Study to Evaluate the Safety and Efficacy of EUR-1008 (APT-1008) Pancreatic Enzyme Product in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00297167
• Collaborator: (none)
• Enrollment: 34
• Location: 1
• Arms: 2
• Duration (Months): 6
• Patients Per Site Per Month: 5.6

Study Details

Study Description

Brief Summary

The primary efficacy objective of this study is to compare the coefficient of fat absorption (CFA) following oral administration of Aptalis Pharma's (formerly Eurand Pharmaceuticals) pancreatic enzyme product (PEP) capsules and placebo in participants with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI).

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis; Exocrine Pancreatic Insufficiency	Drug: EUR-1008 (APT-1008); Drug: Placebo; Drug: Placebo; Drug: EUR-1008 (APT-1008)	Phase 3

Detailed Description

This is a randomized, double-blind, placebo-controlled, 2-treatment, crossover, multicenter trial in participants with CF and EPI. The study consists of a screening period (1 to 14 days), a washout period (2 days), a dose titration/stabilization period (6 to 9 days), a blinded randomized treatment period (6 to 7 days), an open-label normalization period 1 (5 to 14 days), a blinded crossover treatment period (6 to 7 days), followed by an open-label normalization period 2 (7 days). The order of treatments (placebo followed by EUR-1008 [APT-1008] or EUR-1008 [APT-1008] followed by placebo) will be determined by randomization at the beginning of randomization treatment period only and will be carried through the crossover treatment period. The starting dose will be 1,000 lipase units per kilogram per meal (lipase units/kg/meal), which will be titrated to control symptoms of EPI, with the total dose not exceeding 10,000 lipase units/kg/day.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Two-Treatment, Crossover Study to Evaluate the Safety and Efficacy of Eurand Pancreatic Enzyme Product (PEP) in Patients With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Nov 1, 2006
• Actual Study Completion Date: Nov 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: EUR-1008 (APT-1008) First, Then Placebo	Drug: EUR-1008 (APT-1008); EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule will be given orally daily in first double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for first double-blind intervention period will be 2 days home treatment and 3 to 5 days hospital treatment.; Drug: Placebo; Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule will be given orally daily in second double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for second double-blind intervention period will be 2 days home treatment and 3 to 5 days hospital treatment.
Experimental: Placebo First, Then EUR-1008 (APT-1008)	Drug: Placebo; Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule will be given orally daily in first double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for first double-blind intervention period will be 2 days home treatment and 3 to 5 days hospital treatment.; Drug: EUR-1008 (APT-1008); EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule will be given orally daily in second double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for second double-blind intervention period will be 2 days home treatment and 3 to 5 days hospital treatment.

Outcome Measures

Primary Outcome Measures

1. Percent Coefficient of Fat Absorption (CFA%) [Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods]

   Percent CFA was calculated as ([fat intake - fat excretion]/fat intake)multiplied by 100, determined in the stools collected during the 72-hour hospitalization period. Mean percent CFA was calculated for Day 3 to Day 6 during hospital treatment in first and second double-blind (DB) intervention periods.

Secondary Outcome Measures

1. Percent Coefficient of Nitrogen Absorption (CNA%) [Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods]

   Percent CNA was calculated as ([nitrogen intake-nitrogen excretion]/nitrogen intake)*100, determined in the stools collected during the 72-hour hospitalization period. Nitrogen intake was calculated as protein intake/6.2. Nitrogen excretion was measured as total fecal nitrogen. Mean percent CNA was calculated for Day 3 to Day 6 during hospital treatment in first and second double-blind intervention periods.

2. Lipid Levels [End of treatment (Day 6 during first and second double-blind intervention periods)]

   Lipid levels were reported for total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) from fasted blood and urine samples. Mean lipid levels for Day 6 during first and second double-blind intervention periods were calculated.

3. Vitamin A Levels [End of treatment (Day 6 during first and second double-blind intervention periods)]

   Mean Vitamin A levels for Day 6 during first and second double-blind intervention periods were calculated.

4. Vitamin E Levels [End of treatment (Day 6 during first and second double-blind intervention periods)]

   Mean Vitamin E levels for Day 6 during first and second double-blind intervention periods were calculated.

5. Mean Daily Number of Stools [Day 3 up to Day 6 during first and second double-blind intervention periods]

   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 3 to Day 6 in first and second double-blind intervention periods) for total participants was summarized.

6. Percentage of Stool Categorized as Per Consistency [Day 3 up to Day 6 during first and second double-blind intervention periods]

   Stool consistency was categorized as hard, formed/normal, soft, watery, or overt diarrhea. Percentage of stools of a specific consistency for each participant at first and second double-blind intervention periods was calculated. Mean percentage of stool consistency during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized.

7. Mean Number of Abdominal Symptoms [Day 3 up to Day 6 during first and second double-blind intervention periods]

   Abdominal symptoms included abdominal pain, flatulence and bloating. 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). Mean number of symptom of specific severity per day for each participant was calculated. Mean number of symptoms per day was calculated for Day 3 to Day 6 in first and second double-blind intervention periods for total participants.

Other Outcome Measures

1. Percentage of Visible Oil or Grease in Stool [Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods]

   Mean percentage of stools with visible oil or grease during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized. Percentage was calculated as the number of stools with visible oil or grease divided by the total number of stool per day.

2. Percentage of Stools With Blood [Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods]

   Mean percentage of stools with blood during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized. Percentage was calculated as the number of stools with blood divided by the total number of stool per day.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants with age greater than or equal to (>=) 7 years at the time of enrollment

• Participants with weight 70 kg or less and be in an adequate nutritional status as indicated by a body mass index (BMI) >=20 kg/m^2 for ages 18 and above, or a BMI above the twenty fifth percentile for participants aged 7 to 17 years

• Participants with confirmed diagnosis of CF who have 2 clinical features consistent with CF, and have either a genotype with 2 identifiable mutations consistent with CF or a sweat chloride concentration that is more than 60 milliequivalent per liter by quantitative pilocarpine iontophoresis

• Participants with confirmed diagnosis of EPI who are currently receiving treatment with a commercially available PEP and have documented with a fecal elastase of <100 microgram per gram stool (if no documentation was available, a stool sample was taken at Screening for determination of fecal elastase).

• Clinically stable participants with no evidence of acute respiratory disease or any other acute condition

• Participants who are willing and able to interrupt current CF treatment for CF-related malabsorption along with any medications that may affect gastric motility or stomach power of hydrogen (pH)

• Participants 18 years of age and older had to a) understand the requirements of the study, b) provide written informed consent, c) agree to abide by the study restrictions, and d) return for the required assessments

• Participants 7 to 17 years of age must have a parent(s) or legal guardian who provides written informed consent, agree to abide by the study restrictions

• Females participants of childbearing potential must have a negative serum pregnancy test at screening and must agree to use adequate birth control during the study

Exclusion Criteria:

• Participants with fibrosing colonopathy, hyperuricemia or hyperuricosuria

• Participants who are allergic to pork or other porcine PEPs

• Participants with forced expiratory volume (FEV1) <30 percent of predicted FEV1 at screening

• Participants with any acute systemic administration of an antibiotic for any reason in the previous 4 weeks; however, a low stable dose of an antibiotic or chronic treatment with an inhalatory antibiotic is allowed

• Participants with hepatic insufficiency as defined by history or presence of ascites or serum albumin level of < 3.0 milligram/deciliter, or a coagulopathy with an international normalized ratio that is greater than 1.7

• Participants who have used an acute dose of any steroid in the previous 2 weeks; however, low chronic doses of a steroid is allowed

• Participants with history of or current diagnosis of distal ileal obstruction syndrome (DIOS) as evidenced or suggested by constipation, abdominal pain, anorexia, early satiety, recurrent vomiting, and palpable fecal mass on physical examination (the absence of DIOS will be confirmed by an X-ray of the abdomen taken at screening)

• Participants with any solid organ transplant or surgery affecting the bowel. Participants with a history of appendectomy and inguinal (non-incarcerated) hernioplasty or meconium ileus without the need for bowel resection could be enrolled. Gastrointestinal-tube-fed patients, in absence of dumping syndrome, were also eligible

• Participants with history of or current screening evaluation of hyperglycemia as defined by an 8-hour fasting blood glucose (FBG) of >126 mg/dL, or of CF-related diabetes as determined according to the Cystic Fibrosis Foundation (CFF) Consensus Conference of January 1999 (Section IX Part II), that is: a) FBG >126 mg/dL (7.0 millimoles per liter [mmol/L]) on two or more occasions b)FBG >126 mg/dL (7.0 mmol/L) plus casual (without regard to time of day or last meal consumed) glucose level >200 mg/dL (11.1 mmol/L) c)Casual (previously called random) glucose levels >200 mg/dL (11.1 mmol/L) on two or more occasions with symptoms

• Participants using an enzyme preparation in excess of 10,000-lipase units/kg/day

• Participants using an immunosuppressive drug

• Participants who are expecting an inability to tolerate the washout period and/or the placebo treatment

• Participants participating in an investigational study of a drug, biologic, or device not currently approved for marketing, within 30 days of screening visit

• Female participants who are pregnant or breastfeeding, or unwilling to use effective birth control during study

• Participants with any condition that would, in the investigator's opinion, limit the participant's ability to complete the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Health Center at Tyler	Tyler	Texas	United States	75708

Sponsors and Collaborators

• Forest Laboratories

Investigators

• Study Director: Aptalis Medical Information, Forest Laboratories

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT00297167
• Other Study ID Numbers: EUR-1008-M
• First Posted: Feb 28, 2006
• Last Update Posted: Mar 16, 2017
• Last Verified: Feb 1, 2017

• Keywords provided by Forest Laboratories: CF; Cystic Fibrosis; EPI; Exocrine Pancreatic Insufficiency; Pancreatic; Enzyme; PEP
• Additional relevant MeSH terms: Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Fibrosis

Study Results

Participant Flow

Pre-assignment Detail	Out of 34 participants who were enrolled and treated during open-label dose titration and stabilization period, 1 participant withdrew from the study before randomization to first double-blind intervention period.

Arm/Group Title	Placebo First, Then EUR-1008 (APT-1008)	EUR-1008 (APT-1008) First, Then Placebo	EUR-1008 (APT-1008) (Open-label)
Arm/Group Description	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first double-blind intervention period followed by EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the second double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units per kilogram body weight per day (lipase units/kg/day).	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first double-blind intervention period followed by placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the second double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily at a fixed stabilized dose during open-label normalization period 1 (5 to 14 days) after first double-blind interventional period and during open-label normalization period 2 (7 days) after second double-blind interventional period.
Period Title: First Double-blind Intervention Period
STARTED	17	16	0
COMPLETED	17	16	0
NOT COMPLETED	0	0	0
Period Title: First Double-blind Intervention Period
STARTED	0	0	33
COMPLETED	0	0	32
NOT COMPLETED	0	0	1
Period Title: First Double-blind Intervention Period
STARTED	17	15	0
COMPLETED	16	15	0
NOT COMPLETED	1	0	0
Period Title: First Double-blind Intervention Period
STARTED	0	0	31
COMPLETED	0	0	31
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes participants who received EUR-1008 (APT-1008) in open-label dose titration and stabilization phase; and EUR-1008 (APT-1008) first and placebo first after randomization to study treatment.
Overall Participants	34
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.9 (4.75)
Sex: Female, Male (Count of Participants)
Female	17 50%
Male	17 50%

Outcome Measures

1. Primary Outcome

Title	Percent Coefficient of Fat Absorption (CFA%)
Description	Percent CFA was calculated as ([fat intake - fat excretion]/fat intake)multiplied by 100, determined in the stools collected during the 72-hour hospitalization period. Mean percent CFA was calculated for Day 3 to Day 6 during hospital treatment in first and second double-blind (DB) intervention periods.
Time Frame	Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period. Here "N" (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	32	31
Least Squares Mean (Standard Error) [percent CFA]	88.28 (2.599)	62.76 (2.639)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUR-1008 (APT-1008), Placebo
	Comments	P-Value was calculated using analysis of variance (ANOVA) model which included main effects for treatment and sequence and participant nested in sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	-25.52
	Confidence Interval	(2-Sided) 95%; -31.73 to -19.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percent Coefficient of Nitrogen Absorption (CNA%)
Description	Percent CNA was calculated as ([nitrogen intake-nitrogen excretion]/nitrogen intake)*100, determined in the stools collected during the 72-hour hospitalization period. Nitrogen intake was calculated as protein intake/6.2. Nitrogen excretion was measured as total fecal nitrogen. Mean percent CNA was calculated for Day 3 to Day 6 during hospital treatment in first and second double-blind intervention periods.
Time Frame	Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period. Here "N" (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	32	31
Least Squares Mean (Standard Error) [percent CNA]	87.17 (2.179)	65.67 (2.213)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUR-1008 (APT-1008), Placebo
	Comments	P-Value was calculated using analysis of variance (ANOVA)model which included main effects for treatment and sequence and participant nested in sequence as a random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-21.50
	Confidence Interval	(2-Sided) 95%; -26.85 to -16.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Lipid Levels
Description	Lipid levels were reported for total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) from fasted blood and urine samples. Mean lipid levels for Day 6 during first and second double-blind intervention periods were calculated.
Time Frame	End of treatment (Day 6 during first and second double-blind intervention periods)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of study treatment. Here "N" (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and "n" signifies participants who were evaluable at specific time point in each treatment arm.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	33	30
TC: End of Treatment (n=33, 30)	128.8 (28.98)	109.1 (29.76)
HDL-C: End of Treatment (n=33, 30)	45.5 (10.85)	37.2 (9.23)

4. Secondary Outcome

Title	Vitamin A Levels
Description	Mean Vitamin A levels for Day 6 during first and second double-blind intervention periods were calculated.
Time Frame	End of treatment (Day 6 during first and second double-blind intervention periods)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of study treatment. Here "N" (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	33	30
Mean (Standard Deviation) [microgram per liter (mcg/L)]	422.3 (111.67)	363.2 (100.33)

5. Secondary Outcome

Title	Vitamin E Levels
Description	Mean Vitamin E levels for Day 6 during first and second double-blind intervention periods were calculated.
Time Frame	End of treatment (Day 6 during first and second double-blind intervention periods)

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of study treatment. Here "N" (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	33	30
Mean (Standard Deviation) [mg/L]	8.25 (3.115)	6.69 (2.648)

6. Secondary Outcome

Title	Mean Daily Number of Stools
Description	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 3 to Day 6 in first and second double-blind intervention periods) for total participants was summarized.
Time Frame	Day 3 up to Day 6 during first and second double-blind intervention periods

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	32	32
Mean (Standard Deviation) [stools per day]	1.76 (0.898)	2.66 (1.418)

7. Secondary Outcome

Title	Percentage of Stool Categorized as Per Consistency
Description	Stool consistency was categorized as hard, formed/normal, soft, watery, or overt diarrhea. Percentage of stools of a specific consistency for each participant at first and second double-blind intervention periods was calculated. Mean percentage of stool consistency during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized.
Time Frame	Day 3 up to Day 6 during first and second double-blind intervention periods

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	32	32
Hard	16.54 (29.637)	6.24 (18.845)
Formed/Normal	53.86 (37.253)	33.25 (34.414)
Soft	29.24 (34.096)	57.11 (36.105)
Watery	0.36 (1.421)	2.59 (4.836)
Overt diarrhea	0.00 (0.000)	0.82 (3.670)

8. Secondary Outcome

Title	Mean Number of Abdominal Symptoms
Description	Abdominal symptoms included abdominal pain, flatulence and bloating. 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). Mean number of symptom of specific severity per day for each participant was calculated. Mean number of symptoms per day was calculated for Day 3 to Day 6 in first and second double-blind intervention periods for total participants.
Time Frame	Day 3 up to Day 6 during first and second double-blind intervention periods

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	32	32
Bloating: Mild	0.10 (0.300)	0.31 (0.718)
Bloating: Moderate	0.05 (0.191)	0.10 (0.329)
Bloating: Severe	0.00 (0.000)	0.09 (0.495)
Flatulence: Mild	0.40 (0.688)	0.70 (1.134)
Flatulence: Moderate	0.08 (0.275)	0.41 (1.160)
Flatulence: Severe	0.00 (0.000)	0.18 (0.719)
Pain: Mild	0.16 (0.433)	0.62 (0.901)
Pain: Moderate	0.08 (0.379)	0.32 (0.754)
Pain: Severe	0.00 (0.022)	0.09 (0.228)

9. Other Pre-specified Outcome

Title	Percentage of Visible Oil or Grease in Stool
Description	Mean percentage of stools with visible oil or grease during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized. Percentage was calculated as the number of stools with visible oil or grease divided by the total number of stool per day.
Time Frame	Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	32	32
Mean (Standard Deviation) [percentage of visible oil or grease/day]	6.78 (17.354)	27.97 (33.571)

10. Other Pre-specified Outcome

Title	Percentage of Stools With Blood
Description	Mean percentage of stools with blood during the collection period (Day 3 to Day 6 in first and second intervention periods) for total participants was summarized. Percentage was calculated as the number of stools with blood divided by the total number of stool per day.
Time Frame	Day 3 up to Day 6 of hospital treatment in first and second double-blind intervention periods

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all randomized and treated participants with at least 1 post-baseline measurement for each double-blind intervention period.

Arm/Group Title	EUR-1008 (APT-1008)	Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule and was given orally daily in the first and second double-blind intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be opened and sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. The stabilized dose was not to exceed 10,000 lipase units/kg/day.	Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule and was given orally daily in the first and second intervention periods; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
Measure Participants	32	32
Mean (Standard Deviation) [percentage of stools with blood per day]	0.17 (0.174)	1.13 (4.647)

Adverse Events

Adverse Event Reporting Description	Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) 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 or assessed as important medical event.
Arm/Group Title	EUR-1008 (APT-1008)		Placebo
Arm/Group Description	EUR-1008 (APT-1008) microtablets (5000 lipase units) or minitablets (10000, 15000 or 20000 lipase units) contained in a capsule was given orally daily in the first and second double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). The capsules could be sprinkled on acidic food and half of the established dose was used with snacks. Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment. Participants received EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule was given orally daily at a fixed stabilized dose for 5 to 14 days during open-label dose normalization period 1 and for 7 days during open-label dose normalization period 2 which was maintained after each double-blind intervention period. The stabilized dose was not to exceed 10,000 lipase units per kilogram body weight per day (units/kg/day).		Placebo matched to EUR-1008 (APT-1008) microtablets or minitablets contained in a capsule was given orally daily in the first and second double-blind intervention period; at a dose based on investigator's discretion as achieved during dose titration and stabilization period (6 to 9 days). Treatment duration for each double-blind intervention period was 2 days home treatment and 3 to 5 days hospital treatment.
All Cause Mortality
	EUR-1008 (APT-1008)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	EUR-1008 (APT-1008)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/34 (5.9%)		0/32 (0%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	1/34 (2.9%)		0/32 (0%)
Lung disorder	1/34 (2.9%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	EUR-1008 (APT-1008)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/34 (55.9%)		16/32 (50%)
Gastrointestinal disorders
Abdominal discomfort	1/34 (2.9%)		0/32 (0%)
Abdominal distension	2/34 (5.9%)		3/32 (9.4%)
Abdominal pain	4/34 (11.8%)		6/32 (18.8%)
Abdominal pain upper	2/34 (5.9%)		3/32 (9.4%)
Abnormal faeces	1/34 (2.9%)		3/32 (9.4%)
Flatulence	2/34 (5.9%)		3/32 (9.4%)
Frequent bowel movements	1/34 (2.9%)		2/32 (6.3%)
Nausea	1/34 (2.9%)		1/32 (3.1%)
Steatorrhoea	0/34 (0%)		4/32 (12.5%)
Vomiting	1/34 (2.9%)		0/32 (0%)
Abdominal tenderness	1/34 (2.9%)		0/32 (0%)
Bowel sounds abnormal	0/34 (0%)		1/32 (3.1%)
Constipation	1/34 (2.9%)		0/32 (0%)
Infrequent bowel movements	0/34 (0%)		1/32 (3.1%)
General disorders
Early satiety	2/34 (5.9%)		0/32 (0%)
Chest pain	1/34 (2.9%)		0/32 (0%)
Oedema mucosal	1/34 (2.9%)		0/32 (0%)
Pyrexia	1/34 (2.9%)		0/32 (0%)
Infections and infestations
Otitis externa	0/34 (0%)		1/32 (3.1%)
Injury, poisoning and procedural complications
Contusion	2/34 (5.9%)		0/32 (0%)
Injury	1/34 (2.9%)		0/32 (0%)
Anal injury	1/34 (2.9%)		0/32 (0%)
Fall	0/34 (0%)		1/32 (3.1%)
Investigations
Weight decreased	2/34 (5.9%)		2/32 (6.3%)
Metabolism and nutrition disorders
Anorexia	0/34 (0%)		1/32 (3.1%)
Musculoskeletal and connective tissue disorders
Clubbing	1/34 (2.9%)		0/32 (0%)
Nervous system disorders
Headache	5/34 (14.7%)		0/32 (0%)
Dizziness	0/34 (0%)		1/32 (3.1%)
Reproductive system and breast disorders
Vaginal burning sensation	0/34 (0%)		1/32 (3.1%)
Respiratory, thoracic and mediastinal disorders
Cough	2/34 (5.9%)		0/32 (0%)
Nasal congestion	1/34 (2.9%)		0/32 (0%)
Crackles lung	1/34 (2.9%)		1/32 (3.1%)
Skin and subcutaneous tissue disorders
Rash	1/34 (2.9%)		0/32 (0%)
Vascular disorders
Haematoma	1/34 (2.9%)		0/32 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Restrictions may vary in accordance with each agreement that is negotiated with individual investigators. Sponsor will allow publication after 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 defer publication for period of time to allow Sponsor to obtain patent or other intellectual property right protection.