The purpose of this study is to measure the safety and explore the efficacy of 4 different doses of the new lipase NHS7108 in participants with EPI. In this study, all participants will take NHS7108 daily for 14 days and a matching dose of standard-of-care, pancrelipase (Zenpep®) for 14 days according to Treatment Sequence assignment. Both NHS7108 and Zenpep® are oral capsules that will be taken with each of the daily 3 meals and 2 snacks. Participants will interrupt all of their usual pancrelipase/pancreatin treatment for up to 8 days during screening and for the entire 2 treatment periods, where participants will take either the new lipase NHS7108 or a matching dose of the standard-of-care pancrelipase (Zenpep®). Participants will be asked to stay in a setting that allows controlled diet and 72-hour stool collection for approximately 7 days during the screening period and again for approximately 7 days at the end of each treatment period. During these 3 supervised periods, participants will receive a standardized diet with a predefined amount of fat and protein, stools will be collected in special containers and during the last day of the treatment period, blood samples will be obtained to measure fat absorption. These are essential to ensure valid assessment of participants' fat and protein absorption. Outside the 3 supervised periods, participants will be provided with guidelines and recommendations to create their own home-controlled meals and snacks according to their preferences for the remainder of the study duration.
Number of Participants:
The aim is to have 56 participants completing the study. Assuming approximately 14% drop-out rate, approximately 66 participants will be randomized to study intervention.
Study Arms and Duration:
The total study duration for each participant will be about 100 days (approximately 14 weeks), including:
* A screening period of up to approximately 28 days (might be extended up to a total of 56 days) prior to the first dose administration. * A crossover treatment period (2 treatment periods: approximately 14 days each, with no washout in between). For each treatment period, study intervention will be administered 5 times a day (with 3 main meals and 2 snacks). After completion of Treatment Period 1, the participant will receive and start the new treatment for Treatment Period 2. * An end of treatment/early discontinuation visit within approximately 7 days of the last study intervention dose. * An end-of-study safety follow-up visit at 14 (±2) days after the last dose administration.
Very low dose group: 10 mg NHS7108 (approximately 25,000 LU)/main meal and snack; 25,000 LU Zenpep/main meal and snack (50 mg NHS7108 \[approximately 125,000 LU\] per day; 125,000 LU Zenpep per day)
Low dose group: 20 mg NHS7108 (approximately 50,000 LU)/main meal and 10 mg NHS7108 (approximately 25,000 LU)/snack; 50,000 LU Zenpep/main meal and 25,000 LU Zenpep/snack (80 mg NHS7108 \[approximately 200,000 LU\] per day; 200,000 LU Zenpep per day)
Medium dose group: 40 mg NHS7108 (approximately 100,000 LU)/main meal and 20 mg (approximately 50,000 LU) NHS7108/snack; 100,000 LU Zenpep/main meal and 50,000 LU Zenpep/snack (160 mg \[approximately 400,000 LU\] NHS7108 per day; 400,000 LU Zenpep per day)
High dose group: 60 mg NHS7108 (approximately 150,000 LU)/main meal and 30 mg NHS7108 (approximately 75,000 LU)/snack; 150,000 LU Zenpep/main meal and 75,000 LU Zenpep/snack (240 mg NHS7108 \[approximately 600,000 LU\] per day; 600,000 LU Zenpep per day).
The dose for participants \< 60 kg who are assigned to the high dose group will need to be weight-adjusted to ensure that they receive no more than 10,000 LU/kg/day.
Participant is a male or female between 18 to 85 years of age, inclusive, at the time of signing the informed consent.
Participants with clinically confirmed* chronic established (not due to a transient clinical diagnosis, i.e., acute pancreatitis) EPI and with a clinical indication for PERT.
CFA off PERT of <80% at screening
Normal body mass index (BMI) by age and sex to ensure participant's EPI is adequately controlled in the opinion of the investigator (BMI of at least 17.0 and no greater than 35.0 kg/m²)
Female participants who are breastfeeding at the time of screening.
Previous GI surgery, except for non-invasive neonatal or early childhood procedures such as correction of hypertrophic pyloric stenosis, surgical correction of Meckel's diverticulum, volvulus, or intestinal intussusception. Hernia repair, appendectomy, cesarean section, tubal ligation, hysterectomy, polypectomy, hemorrhoidectomy, or cholecystectomy are allowed if performed at least 2 years before randomization and have no impact on intestinal transit or absorption.
Participants on enteral feeding.
Participants with celiac disease.
Crossover
NHS7108
DrugNHS7108 is the experimental drug. It is a recombinant, modified version of a triacylglycerol lipase enzyme derived from the bacteria Bacillus thermoamylovorans and produced by fermentation of recombinant Escherichia coli. Unit dose strength: 10 mg (approximately 25,000 LU) per capsule.
Zenpep®
DrugZenpep® is the active comparator. It is a combination of lipases, proteases, and amylases. Unit dose strength: 25,000 LU per capsule.
Primary Objectives: Safety of different doses of NHS7108 administered daily for 14 days in participants with exocrine pancreatic insufficiency (EPI). Coefficient of nitrogen absorption (CNA) will be measured as part of safety.
Endpoint: Number of participants reporting 1 or more adverse events. Events Meeting the AE Definition: * Any abnormal laboratory test results or other safety assessments including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the Investigator. * Exacerbation of a chronic or in or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition. * New condition detected or diagnosed after study intervention administration even though it may have been present before the start of the study. * Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention interaction. * Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant medication.
Primary Objective: Safety of different doses of NHS7108 administered daily for 14 days in participants with exocrine pancreatic insufficiency (EPI). Coefficient of nitrogen absorption (CNA) will be measured as part of safety.
A complete physical examination will be performed and include, at a minimum, assessments of general appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, respiratory system, GI system, musculoskeletal system, lymph nodes, and nervous system.
Primary Objective: Safety of different doses of NHS7108 administered daily for 14 days in participants with exocrine pancreatic insufficiency (EPI). Coefficient of nitrogen absorption (CNA) will be measured as part of safety.
Endpoint: Changes from baseline in safety parameters include vital sign measurement, which will include Blood Pressure. Units of measurement for Blood Pressure: Millimeters of mercury (mm Hg)
Primary Objective: Safety of different doses of NHS7108 administered daily for 14 days in participants with exocrine pancreatic insufficiency (EPI). Coefficient of nitrogen absorption (CNA) will be measured as part of safety.
Endpoint: Changes from baseline in safety parameters include vital sign measurement, which will include Heart Rate. Units of measurement for Heart Rate: Beats Per Minute (BPM)
Exploratory Objective: A) The effect of different doses of NHS7108 administered for 14 days in participants with EPI on fat absorption
Endpoint: 1. Change from baseline in the CFA. CFA expresses the ratio between the amount of fat absorbed and the amount of fat provided with the diet and is considered the gold standard for the evaluation of efficacy of PERT. It requires collection of stools produced over a 72-hour period within a timeframe of approximately 7 days at the end of each treatment period, while the participant consumes a controlled diet providing a predefined amount of fat.
Exploratory Objective: A) The effect of different doses of NHS7108 administered for 14 days in participants with EPI on fat absorption
2\. Omega-3 absorption test: change from baseline in post-prandial EPA and DHA content of plasma over a 24-hour period after standard breakfast along with area under the plasma level of EPA- and DHA-time curve from 0 (before breakfast) to 24 hours post-prandial (AUC0-24) and maximum plasma level of EPA and DHA (Cmax).
Exploratory objective: B) Effects of NHS7108 on gastrointestinal (GI) symptoms
Endpoint: 1.Change from baseline in the Gastrointestinal Symptom Rating Scale (included in the eDiary)
Exploratory objective: B) Effects of NHS7108 on gastrointestinal (GI) symptoms
Endpoint: 2. Stool frequency as assessed by the eDiary
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Aimmune Nestlé Health Science US R&D, LLC
Lead sponsor
Parexel
Collaborator
