Mantovani et al. (2010): Randomized Phase III Clinical Trial of Five Different Arms of Treatment in 332 Patients with Cancer Cachexia

Reference ↗
Title	Randomized Phase III Clinical Trial of Five Different Arms of Treatment in 332 Patients with Cancer Cachexia
Topic	Carnitine
Author	Mantovani, G, Macciò, A, Madeddu, C, Serpe, R, Massa, E, Dessì, M, Panzone, F, Contu, P
Year	2010
Journal	The oncologist
DOI	https://doi.org/10.1634/theoncologist.2009-0153

Brief summary

This study was conducted with 332 patients and investigated the influence of carnitine, MPA/MA, EPA, thalidomide and a combination medication (carnitine + MPA/MA + EPA + thalidomide) on weight (fat mass and muscle mass) over 16 weeks in patients with acute weight loss due to cancer. The results show consistent improvements for the arm with the combination medication on fatigue/fatigue, appetite and general performance. However, there were no significant differences to the other groups, partly because the study did not compare groups on all measurements. However, the study focused on the influence of medication on weight. Here, an improvement was shown in the combination medication group with two of three survey instruments. However, only 144 and 25 of all patients were recorded with these two instruments and it is unclear how these patients were selected or how many patients were in the arms. In addition, only the survey method with 144 patients showed a significant difference between the combination medication arm and the carnitine or thalidomide arm. This result cannot be interpreted due to the lack of information on the patient breakdown and a possibly selective patient selection. Apart from this, the increased weight was largely due to increased fat mass and not to the desired muscle mass. Overall, no statement can be made about the mode of action of carnitine, as there is no comparison arm without medication and in the combination medication the individual influences of the drugs cannot be separated from each other.

Diese Studie wurde mit 332 Patienten durchgeführt und untersuchte den Einfluss von u.a. Carnitin, von MPA/MA, von EPA, von Thalidomid und einer Kombinationsmedikation (Carnitin + MPA/MA + EPA + Thalidomid) auf das Gewicht (Fettmasse und Muskelmasse) über 16 Wochen bei Patienten mit akutem Gewichtsverlust aufgrund einer Krebserkrankung. Die Ergebnisse zeigen durchgehen Besserungen für die Gruppe mit der Kombinationsmedikation auf Müdigkeit/Erschöpfung, Appetit und der generellen Leistungsfähigkeit. Allerdings zeigten sich keine bedeutsamen Unterschiede zu den anderen Gruppen, auch weil die Studie nicht zu allen Messungen Gruppenvergleiche durchgeführt hat. Das Augenmerk der Studie lag allerdings auf den Einfluss der Medikation auf das Gewicht. Hier zeigte sich eine Verbesserung in der Kombinationsmedikationsgruppe mit zwei von drei Erhebungsinstrumenten. Allerdings wurden mit diesen zwei Instrumenten jeweils nur 144 und 25 aller Patienten erfasst und es ist unklar wie diese Patienten ausgewählt wurden, bzw. wie viele Patienten in den Gruppen waren. Zudem zeigte sich nur bei der Erhebungsmethode mit 144 Patienten ein bedeutsamer Unterschied zwischen der Kombinationsmedikationsgruppe und der Carnitin- bzw. der Thalidomidgruppe. Durch die fehlende Angabe der Patientenaufteilung und einer möglicherweise selektiven Patientenauswahl ist dieses Ergebnis nicht interpretierbar. Davon abgesehen ist das erhöhte Gewicht größtenteils durch erhöhte Fettmasse entstanden und nicht durch die gewünschte Muskelmasse. Insgesamt ist keine Aussage über die Wirkweise von Carnitin möglich, da es keine Vergleichsgruppe ohne eine Medikation gibt und in der Kombinationsmedikation sind die einzelnen Einflüsse der Medikamente nicht voneinander trennbar.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	No
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	5

Study characteristics

Inclusion criteria	Histologically confirmed advanced stage tumor at any site, loss of >5% of ideal or preillness body weight in the previous 3 months with or without abnormal values of proinflammatory cytokines predictive of the onset of clinical cachexia, and a life expectancy ≥ 4 months, were eligible. Patients could be receiving concomitant antineoplastic chemotherapy or hormone therapy with palliative intent or supportive care.
Exclusion criteria	Women of child-bearing age and patients with a mechanical obstruction to feeding, medical treatments inducing significant changes in patient metabolism or body weight, and a history of thromboembolism.
N randomized	332
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	ITT Analysis
Specifications on analyses	The analysis was performed on an intent-to treat basis. An interim analysis was planned every 100 randomized patients to test the efficacy (primary efficacy endpoints) and the toxicity of the different arms according to the following “early stopping rules”: the arm(s) in which the efficacy values were significantly lower (p .05), by a t-test for changes, than in the other arms would be stopped. Likewise wise, the arm(s) in which grade 3 or 4 toxicity values were significantly higher by a t-test for changes, than in the other arms would be stopped. A very low level for the significance of p-values (p .001) was chosen considering that there are 10 possible pairs of between-arm comparisons and three endpoints, implying 30 possible candidate analyses; p-values are reported including Bonferroni’s corrections for multiple comparisons.
Countries of data collection	Italy
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: 4 weeks T2: 8 weeks T3: 16 weeks

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Palliative, NI
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Bile Duct Cancer, Breast Cancer, Colorectal Cancer, Gastrointestinal Cancers - Esophageal Cancer, Gastrointestinal Cancers - Pancreatic Cancer, Gastrointestinal Cancers - Liver Cancer, Genitourinary Cancers - Bladder Cancer, Genitourinary Cancers - Kidney (Renal) Cancer, Gynecologic Cancers - Ovarian Cancer, Gynecologic Cancers - Uterine Cancer, Head and Neck Cancers, Lung Cancer, Prostate Cancer, Stomach Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Advanced Stage
Specifications on cancer stages	Stage III and IV
Comorbidities	Cancer Cachexia
Current cancer therapies	Chemotherapy, Hormone therapy, No therapy
Specifications on cancer therapies	Concomitant antineoplastic palliative chemotherapy in 77.1-81.8% of patients per arm, NI on percentage of patients receiving hormone therapy
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	47% female
Age groups	Adults (18+)
Age groups specification	Mean(SD): 63(12) years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	44
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Death due to progression
Intervention	Magestrol Acetat (MA)/ Medroxyprogesteron Acetat (MPA) + all patients basic treatment (polyphenols + lipoic acid, carbocysteine and Vitamine A, C and E)
Dosage and regime	Oral, 320mg daily MA or 500mg daily MPA Duration: 4 month
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	121
Side effects / Interactions	No side effects reported. No significant difference between arms (p=NI)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	25
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Death due to progression
Intervention	Eicosapentaensäure (EPA) + all patients basic treatment (polyphenols + lipoic acid, carbocysteine and Vitamine A, C and E)
Dosage and regime	Oral, 2.2g EPA daily + 2g/daily Resource Support Duration: 4 month
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	121
Side effects / Interactions	No side effects reported No significant difference between arms (p=NI)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	88
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	Death due to progression
Intervention	L-Carnitin + all patients basic treatment (polyphenols + lipoic acid, carbocysteine and Vitamine A, C and E)
Dosage and regime	Oral, 2x 2g daily Duration: 4 month
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	121
Side effects / Interactions	2x grade 3 or 4 diarrhoe No significant difference between arms (p=NI)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	87
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	Death due to progression
Intervention	Thalidomid + all patients basic treatment (polyphenols + lipoic acid, carbocysteine and Vitamine A, C and E)
Dosage and regime	Oral, 2x 100mg daily Duration: 4 month
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	121
Side effects / Interactions	No side effects reported. No significant difference between arms (p=NI)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	-999
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2
Drop-out reasons	Death due to progression
Intervention	MA/ MPA + EPA + L-Carnitin + Thalidomid
Dosage and regime	Oral, 320mg daily MA or 500mg daily MPA Oral, 2.2g EPA daily + 2g/daily Resource Support Oral, 2x 2g daily L-Carnitine Oral, 2x 100mg daily Thalidomid Duration: 4 month
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	121
Side effects / Interactions	2x grade 3 or 4 diarrhoe No significant difference between arms (p=NI)

Outcomes

"Electronic device" is not in the list (AQoL-8D (Assessment of Quality of Life), ASAT (Auditory Sustained Attention Test), BIA (Bioelectrical impedance analysis), BPI-SF (Brief Pain Inventory - Short Form), CTCAE (Common Terminology Criteria of Adverse Events), ESAS (Edmonton Symptom Assessment Scale), FAACT (Functional Assessment of Anorexia-Cachexia Therapy), FACIT (Functional Assessment of Chronic Illness Therapy), FLIE (Functional Living Index for Emesis), Genitourinary atrophy self-assessment tool, ...) of allowed values for the "Type of measurement" property.

Body composition

Outcome type As specificed by the authors	Primary
Outcome specification	Lean body mass (LBM) with BIA (all patients); D(E)XA (n=144), CT at L3 (n=25)
Type of measurement	BIA (Bioelectrical impedance analysis), DXA (Dual energy X-ray Absorptiometry), CT (Computed Tomography)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	At 16 weeks: Significant increase in combination arm (MA/ MPA + EPA + L-Carnitin + Thalidomid) with DEXA (p=0.015), and with CT (increase LBM; kg; p=0.001), but not with BIA ANOVA: significant group effect for DEXA (p=0.007): between L-Carnitin arm (Mean Change= -0.7 ±2.2; 95% CI: -1.2, -0.2) and combination arm (MC= 2.1 ± 2.1; 95% CI: 1.6, 2.7; p<0.001) and between Thalidomid arm (MC= -0.8 ± 2.6; 95% CI: -1.5,-0.2) and combination arm (p<0.001), both in favor of combination arm
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

REE (Resting Energy Expenditure)

Outcome type As specificed by the authors	Primary
Outcome specification	NA
Type of measurement	Indirect calorimetry
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 16 weeks: Significant reduction in combination arm (MA/ MPA + EPA + L-Carnitin + Thalidomid, p=0.044); ANOVA: significant group effect (p=0.028): between L-Carnitin arm (MC= 12.08 ± 246; 95% CI: -47.9, -72.08) and combination arm (MC: -133 ± 259; 95% CI: -200, -65.4; p=0.004); in favor of combination arm
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Fatigue

Outcome type As specificed by the authors	Primary
Outcome specification	Multidimensional Fatigue Symptom Inventory - Short Form
Type of measurement	MFSI (Multidimensional Fatigue Symptom Inventory)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 16 weeks: Significant improvement in combination arm (MA/ MPA + EPA + L-Carnitin + Thalidomid, p=0.047); ANOVA: significant group effect [p.035]), between L-Carnitin arm (MC= 0.85 ±19.5 [95% CI: -3.6, -5.3]) and combination arm (MC= -7.5 ± 12.8 [95% CI:-10.4,-4.6]); p=0.004), in favor of combination arm
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Appetite

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	VAS (Visual Analogue Scale)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 16 weeks: significant increase in combination arm (MA/ MPA + EPA + L-Carnitin + Thalidomid; p=0.00037); no comparison between arms conducted
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	EORTC QLQC30 and EQ-5Dindex, and EQ-5DVAS
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire), EQ-5D (European Quality of Life 5 Dimensions)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No comparison between arms conducted.
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Hand grip strength

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	Dynamometer
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No comparison between arms conducted.
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Performance Status

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	ECOG Performance Status Scale (Eastern Cooperative Oncology Group), GPS (Glasgow Prognostic Score)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 16 weeks: Significant decrease in combination arm (MA/ MPA + EPA + L-Carnitin + Thalidomid; p=0.008, p<0.0001), Thalidomid arm (p=0.006, p<0.0001), and L-Carnitin arm (p=0.030, p=0.0001; GPS and ECOG PS); no comparison between arms conducted.
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Physical functioning

Outcome type As specificed by the authors	Secondary
Outcome specification	Total daily physical activity and the associated energy expenditure SenseWear PRO2 wristband: able to assess total energy expenditure (TEE), that is, the sum of REE plus the energy spent in physical activity (active energy expenditure [AEE]), which is able to identify the specific type of physical activity (e.g., walking, running, lying down) in such a wayastoattribute to it a “functional quality”
Type of measurement	Electronic monitoring device
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	After 16 weeks: TEE and AEE significantly increased in arm MA/ MPA + EPA + L-Carnitin + Thalidomid (p<0.05); no comparison beetween arms performed
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No sign. difference between arms (p=NI)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

OS (Overall Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	NA
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No sign. difference between arms (p=NI)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No sign. difference between arms (p=NI)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	Financed by first author (Giovanni Mantovani).
Conflicts of Interest	According to authors no conflict of interest.

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO:

• Ethics vote available.
• Intent-to-treat analysis
• Interim studies for patient safety
• Due to high number of arms and comparisons, significance level set to p≤.001 and Bonferroni corrections applied

CONTRA:

• No control arm (according to the authors, for ethical reasons), also MA/MPA not suitable as a comparison arm.
• LBM with 3 different instruments, but not all patients → Significant increase with DEXA and ANOVA with only 144 patients; survey with CT conducted on only 25 patients (unclear which ones), Group size too small for comparisons.
• No mention of the ANOVA analysis for Arms MA/MPA and EPA
• No statistical data for group comparisons for secondary endpoints
• Arms MA/MPA and EPA removed during interim analysis (unclear when), but analyses still conducted
• No data for time points T1 or T2