A Randomized, Double-Blind, Dose Response-Control, Crossover Study to Evaluate the Safety and Efficacy of Two Doses of EUR-1008 (APT-1008) in Chronic Pancreatitis (CP) Participants With Exocrine Pancreatic Insufficiency (EPI)

Chronic Pancreatitis Clinical Trial

Official title:

A Randomized, Double-Blind, Dose Response-Control, Crossover Study to Evaluate the Safety and Efficacy of Two Doses of EUR-1008 in Chronic Pancreatitis (CP) Patients With Exocrine Pancreatic Insufficiency (EPI)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00788593
• Other study ID #: PR-002
• Status: Completed
• Phase: Phase 3
• First received: November 10, 2008
• Last updated: January 27, 2014
• Start date: January 2008
• Est. completion date: March 2009

Study information

• Verified date: January 2014
• Source: Forest Laboratories
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUkraine: State Pharmacological Center - Ministry of HealthItaly: National Monitoring Centre for Clinical Trials - Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The primary efficacy objective of this study is to evaluate the difference in coefficient of fat absorption (CFA) of participants treated with high dose EUR-1008 (APT-1008) versus low dose of EUR-1008 (APT-1008) in the treatment of signs and symptoms of malabsorption in participants with EPI associated with CP. This study is sponsored by Aptalis Pharma (formerly Eurand).

Description:

After screening, eligible participants will start the placebo baseline ambulatory phase (4 days). On day 5, they will be hospitalized for three to five days, to undergo a "baseline" 72-hour CFA determination under a controlled diet and using a stool marker to indicate the beginning and end of the controlled diet period, while they continue receiving placebo treatment. At the end of the placebo baseline phase, participants will be randomized to a "high dose followed by a low dose" or to a "low dose followed by a high dose" EUR-1008 (APT-1008) dose sequence and proceed to the first crossover (treatment) phase. Each crossover (treatment) phase will consist of a stabilization period for six days at home, followed by a hospitalization of three to five days to undergo a 72-hour CFA determination using a controlled diet and using a stool marker to indicate the beginning and end of the controlled diet period.

Participants will immediately proceed from the first crossover (treatment) phase to the second without a washout period or return-to-baseline period in between phases. Participants will be stabilized at home for 6 days. Any residual lipase from the prior treatment phase is likely to be a negligible influence on the subsequent CFA determination because participants will be taking the new dose level (high or low) for six days before the beginning of sample collection for a new CFA. This interval is more than enough time for the CFA to be reflective of only the new dose.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: March 2009
• Est. primary completion date: March 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants are male or female

• Participants with age over 18 years

• Participants who have written, legally valid informed consent

• Women of childbearing potential must be using a medically acceptable form of birth control for the 30 days prior to the beginning of the study and agree to maintain adequate birth control measures during the whole duration of the study plus an additional 30 days as well as have a negative pregnancy test at screening Visit 3 and Visit 7

• Participants with documented diagnosis of CP by medical history and it is preferred that it is supported by imaging evidence confirming CP which include: abnormal endoscopic retrograde cholangio-pancreatography (ERCP) (Cambridge Class 4), abnormal computed tomography (CT) scan (dilated main pancreatic duct, atrophy of the pancreas or calcification), abnormal ultrasound, or endoscopic ultrasound with at least 5 abnormalities noted

• In the case of pancreatic surgery, the participant can be included with partial or distal resection of the pancreas (not due to cancer)

• Participants with documented EPI with target fecal elastase (FE) less than or equal to 100 microgram per gram (mcg/g) of stool using the monoclonal test (pancreatic elastase 1 [PE1] by Genova Diagnostics) performed at the screening visit. The mean coefficient of variation (CV) for the FE test is 20 percent (%)

Exclusion Criteria:

• Participants known to the investigator to have a significant medical and/or mental disease that would compromise the participant's welfare, pose an unacceptable risk to him/her or confound the study results

• Participants who participated in a clinical trial within 30 days of randomization or per specific country regulations/guidelines

• Participants with cystic fibrosis

• Participants with excessive alcohol consumption

• Participants with drug abuse

• Participants with contraindicated medications or who are unable to discontinue prohibited concomitant medication

• Participants with uncontrolled diabetes mellitus

• Participants allergic to pork protein/unwilling to ingest pork products

• Participants with atopic predisposition such as multiple drug hypersensitivity, allergic asthma, urticaria, or other relevant allergic diathesis

• Participants who are pregnant or lactating

• Participants with acute pancreatitis or acute exacerbation in chronic pancreatitis

• Participants with acute biliary disease

• Participants with malabsorption syndrome caused by a metabolic disease or by surgery, not related to exocrine pancreatic insufficiency

• Participants with any resection of the stomach or the gastrointestinal tract that will affect transit time and/or gastric emptying.

• Participants with evidence of active gastric or duodenal ulcer

• Participants with chronic inflammatory bowel disease

• Participants with any history of pancreatic cancer and other non-cutaneous malignancies (except basal cell and squamous cell carcinoma of the skin in situ that have been removed and not reoccurred in 5 years)

• Participants with viral hepatitis with infectious virions in blood and/or body fluids (any etiology)

• Participants with human immunodeficiency virus (HIV) infection

• Participants with hyperuricemia ( greater than [>] 1.5 times upper normal value for lab)

• Participants with any acute or chronic disease, which in the opinion of the investigator could influence study results or pose a risk to the participants' safety

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Pancreatitis
• Exocrine Pancreatic Insufficiency
• Pancreatitis
• Pancreatitis, Chronic

Intervention

Drug:
• Placebo
Placebo matching to EUR-1008 (APT-1008) capsules orally daily for 4 days home treatment and 3 to 5 days hospital treatment in the baseline run-in phase, which will then be randomized to either high dose or low dose of EUR-1008 (APT-1008).
• EUR-1008 (APT-1008) High Dose
EUR-1008 (APT-1008) total high dose 140,000 lipase USP Lipase units will be given as 7 capsules containing 20,000 USP Lipase units each, orally daily, distributed over the day per gram of fat in diet (possible example: 2 capsules with breakfast, 2 capsules with lunch, 2 capsules with dinner and 1 capsule with a snack) for 6 days home treatment and 3 to 5 days hospital treatment in either first intervention period or second intervention period.
• EUR-1008 (APT-1008) Low Dose
EUR-1008 (APT-1008) total low dose 35,000 lipase USP Lipase units will be given as 7 capsules containing 5,000 USP Lipase units each, orally daily, distributed over the day per gram of fat in diet (possible example: 2 capsules with breakfast, 2 capsules with lunch, 2 capsules with dinner and 1 capsule with a snack) for 6 days home treatment and 3 to 5 days hospital treatment in either first intervention period or second intervention period.

Locations

Country	Name	City	State
Italy	Istituto di Clinica Chirurgica (Ensoscopia Digestive Chirurgica) Policlinico Gemelli-Universita Cattolica del Sacro Cuore	Largo Agostino Gemelli	Roma
Italy	Centro Richerche Cliniche di Verona	le Ludovico Scuro	Verona
Italy	Dipartmento di Malattie dell' apparato digerente e Medicina Interna- Unita Operativa di MedicinaInterna Corinaldesi Azienda Ospedaliero- Universitaria Policlinico Sant'Orsola Malpighi Via Massarenti	Massarenti	Bologna
Italy	Istituto Clinico Humanitas - Universita' Di Milano Via Manzoni	Rozzano	Milano
Ukraine	Department of Internal Medicine No 2 of Donetsk State University named after M. Gorkly, City Clinical Hospital No 3	Donetsk
Ukraine	Department of Liver and Gastrointestinal Tract Disease Institute of Therapy named after L.T. Maylaya of Academy of Medical Sciences of the Ukraine	Kharkiv	Kharklv
Ukraine	Department of Faculty Therapy No 1 with the Course of Postgraduate Training of Physicians for Gastroenterology and Endoscopy, National Medical University named after O.O. Bogomolets, City Hospital No 18	Kyiv	Kylv
Ukraine	General Therapy Clinic, Military Clinical Hospital of Ministry of Defense of Ukraine 18	Kyiv	Kylv
Ukraine	Department of Therapy and Family Medicine of the Facility of Post graduate Education of Crimea State Medical University named after S.I. Georglyevskyy Republic Clinical Hospital named after M.O. Semashko	Simferopol	Crimea
United States	University of Missouri Health Care	Columbia	Missouri
United States	University of Florida, General Clinical Research Center	Gainesville	Florida
United States	Veterans Affairs Edward Jr. Hines Hospital, Building #1	Hines	Illinois
United States	University of Iowa Hospitals and Clinics	Iowa Ctiy	Iowa
United States	University of Kentucky, Medical Center, Department of Gastroenterology	Lexington	Kentucky
United States	Woodland International Research Group	Little Rock	Arkansas
United States	HealthCare Partners Medical Group	Los Angeles	California
United States	University of Louisville, Carmichael Building	Louisville	Kentucky
United States	Advanced Medical Research Center	Port Orange	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Forest Laboratories

Countries where clinical trial is conducted

United States,  Italy,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Coefficient of Fat Absorption (CFA) of Participants Treated With High Dose EUR-1008 and Low Dose EUR-1008	Percent CFA was calculated as ([fat intake - fat excretion]/fat intake)*100, determined in the stools collected during the 72-hour CFA determination period. Mean percent CFA was calculated for the 3 to 5 days of hospital treatment in first and second intervention periods.	3 to 5 days of hospital treatment in first and second intervention periods	No
Secondary	Change From Placebo Baseline in Percent Coefficient of Fat Absorption (CFA) in High Dose EUR-1008 and Low Dose EUR-1008 During Hospital Treatment	Percent CFA was calculated as ([fat intake - fat excretion]/fat intake)*100, determined in the stools collected during the 72-hour CFA determination period. Mean percent CFA was calculated for 3 to 5 days of hospital treatment in first and second intervention periods.	Baseline, 3 to 5 days of hospital treatment in first and second intervention periods	No
Secondary	Change From Placebo Baseline in Percent Coefficient of Nitrogen Absorption (CNA) During Hospital Treatment	Percent CNA was calculated as [(nitrogen intake - nitrogen excretion)/nitrogen intake]*100 , determined in the stools collected during the 72-hour CNA determination period. Nitrogen intake was calculated as protein intake/6.2. Nitrogen excretion was measured as total fecal nitrogen. Mean percent CNA was calculated for 3 to 5 days of hospital treatment in first and second intervention periods.	Baseline, 3 to 5 days of hospital treatment in first and second intervention periods	No
Secondary	Change From Placebo Baseline in Weight at End of Each Treatment Period	Mean change from baseline in weight was calculated for end of treatment (6 days home treatment and 3-5 days hospital treatment) in first and second intervention periods.	Baseline, end of treatment (6 days home treatment and 3-5 days hospital treatment in first and second intervention periods)	No
Secondary	Change From Placebo Baseline in Body Mass Index (BMI) at End of Treatment	BMI was calculated by weight divided by height squared and measured as kilogram per square meter (kg/m^2). Mean change from baseline in BMI was calculated for end of treatment (6 days home treatment and 3-5 days hospital treatment) in first and second intervention periods.	Baseline, end of treatment (6 days home treatment and 3-5 days hospital treatment in first and second intervention periods)	No