Safety and Efficacy Study of Viokase® 16 for the Correction of Steatorrhea

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00559364
• Collaborator: (none)
• Enrollment: 50
• Locations: 18
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study assesses the efficacy and safety of Viokase® 16 for the correction of steatorrhea (malabsorption of dietary fats) in patients with a history of exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP) or pancreatectomy. This study is sponsored by Aptalis Pharma (formerly Axcan).

Condition or Disease	Intervention/Treatment	Phase
Exocrine Pancreatic Insufficiency; Chronic Pancreatitis; Pancreatectomy	Drug: Viokase® 16; Drug: Placebo; Drug: Proton pump inhibitor (PPI); Drug: Omeprazole	Phase 3

Detailed Description

This study is a Phase III, multicenter, randomized, double-blind, parallel, placebo-controlled study, to assess the efficacy and safety of Viokase® 16 for the correction of steatorrhea in patients with EPI due to CP or pancreatectomy. The study will include the following phases: screening phase (up to 10 days), wash-out phase (6 to 7 days), randomization phase (up to 10 days), and treatment phase (6 to 7 days).

In screening phase, patients will undergo screening procedures prior to entry into the study.

In wash-out phase, stool collection will be performed to allow determination of the baseline CFA.

In randomization phase, patients who qualify for the Treatment Phase (that is, patients who have a CFA% below 80%) will be randomized in the study.

In the treatment phase, patients will be randomized in a 2:1 ratio (Viokase® 16 or Placebo). In treatment phase, stool collection period will be performed to allow determination of the CFA% that will serve to assess the efficacy of Viokase® 16 for the correction of steatorrhea. Follow-up procedures will be scheduled 7 to 10 days after discharge. Patients who do not show abnormal findings, adverse events or concomitant medications during the treatment phase will be assessed via follow-up telephone call. Patients who show abnormal findings (physical examination, vital signs, clinical laboratory tests, adverse events, concomitant medications) during the treatment phase will complete a follow-up visit.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Parallel, Placebo-controlled, Phase III Study to Assess the Safety and Efficacy of Viokase® 16 for the Correction of Steatorrhea in Patients With Exocrine Pancreatic Insufficiency
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Viokase® 16	Drug: Viokase® 16; Patients assigned to Viokase® 16 will be given 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase.; Drug: Proton pump inhibitor (PPI); Patients on PPI during Screening will continue their usual PPI therapy throughout the study.; Drug: Omeprazole; Patients not using PPI therapy at Screening will be given omeprazole 20 milligram orally once daily throughout the study.
Placebo Comparator: Placebo	Drug: Placebo; Patients assigned to placebo will be given 22 matching placebo tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase.; Drug: Proton pump inhibitor (PPI); Patients on PPI during Screening will continue their usual PPI therapy throughout the study.; Drug: Omeprazole; Patients not using PPI therapy at Screening will be given omeprazole 20 milligram orally once daily throughout the study.

Outcome Measures

Primary Outcome Measures

1. Percent Coefficient of Fat Absorption (CFA) [Day 1 up to Day 4 or Day 5 in inpatient period of treatment phase]

   Percent CFA was calculated as ([fat intake - fat excretion]/fat intake)*100, determined in the stools which was collected from Day 1 to Day 4 or Day 5 during the inpatient period of treatment phase. Mean percent (%) CFA was calculated for Day 1 to Day 4 or Day 5 in inpatient period of treatment phase.

Secondary Outcome Measures

1. Mean Daily Number of Stools [Day 1 up to Day 4 or Day 5 in inpatient period of treatment phase]

   Mean daily number of stools of each patient was calculated from frequency of stools by the patient per day. Mean daily number of stools during the collection period (Day 1 to Day 4 or Day 5 in inpatient period of treatment phase) for total patients was summarized.

2. Percentage of Stools Categorized as Per Consistency [Day 1 up to Day 4 or Day 5 in inpatient period of treatment phase]

   Stool consistency was categorized as hard, formed/normal, soft and watery. Percentage of stools of a specific consistency for each patient was calculated as: (total number of stools of specific consistency during the completed days of the inpatient period/ total number of stools during the completed days of the inpatient period)*100. Mean percentage of stool categorized as per consistency for total patients was summarized.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient must be male or female, aged 18-80 years

• Patients must have the ability to provide informed consent

• Female patients of childbearing potential must have a negative pregnancy test at screening, must use adequate contraception prior to and during the study and must agree not to attempt to become pregnant during the study; and female patients of non-childbearing potential must be surgically sterile or postmenopausal for at least 12 consecutive months

• Patients must have a medical condition compatible with EPI such as chronic pancreatitis or partial or total resection of the pancreas

• Patients with CP due to alcohol abuse may be included provided they show no clinical symptoms of recent alcohol consumption and no alcohol withdrawal symptoms

• Patients with CP must have at least one of the following conditions: an abnormal secretin test, diffuse calcification of the pancreas on plain film of the abdomen, an abnormal endoscopic retrograde cholangiopancreatography (ERCP) or endoscopic ultrasound, an abnormal computed tomography (CT) (dilated main pancreatic duct, atrophy or calcification of the pancreas) or serum trypsin concentration below 20 nanogram per milliliter (ng/mL)

• Patients must have evidence of EPI as demonstrated by a fecal elastase (FE-1) determination equal to or below 100 microgram/gram (mcg/g) of stools (FE-1 ScheBo test) at screening

• Patients must have evidence of EPI as manifested by a CFA% below 80% after the wash-out phase

• Patients must be able to comply with a high-fat diet

Exclusion Criteria:

• Patients with a known hypersensitivity and/or contraindication to any of the study medications, to their excipients, components or to Federal Food, Drug, and Cosmetic (FD and C) Blue No. 2 dye marker

• Patients with acute pancreatitis or with an acute exacerbation of CP at screening or within the last 2 weeks before screening

• Patients with any active or recurrent malignant pancreatic tumor

• Patients with a history of significant bowel resection

• Patients with a dysmotility disorder

• Patients with insufficient body mass (body mass index less than 18)

• Patient not willing to be off therapeutic doses for at least 7 days prior to study entry and throughout the course of the study, medications or products that could interfere with fecal fat excretion

• Patients who do not limit alcohol intake to less than or equal to 1 drink per day during screening and randomization phases and patients who do not refrain from drinking during inpatient periods of the study

• Patients who have been treated with the following drugs within 7 days prior to screening: H2-receptor antagonists, gastrointestinal anticholinergics and antispasmodics

• Patients known to have a significant medical and/or mental disease that would compromise the patient's welfare or confound the study results

• Patients with a history of fibrosing colonopathy, cirrhosis of the liver, or portal hypertension

• Patients who have a condition known to increase fecal fat loss including celiac disease, biliary cancer, biliary stricture, cholelithiasis, Crohn's disease, pancreatic cancer, radiation enteritis, tropical sprue, whipple's disease, lactose intolerance, pseudomembranous colitis

• Female patients who are pregnant or breastfeeding

• Patients who have received an investigational drug within 30 days prior to entering the screening phase of the study

• Patients with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 3 times the upper limit of normal values or elevated uric acid levels greater than 1.5 times the upper limit of normal values

• Patients with causes for EPI other than CP and partial/total pancreas resection, example, cystic fibrosis, primary sclerosing cholangitis, hemochromatosis, isolated enzyme deficiency, deficiency in activation of enzymes in the small intestine etc

• Patients with a history or clinical evidence of any relevant cardio- or cerebrovascular, renal, endocrine, neurologic, infectious, other gastrointestinal, hematological, oncological or psychiatric disease or emotional problems, which, in the opinion of the investigator, would pose a significant risk for the patient, invalidate the giving of informed consent or limit the ability of the patients to comply with study requirements or interfere otherwise with the conduct of the study and the same applies for immunocompromised patients and/or neutropenic patients

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Darmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
2	Hotel-Dieu de Levis	Levis	Quebec	Canada	G6V 3Z1
3	III Oddzial Chorób Wewnetrznych i Gastroenterologii	Bialystok		Poland	15 950
4	Akademickie Centrum Kliniczne	Gdansk		Poland	80 952
5	Samodzielny Publiczny Centralny	Katowice		Poland	40 752
6	Klinika Chorob Wewnetrznych z Poliklinika	Krakow		Poland	30 901
7	Uniwersytecki Szpital Kliniczny nr 1 im	Lodz		Poland	90 153
8	SP Szpital Kliniczny nr 4 w Lublinie	Lublin		Poland	20 954
9	Wojewodzki Szpital Specjalistyczny Nr5	Sosnowiec		Poland	40 200
10	SP Szpital Kliniczny nr 1 Klinika Gastroenterologii	Szczecin		Poland	71 252
11	Klinika Gastroenterologii i Chorób Przemiany Materii	Warszawa		Poland	02 097
12	Klinika Chorob Wewnetrznych i Gastroenterologii	Warszawa		Poland	02 507
13	Wojewodzki Szpital Brodnowski	Warszawa		Poland	03 242
14	Katedra Klinika Gastroenterologii	Wroclaw		Poland	50 376
15	University Hospital Brastislava	Brastislava		Slovakia	851 07
16	University Hospital Bratislava	Bratilslava		Slovakia	826 06
17	NZZ Management spol.S.r.o.	Nitra		Slovakia	949 01
18	Gastro I. s.r.o., Gastroenterologicka	Presov		Slovakia	080 01

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: NCT00559364
• Other Study ID Numbers: VIO16EPI07-01
• First Posted: Nov 16, 2007
• Last Update Posted: Mar 16, 2017
• Last Verified: Feb 1, 2017

• Additional relevant MeSH terms: Pancreatitis; Pancreatitis, Chronic; Exocrine Pancreatic Insufficiency; Steatorrhea; Omeprazole; Pancrelipase; Proton Pump Inhibitors

Study Results

Participant Flow

Pre-assignment Detail	Patients underwent screening phase (up to 10 days) and wash-out phase (6 to 7 days, where baseline coefficient of fat absorption [CFA] was determined) before entering randomization phase. Out of 218 patients, who entered screening and washout phases, 168 discontinued due to screen failure; 50 patients were randomized to treatment phase.

Arm/Group Title	Viokase®	Placebo
Arm/Group Description	Patients received Viokase® 16, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.	Patients received matching placebo, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.
Period Title: Overall Study
STARTED	30	20
COMPLETED	29	20
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Viokase®	Placebo	Total
Arm/Group Description	Patients received Viokase® 16, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.	Patients received matching placebo, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.	Total of all reporting groups
Overall Participants	30	20	50
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.9 (9.91)	50.6 (7.63)	50.8 (8.98)
Sex: Female, Male (Count of Participants)
Female	8 26.7%	1 5%	9 18%
Male	22 73.3%	19 95%	41 82%

Outcome Measures

1. Primary Outcome

Title	Percent Coefficient of Fat Absorption (CFA)
Description	Percent CFA was calculated as ([fat intake - fat excretion]/fat intake)*100, determined in the stools which was collected from Day 1 to Day 4 or Day 5 during the inpatient period of treatment phase. Mean percent (%) CFA was calculated for Day 1 to Day 4 or Day 5 in inpatient period of treatment phase.
Time Frame	Day 1 up to Day 4 or Day 5 in inpatient period of treatment phase

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all randomized patients. Missing values at treatment phase were imputed using the median (50th percentile) of all non-missing values within a treatment group.

Arm/Group Title	Viokase®	Placebo
Arm/Group Description	Patients received Viokase® 16, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.	Patients received matching placebo, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.
Measure Participants	30	20
Mean (Standard Deviation) [percent CFA]	85.52 (8.902)	58.02 (24.249)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Viokase®, Placebo
	Comments	Analysis of covariance (ANCOVA) model using treatment group and pooled site as fixed effects and wash-out phase CFA% value as covariate was used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Mean Daily Number of Stools
Description	Mean daily number of stools of each patient was calculated from frequency of stools by the patient per day. Mean daily number of stools during the collection period (Day 1 to Day 4 or Day 5 in inpatient period of treatment phase) for total patients was summarized.
Time Frame	Day 1 up to Day 4 or Day 5 in inpatient period of treatment phase

Outcome Measure Data

Analysis Population Description

ITT population included all randomized patients.

Arm/Group Title	Viokase®	Placebo
Arm/Group Description	Patients received Viokase® 16, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.	Patients received matching placebo, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.
Measure Participants	30	20
Mean (Standard Deviation) [stools per day]	1.93 (0.989)	2.33 (0.950)

3. Secondary Outcome

Title	Percentage of Stools Categorized as Per Consistency
Description	Stool consistency was categorized as hard, formed/normal, soft and watery. Percentage of stools of a specific consistency for each patient was calculated as: (total number of stools of specific consistency during the completed days of the inpatient period/ total number of stools during the completed days of the inpatient period)*100. Mean percentage of stool categorized as per consistency for total patients was summarized.
Time Frame	Day 1 up to Day 4 or Day 5 in inpatient period of treatment phase

Outcome Measure Data

Analysis Population Description

ITT population included all randomized patients.

Arm/Group Title	Viokase®	Placebo
Arm/Group Description	Patients received Viokase® 16, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.	Patients received matching placebo, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.
Measure Participants	30	20
Hard stools	5.08 (13.61)	0.67 (2.98)
Formed/normal stools	45.86 (33.27)	37.23 (37.91)
Soft stools	47.80 (33.31)	55.48 (39.46)
Watery stools	1.26 (4.82)	5.80 (14.57)

Adverse Events

Time Frame	Day 1 of treatment phase up to 30 days after last dose administration
Adverse Event Reporting Description	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 or is assessed as important medical event.
Arm/Group Title	Viokase®		Placebo
Arm/Group Description	Patients received Viokase® 16, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.		Patients received matching placebo, 22 tablets orally daily (that is, 6 tablets per meal and 2 tablets with 2 of 3 snacks) for 6 to 7 days in treatment phase. Patients on proton pump inhibitor (PPI) therapy during Screening continued their usual (those not using PPI therapy at screening received omeprazole 20 milligram orally once daily) throughout the study.
All Cause Mortality
	Viokase®		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Viokase®		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/30 (6.7%)		0/20 (0%)
Cardiac disorders
Cardiac failure	1/30 (3.3%)		0/20 (0%)
General disorders
Disease progression	1/30 (3.3%)		0/20 (0%)
Hepatobiliary disorders
Cholelithiasis	1/30 (3.3%)		0/20 (0%)
Investigations
Coagulation factor decreased	1/30 (3.3%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary oedema	1/30 (3.3%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Viokase®		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/30 (23.3%)		2/20 (10%)
Blood and lymphatic system disorders
Anaemia	1/30 (3.3%)		0/20 (0%)
Gastrointestinal disorders
Anal pruritus	2/30 (6.7%)		0/20 (0%)
Abdominal pain	1/30 (3.3%)		0/20 (0%)
Ascites	1/30 (3.3%)		0/20 (0%)
Flatulence	1/30 (3.3%)		0/20 (0%)
General disorders
Oedema peripheral	1/30 (3.3%)		0/20 (0%)
Hepatobiliary disorders
Bile duct stone	1/30 (3.3%)		0/20 (0%)
Hydrocholecystis	1/30 (3.3%)		0/20 (0%)
Infections and infestations
Viral infection	1/30 (3.3%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	0/30 (0%)		1/20 (5%)
Nervous system disorders
Headache	1/30 (3.3%)		0/20 (0%)
Renal and urinary disorders
Renal cyst	1/30 (3.3%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/30 (3.3%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Rash	1/30 (3.3%)		0/20 (0%)

Limitations/Caveats

Results for percentage of stool characteristics per bowel movement and number of days with at least 1 stool of specific characteristic were not reported due to change in planned analysis.

More Information

Certain Agreements

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

Restrictions vary in accordance with each agreement with the individual investigators. Sponsor will allow publication but will prohibit disclosure of Sponsor's confidential information within any publication and can defer publication for a period of time to allow for Sponsor to obtain patent or other intellectual property right protection.