Trial Outcomes & Findings for Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency (NCT NCT01327703)

Last Updated: 2014-04-10

Results Overview

Percent CFA was calculated as (\[fat intake - fat excretion\]/fat intake)\*100, determined in the stools which were collected over a 3-day period (Day 12 to morning of Day 15) during each treatment period. Least squares mean percent (%) CFA was calculated for Day 12 to Day 15 in first and second treatment periods. Percent CFA was based on log transformed data.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

87 participants

Primary outcome timeframe

Day 12 up to Day 15 in first and second treatment periods

Results posted on

2014-04-10

Participant Flow

Participant milestones

Participant milestones
Measure	Panzytrat® First, Then Kreon® Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in first treatment period followed by Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in second treatment period. Stabilized dose for a participant was the optimal dose determined during a qualification phase that preceded the first treatment period and was based upon the participant's usual lipase and lipid intake and total dose was not to exceed 10,000 European Pharmacopoeia (Ph.Eur.) units lipase/kilogram (kg) body weight/day.	Kreon® First, Then Panzytrat® Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in first treatment period followed by Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in second treatment period. Stabilized dose for a participant was the optimal dose determined during a qualification phase that preceded the first treatment period and was based upon the participant's usual lipase and lipid intake and total dose was not to exceed 10,000 Ph.Eur. units lipase/kg body weight/day.
First Treatment Period STARTED	42	45
First Treatment Period COMPLETED	42	45
First Treatment Period NOT COMPLETED	0	0
Second Treatment Period STARTED	40	44
Second Treatment Period COMPLETED	39	42
Second Treatment Period NOT COMPLETED	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Panzytrat® First, Then Kreon® Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in first treatment period followed by Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in second treatment period. Stabilized dose for a participant was the optimal dose determined during a qualification phase that preceded the first treatment period and was based upon the participant's usual lipase and lipid intake and total dose was not to exceed 10,000 European Pharmacopoeia (Ph.Eur.) units lipase/kilogram (kg) body weight/day.	Kreon® First, Then Panzytrat® Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in first treatment period followed by Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in second treatment period. Stabilized dose for a participant was the optimal dose determined during a qualification phase that preceded the first treatment period and was based upon the participant's usual lipase and lipid intake and total dose was not to exceed 10,000 Ph.Eur. units lipase/kg body weight/day.
Second Treatment Period Adverse Event	1	1
Second Treatment Period Protocol Violation	0	1

Baseline Characteristics

Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Entire Study Population n=87 Participants Includes randomized participants who received Panzytrat® 25,000 first and Kreon® 25,000 first.
Age, Continuous	13.6 years STANDARD_DEVIATION 6.14 • n=5 Participants
Sex: Female, Male Female	34 Participants n=5 Participants
Sex: Female, Male Male	53 Participants n=5 Participants
Nutritional status as assessed by Vitamin A and E level Vitamin A (n=87)	1.403 micromole/liter (mcmol/L) STANDARD_DEVIATION 0.5329 • n=5 Participants
Nutritional status as assessed by Vitamin A and E level Vitamin E (Alpha-Tocopherol) (n=87)	18.554 micromole/liter (mcmol/L) STANDARD_DEVIATION 8.9713 • n=5 Participants
Nutritional status as assessed by Vitamin A and E level Vitamin E (Beta-Gamma-Tocopherol) (n=83)	1.231 micromole/liter (mcmol/L) STANDARD_DEVIATION 2.0781 • n=5 Participants
Nutritional status as assessed by Vitamin D level	55.4 nanomole/L (nmol/L) STANDARD_DEVIATION 33.24 • n=5 Participants

PRIMARY outcome

Timeframe: Day 12 up to Day 15 in first and second treatment periods

Population: Per protocol population included all randomized participants who completed both treatment periods and had all bowel movements appropriately collected with no major protocol violations/deviations or other events considered to potentially bias the study evaluations.

Outcome measures

Outcome measures
Measure	Panzytrat® n=38 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=38 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Percent Coefficient of Fat Absorption (CFA)	78.27 percent CFA Standard Error 1.033	80.35 percent CFA Standard Error 1.033

SECONDARY outcome

Timeframe: Day 12 up to Day 15 in first and second treatment periods

Population: Intent-to-treat (ITT) population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.

Mean daily number of stools of each participant was calculated from frequency of stools by the participant per day. Mean daily number of stools during the collection period (Day 12 to Day 15 in first and second treatment periods) for total participants was summarized.

Outcome measures

Outcome measures
Measure	Panzytrat® n=85 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=84 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Mean Daily Number of Stools	4.5 stools per day Standard Deviation 2.43	4.2 stools per day Standard Deviation 2.14

SECONDARY outcome

Timeframe: Day 12 up to Day 15 in first and second treatment periods

Population: ITT population included all randomized participants. Here, 'N' (number of participants analyzed) specify signifies those participants who were evaluable for this outcome measure.

Normal consistency of stool was defined as formed hard, normal or soft stool and abnormal consistency was defined as loose and unformed, liquid stool and diarrhea. Percentage of stools with normal consistency of each participant was calculated as the number of stools with normal consistency relative to the total number of stools during the collection period. Mean percentage of stool with normal consistency during the collection period (Day 12 to Day 15 in first and second treatment periods) for total participants was summarized.

Outcome measures

Outcome measures
Measure	Panzytrat® n=83 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=83 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Percentage of Stools With Normal Consistency	0.644 percentage of stools Standard Deviation 0.3442	0.635 percentage of stools Standard Deviation 0.3517

SECONDARY outcome

Timeframe: Day 12 up to Day 15 in first and second treatment periods

Population: ITT population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who had 1 or more bowel movements over the 72-hour collection period.

Mean total weight of stools was calculated for Day 12 to Day 15 in first and second treatment periods.

Outcome measures

Outcome measures
Measure	Panzytrat® n=85 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=84 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Total Weight of Stools	521.6 gram Standard Deviation 301.95	484.0 gram Standard Deviation 326.81

SECONDARY outcome

Timeframe: Day 12 up to Day 15 in first and second treatment periods

Mean weight per stool sample was calculated for Day 12 to Day 15 in first and second treatment periods.

Outcome measures

Outcome measures
Measure	Panzytrat® n=83 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=82 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Mean Weight Per Stool Sample	131.7 gram Standard Deviation 79.67	124.0 gram Standard Deviation 81.71

SECONDARY outcome

Timeframe: Day 1 up to Day 15 in first and second treatment periods

Population: ITT population included all randomized participants. Here, 'N' specifies number of participants who were evaluable for this outcome measure and 'n' specifies the number of participants with at least one report of the symptom at that severity level during a treatment period.

Abdominal symptoms included abdominal pain and flatulence. Symptoms were classified by severity as mild (no impairment of daily activities), moderate (slight impairment of daily activities), or severe (unable to perform daily activities). For each type of abdominal symptom, the relative frequency of days with the symptom for each participant in a treatment period was calculated as the number of days in which the symptom was reported divided by the total number of days in which the abdominal symptom case report form (CRF) was completed. Mean relative frequency of days with abdominal symptoms was calculated during each treatment period (Day 1 to Day 15).

Outcome measures

Outcome measures
Measure	Panzytrat® n=86 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=85 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Relative Frequency of Days With Abdominal Symptoms Moderate abdominal pain (n=37, 39)	0.434 days Standard Deviation 0.2496	0.374 days Standard Deviation 0.2269
Relative Frequency of Days With Abdominal Symptoms Severe abdominal pain (n=14, 12)	0.429 days Standard Deviation 0.2646	0.400 days Standard Deviation 0.2741
Relative Frequency of Days With Abdominal Symptoms Flatulence (n=86, 85)	0.365 days Standard Deviation 0.3215	0.329 days Standard Deviation 0.3290
Relative Frequency of Days With Abdominal Symptoms Mild flatulence (n=67, 61)	0.467 days Standard Deviation 0.2912	0.459 days Standard Deviation 0.3018
Relative Frequency of Days With Abdominal Symptoms Moderate flatulence (n=35, 40)	0.351 days Standard Deviation 0.2649	0.577 days Standard Deviation 0.2806
Relative Frequency of Days With Abdominal Symptoms Severe flatulence (n=20, 13)	0.616 days Standard Deviation 0.2959	0.554 days Standard Deviation 0.1968
Relative Frequency of Days With Abdominal Symptoms Abdominal pain (n=86, 85)	0.227 days Standard Deviation 0.2500	0.216 days Standard Deviation 0.2251
Relative Frequency of Days With Abdominal Symptoms Mild abdominal pain (n=58, 57)	0.302 days Standard Deviation 0.2440	0.308 days Standard Deviation 0.2199

SECONDARY outcome

Timeframe: Day 1 up to Day 15 in first and second treatment periods

Population: ITT population included all randomized participants. Here, 'N' specifies number of participants who had abdominal distension assessment at screening and end of specified treatment.

Abdominal distension is a sense of increased abdominal pressure by the participant that involves an actual measurable change in the circumference of a participant's abdomen on physical examination. Percentage of participants with abdominal distension was calculated for each treatment period (Day 1 to Day 15).

Outcome measures

Outcome measures
Measure	Panzytrat® n=86 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=85 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Percentage of Participants With Abdominal Distension	12.8 percentage of participants	11.8 percentage of participants

SECONDARY outcome

Timeframe: Day 12 up to Day 15 in first and second treatment periods

Population: Per protocol population. Here, 'n' specifies number of participants who were evaluable for specific categories for each arm group, respectively.

Outcome measures

Outcome measures
Measure	Panzytrat® n=38 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=38 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Percent Coefficient of Fat Absorption (CFA) Based on Concomitant Use of Proton Pump Inhibitors (PPIs) PPIs not used (n=31, 31)	80.89 percent CFA Standard Error 1.037	79.24 percent CFA Standard Error 1.037
Percent Coefficient of Fat Absorption (CFA) Based on Concomitant Use of Proton Pump Inhibitors (PPIs) PPIs used (n=7, 7)	79.66 percent CFA Standard Error 1.071	94.29 percent CFA Standard Error 1.071

SECONDARY outcome

Timeframe: Baseline up to 30 days after last dose

Population: Safety population included all randomized participants who received at least 1 dose of study medication. Here, 'N' (number of participants analyzed) specifies number of participants who were evaluable for this measure.

An AE was defined as any untoward medical occurrence regardless of its causal relationship to study drug. A TEAE was defined as any event not present prior to exposure to study drug or any event already present that worsens in either intensity or frequency following exposure to test drug. A SAE was defined as any event that results in death, is immediately life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect or is assessed as medically important.

Outcome measures

Outcome measures
Measure	Panzytrat® n=86 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=85 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) AEs	32 participants	20 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) SAEs	0 participants	0 participants

SECONDARY outcome

Timeframe: Baseline, end of treatment (within 3 days after Day 15 of first and second treatment periods) or early discontinuation

Population: Safety population included all randomized participants who received at least 1 dose of study drug. Here, 'N' specifies number of participants who were evaluable for this outcome measure.

Mean body weight was calculated at end of treatment (within 3 days after Day 15 of first and second treatment periods).

Outcome measures

Outcome measures
Measure	Panzytrat® n=86 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=85 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Nutritional Status as Assessed by Body Weight Baseline	40.82 kg Standard Deviation 16.001	41.43 kg Standard Deviation 15.861
Nutritional Status as Assessed by Body Weight End of treatment	41.22 kg Standard Deviation 15.999	41.88 kg Standard Deviation 15.886

SECONDARY outcome

Timeframe: Baseline, end of treatment (within 3 days after Day 15 of first and second treatment periods) or early discontinuation

Population: Safety population included all randomized participants who received at least 1 dose of study drug. Here, 'N' specifies number of participants who were evaluable for this outcome measure.

Nutritional status of participants was assessed by determining their BMI. BMI was calculated by dividing body weight (kg) by square of height in meter (m). Mean BMI was calculated at end of treatment (within 3 days after Day 15 of first and second treatment periods).

Outcome measures

Outcome measures
Measure	Panzytrat® n=85 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=85 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Nutritional Status as Assessed by Body Mass Index (BMI) Baseline	17.84 kg/m^2 Standard Deviation 3.296	17.90 kg/m^2 Standard Deviation 3.264
Nutritional Status as Assessed by Body Mass Index (BMI) End of treatment	17.94 kg/m^2 Standard Deviation 3.244	18.01 kg/m^2 Standard Deviation 3.240

SECONDARY outcome

Timeframe: Baseline, end of treatment (within 3 days after Day 15 of first and second treatment periods) or early discontinuation

Population: Safety population included all randomized participants who received at least 1 dose of study drug. Here, 'N' specifies number of participants who were evaluable for this outcome measure and 'n' specifies number of participants who were evaluable for specific categories at each time point for each arm group, respectively.

Nutritional status of participants was assessed by determining their electrolytes (sodium, potassium and chloride) level. Mean electrolytes level was calculated at end of treatment (within 3 days after Day 15 of first and second treatment periods).

Outcome measures

Outcome measures
Measure	Panzytrat® n=42 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=43 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Nutritional Status as Assessed by Electrolytes Level Sodium: Baseline (n=42, 43)	138.41 millimole/L (mmol/L) Standard Deviation 3.026	138.54 millimole/L (mmol/L) Standard Deviation 3.356
Nutritional Status as Assessed by Electrolytes Level Sodium: End of treatment (n=42, 43)	139.11 millimole/L (mmol/L) Standard Deviation 2.350	139.07 millimole/L (mmol/L) Standard Deviation 2.466
Nutritional Status as Assessed by Electrolytes Level Potassium: Baseline (n=42, 42)	4.441 millimole/L (mmol/L) Standard Deviation 0.4799	4.371 millimole/L (mmol/L) Standard Deviation 0.3721
Nutritional Status as Assessed by Electrolytes Level Potassium: End of treatment (n=42, 42)	4.322 millimole/L (mmol/L) Standard Deviation 0.4113	4.344 millimole/L (mmol/L) Standard Deviation 0.3506
Nutritional Status as Assessed by Electrolytes Level Chloride: Baseline (n=38, 40)	102.08 millimole/L (mmol/L) Standard Deviation 3.436	101.40 millimole/L (mmol/L) Standard Deviation 3.193
Nutritional Status as Assessed by Electrolytes Level Chloride: End of treatment (n=38, 40)	102.13 millimole/L (mmol/L) Standard Deviation 2.796	102.18 millimole/L (mmol/L) Standard Deviation 2.541

SECONDARY outcome

Timeframe: Baseline, end of treatment (within 3 days after Day 15 of first and second treatment periods) or early discontinuation

Nutritional status of participants was assessed by determining their albumin, serum transferrin and hemoglobin level. Mean albumin, serum transferrin and hemoglobin level was calculated at end of treatment (within 3 days after Day 15 of first and second treatment periods).

Outcome measures

Outcome measures
Measure	Panzytrat® n=42 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=42 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Nutritional Status as Assessed by Albumin, Serum Transferrin and Hemoglobin Level Albumin: Baseline (n=41, 42)	40.553 gram/L (g/L) Standard Deviation 11.3568	37.995 gram/L (g/L) Standard Deviation 14.8405
Nutritional Status as Assessed by Albumin, Serum Transferrin and Hemoglobin Level Albumin: End of treatment (n=41, 42)	40.785 gram/L (g/L) Standard Deviation 11.1893	37.991 gram/L (g/L) Standard Deviation 14.9636
Nutritional Status as Assessed by Albumin, Serum Transferrin and Hemoglobin Level Serum transferrin: Baseline (n=40, 41)	2.877 gram/L (g/L) Standard Deviation 0.9769	2.618 gram/L (g/L) Standard Deviation 1.1857
Nutritional Status as Assessed by Albumin, Serum Transferrin and Hemoglobin Level Serum transferrin: End of treatment (n=40, 41)	2.916 gram/L (g/L) Standard Deviation 0.9416	2.626 gram/L (g/L) Standard Deviation 1.1618
Nutritional Status as Assessed by Albumin, Serum Transferrin and Hemoglobin Level Hemoglobin: Baseline (n=42, 42)	137.337 gram/L (g/L) Standard Deviation 11.7570	141.118 gram/L (g/L) Standard Deviation 11.4577
Nutritional Status as Assessed by Albumin, Serum Transferrin and Hemoglobin Level Hemoglobin: End of treatment (n=42, 42)	137.935 gram/L (g/L) Standard Deviation 11.4543	141.263 gram/L (g/L) Standard Deviation 11.4412

SECONDARY outcome

Timeframe: Baseline, end of treatment (within 3 days after Day 15 of first and second treatment periods) or early discontinuation

Population: Safety population included all randomized participants who received at least 1 dose of study drug. Here, 'N' specifies number of participants who were evaluable for this outcome measure.

Nutritional status of participants was assessed by determining their hematocrit level. Mean hematocrit level was calculated at end of treatment (within 3 days after Day 15 of first and second treatment periods).

Outcome measures

Outcome measures
Measure	Panzytrat® n=42 Participants Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=42 Participants Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Nutritional Status as Assessed by Hematocrit Level Baseline	0.408 proportion of hematocrit Standard Deviation 0.0324	0.417 proportion of hematocrit Standard Deviation 0.0333
Nutritional Status as Assessed by Hematocrit Level End of treatment	0.409 proportion of hematocrit Standard Deviation 0.0311	0.416 proportion of hematocrit Standard Deviation 0.0328

Adverse Events

Panzytrat®

Serious events: 0 serious events

Other events: 32 other events

Deaths: 0 deaths

Kreon®

Serious events: 0 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Robert Winkler, MD, VP, Clinical Development and Operations

Aptalis Pharma US, Inc.

Phone: 1-800-472-2634

Results disclosure agreements

Principal investigator is a sponsor employee Restrictions vary in accordance with each agreement with the individual investigators. Sponsor will allow publication after a multi-center publication has been published or after an agreed period of time if no such multi-center publication is submitted for publication. Sponsor can ask that Sponsor's confidential information be removed from any publication and can defer publication for a period of time to allow for Sponsor to obtain patent or other intellectual property right protection.
Publication restrictions are in place

Restriction type: OTHER

Measure	Panzytrat® n=86 participants at risk Panzytrat® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.	Kreon® n=85 participants at risk Kreon® 25,000 capsule orally daily at a stabilized dose, as per investigator's discretion, for 14 days in either first treatment period or second treatment period.
Gastrointestinal disorders Flatulence	17.4% 15/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	7.1% 6/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Gastrointestinal disorders Abdominal pain	12.8% 11/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	10.6% 9/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Gastrointestinal disorders Diarrhoea	2.3% 2/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Gastrointestinal disorders Vomiting	2.3% 2/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Infections and infestations Upper respiratory tract infection	3.5% 3/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Infections and infestations Nasopharyngitis	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	1.2% 1/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Infections and infestations Rhinitis	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	1.2% 1/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Infections and infestations Gastrointestinal infection	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Infections and infestations Infective pulmonary exacerbation of cystic fibrosis	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Infections and infestations Pharyngitis	0.00% 0/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	1.2% 1/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Infections and infestations Varicella	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.3% 2/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	1.2% 1/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Respiratory, thoracic and mediastinal disorders Cough	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Respiratory, thoracic and mediastinal disorders Epistaxis	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Respiratory, thoracic and mediastinal disorders Sputum increased	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
General disorders Pyrexia	2.3% 2/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	2.4% 2/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Nervous system disorders Headache	2.3% 2/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	1.2% 1/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Investigations Pseudomonas test positive	0.00% 0/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	1.2% 1/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Investigations Vitamin A decreased	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Eye disorders Conjunctivitis	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Musculoskeletal and connective tissue disorders Neck pain	1.2% 1/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	0.00% 0/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.
Vascular disorders Haematoma	0.00% 0/86 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.	1.2% 1/85 • Baseline up to 30 days after last dose Adverse event (AE) was any untoward medical occurrence regardless of causal relationship to study drug. Serious AE was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity, or was a congenital anomaly/birth defect. Participants at risk: Panzytrat®=86 and Kreon®=85.