Gujral et al. (2001): Efficacy of hydrolytic enzymes in preventing radiation therapy-induced side effects in patients with head and neck cancers

Reference ↗
Title	Efficacy of hydrolytic enzymes in preventing radiation therapy-induced side effects in patients with head and neck cancers
Topic	Enzymes (bromelain papain)
Author	Gujral, MS, Patnaik, PM, Kaul, R, Parikh, HK, Conradt, C, Tamhankar, CP, Daftary, GV
Year	2001
Journal	Cancer Chemotherapy and Pharmacology
DOI	https://doi.org/10.1007/s002800170005

Brief summary

This study included 100 patients with head and neck cancer who received radiotherapy. One arm of 53 people also received enzyme therapy in tablet form (10mg papain, 40mg trypsin, 40mg chymotrypsin), which was taken during radiotherapy. A further arm of 47 people, on the other hand, received no other therapy or medication apart from the planned radiotherapy. The question of this study is whether the additional enzyme intake can reduce the side effects of radiotherapy in the head and neck area. Typical side effects of radiotherapy are inflammation of the mucous membranes, skin reactions and swallowing disorders. On the one hand, the maximum severity of the side effects and how high they were over the study period is analysed. The study describes graphically that the side effects in patients with additional enzyme intake increase more slowly and later, are less severe and also subside significantly earlier. Based on their results, the authors suggest that the enzymes play a role in reducing side effects in head and neck cancer. This study makes a comparison with patients who do not receive any additional treatment, so that the placebo effect may also have an influence. It is also noticeable that the number of patients varies in the different analyses. In some cases this is explained, but in others there is no explanation.

In dieser Studie wurden 100 Patienten mit Krebs im Kopf-Hals Bereich eingeschlossen, welche eine Strahlentherapie erhielten. Ein Arm mit 53 Personen erhielt dabei zusätzlich eine Enzymtherapie in Tablettenform (10mg Papain, 40mg Trypsin, 40mg Chymotrypsin), die während der Bestrahlung eingenommen wurde. Ein weiterer Arm mit 47 Personen erhielt hingegen, außer der vorgesehenen Strahlentherapie, keine weitere Therapie oder Medikamente. Die Fragestellung dieser Studie ist nun, ob durch die zusätzliche Enzymeinnahme die Nebenwirkungen der Strahlentherapie im Kopf-Hals-Bereich gemindert werden können. Typische Nebenwirkungen der Strahlentherapie sind Schleimhautentzündungen, Hautreaktionen und Schluckstörungen. Zum einen wird ausgewertet, welche maximale Stärke die Nebenwirkungen erreicht haben und wie hoch sie über den Studienzeitraum waren. Grafisch wird in der Studie beschrieben, dass die Nebenwirkungen bei den Patienten mit zusätzlicher Enzymeinnahme langsamer und später ansteigen, weniger hoch ausfallen und auch deutlich früher abklingen. Die Autoren sprechen aufgrund ihrer Ergebnisse davon, dass die Enzyme eine Rolle zur Reduzierung von Nebenwirkungen bei Krebs im Kopf- und Halsbereich spielen. Diese Studie zieht einen Vergleich mit Patienten, die gar keine zusätzliche Behandlung erhalten, sodass möglicherweise auch der Placeboeffekt einen Einfluss haben kann. Zudem fällt auf, dass in den verschiedenen Auswertungen die Anzahl der Patienten variiert. In manchen Fällen wird dies erklärt, zum Teil gibt es jedoch keine Begründungen.

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	2

Study characteristics

Inclusion criteria	Biopsy-proven squamous cell carcinoma of the head and neck: oral cavity or oropharynx staged T1-T3 at subsites, alveolo-buccal, oral tongue, base of tongue, epiglottis/vallecula, tonsil and pharyngeal wall (lateral or posterior); previous chemotherapy was allowed
Exclusion criteria	Prior radiation therapy; patients with distant metastasis, Kornovsky Index <70; altered hematological or biochemical parameters
N randomized	100
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.	PP Analysis, ITT Analysis
Specifications on analyses	Primary endpoints: all patients were analysed (ITT), secondary endpoints: just 93 patients were analysed (PP)
Countries of data collection	India
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: weekly for 8 weeks during radiation Follow up 1: 6-8 weeks after end of radiation Follow-up 2: 2-3 month after end of radiation Follow-up 3: 5-6 month after end of radiation

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	Head and Neck Cancers
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	Enzyme-arm: T-Stage 0=2 T-Stage 1=1 T-Stage 2=26 T-Stage 3=13 T-Stage 4=11 Control-arm: T-Stage 0=4 T-Stage 1=3 T-Stage 2=18 T-Stage 3=8 T-Stage 4=14 Enzyme-arm: N-Stage 0=17 N-Stage 1=23 N-Stage 2=10 N-Stage 3=2 N-Stage x=1 Control-arm: N-Stage 0=18 N-Stage 1=18 N-Stage 2=11 N-Stage 3=0 N-Stage x=0 Site of disease per arm: Alveolo-buccal: Enyzme-arm=21; control-arm=23 Tongue: Enzyme-arm=19; control-arm=19 Others: Enzyme-arm=13; control-arm=12
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	All patients received 50 to 70 Gy telecobalt therapy using a standard daily radiation dose of 2 Gy in 25-35 fractions over a period of 6-7 weeks
Previous cancer therapies	Chemotherapy, NI
Gender	Mixed
Gender specifications	Gender per arm: Enzyme-arm: male= 34(64%); female= 16(36%) Control-arm: male= 35(74%); female= 12(26%)
Age groups	Adults (18+)
Age groups specification	Mean age (SD) per arm: Enzyme-arm: 50.3 (9.4) years Control-arm: 51.2 (11.2) 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	53
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	Personal reasons (n=1); died after the end of radiation (n=2)
Intervention	Enzyme
Dosage and regime	3x3 tablets WOBE-MUGOS E (10mg papain, 40mg trypsin, 40mg chymotrypsin) daily, starting 3 days before the first radiotherapy treatment over a period of 54(+/-9) days until 5 days after completion of radiation therapy + all patients received 50 to 70 Gy telecobalt therapy using a standard daily radiation dose of 2 Gy in 25-35 fractions over a period of 6-7 weeks
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.	54
Side effects / Interactions	Pain, fever, weakness, vomiting, itching, swelling, haemoptysis; no difference between the arms (p=kA) Radiation therapy gaps: 9 patients from the Enzyme-arm because of social/technical problems

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	47
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	1
Drop-out reasons	Personal reasons (n=1)
Intervention	No additional intervention
Dosage and regime	+ all patients received 50 to 70 Gy telecobalt therapy using a standard daily radiation dose of 2 Gy in 25-35 fractions over a period of 6-7 weeks
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.	49
Side effects / Interactions	Pain, fever, weakness, vomiting, itching, swelling, haemoptysis; no difference between the arms (p=kA) Radiation therapy gaps: 3 gaps because of social/technical problems; in 2 patients in the control-arm, radiation had to be temporarily discontinued due to severe radiation therapy-related reactions

Outcomes

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Mucositis Maximum extent: Evaluation for tissue responses for acute radiation side effects by grading mucositis at each visit Grade of mucosits: 0 = nil 1 = mild 2 = moderate 3 = severe Evaluation was continued at weekly intervals for 6 to 8 weeks covering the period of radiation therapy, and for another 5 to 6 month after the end of radiation therapy. The maximum score for the respective observation time were recorded. Grading was always done be the same investigator.
Type of measurement	Toxicity criteria of RTOG (Radiation Therapy Oncology Group) and EORTC (European Organization for Research and Treatment of Cancer)
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".	The maximum extent of acute radiation side effects such as mucositis was significantly lower in the enzyme-arm than in the control-arm (p<0.0001): Enzyme-arm = 1.32(0.64); control-arm =2.24 (0.60). Mucosal reactions were graded about one grade lower and the number of patients with severe mucositis was considerably less: Numbers of patients per grade: Enzyme-arm: Grade 0 = 2; Grade 1 = 35; Grade 2 = 13; Grade 3 = 3 Control-arm: Grade 0 = 0; Grade 1 = 4; Grade 2 = 27; Grade 3 = 15

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	?

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Skin reaction Maximum extent: Evaluation for tissue responses for acute radiation side effects by grading skin reactions at each visit Grade of skin reaction: 0 = nil 1 = erythema 2 = early desquamation/pigmentation 3 = moderate dry/ early moist desquamation 4 = blister formation/ skin peel Evaluation was continued at weekly intervals for 6 to 8 weeks covering the period of radiation therapy, and for another 5 to 6 month after the end of radiation therapy. The maximum score for the respective observation time were recorded. Grading was always done be the same investigator.
Type of measurement	Toxicity criteria of RTOG (Radiation Therapy Oncology Group) and EORTC (European Organization for Research and Treatment of Cancer)
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".	NA
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 none of the patients of the enzyme-arm were skin reactions of grade 4. The difference between the two arms was statistically significant (p<0.0001): Enzyme-arm: 1.23(0.75); control-arm: 2.39(1.10) Numbers of patients per grade: Enzyme-arm: Grade 1 = 8; Grade 2 = 27; Grade 3 = 16; Grade 4 = 2 Control-arm: Grade 1 = 0; Grade 2 = 11; Grade 3 = 17; Grade 4 = 11

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	?

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Dysphagia Maximum extent: Evaluation for tissue responses for acute radiation side effects by grading dysphagia at each visit Grade of dysphagia: 0 = nil 1 = for solids 2 = for semisolids 3 = for liquids 4 = requiring ryles tube/feeding gastrostomy Evaluation was continued at weekly intervals for 6 to 8 weeks covering the period of radiation therapy, and for another 5 to 6 month after the end of radiation therapy. The maximum score for the respective observation time were recorded. Grading was always done be the same investigator.
Type of measurement	Toxicity criteria of RTOG (Radiation Therapy Oncology Group) and EORTC (European Organization for Research and Treatment of Cancer)
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".	NA
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".	The difference between the arms was statistically significant (p<0.0001): Enzyme-arm: 1.33(0.63); Control-arm:2.24 (0.60). The number of patients with severe problems in swallowing was considerably less. Numbers of patients per grade: Enzyme-arm: Grade 0 = 0; Grade 1 = 37; Grade 2 = 12; Grade 3 = 4; Grade 4 = 0 Control-arm: Grade 0 = 0; Grade 1 = 5; Grade 2 = 29; Grade 3 = 12; Grade 4 = 0

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	?

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Area under curve Secondary criteria for efficacy were the areas under the curves in graphs for muscositis, skin reactions and dysphagia after commencement of radiation therapy. "Area under the curve" indicates the average score for muscositis, skin reactions and dysphagia; only patients with complete data set: Enzyme-arm: N=50, control-arm: N=43
Type of measurement	Toxicity criteria of RTOG (Radiation Therapy Oncology Group) and EORTC (European Organization for Research and Treatment of Cancer)
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".	The average score for mucositis, skin reactions and dysphagia was lower in the enzyme-arm than in the control-arm, the differences between the arms are statistically significant. Mucositis: Enzyme-arm = 5.4(3.6); control-arm = 10.2(3.6), p=0.0001 Skin reactions: Enzyme-arm = 3.9(2.9); control-arm = 9.5(3.9), p=0.0001 Dysphagia: Enzyme-arm = 5.2(3.4); control-arm = 10.1(3.6), p=0.0001

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	?

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Onset of grade II side effects Secondary criteria for efficacy was the time to reach a certain grade after commencement of radiation therapy; only patients with complete data set: Enzyme-arm: N=50, control-arm: N=43
Type of measurement	Toxicity criteria of RTOG (Radiation Therapy Oncology Group) and EORTC (European Organization for Research and Treatment of Cancer)
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".	The same grade of mucositis, skin reactions and dysphagia was reached later in patients from the enzyme-arm, the differences between the arms were statistically significant. Mucositis grade 2: Enzyme-arm = 6.9(0.8) weeks; control-arm = 5.7(1.2) weeks, p=0.0014 Skin reactions grade 2: Enzyme-arm = 6.6(1.6) weeks; control-arm = 5.7(1.4) weeks, p=0.0048 Dysphagia Grade 1/2: Enzyme-arm = 5.2/7.3(1.5/0.8) weeks; control-arm = 3.6/6.1(0.5/1.3), p=0.0092/0.0064

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	Secondary
Outcome specification	Disease response at the end of radiation (after 8 weeks)
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: no evaluation N=3, complete/good response in N=32/16, moderate response N=1, poor/no response/progress N=1 Control-arm: no evaluation N=4, complete/good response N=23/15, moderate response N=5, poor/no response/progress N=0, but arm difference is not statistically significant (p=0.23)

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	Secondary
Outcome specification	Therapy result 5-6 months after completion of radiotherapy (at Follow-up 3)
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".	In both arms a comparable rate of complete and partial remissions was observed, but the proportion of patients with complete regression was slightly higher in the enzyme-arm.

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 "The authors thank Dr. W. Schiess (Mucos Pharma Geretsried, Germany) for his contributions during study conduct and manuscript preparation"

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
• Bonferroni Holm correction for multiple testing applied
• Detailed specification of baseline criteria
• Verification of patient compliance (tablet count)
• Follow-up performed (even if high attrition)

CONTRA:

• No blinding
• No placebo group, although it would have been easy to implement
• In the analyses, the number of patients differed, sometimes with an associated explanation and sometimes without
• Only one individual carried out all analyses