1 Introduction
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Reduced catabolism, through non-selective β-blockade,
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Reduced fatigue and thermogenesis, through central 5-HT1a antagonism,
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Increased anabolism, through partial β2-receptor agonism,
2 Methods
2.1 Study objectives
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the slope of weight change
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the short physical performance battery test(SPPB)
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the six-minute walk test (SMWT)
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hand grip strength (HGS)
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measures of quality of life (QOL)
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change of body composition according to dual energy X-ray absorbitometry (DEXA)
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all cause mortality
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the adverse event profile
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inflammatory, neuroendocrine and catabolic/anabolic biomarkers
2.2 Overall design and planning
2.3 Patient selection
Inclusion criteria | Exclusion criteria |
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Aged between 25 and 80 years of age and with a life expectancy of greater than 3 months as judged by the treating physician | Age greater than 80 or less than 25 at baseline visit |
Confirmed diagnosis of one of | Previous history of administration of MT-102 or related products, or any history of allergy or reaction to any component of the MT 102/study drug formulation |
Non-curative stage III or stage IV CRC not suitable for surgery, or | |
Non-curative stage III or stage IV NSCLC not suitable for surgery; | |
Patients who are on first-line chemotherapy or those who have a documented failure to respond or who have documented progression following a first-line course of chemotherapy, with or without radiotherapy, with one of the following regimes | Congestive heart failure or uncontrolled hypertension, pacemaker, implantable defibrillator, or internalized metal stent, resting pulse rate less than 68 bpm or high degree conduction defect; resting supine SBP less than 100 mm Hg; or ≥20% weight loss in the previous 3 Months or a body mass index (BMI) of less than 16 kg/m2
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For non-small cell lung cancer, a platinum-based regimen | |
For colorectal cancer, a 5FU or irinotecan-based regimen | |
Evidence of cachexia as judged by one of | Current or planned treatment with any oral |
≥5% documented weight loss in the previous 12 months | Adrenal corticosteroids, beta-blockers, non-dihydropyridine calcium antagonists, alpha adrenergic blockers, ivabradine, 5HT agonists or antagonists, MAOI's, beta agonists, amiodarone,, megestrol, anabolic steroids or any other prescription medication intended to increase appetite or to treat unintentional weight loss |
A subjective report of weight loss in the previous 12 months and a recorded BMI less than 20.0 kg/m2
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Ongoing documented weight loss of at least 1 kg in the week prior to day 0; or 1.25 kg in the 2 weeks prior to day 0, or 1.5 kg in the 3 to 6 weeks prior to day 0; provided that BMI is not more than 25 kg/m2. | |
At least two of the following | Any mechanical obstruction of the alimentary canal or any history or evidence of intractable vomiting; or any physical, medical, socioeconomic or other non-cancer-related cause for simple starvation, muscle wasting or weight loss |
Subjective report of decreased muscle strength | |
Subjective report of fatigue | |
Subjective report of anorexia | |
Abnormal biochemistry with one or more of the following | |
CRP > ULN (as per Central Lab normal value) | |
Anaemia (<12 g/dl) | |
Low serum albumin (<3.2 g/dl) | |
Patients of childbearing potential must use an effective method of avoiding pregnancy (including oral, transdermal or implanted contraceptives; an intrauterine device; male or female condoms; diaphragm or cervical cap with spermicide; or abstinence) prior to randomisation and must agree to continue using such precautions until the end of the 140 day safety follow up | Scheduled to start any new course of chemotherapy or to undergo a change in present chemotherapeutic regimen during the dose escalation phase of the study (the first 3 weeks after randomisation); any surgical procedure within the past month or any planned surgical procedure |
Willing and able to comply with the protocol and to complete the study period; | Any clinical evidence of ascites or significant oedema or significant pleural effusion at screening or baseline visit; A history of bronchospasm and bronchial asthma; or a history or diagnosis of brain metastases |
ECOG performance status 0, 1 or 2 | Receiving enteral tube feeding or parenteral nutrition at screening or baseline visit |
Able to complete the performance tests (SCP, SMWT, SPPB, HGS) at the screening visit and with two consecutive pre-randomisation SMWT results that differ by no more than 30% from each other | A history or clinical evidence of hyperthyroidism, cirrhosis, hepatic failure, HIV, renal failure (as determined by a serum creatinine >250 μmol/l or >2.83 mg/dl at screen) or active tuberculosis |
At least 80% compliant during the placebo run-in period | Pregnancy or lactation |
Signed and dated informed consent, prior to receipt of any study medication or any study related procedures. | Treatment with any investigational therapy within 28 days prior to the screening visit |
2.4 Randomisation
2.5 Treatment regimens
Group | Patient no. | Daily dose (mg) | Day nos.a
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A | 22 | 5 | 0–6 |
5 | 7–13 | ||
5 | 14 onwards | ||
B | 66 | 5 | 0–6 |
10 | 7–13 | ||
20 | 14 onwards | ||
C | 44 | 0 | 0–6 |
0 | 7–13 | ||
0 | 14 onwards |
3 Assessments
3.1 Functional evaluations
3.2 Biomarker studies
3.3 Pharmaco-vigilance and safety assessments
3.4 Sample size and statistical considerations
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the null-hypothesis (Ho) that there is no difference in the mean weight loss rate between high-dose MT-102 and placebo,
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a two-sided significance test for the rejection of Ho with a level α of 0.05,
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a power of 85%,
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an expected mean weight change per 4-week period of −0.8 kg in the placebo group and a mean weight change per 4-week period of 0 kg in the high-dose MT-102 arm,
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a standard deviation of 1.2 kg per 4-week period,
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an allocation ratio of 3:2:1, i.e. MT-102 10 mg BD/MT-102 2.5 mg BD/placebo.
3.5 Statistical and analytical plan
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body weight and body weight changes;
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DEXA scan
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stair climbing power;
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six-minute walk test;
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short physical performance battery test;
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hand grip strength;
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EQ-5D QoL data.