomisation.
Written informed consent
ECOG performance status 0-2 (The Eastern Cooperative Oncology Group (ECOG) performance status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis).
At least 3 weeks since last received systemic anticancer therapy
Ability to provide written informed consent in English and comply with trial procedures.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Peritoneal spread of mesothelioma
Other significant comorbidity or organ dysfunction which may affect outcome measures or safety,
Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
*History or presence of ventricular tachyarrhythmia
*Presence of unstable atrial fibrillation (ventricular response > 120 beats per minute at rest); Patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria
*Other clinically significant heart disease
*Corrected QT interval (QTcF) >480 milliseconds on baseline ECG. If electrolytes are abnormal, they may be corrected and baseline ECGs should be repeated
Patients with abnormal liver function tests, defined as any of the following:
*Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal (ULN), or AST or ALT > 5 times ULN for patients with liver metastases
*Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
Participation in another study (drug or non-drug study) that may affect ANTHEM outcome measures,
Concurrent chemotherapy or radiotherapy (immunotherapy is accepted), including planned chemo- or radiotherapy commencing during the study period
Concurrent use of appetite stimulants including oral corticosteroids (other than for adrenal replacement), mirtazapine (other than for major depressive disorder), or progesterones
Patients who are receiving treatment with medications, that cannot be discontinued prior to study entry and that are considered to be any of the following:
*known risk for QT prolongation
*known to be strong inducers or inhibitors of CYP3A4/5
Uncontrolled diabetes mellitus (defined as random blood glucose >11.1mmol/L and/or HbA1c >7.0%)
Significant active gastrointestinal disease (e.g., malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, gastrointestinal perforation, or partial or complete bowel obstruction, ascites of any cause) that might impair absorption of study treatment
Inability to readily swallow oral tablets or intractable or frequent vomiting

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation completed by contacting data manager who is off-site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
In order to reduce the chance of an imbalance between the groups, minimisation with a random element will be performed with a 1:1 ratio between the 2 groups using an online computer-generated randomisation sequence. Minimisation will be according to: ECOG performance status (0-1 or 2), and histological sub-type of malignant mesothelioma (epithelioid versus non-epithelioid (biphasic, sarcomatoid, not defined)).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Participants will be divided into two groups. Both groups will receive 28 days of either the placebo or the study drug followed by a washout period of 3 days followed by either the study drug or the placebo (opposite to what they had the first time-so all participants receive 28 days of placebo and 28 days of study drug overall).
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Source data will be collected on standardised paper case record forms, and then entered into a REDCap database.

Data collected will be exported to a statistical software (Stata). They will be checked and cleaned where necessary. Participant baseline characteristics (age, gender, etc) will be reported using frequency and percentages for categorical data and mean and standard deviation for continuous data with a Normal-distribution. Skewed variables will be reported using median and interquartile range. The characteristics and baseline scores will be compared between the intervention group and control group to check for equal variance across groups.

Differences between Appendicular Skeletal Muscle (ASM) (and other secondary endpoints) at baseline and across the follow-up time points will be assessed using general linear mixed effects model. The model will allow comparison within participants over time and between the groups, while allowing a time*group interaction (i.e. ‘period’ and ‘intervention’). Analysis for the presence of a period effect and/or carry-over effect will be performed with a null hypothesis of no difference between period 1 and 2.

Survival will be calculated from date of randomisation until date of death or end of study. Survival curves of the two groups will be estimated using the Kaplan-Meier method and compared statistically using the log rank test. As the intervention may influence the presence (or absence) of missing data we will not assume data is missing at random, instead, we will use a joint modelling approach (combining linear mixed effects models for repeated measurements and Cox models for censored survival outcomes to assess the robustness of any assumptions with missing data for repeated measurements. Covariates for the mixed effects submodel will include baseline measurements of the outcome, treatment group, time since diagnosis, measurements at each time point and a treatment group-measurement time point interaction. Sensitivity analyses will include physical activity and dietary intake data.

Correlation between biomarkers of anorexia/cachexia and major nutrients will be assessed using linear regression while adjusting for total energy intake.

Patient experience data will be assessed using content analysis to identify the key themes.

The alpha significance level will be 5%

Recruitment
Recruitment status
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)
WA
Recruitment hospital [1] 14835 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 28087 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 303865 0
Charities/Societies/Foundations
Name [1] 303865 0
Cancer Council of Western Australia
Address [1] 303865 0
420 Bagot Road, Subiaco, WA 6008
Country [1] 303865 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Institute for Respiratory Health
Address
QEII Medical Centre, QQ Block, Level 2, 6 Verdun Street, Nedlands, WA 6009
Country
Australia
Secondary sponsor category [1] 304009 0
None
Name [1] 304009 0
Address [1] 304009 0
Country [1] 304009 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304375 0
Sir Charles Gairdner and Osborne Park Health Care Group Human Ethics Committee
Ethics committee address [1] 304375 0
Sir Charles Gairdner Hospital, Level 2, A Block, Hospital Avenue, Nedlands WA 6009
Ethics committee country [1] 304375 0
Australia
Date submitted for ethics approval [1] 304375 0
29/08/2019
Approval date [1] 304375 0
10/02/2020
Ethics approval number [1] 304375 0

Summary
Brief summary
The purpose of this study is to see if a medication called anamorelin improves muscle mass and outcomes in patients with malignant mesothelioma.

Who is it for?
You may be eligible for this study if you are aged 18 or over, have confirmed malignant mesothelioma and have lost more than 5% of your body weight in 6 months (i.e. ‘cachexia’).

Study details
Participants will be randomised by chance (like flipping a coin) into two groups. One group will take the active drug anamorelin per day for 28 days, before switching to an inactive placebo medication for another 28 days (after a 3 day break). The other group will follow the same pattern, only they will have the placebo first and then the active medication. Neither the researchers nor participants will know which order the medication/placebo are taken in. As part of this study, all participants will complete a number of questionnaires, a food diary, provide blood samples for testing and have body scans that measure muscle mass.

It is hoped this research will show that the medication anamorelin can help patients with malignant mesothelioma maintain or gain weight, which might help them feel better, and shed some insight into body markers of cancer-related weight-loss.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96738 0
Prof Fraser Brims
Address 96738 0
Curtin University
Kent Street, Bentley, Perth
Western Australia, 6102
GPO Box U1987, Perth, WA 6845
Country 96738 0
Australia
Phone 96738 0
+61 8 9266 2333
Fax 96738 0
Email 96738 0
fraser.brims@curtin.edu.au
Contact person for public queries
Name 96739 0
Prof Fraser Brims
Address 96739 0
Curtin University
Kent Street, Bentley, Perth
Western Australia, 6102
GPO Box U1987, Perth, WA 6845
Country 96739 0
Australia
Phone 96739 0
+61 8 9266 2333
Fax 96739 0
Email 96739 0
fraser.brims@curtin.edu.au
Contact person for scientific queries
Name 96740 0
Prof Fraser Brims
Address 96740 0
Curtin University
Kent Street, Bentley, Perth
Western Australia, 6102
GPO Box U1987, Perth, WA 6845
Country 96740 0
Australia
Phone 96740 0
+61 8 9266 2333
Fax 96740 0
Email 96740 0
fraser.brims@curtin.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Only summarised results will be reported. No individual participant data will be available as per ethics requirements.
What supporting documents are/will be available?
No other documents available
Summary results
No Results