Revision as of 17:07, 26 August 2024

Reference ↗
Title	Unterstützung der Chemotherapie inoperabler Karzinome durch proteolytische Fermente
Topic	Enzymes (bromelain papain)
Author	Wrbka, E, Kodras, B
Year	1978
Journal	Wiener Medizinische Wochenschrift
DOI

Study Note

Brief summary

A total of 51 patients with various forms of lung cancer were included in this study. All patients included received the same radiotherapy. However, one arm with 25 patients also received enzyme therapy using klysms. The question of this study is whether this enzyme therapy can positively influence the tolerability of chemotherapy and even improve the success of the therapy. This means that either the quality of life improves while the radiological findings remain the same or the quality of life and radiological findings improve in equal measure. The results of the study show that there are fewer treatment cancellations in the enzyme-arm and that survival times and quality of life are higher in this arm. Unfortunately, these results were not further analysed statistically, only quantitative comparisons were made. However, the authors are in favour of enzyme therapy.

In dieser Studie werden insgesamt 51 Patienten mit verschiedenen Ausprägungen von Lungenkrebs eingeschlossen. Alle eingeschlossenen Patienten erhalten dabei die gleiche Strahlentherapie. Ein Arm mit 25 Patienten erhält jedoch zusätzlich eine Enzymtherapie mittels Klysmen. Die Fragestellung dieser Studie ist nun, ob diese Enzymtherapie die Verträglichkeit der Chemotherapie positiv beeinflussen kann und sogar den Erfolg der Therapie verbessert. Damit ist gemeint, dass entweder sich die Lebensqualität bei gleichbleibendem Röntgenbefund verbessert oder sich Lebensqualität und Röntgenbefund gleichermaßen verbessern. Die Ergebnisse der Studie sind, dass es zu weniger Therapieabbrüchen im Enzym-Arm kommt und die Überlebenszeiten und die Lebensqualität in diesem Arm höher sind. Leider sind diese Ergebnisse nicht weiter statistisch ausgewertet, sondern es sind nur quantitative Vergleiche gezogen worden. Die Autoren sprechen sich jedoch für eine Enzymtherapie aus.

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	?
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	2

Study characteristics

Inclusion criteria	Patients with untreated inoperable bronchopulmonary carcinomas of various entities
Exclusion criteria	?
N randomized	51
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 specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study
Countries of data collection	Austria
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: on average 2 weeks (1-4 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.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Lung 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	Early Stage, Advanced Stage
Specifications on cancer stages	51 Patients with untreated inoperable bronchopulmonary carcinomas of various entities: Enzyme-arm: stage II = 5; stage III = 6; stage IV = 15 Control-arm: stage II = 3; stage III = 6; stage IV = 16
Comorbidities	Concomitant diseases in 51 patients in enzyme-arm (E) and control-arm (C): Cardiopathy (temporarily decompensated): E = 5; C = 3 Inactive tuberculosis: E = 0; C = 1 Chronic duodenal ulcer: E = 1; C = 0 Renal cysts on both sides: E = 1; C = 0 Emphysema bronchitis: E = 1; C = 1 Diabetes mellitus: E = 1; C = 0 Alcoholic epilepsy: E = 0; C = 1 Previous carcinoma of another organ: E = 2; C = 2
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	Patients with untreated inoperable bronchopulmonary carcinomas of various entities; 4 out of 51 patients had previously undergone surgery or radiotherapy for carcinoma in another organ
Previous cancer therapies	No therapy, Surgery, Radiation therapy
Gender	Mixed
Gender specifications	Gender per arm: Enzyme-arm: male = 23 (84.6%); female = 2(15.4%) Control-arm: male = 22(92%); female = 4(8%)
Age groups	Adults (18+)
Age groups specification	Age groups per arm (n) Enzyme-arm: 41-50 = 1; 51-60 = 2; 61-70 = 10; 71-80 = 12 Control-arm: 41-50 = 0; 51-60 = 3; 61-70 = 11; 71-80 = 12

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	25
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NI
Drop-out reasons	NI
Intervention	Enzyme
Dosage and regime	2x daily Wobe Mugos microclysms, 5g each, for 1 to 4 weeks (average 2 weeks) and further outpatient treatment with dragees + all patients: Poly-chemotherapy (Fluoro-Uracil, Vinblastin, Metothrexat, Cyclophosphamid)
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.	14
Side effects / Interactions	Treatment with Wobe Mugos E: Tolerance of microclysms (67 patients in the evaluation): 87.3% of patients with good tolerance, 4 patients with sphincter weakness and limited ability to administer, 12.7% of patients with discontinuation due to gastrointestinal side effects Tolerance of dragées (58 patients in the evaluation): 71.4% of patients with good tolerance, 28.6% of patients with discontinuation; in 27% of patients, intake could not be assessed due to unauthorised discontinuation or incorrect information Tolerance of local intrapleural application (33 patients in the evaluation): 96.9% of patients with good tolerance, 3.1% of patients with discontinuation

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	26
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	NI
Drop-out reasons	NI
Intervention	No additional medication
Dosage and regime	+ All patients: Poly-chemotherapy (Fluoro-Uracil, Vinblastin, Metothrexat, Cyclophosphamid)
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.	14
Side effects / Interactions	NI

Outcomes

"Tolerability" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.

"Therapy success" is not in the list (Anorexia/Cachexia, Anxiety, Appetite, Cerebral oedema, Cognitive functioning, Cognitive impairment, Depression, Dermatitis, Distress, Dysgeusia, ...) of allowed values for the "Outcome name" property.

Tumor response

Outcome type As specificed by the authors	Primary
Outcome specification	Interaction with cancer treatment Tolerance of cytostatic therapy/survival time (reference date 30 September 1977) regarding side effects and the infusions administered
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".	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".	Treatment discontinuations: There were 2 treatment discontinuations in the enzyme-arm and 9 treatment discontinuations in the control-arm due to more severe side effects such as leukocyte fall, apthae of the oral mucosa or increase in the BUN value. Patients with a survival time of more than 6 months are considered here (16 subjects): Enzyme-arm: 8 patients with an average of 11 infusions and a mean survival time of 20 months Control-arm: 8 patients with an average of 3.37 infusions and a mean survival time of 16.3 months; Distribution across all patients in both arms: Enzyme-arm = 6.88 infusions; Control-arm = 4.50 infusions

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	?

Tumor response

Outcome type As specificed by the authors	Primary
Outcome specification	Treatment success Based on the radiological findings and quality of life (improved if general condition increased and radiological findings remain the same or improved)
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".	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".	Enzyme-arm: 68% improvement compared to control-arm: 57.69% improvement

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	Primary
Outcome specification	Vitagramm: 4 qualities of life: 1. employable or able to work, free of complaints 2. care-free, only minor complaints 3. in need of care, more severe symptoms 4. bedridden and/or very severe discomfort
Type of measurement	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".	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".	In patients with survival > 6 months, more patients with better quality of life in enzyme-arm (n=8) compared to control-arm (n=8): (Class I, II enzyme-arm: 81.9% vs. control-arm: 73.3%); similar quality of life in patients with < 6 months survival

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	NI
Conflicts of Interest	NI

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: - CONTRA:

Results almost unusable, no baseline values, graphs barely legible, many different cancer entities despite small sample, monocentric? etc.
Only 16 patients in the evaluation of treatment success (even if this was unavoidable due to deaths)
No statistical group comparisons carried out
No information on the ethics vote

@@ Line 5: / Line 5: @@
 =Brief summary=
 A total of 51 patients with various forms of lung cancer were included in this study. All patients included received the same radiotherapy. However, one arm with 25 patients also received enzyme therapy using klysms. The question of this study is whether this enzyme therapy can positively influence the tolerability of chemotherapy and even improve the success of the therapy. This means that either the quality of life improves while the radiological findings remain the same or the quality of life and radiological findings improve in equal measure. The results of the study show that there are fewer treatment cancellations in the enzyme-arm and that survival times and quality of life are higher in this arm. Unfortunately, these results were not further analysed statistically, only quantitative comparisons were made. However, the authors are in favour of enzyme therapy.
 In dieser Studie werden insgesamt 51 Patienten mit verschiedenen Ausprägungen von Lungenkrebs eingeschlossen. Alle eingeschlossenen Patienten erhalten dabei die gleiche Strahlentherapie. Ein Arm mit 25 Patienten erhält jedoch zusätzlich eine Enzymtherapie mittels Klysmen. Die Fragestellung dieser Studie ist nun, ob diese Enzymtherapie die Verträglichkeit der Chemotherapie positiv beeinflussen kann und sogar den Erfolg der Therapie verbessert. Damit ist gemeint, dass entweder sich die Lebensqualität bei gleichbleibendem Röntgenbefund verbessert oder sich Lebensqualität und Röntgenbefund gleichermaßen verbessern. Die Ergebnisse der Studie sind, dass es zu weniger Therapieabbrüchen im Enzym-Arm kommt und die Überlebenszeiten und die Lebensqualität in diesem Arm höher sind. Leider sind diese Ergebnisse nicht weiter statistisch ausgewertet, sondern es sind nur quantitative Vergleiche gezogen worden. Die Autoren sprechen sich jedoch für eine Enzymtherapie aus.
@@ Line 23: / Line 24: @@
 |Inclusion criteria=Patients with untreated inoperable bronchopulmonary carcinomas of various entities
 |Exclusion criteria=?
-|N randomized=-999
+|N randomized=51
 |Analysis=ITT Analysis
-|Specifications on analyses=?
+|Specifications on analyses=The specific analysis method is not stated in the study, however, according to the authors, all included patients were evaluated at the end of the study
 |Countries of data collection=Austria
 |LoE=2b Oxford 2009
 |Outcome timeline=T0: Baseline
-T1:
+T1: on average 2 weeks (1-4 weeks)
 }}
 =Characteristics of participants=
@@ Line 38: / Line 39: @@
 |Stage cancer=Early Stage, Advanced Stage
 |Cancer stage specification=51 Patients with untreated inoperable bronchopulmonary carcinomas of various entities:
 Enzyme-arm:
 stage II = 5; stage III = 6; stage IV = 15
 Control-arm:
 stage II = 3; stage III = 6; stage IV = 16
-|Comorbidity=Concomitant diseases in 51 patients in enzyme-arm (E) and control-arm (C)
+|Comorbidity=Concomitant diseases in 51 patients in enzyme-arm (E) and control-arm (C):
 Cardiopathy (temporarily decompensated): E = 5; C = 3
 Inactive tuberculosis: E = 0; C = 1
@@ Line 53: / Line 54: @@
 Previous carcinoma of another organ: E = 2; C = 2
 |Current cancer therapy=Chemotherapy
-|Specifications on cancer therapies=Patients with untreated inoperable bronchopulmonary carcinomas of various entities
+|Specifications on cancer therapies=Patients with untreated inoperable bronchopulmonary carcinomas of various entities; 4 out of 51 patients had previously undergone surgery or radiotherapy for carcinoma in another organ
-|Previous cancer therapies=No therapy
+|Previous cancer therapies=No therapy, Surgery, Radiation therapy
 |Gender=Mixed
 |Gender specifications=Gender per arm:
@@ Line 76: / Line 77: @@
 |One-time application=No
 |Duration in days=14
-|Side Effects / Interactions=Treatment with Wobe Mogos E: 67 patients
+|Side Effects / Interactions=Treatment with Wobe Mogos E:
-patients with untreated inoperable bronchopulmonary carcinomas
-+16 patients with carcinomatous pleurisy
-+10 special cases
-Clysm = 67 patients; dragees = 58 patients; local = 33 patients
 Tolerance of microclysms (67 patients in the evaluation): 87.3% of patients with good tolerance, 4 patients with sphincter weakness and limited ability to administer, 12.7% of patients with discontinuation due to gastrointestinal side effects
-Tolerance Dragées (58 patients in the evaluation): 71.4% of patients with good tolerance, 28.6% of patients with discontinuation; in 27% of patients, intake could not be assessed due to unauthorised discontinuation or incorrect information
+Tolerance of dragées (58 patients in the evaluation): 71.4% of patients with good tolerance, 28.6% of patients with discontinuation; in 27% of patients, intake could not be assessed due to unauthorised discontinuation or incorrect information
-Tolerance of local intrapleural application (here 33 patients in the evaluation): 96.9% of patients with good tolerance, 3.1% of patients with discontinuation
+Tolerance of local intrapleural application (33 patients in the evaluation): 96.9% of patients with good tolerance, 3.1% of patients with discontinuation
 |Order number=1
 }}
 {{Arm
-|Arm type=?, Passive control
+|Arm type=Passive control
 |Number of participants (arm)=26
 |Drop-out=NI
@@ Line 99: / Line 94: @@
 |One-time application=No
 |Duration in days=14
-|Side Effects / Interactions=NA
+|Side Effects / Interactions=NI
 |Order number=2
 }}
@@ Line 108: / Line 103: @@
 |Outcome type=Primary
 |Outcome name=Tolerability
-|Outcome specification=Tolerance of cytostatic therapy/survival time (reference date 30 September 1977)
+|Outcome specification=Tolerance of cytostatic therapy/survival time (reference date 30 September 1977) regarding side effects and the infusions administered
 |Type of measurement=Observation
-|Results during intervention=NA
+|Results during intervention=NI
-|Results after intervention=Treatment discontinuations:There were 2 treatment discontinuations in the enzyme-arm and 9 treatment discontinuations in the control arm due to more severe side effects such as leukocyte fall, apthae of the oral mucosa or increase in the BUN value.
+|Results after intervention=Treatment discontinuations: There were 2 treatment discontinuations in the enzyme-arm and 9 treatment discontinuations in the control-arm due to more severe side effects such as leukocyte fall, apthae of the oral mucosa or increase in the BUN value.
 Patients with a survival time of more than 6 months are considered here (16 subjects):
@@ Line 117: / Line 112: @@
 Control-arm: 8 patients with an average of 3.37 infusions and a mean survival time of 16.3 months;
-Distribution across all patients in both arms: Enzyme-arm = 6.88 infusions; control-arm = 4.50 infusions
+Distribution across all patients in both arms: Enzyme-arm = 6.88 infusions; Control-arm = 4.50 infusions
 |Bias arising from the randomization process=?
 |Bias due to deviation from intended intervention (assignment to intervention)=?
@@ Line 131: / Line 126: @@
 |Outcome type=Primary
 |Outcome name=Quality of life
-|Outcome specification=?
+|Outcome specification=Vitagramm: 4 qualities of life:
-|Type of measurement=?
+. employable or able to work, free of complaints
-|Results during intervention=?
+. care-free, only minor complaints
-|Results after intervention=In patients with survival > 6 months, more patients with better quality of life than in enzyme-arm (N=8) compared to control-arm (N=8): (Class I, II Enzyme-arm: 81.9% vs. Control-arm: 73.3%); similar quality of life in patients with < 6 months survival
+. in need of care, more severe symptoms
+. bedridden and/or very severe discomfort
+|Type of measurement=Scale
+|Results during intervention=NI
+|Results after intervention=In patients with survival > 6 months, more patients with better quality of life in enzyme-arm (n=8) compared to control-arm (n=8): (Class I, II enzyme-arm: 81.9% vs. control-arm: 73.3%); similar quality of life in patients with < 6 months survival
 |Bias arising from the randomization process=?
 |Bias due to deviation from intended intervention (assignment to intervention)=?
@@ Line 148: / Line 147: @@
 |Outcome type=?
 |Outcome name=Therapy success
-|Outcome specification=?
+|Outcome specification=Treatment success based on the radiological findings and quality of life (improved if general condition increased and radiological findings remain the same or improved)
-|Type of measurement=?
+|Type of measurement=Observation
-|Results during intervention=?
+|Results during intervention=NA
-|Results after intervention=Enzyme-arm: 68% improvement compared to control-arm: 57.69% improvement, Carcinomatous pleuritis and special cases with indication are considered as a separate group. As there is no comparison group, the results are not reported here.
+|Results after intervention=Enzyme-arm: 68% improvement compared to control-arm: 57.69% improvement
 |Bias arising from the randomization process=?
 |Bias due to deviation from intended intervention (assignment to intervention)=?
@@ Line 172: / Line 171: @@
 {{Further points for assessing the study
+|power analysis performed=?
+|Sample size corresponds to power analysis=?
+|Reasons given for samples being too small according to power analysis=?
 |Samples sufficiently large=?
-|power analysis performed=?
-|reasons given for samples being too small according to power analysis=?
 |Ethnicity mentioned=?
+|Other explanations for an effect besides the investigated intervention=?
 |Possibility of attention effects=?
 |Possibility of placebo effects=?
 |Other reasons=?
-|Testing for normal distribution=?
+|Correct use of parametric and non-parametric tests=?
-|Correct application of statistical tests=?
 |Correction for multiple testing=?
 |Measurement of compliance=?
@@ Line 186: / Line 186: @@
 |Check whether blinding was successful=?
 |Consistent reporting in numbers=?
+|Comprehensive and coherent reporting=?
+|Cross-over=?
 |sufficient washout period=?
 |Tested for carry-over effects=?
 |Were sequence effects tested=?
-|Comprehensive and coherent reporting=?
+|Effect sizes reported=?
 |Were side effects systematically recorded=?
-|Effect sizes reported=?
 |Side effects taken into account in the interpretation of the results=?
+|Ethics / CoI / Funding=?
+|reasons given for samples being too small according to power analysis=?
+|Testing for normal distribution=?
+|Correct application of statistical tests=?
 |mono- or multicentric=?
-|Ethics / CoI / Funding=?
 }}
 {{Additional Notes