Safety and Efficacy Study of ULTRASE® MT20 in Participants With Cystic Fibrosis (CF) and Exocrine Pancreatic Insufficiency (PI)

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00408317
• Collaborator: (none)
• Enrollment: 36
• Locations: 4
• Arms: 2
• Duration (Months): 5
• Patients Per Site: 9
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety and efficacy of Ultrase® MT20 compared to placebo for the correction of fat and protein malabsorption in participants with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI). This study is sponsored by Aptalis Pharma (formerly Axcan).

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis; Exocrine Pancreatic Insufficiency	Drug: Ultrase® MT20; Drug: Placebo	Phase 3

Detailed Description

This is a Phase III, multicenter, randomized, double-blind, two-period cross-over, placebo-controlled study designed to compare the efficacy and safety of Ultrase® MT20 to placebo in participants with CF and pancreatic insufficiency. The study consists of a screening period (up to 11 days) and two treatment periods (6-7 days). During screening period participants will be treated with open-label Ultrase® MT18 or MT20. Each treatment period will be preceded by a stabilization period (4 days) and the two treatment periods are separated by a break period (3-6 days). A safety follow-up visit will be performed 7-10 days after discharge from the last treatment period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Crossover Study to Compare the Safety and Efficacy of Ultrase® MT20 to Placebo for the Correction of Steatorrhea in Patients With Cystic Fibrosis (CF)
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Apr 1, 2007
• Actual Study Completion Date: Apr 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ultrase® MT20	Drug: Ultrase® MT20; Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in either first intervention period or second intervention period.; Other Names: Pancreatic enzyme product
Placebo Comparator: Placebo	Drug: Placebo; Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.

Outcome Measures

Primary Outcome Measures

1. Percent Coefficient of Fat Absorption (CFA) [Day 3 to Day 7 in first intervention period and second intervention period]

   Percent (%) CFA was calculated as ([fat intake - fat excretion]/fat intake)*100, determined by the stools collected during the 72-hour period which could extend to 96 hours during both intervention periods. Mean CFA percent was calculated for 72-hour/96-hour period during Day 3 to Day 7 in the first and second intervention periods.

Secondary Outcome Measures

1. Percent Coefficient of Nitrogen Absorption (CNA) [Day 3 to Day 7 in first intervention period and second intervention period]

   Percent (%) CNA was calculated as [(nitrogen intake-nitrogen excretion)/nitrogen intake]*100, determined by the stools collected during the 72-hour period which could extend to 96 hours during both intervention periods. Nitrogen intake was calculated as protein intake/6.25. Mean percent CNA was calculated for 72-hour/96-hour period during Day 3 to Day 7 in the first and second intervention periods.

Other Outcome Measures

1. Number of Bowel Movements [Day 3 on first intervention period and second intervention period]

   Number of bowel movements of each participant was calculated from frequency of stools by the participant per day. Mean daily number of bowel movements on Day 3 for the first treatment period and second treatment period was summarized.

2. Percentage of Stool Categorized by Consistency [Day 4 on first intervention period and second intervention period]

   Stool consistency was categorized as hard, formed/normal, soft or watery stool. Percentage of stools of a specific consistency of each participant was calculated as the number of stools with a specific consistency relative to the total number of stools during the collection period. Mean percentage of stool with specific consistency on Day 4 for the first treatment period and second treatment period period for total participants was summarized.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants or their legally authorized representative must understand the nature of the study and sign an informed consent or assent form along with a parental form

• Participants must have a confirmed diagnosis of CF based on 1 or more clinical features consistent with the CF phenotype, and one of the following:

• A genotype with 2 identifiable mutations consistent with CF

• A sweat chloride test greater than 60 millimole per liter (mmol/L) by quantitative pilocarpine iontophoresis

• Participants must have PI as demonstrated by a fecal elastase-1 (FE-1) concentration less than 100 microgram per gram (mcg/g) of stools (ScheBo test) and must require pancreatic enzyme supplementation

• Participants must be clinically stable as evidenced by medical and medication history, baseline physical examination including vital signs and laboratory analyses

• Participants must be 7 years and older

• Participants must have an adequate nutritional status based on the following body mass index (BMI):

• Participants 7 to 20 years old must have a BMI greater than or equal to fifth percentile

• Female participants greater than 20 years old must have a BMI greater than or equal to 16

• Male participants greater 20 years old must have a BMI greater than or equal to 16.5

• Participants must be on an optimal clinical dose of pancreatic enzymes (Ultrase® MT18 or MT20 or other pancreatic enzymes preparations including Ultrase® MT12) prior to entry in the study, and must tolerate this medication in the opinion of the investigator

• Participants must be able to swallow capsules and must be able to eat a high fat diet calculated as 2 gram (± 15%) fat per kilogram body weight per day

• Participants must be, in the opinion of the investigator, able and willing to complete this study

• Female participants must be premenarcheal, surgically sterile or postmenopausal for at least 12 consecutive months. Otherwise, the women of childbearing potential (WOCBP) must not be pregnant and must have practiced an acceptable method of contraception for at least one month prior to the study entry

Exclusion Criteria:

• Participants with a known contraindication, sensitivity or hypersensitivity to Ultrase or any porcine protein

• Participants with a known allergy to the food drug and cosmetic (FD&C) Blue No. 2 dye indicator (stool marker)

• Participants not willing to stop the prohibited medications or products at study entry and throughout the study

• Participants who are using narcotics

• Participants who are using bowel stimulants and/or laxatives on a regular basis

• Participants with acute pancreatitis or acute exacerbation of chronic pancreatic disease

• Participants with an acute pulmonary infection

• Participants with a history of bowel resection

• Participants suffering from any dysmotility disorders

• Participants with chronic or severe abdominal pain

• Participants receiving enteral tube feeding and not willing to stop during the course of the study

• Participants known to have a significant medical disease that would compromise their welfare or confound the study results

• Participants with a history of or a current diagnosis of clinically significant portal hypertension

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

• Participants with a current diagnosis or a history of complete distal intestinal obstruction syndrome (DIOS) in the past 6 months; or, participants who had 2 or more episodes of DIOS in the past year

• Participants with poorly controlled diabetes to the investigator's opinion

• Female participants who are pregnant or lactating

• Participants who received an investigational drug within 30 days prior to entry into the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	DeVos Children's Hospital	Grand Rapids	Michigan	United States	49503
2	Rainbow Babies & Children's Hospital	Cleveland	Ohio	United States	44106
3	Pennsylvania State University, The Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
4	University of Utah Health Sciences Center	Salt Lake City	Utah	United States	84112

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: NCT00408317
• Other Study ID Numbers: UMT20CF05-01
• First Posted: Dec 6, 2006
• Last Update Posted: Mar 16, 2017
• Last Verified: Feb 1, 2017

• Keywords provided by Forest Laboratories: Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Ultrase® MT20
• Additional relevant MeSH terms: Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Fibrosis; Pancrelipase; Pancreatin

Study Results

Participant Flow

Recruitment Details	Participants with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI) were recruited from centers with CF specialists.
Pre-assignment Detail	Out of 36 participants who entered the screening period (11 days), and treated with Ultrase® MT20, 31 were randomized to first intervention period.

Arm/Group Title	Ultrase® MT20 First, Then Placebo	Placebo First, Then Ultrase®MT20
Arm/Group Description	Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in the first intervention period followed by placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in the second intervention period. Break period of 3 to 6 days and fixed dose second stabilization period of 4 days was maintained after first intervention period.	Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in the first intervention period followed by Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in the second intervention period. Break period of 3 to 6 days and fixed dose second stabilization period of 4 days was maintained after first intervention period.
Period Title: First Intervention Period
STARTED	14	17
COMPLETED	14	16
NOT COMPLETED	0	1
Period Title: First Intervention Period
STARTED	14	16
COMPLETED	12	14
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes all participants who received Ultrase® MT20 first and placebo first.
Overall Participants	31
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	19.6 (6.6)
Sex: Female, Male (Count of Participants)
Female	11 35.5%
Male	20 64.5%

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 by the stools collected during the 72-hour period which could extend to 96 hours during both intervention periods. Mean CFA percent was calculated for 72-hour/96-hour period during Day 3 to Day 7 in the first and second intervention periods.
Time Frame	Day 3 to Day 7 in first intervention period and second intervention period

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who were evaluated for this outcome measure.

Arm/Group Title	Ultrase® MT20	Placebo
Arm/Group Description	Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in either first intervention period or second intervention period.	Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Measure Participants	25	27
Mean (Standard Deviation) [Percent CFA]	88.55 (4.94)	55.61 (25.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ultrase® MT20, Placebo
	Comments	P-values are from a semi-parametric mixed model on ranked CFA% values including sequence, period, and treatment group as fixed effects; participant identification (ID) as random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	34.74
	Confidence Interval	() %; to
	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 by the stools collected during the 72-hour period which could extend to 96 hours during both intervention periods. Nitrogen intake was calculated as protein intake/6.25. Mean percent CNA was calculated for 72-hour/96-hour period during Day 3 to Day 7 in the first and second intervention periods.
Time Frame	Day 3 to Day 7 in first intervention period and second intervention period

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ultrase® MT20	Placebo
Arm/Group Description	Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in either first intervention period or second intervention period.	Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Measure Participants	25	27
Mean (Standard Deviation) [Percent CNA]	84.05 (7.24)	58.78 (20.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ultrase® MT20, Placebo
	Comments	P-values are from a semi-parametric mixed model on ranked CNA% values including sequence, period, and treatment group as fixed effects, and participant ID as random effect.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	25.68
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Other Pre-specified Outcome

Title	Number of Bowel Movements
Description	Number of bowel movements of each participant was calculated from frequency of stools by the participant per day. Mean daily number of bowel movements on Day 3 for the first treatment period and second treatment period was summarized.
Time Frame	Day 3 on first intervention period and second intervention period

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ultrase® MT20	Placebo
Arm/Group Description	Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in either first intervention period or second intervention period.	Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Measure Participants	29	30
Mean (Standard Deviation) [bowel movements]	1.5 (1.0)	3.1 (1.8)

4. Other Pre-specified Outcome

Title	Percentage of Stool Categorized by Consistency
Description	Stool consistency was categorized as hard, formed/normal, soft or watery stool. Percentage of stools of a specific consistency of each participant was calculated as the number of stools with a specific consistency relative to the total number of stools during the collection period. Mean percentage of stool with specific consistency on Day 4 for the first treatment period and second treatment period period for total participants was summarized.
Time Frame	Day 4 on first intervention period and second intervention period

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ultrase® MT20	Placebo
Arm/Group Description	Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in either first intervention period or second intervention period.	Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Measure Participants	28	28
Hard Stools	11.31 (27.98)	3.57 (18.90)
Formed/Normal Stools	76.19 (39.13)	25.71 (43.84)
Soft Stools	12.50 (29.27)	66.73 (45.08)
Watery Stools	0 (0)	3.99 (13.65)

Adverse Events

Time Frame	Day 1 of first stabilization period up to Day 7 of second intervention period
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.
Arm/Group Title	Ultrase® MT20		Placebo
Arm/Group Description	Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion,for 6 to 7 days in either first intervention period or second intervention period.		Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
All Cause Mortality
	Ultrase® MT20		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ultrase® MT20		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		1/31 (3.2%)
General disorders
General physical health deterioration	0/30 (0%)		1/31 (3.2%)
Pyrexia	0/30 (0%)		1/31 (3.2%)
Investigations
Breath sounds abnormal	0/30 (0%)		1/31 (3.2%)
Pulmonary function test decreased	0/30 (0%)		1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
Cough	0/30 (0%)		1/31 (3.2%)
Dyspnoea	0/30 (0%)		1/31 (3.2%)
Productive cough	0/30 (0%)		1/31 (3.2%)
Rales	0/30 (0%)		1/31 (3.2%)
Other (Not Including Serious) Adverse Events
	Ultrase® MT20		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/30 (56.7%)		27/31 (87.1%)
Gastrointestinal disorders
Abdominal pain	2/30 (6.7%)		12/31 (38.7%)
Abdominal pain upper	4/30 (13.3%)		6/31 (19.4%)
Constipation	2/30 (6.7%)		2/31 (6.5%)
Flatulence	1/30 (3.3%)		5/31 (16.1%)
Abdominal tenderness	0/30 (0%)		2/31 (6.5%)
Diarrhoea	0/30 (0%)		3/31 (9.7%)
Nausea	0/30 (0%)		5/31 (16.1%)
Vomiting	0/30 (0%)		3/31 (9.7%)
Investigations
Alaninie aminotransferase increased	1/30 (3.3%)		2/31 (6.5%)
Fecal fat increased	4/30 (13.3%)		9/31 (29%)
Weight decreased	0/30 (0%)		3/31 (9.7%)
Blood glucose increased	0/30 (0%)		2/31 (6.5%)
Laboratory test abnormal	3/30 (10%)		7/31 (22.6%)
Metabolism and nutrition disorders
Decreased appetite	0/30 (0%)		2/31 (6.5%)
Nervous system disorders
Headache	2/30 (6.7%)		1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	2/30 (6.7%)		1/31 (3.2%)
Rales	2/30 (6.7%)		1/31 (3.2%)
Rhinorrhoea	1/30 (3.3%)		3/31 (9.7%)
Vascular disorders
Epistaxis	2/30 (6.7%)		0/31 (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.