A Phase 2a, Randomized, Open-Label, Active-Controlled, Crossover Study to Evaluate Safety and Explore Efficacy of Different Doses of New Lipase NHS7108 Administered Orally in Participants With Exocrine Pancreatic Insufficiency- EPIC
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 66
- 试验地点
- 30
- 主要终点
- 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.
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants are eligible to be included in the study only if all of the following criteria apply:
- •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)
- •Standard-of-care medications are allowed (antibiotics, mucolytic agents, aerosols, antacids), if on stable doses for at least 1 month prior to baseline CFA and CNA assessments and must not be altered in dose or stopped during the study.
- •Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators are allowed if on stable doses for at least 3 months prior to randomization. Participants should not start taking CFTR modulators during the duration of the study.
- •Contraceptive use by men and women must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- •Male Participants:
- •Non-sterilized male participants are eligible to participate if they agree to one of the following starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up: Must agree to stay abstinent (where abstinence is the preferred and usual lifestyle of the participant), OR male participants with a female partner of childbearing potential must agree to use highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method). Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration. These requirements also apply to participants in a same sex relationship.
- •Male participants must agree not to donate sperm starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up.
- •Female Participants:
- •Female participants of childbearing potential (as defined in Appendix 4) are eligible to participate if they meet the following criteria: Agree not to become pregnant during the clinical study period and until the end-of-study safety follow-up. Have a negative serum pregnancy test at screening and a negative urine pregnancy test at Day
- •If heterosexually active, must agree to consistently use a form of highly effective birth control, in combination with a barrier method starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up, OR agree to stay abstinent (where abstinence is the preferred and usual lifestyle of the participant), starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up. These requirements do not apply to participants in a same sex relationship.
- •Female participants of nonchildbearing potential are eligible to participate if one of the following conditions apply: Must have a confirmed clinical history of sterility (documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, as confirmed by review of the participant's medical records, medical examination, or medical history interview). Must be postmenopausal as defined as: amenorrhea for at least 1 year prior to screening and a laboratory confirmed serum follicle-stimulating hormone (FSH) level ≥ 40 mIU/mL. Female participants on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use 1 of the non-estrogen hormonal highly effective contraception methods from screening until at and continuing throughout the clinical study period, and until the end-of-study safety follow-up if they wish to continue their HRT during the study.
- •Female participants must agree not to donate ova starting at screening and continuing throughout the clinical study period, and until the end-of-study safety follow-up.
- •For WOCBP only, serum pregnancy test will be performed at screening and urine pregnancy tests will be performed at the timepoints outlined in the SoA.
- •The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- •Participants are capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- •Participants agree not to participate in another interventional study while participating in the study.
排除标准
- •Participants are excluded from the study if any of the following criteria apply:
- •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.
- •Known allergy or adverse reaction history to any component of NHS7108, Zenpep®, omega-3 oil, and/or to any other product administered during the study, including the blue dye.
- •Concurrent clinically significant, at the discretion of the Investigator, hematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, and seasonal allergies and childhood asthma) or any other disorder that in the opinion of the Investigator may put the participant at greater safety risk, influence response to study intervention, or interfere with study assessments.
- •Concurrent conditions having a clinically significant impact on GI motility function, with the exception of pancreatic insufficiency due to pancreatectomy or CP.
- •Any significant clinical/laboratory/radiological sign of unstable or unexpectedly deteriorating respiratory disease during the study duration, at the discretion of the Investigator.
- •Omega-3 supplements are prohibited during all the study periods and should be stopped at least 7 days prior to the baseline off-treatment fat absorption assessments.
- •Participants starting new medications or changing dose within 1 month before baseline off-treatment screening assessments.
- •Acute use of oral or intravenous antibiotics within 2 weeks prior to the first dose of study intervention.
- •Treatment with any investigational drug or device/treatment within the 30 days or 5 half-lives of the drug (whichever is longer) prior to first dose of study intervention.
- •Participant has any clinically significant abnormalities in hematology, coagulation, clinical chemistry, or urinalysis at screening as judged by the Investigator OR as detailed below:
- •Estimated glomerular filtration rate < 60 mL/min at screening visit.
- •Total bilirubin > 1.5 × upper limit of normal (ULN) at screening visit.
- •Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × ULN at screening visit.
- •Positive human immunodeficiency virus (HIV) antibody test.
- •Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) at screening or within 3 months prior to first dose of study intervention.
- •Positive hepatitis C virus (HCV) antibody test result at screening or within 3 months prior to first dose of study intervention AND positive on reflex to hepatitis C RNA test.
- •Concurrent drug or alcohol addiction that in the opinion of the Investigator would preclude participation and compliance with the study procedures.
研究组 & 干预措施
Very Low Dose Group
10 mg NHS7108 [approximately 25,000 LU]/main meal and snack; 25,000 LU Zenpep/main meal and snack.
干预措施: NHS7108 (Drug)
Very Low Dose Group
10 mg NHS7108 [approximately 25,000 LU]/main meal and snack; 25,000 LU Zenpep/main meal and snack.
干预措施: Zenpep® (Drug)
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.
干预措施: NHS7108 (Drug)
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.
干预措施: Zenpep® (Drug)
Medium Dose Group
40 mg NHS7108 [approximately 100,000 LU]/main meal and 20 mg NHS7108 [approximately 50,000 LU]/snack; 100,000 LU Zenpep/main meal and 50,000 LU Zenpep/snack.
干预措施: NHS7108 (Drug)
Medium Dose Group
40 mg NHS7108 [approximately 100,000 LU]/main meal and 20 mg NHS7108 [approximately 50,000 LU]/snack; 100,000 LU Zenpep/main meal and 50,000 LU Zenpep/snack.
干预措施: Zenpep® (Drug)
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.
干预措施: NHS7108 (Drug)
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.
干预措施: Zenpep® (Drug)
结局指标
主要结局
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.
时间窗: 14 days after NHS7108 Treatment
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.
时间窗: At screening and end-of-study/safety follow-up visit. A brief symptom-directed physical examination may be performed at all other visits and at any time throughout the study, as clinically indicated.
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.
时间窗: After 14 -day NHS7108 treatment
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.
时间窗: After 14 -day NHS7108 treatment.
Endpoint: Changes from baseline in safety parameters include vital sign measurement, which will include body temperature. Units of measurement for body temperature: degrees Celsius (°C).
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.
时间窗: 14-day after NHS7108 treatment
Endpoint: Changes from baseline in safety parameters include clinical laboratory tests, which include- Hematology tests: 1. Platelet count (x10E3/uL) 2. White Blood Cell count with differential (percent and absolute): Neutrophils (x10E3/uL)
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.
时间窗: 14 -day after NHS7108 treatment
Endpoint: Changes from baseline in safety parameters include clinical laboratory tests, which include- Coagulation: 2. Prothrombin time (Sec) , 3. Activated partial thromboplastin time (Sec).
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.
时间窗: Serum Beta-HCG pregnancy test (mIU/mL) (at screening) and urine pregnancy tests (at all other timepoints) as needed for women of childbearing potential.
Endpoint: Changes from baseline in safety parameters include clinical laboratory tests, which include- Pregnancy Testing. Highly sensitive serum Beta-HCG pregnancy test (mIU/mL) and urine pregnancy tests (no units)
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.
时间窗: Will be performed at screening in women with unconfirmed reproductive potential status only (to confirm postmenopausal state).
Endpoint: Changes from baseline in safety parameters include clinical laboratory tests, which include- Other Screening Tests: 1. Follicle Stimulating Hormone- FSH (IU/L).
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
时间窗: 14 days after NHS7108 Treatment
Endpoint: Changes from baseline in safety parameters include clinical laboratory tests, which include- Other Screening Tests: 2. Serology: HIV antibody, hepatitis B surface antigen, and hepatitis C virus antibody, hepatitis B surface antibody and hepatitis B core antibody total. (No units)
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
时间窗: After 14 days NHS7108 treatment
Endpoint: Change from baseline in the Coefficient of Nitrogen Absorption (CNA).CNA expresses the ratio between the amount of nitrogen absorbed and the amount of nitrogen provided with the diet. It will also be analyzed from the stool collection period. CNA is calculated as follows: nitrogen intake (g) - excreted nitrogen (g)/nitrogen intake (g), expressed as percentage (%).
次要结局
未报告次要终点