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Trial registered on ANZCTR


Registration number
ACTRN12616001402437
Ethics application status
Approved
Date submitted
14/09/2016
Date registered
10/10/2016
Date last updated
10/10/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of the effects of a mixture of amino acids (Amixea) on lean body mass and muscle strength of patients with unresectable advanced non small cell lung cancer: A randomized, double blind, placebo controlled, multicentre study
Scientific title
Evaluation of the effects of a stoichiometric mixture of amino acids (Amixea) on lean body mass and muscle strength of patients with unresectable advanced non small cell lung cancer: A randomized, double blind, placebo controlled, multicentre study
Secondary ID [1] 290265 0
Nil known
Universal Trial Number (UTN)
U1111-1187-5450
Trial acronym
Linked study record
Clinicaltrials.gov registration number NCT02877966.
Recently the sponsorship changed and the trial was withdrawn from the previously registered record on Clinicaltrials.gov.

Health condition
Health condition(s) or problem(s) studied:
Advanced non small cell lung cancer 300259 0
Cachexia 300493 0
Condition category
Condition code
Cancer 300125 300125 0 0
Lung - Non small cell
Diet and Nutrition 300352 300352 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This clinical study is aimed to evaluate the efficacy of a new food supplement called "Amixea" in improving muscle strength and body composition in cancer patients, when compared to placebo.
Amixea is a mixture of amino acids. It consists mainly of essential amino acids (EAA).

List of characterizing ingredients in Amixea:

L-leucine
L-lysine chloride
L-isoleucine
L-valine
L-threonine
L-histidine chloride monohydrate
L-cystine
L-phenylalanine
L-methionine
L-tyrosine
L-tryptophan


Each sachet will be of 6.6 mg (including active ingredients abov listed and excipients).
Amixea will be administered orally for 10 weeks: 3 sachets per day. Each sachet will be taken with approximately 150 ml of chilled water, 30 minutes after food.

The patients’ compliance to the treatment will be checked by the study staff by counting the number of used and unused sachets returned by the patients at Visit 3 and 4.
Intervention code [1] 295892 0
Treatment: Drugs
Comparator / control treatment
The comparator is placebo, mainly composed of maltodextrin.
Each sachet will be of 6.6 mg (including maltodextrin and excipients).

Placebo will be administered orally for 10 weeks: 3 sachets per day. Each sachet will be taken with approximately 150 ml of chilled water, 30 minutes after food.
Control group
Placebo

Outcomes
Primary outcome [1] 299605 0
Lean body mass by dual energy x-ray absorptiometry (DXA).
Timepoint [1] 299605 0
Lean body mass will be evaluated at baseline (before study treatment start) and after 10 weeks of treatment.
Primary outcome [2] 299608 0
Quadriceps maximal voluntary contraction force (QMVC) using dynamometer (strain gauge).
Timepoint [2] 299608 0
QMVC will be evaluated at baseline (before study treatment start) and after 10 weeks of treatment.
Secondary outcome [1] 327666 0
1. Predominant energy metabolism substrate using overnight fasted blood metabolites: Fasting Glucose, LDH, C-Reactive Protein, Fasting Insulin, Beta hydroxybutyrate, Free Fatty Acids (i.e. total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides).
Timepoint [1] 327666 0
Predominant energy metabolism substrate will be evaluated before the treatment start and after 10 weeks of treatment.
Secondary outcome [2] 327667 0
2. Nutritional status and risk as assessed by Patient-Generated Subjective Global Assessment (PG-SGA) tool (FD Ottery 2001).
Timepoint [2] 327667 0
Nutritional status will be evaluated before the treatment start and after 10 weeks of treatment.
Secondary outcome [3] 327668 0
3. Health-related quality of life as assessed by the Functional Assessment of Anorexia/Cachexia Treatment (FAACT) Questionnaire (version 4).
Timepoint [3] 327668 0
Health-related quality of life will be evaluated before the treatment start and after 10 weeks of treatment.
Secondary outcome [4] 327669 0
4. Skeletal muscle mass at the L3 level as assessed by CT scan, expressed as square centimetres. This endpoint will be evaluated in a subsample of patients (approximately 40 participants who are willing to undergo the additional scan) .
Timepoint [4] 327669 0
Skeletal muscle mass from L3 will be evaluated before the treatment start and after 10 weeks of treatment.
Secondary outcome [5] 327670 0
Exploratory endpoint
1. Patient satisfaction with treatment as assessed by Likert scale.
Timepoint [5] 327670 0
The patient satisfaction will be evaluated at study end (after 10 weeks of treatment).
Secondary outcome [6] 327673 0
Exploratory endpoint
2. Adherence to the treatment as assessed by sachet count and patient report.
Timepoint [6] 327673 0
Adherence to treatment will be evaluated after 5 weeks of treatment (study product return and new dispensation for the following 5 weeks) and after 10 weeks of treatment.
Secondary outcome [7] 327674 0
Number and type of adverse events and study product tolerability as assessed by the number, frequency, severity, seriousness and relatedness of recorded adverse events.
No adverse events associated with the study product are expected, except than minor gastrointestinal discomfort due to the fact that proteins attract water into the gut. The patient will asked to report adverse events to the Investigator.
The Investigator will record adverse events reported by patients and/or detected at visits on the CRF. All AE will be using the Medical Dictionary for Regulatory Activities (MedDRA) to give a preferred term (PT) and a system/organ class term (SOC).
Timepoint [7] 327674 0
Adverse events and product tolerability will be evaluated at each visit (week 0, week 5, week 10). In case of on-going (serious) adverse events at the last visit (week 10) an additional follow-up visit, after 7-14 days (with a window of plus or minus 3 days) will be done.
Secondary outcome [8] 327675 0
Physical examinations, vital signs:
A general examination of the body will be done by the Investigator and any abnormality will be recorded on the CRF.
Body weight, blood pressure and heart beat after 10 minutes at rest will be taken ad recorded on the CRF.
Timepoint [8] 327675 0
Physical examination and vital signs (blood pressure, and heart beat) will be evaluated before the treatment start and after 10 weeks of treatment.

Eligibility
Key inclusion criteria
1. Females and males at least 18 years of age.
2. Stage III or IV unresectable NSCLC (documented histologic or cytologic diagnosis according to AJCC Cancer Staging).
3. On or planned first line chemotherapy or targeted therapies.
4. ECOG performance status less than or equal to 2.
5. Estimated life expectancy greater than 6 months at the time of screening.
6. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels less than or equal to 5 x upper limit of normal (ULN).
7. Adequate renal function, defined as creatinine less than or equal to 2 x ULN, or calculated creatinine clearance greater than 30 ml/minute.
8. Must be willing and able to give signed informed consent and, in the opinion of the Investigator, to comply with the protocol tests and procedures.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Other forms of lung cancer (eg, small cell, mesothelioma)
2. Women who are pregnant or breast-feeding
3. Known HIV, hepatitis (B & C), or active tuberculosis
4. Had major surgery (central venous access placement and tumor biopsies are not considered major surgery) within 4 weeks prior to randomization. Patients must be well recovered from acute effects of surgery prior to screening. Patients should not have plans to undergo major surgical procedures during the treatment period.
5. Patients undergoing curative radiation therapy.
6. Patients on treatment with levodopa.
7. Patients unable to readily swallow. Patients with severe gastrointestinal disease (including esophagitis, gastritis, malabsorption, or obstructive symptoms) or intractable or frequent vomiting are excluded.
8. Patients with active, uncontrolled infection.
9. Patients with uncontrolled diabetes mellitus.
10. Patients with untreated, clinically relevant hypothyroidism.
11. Patients with known or symptomatic brain metastases.
12. Patients receiving parenteral nutrition (either total or partial).
13. Other clinical diagnosis, ongoing or intercurrent illness that in the Investigator’s opinion would prevent the patient’s participation.
14. Use of other investigational drug(s) within 30 days before study entry or during the study.

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)
The study products (Amixea and Placebo) will be prepared and labelled according a randomization list.. Once patient's eligibility is established the Investigator will assign the first available number of study treatment. The assigned number will be recorded by Investigator on medical records and on the CRF.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A randomization list will be generated using the module PROC PLAN – SAS version 9.4.
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size determination:
According to the literature, the expected mean fat free mass (FFM) as measured by DXA in the control group could be 49.06 kg, with a standard deviation of 10.38. Assuming that the minimum difference of interest between the comparison groups is 15%, the study group is expected to obtain a mean FFM of 56.42 kg. Under this hypothesis and considering a common standard deviation (ie. 10.38), 40 subjects per group (80 total subjects) will be required to detect this difference with 80% power, considering an alpha of 0.025 (two-tailed), to account for the two primary endpoints.
The literature review didn't provide data on quadriceps maximal voluntary contraction (QVMC) among lung cancer that enabled formal estimation of the sample size. However, with 80 subjects, a difference of 7 kg between the two treatment groups can be assessed with a power higher than 80%, considering an alpha of 0.025 and a common standard deviation of 9 kg.
Assuming a refusal rate of 20%, an attrition rate of 40% and allowing 15% extra for probable need to apply multivariable modelling techniques to adjust for confounding, we would need to approach 200 patients to enroll at least 160 subjects enabling 80 valid subjects at the end of the study. This sample size would be necessary not to lose the opportunity to detect clinically relevant differences in all primary and secondary outcomes.

Primary outcomes analysis:
For both continuous primary outcome variables, ANCOVA will be used to evaluate whether outcome means are equal between Amixea and control groups at 10 weeks while controlling for the effects of covariates including baseline values.
The improvement of lean body mass will be assessed by DXA. The improvement of QMVC force will be assessed by dynamometer.

Secondary outcomes analysis:
For all continuous secondary outcome variables, ANCOVA will be used to evaluate whether outcome means are equal between Amixea and control groups at 10 weeks while controlling for the effects of covariates including baseline values.
For categorical secondary outcome variables (i.e., PGSGA ratings), chi squared test will be used to evaluate the sampling distribution between Amixea and control groups at 10 weeks.
Energy-yielding metabolites will be analysed using overnight fasted blood metabolites.
Nutrition status will be assessed using global PG-SGA rating.
Nutrition risk will be assessed using PG-SGA score. Health Related Quality of Life (HRQoL) will be assessed using FAACT. Skeletal muscle mass area from L3 will be assessed in a subsample of patients who have CT scans within the prescribed timeframes.

Safety oucomes analysis:
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) to give a preferred term (PT) and a system/organ class term (SOC) for each event. The number of patients who experienced at least one AE, trial product-related AE, serious AE, severe AE and the number of patients withdrawn due to AE will be summarized by treatment arm.
Descriptive analysis of vital signs will be performed by treatment group and changes from baseline will be analyzed within each treatment group using paired T-test. Comparisons between treatment groups will be performed using ANOVA.

Exploratory outcomes evaluation:
The adherence to the assigned treatment will be assessed by sachet count at Visits 3 and 4. The percentage of treatment correctly assumed will be estimated and compared by treatment group using Student’s T-test.
Patient satisfaction will be assessed by a Likert Scale. The patient satisfaction will be compared by treatment group using t-test for normally distributed data or Mann-Whitney U test for non-normally distributed data, as appropriate.

Population analysed:
The intention to treat (ITT) and per protocol (PP) populations will be analysed under the following conditions:
- If less than 20% of the data are missing; both PP and ITT analyses will be conducted.
- If more than 20% of the data are missing; only a PP analysis will be conducted.
The ITT population will be used to evaluate the effectiveness of the treatment in the clinical setting. That is, all randomized patients will be included in the analysis. Any missing data will be coded as missing at random (MAR) or not missing at random (NMAR) and imputed using multiple imputation techniques.

The PP population will be used to evaluate the efficacy of the treatment. That is, all patients who have completed the entire treatment protocol as originally planned and with perfect compliance will be included in the analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/11/2016
Actual
Date of last participant enrolment
Anticipated
31/12/2018
Actual
Date of last data collection
Anticipated
30/04/2019
Actual
Sample size
Target
160
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 6661 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 6662 0
Gold Coast University Hospital - Southport
Recruitment postcode(s) [1] 14287 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 14288 0
4215 - Southport

Funding & Sponsors
Funding source category [1] 294518 0
Commercial sector/Industry
Name [1] 294518 0
Latis Australian PTY LTD
Country [1] 294518 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Latis Australian PTY LTD
Address
Level 15 Exchange Tower
2 The Esplanade
Perth WA 6000
Country
Australia
Secondary sponsor category [1] 293382 0
None
Name [1] 293382 0
Address [1] 293382 0
Country [1] 293382 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295952 0
The Prince Charles Hospital Human Research Ethics Committee
Ethics committee address [1] 295952 0
Ethics committee country [1] 295952 0
Australia
Date submitted for ethics approval [1] 295952 0
14/07/2016
Approval date [1] 295952 0
15/07/2016
Ethics approval number [1] 295952 0
HREC/15/QPCH/267

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

Contacts
Principal investigator
Name 69002 0
Prof Elisabeth Isenring
Address 69002 0
Faculty of Health Sciences and Medicine
Bond Institute of Health and Sport
Bond University
2 Promethean Way
Robina QLD 4229
Country 69002 0
Australia
Phone 69002 0
+61755953337
Fax 69002 0
+61755953524
Email 69002 0
lisenrin@bond.edu.au
Contact person for public queries
Name 69003 0
Elisabeth Isenring
Address 69003 0
Faculty of Health Sciences and Medicine
Bond Institute of Health and Sport
Bond University
2 Promethean Way
Robina QLD 4229
Country 69003 0
Australia
Phone 69003 0
+61755953337
Fax 69003 0
+61755953524
Email 69003 0
lisenrin@bond.edu.au
Contact person for scientific queries
Name 69004 0
Elisabeth Isenring
Address 69004 0
Faculty of Health Sciences and Medicine
Bond Institute of Health and Sport
Bond University
2 Promethean Way
Robina QLD 4229
Country 69004 0
Australia
Phone 69004 0
+61755953337
Fax 69004 0
+61755953524
Email 69004 0
lisenrin@bond.edu.au

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