Cystic Fibrosis, Exocrine Pancreatic Insufficiency
Conditions
Keywords
Cystic Fibrosis, Exocrine Pancreatic Insufficiency, Ultrase® MT20
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).
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.
Interventions
DRUGUltrase® 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.
DRUGPlacebo
Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Sponsors
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
7 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI) were recruited from centers with CF specialists.
Pre-assignment details
Out of 36 participants who entered the screening period (11 days), and treated with Ultrase® MT20, 31 were randomized to first intervention period.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes all participants who received Ultrase® MT20 first and placebo first. | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period | Adverse Event | 0 | 1 |
| Second Intervention Period | Adverse Event | 2 | 0 |
| Second Intervention Period | Protocol Violation | 0 | 1 |
| Second Intervention Period | Withdrawal of consent | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 19.6 years STANDARD_DEVIATION 6.6 |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 30 | 27 / 31 |
| serious Total, serious adverse events | 0 / 30 | 1 / 31 |
Outcome results
Primary
Percent Coefficient of Fat Absorption (CFA)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ultrase® MT20 | Percent Coefficient of Fat Absorption (CFA) | 88.55 Percent CFA | Standard Deviation 4.94 |
| Placebo | Percent Coefficient of Fat Absorption (CFA) | 55.61 Percent CFA | Standard Deviation 25.1 |
Comparison: 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.p-value: <0.0001Mixed Models Analysis
Secondary
Percent Coefficient of Nitrogen Absorption (CNA)
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
Population: ITT population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ultrase® MT20 | Percent Coefficient of Nitrogen Absorption (CNA) | 84.05 Percent CNA | Standard Deviation 7.24 |
| Placebo | Percent Coefficient of Nitrogen Absorption (CNA) | 58.78 Percent CNA | Standard Deviation 20.57 |
Comparison: 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.p-value: <0.0001Mixed Models Analysis
Other Pre-specified
Number of Bowel Movements
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
Population: ITT population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who were evaluated for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ultrase® MT20 | Number of Bowel Movements | 1.5 bowel movements | Standard Deviation 1 |
| Placebo | Number of Bowel Movements | 3.1 bowel movements | Standard Deviation 1.8 |
Other Pre-specified
Percentage of Stool Categorized by Consistency
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
Population: ITT population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who were evaluated for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ultrase® MT20 | Percentage of Stool Categorized by Consistency | Hard Stools | 11.31 percentage of stools | Standard Deviation 27.98 |
| Ultrase® MT20 | Percentage of Stool Categorized by Consistency | Formed/Normal Stools | 76.19 percentage of stools | Standard Deviation 39.13 |
| Ultrase® MT20 | Percentage of Stool Categorized by Consistency | Soft Stools | 12.50 percentage of stools | Standard Deviation 29.27 |
| Ultrase® MT20 | Percentage of Stool Categorized by Consistency | Watery Stools | 0 percentage of stools | Standard Deviation 0 |
| Placebo | Percentage of Stool Categorized by Consistency | Watery Stools | 3.99 percentage of stools | Standard Deviation 13.65 |
| Placebo | Percentage of Stool Categorized by Consistency | Hard Stools | 3.57 percentage of stools | Standard Deviation 18.9 |
| Placebo | Percentage of Stool Categorized by Consistency | Soft Stools | 66.73 percentage of stools | Standard Deviation 45.08 |
| Placebo | Percentage of Stool Categorized by Consistency | Formed/Normal Stools | 25.71 percentage of stools | Standard Deviation 43.84 |