A 3-part, Phase 1a/1b, First-in-human, Randomized, Double-blind, Placebo-controlled Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of Oral CDX-7108 in Healthy Adult Subjects and to Evaluate Proof-of-concept Via Pharmacodynamics of a Single Dose of Oral CDX-7108 in Subjects With Exocrine Pancreatic Insufficiency
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 54
- 试验地点
- 3
- 主要终点
- Changes in physical examination from baseline: General Appearance
研究概览
简要总结
Phase 1a/1b single and multiple ascending dose study of oral CDX-7108 in healthy adult subjects and a single dose proof-of-concept study of oral CDX-7108 in subjects with exocrine pancreatic insufficiency.
No clinical studies have yet been performed with CDX-7108 and its effects in humans are unknown. This is the first-in-human (FIH) study of CDX-7108, which aims to assess the safety, tolerability, pharmacokinetics (PK) of escalating single and multiple oral doses of CDX-7108 in healthy adult subjects and to evaluate the pharmacodynamics of a single dose of oral CDX-7108 in a proof-of-concept (POC) study in subjects with exocrine pancreatic insufficiency (EPI).
详细描述
This is an integrated 3-part study to investigate the safety, tolerability, PK, and PD of CDX-7108. The Parts A and B are randomized, double-blind, placebo-controlled dose escalation parts to investigate the safety, tolerability, immunogenicity, and PK of CDX-7108 after single and multiple oral dose administration in healthy adult subjects. Part C is a randomized, double-blind, placebo-controlled, single-dose, 2-way crossover part to assess POC of CDX-7108 in terms of PD as well as its safety, tolerability, and immunogenicity in subjects with EPI. The study will commence with Part A (single ascending dose [SAD] study) and will progress to Part B (multiple ascending dose [MAD] study), and Part C (POC study)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •All subjects:
- •Capable of giving signed informed consent prior to initiation of any protocol-specific procedures, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- •Body mass index (BMI) between 18.0 and 30.0 kg/m
- •Nonsterilized male subjects are eligible to participate if they agree to ONE of the following starting at Screening and continuing throughout the clinical study period, and for 90 days after IP administration:
- •Must agree to stay abstinent (where abstinence is the preferred and usual lifestyle of the subject), OR
- •Male subjects with a female partner of childbearing potential must agree to use highly effective contraception consisting of 2 forms of birth control.
- •Male subjects 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 do not apply to subjects in a same sex relationship.
- •Male subjects must agree not to donate sperm starting at Screening and continuing throughout the clinical study period, and for 90 days after IP administration.
- •Female subjects of childbearing potential are eligible to participate if they meet the following criteria:
- •Must agree not to become pregnant during the clinical study period and for 30 days after IP administration.
- •Must have a negative serum pregnancy test at Screening and Day -
- •If heterosexually active, must agree to consistently use a form of highly effective birth control, in combination with a barrier method (as defined in Appendix 3) starting at Screening (signing the ICF) and continuing throughout the clinical study period, and for 30 days after IP administration, OR
- •Must agree to stay abstinent (where abstinence is the preferred and usual lifestyle of the subject), starting at Screening (signing the ICF) and continuing throughout the clinical study period, and for 30 days after IP administration.
- •These requirements do not apply to subjects in a same sex relationship.
- •Female subjects of non-childbearing potential are eligible to participate if 1 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 subject'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 subjects 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 (Appendix 3) from Screening (signing the ICF) until at and continuing throughout the clinical study period, and for 30 days after IP administration if they wish to continue their HRT during the study.
- •Female subjects must agree not to donate ova starting at Screening (signing the ICF) and continuing throughout the clinical study period, and for 30 days after IP administration.
- •Subject agrees not to participate in another interventional study while participating in the present clinical study.
- •Parts A (Single Ascending Dose Study) and B (Multiple Ascending Dose Study)
- •Healthy male and female, non-smoking, subjects between the ages of 18 and 55 years, inclusive, at the time of Screening. In each cohort, at least 2 male subjects and 2 female subjects should be enrolled.
- •Appropriate general health, as determined by an experienced physician based on a medical evaluation including detailed medical history, clinical laboratory tests, vital signs, 12-lead ECG, and full physical examination (and neurological assessment).
- •Part C (Proof-of-Concept Study)
- •Male and female subjects between the ages of 18 and 75 years (inclusive) who have undergone total or partial pancreatectomy or have an established diagnosis of CP, as confirmed by fecal pancreatic elastase-1 <100 μg/g in formed stools within 12 months of the Screening visit.
- •Subjects with clinically well controlled EPI under the regular use of PERT (remission or adequate improvement of steatorrhea on PERT), as determined by an experienced physician based on a medical evaluation including detailed medical history, clinical laboratory tests, vital signs, 12-lead ECG, and full physical examination (and neurological assessment).
- •150min percentage 13CO2 excretion rate <4.4% dose/h using the Pancreo-Lip breath test at Screening.
排除标准
- •All subjects
- •Female subject who has been pregnant within the 6 months prior to Screening or breastfeeding within the 3 months prior to Screening.
- •Treatment with any antiplatelet and/or anticoagulant medication, except low-dose aspirin.
- •Evidence or history of specific food intolerance. Examples include gluten intolerance, lactose intolerance, or dairy food intolerance or any food/ingredient included in the standard breakfast provided at the study site.
- •A positive result, on Screening, for serum hepatitis B surface antigen, hepatitis A virus antibodies, hepatitis C virus antibodies or antibodies to human immunodeficiency virus type 1 and/or type
- •Known active infection with COVID-19, or a suspected infection with severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]).
- •Chronic alcoholic intoxication that would preclude compliance with the study procedures.
- •Habitual use of nicotine products or smoking within 3 months (>10 cigarettes per day) prior to Screening, and/or unwilling to refrain from smoking during the confinement period. Nicotine replacement therapy is allowed during the study.
- •Drug addiction that would preclude participation and compliance with study procedures.
- •Subject has a pulse rate <40 or >100 bpm; mean systolic blood pressure (SBP) >150 mmHg; mean diastolic blood pressure (DBP) >95 mmHg at Screening. Repeat measurements are allowed at the discretion of the Investigator.
- •Subject has any clinically significant abnormalities at Screening in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the Investigator, that may interfere with the interpretation of QTc interval changes including abnormal ST-T wave morphology.
- •Subject has prolonged QTcF >450 msec for male subjects or >470 msec for female subjects or a family history of prolonged QT syndrome, at Screening.
- •Plasma donation within the 14 days prior to the first dose of IP or any whole blood donation/significant blood loss >500 mL during the 3 months prior to the first dose of IP.
- •Treatment with any investigational drug or device/treatment within the 30 days or 5 half-lives of the drug (whichever is longer) prior to the administration of IP.
- •Known allergy or adverse reaction history to any component of the CDX-7108 oral dose formulation.
- •Part A (Single Ascending Dose Study) and Part B (Multiple Ascending Dose Study)
- •Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies and childhood asthma) at time of Screening or IP administration, that in the opinion of the Investigator may put the subject at greater safety risk, influence response to study drug, or interfere with study assessments.
- •Current or chronic history of GI disorders or conditions interfering with normal GI anatomy or function. Examples include GI bypass surgery, partial or total gastrectomy, gastric band surgery, major (>1 m) small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac sprue, and small intestinal bacterial overgrowth.
- •A positive Screening test for use of drugs (amphetamines, cocaine, marijuana, opiates, barbiturates, benzodiazepines, methadone, and methamphetamines) and alcohol (breath test). However, there is the option to re-screen once during the Screening period at the discretion of the Investigator or delegate in the case of a positive result at Screening for a prescribed medication, eg, codeine.
- •Subject has any clinically significant abnormalities in hematology, coagulation, clinical chemistry, or urinalysis at Screening as judged by the Investigator, including aspartate aminotransferase (AST) or ALT >1.5 times above the ULN. Repeat measurements are allowed at the discretion of the Investigator.
- •Use of any prescribed or nonprescribed medication in the 2 weeks preceding the first dose of IP. EXCEPTION: Subjects who have received approved vaccines (including approved COVID-19 vaccines) may be allowed if these vaccines are taken no less than 72 hours prior to the IP dose at the discretion of the Investigator.
- •Part C (Proof-of-Concept Study)
- •Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies and childhood asthma) at time of Screening or IP administration, that in the opinion of the Investigator may put the subject at greater safety risk, influence response to study drug, or interfere with study assessments. NOTE: Subjects with treated diabetes secondary to CP or pancreatectomy are allowed.
- •Subject has any clinically significant abnormalities in hematology, coagulation, clinical chemistry, or urinalysis at Screening as judged by the Investigator, including AST or ALT >1.5 times above the ULN, or cholesterol or triglycerides >400 mg/dL. Repeat measurements are allowed at the discretion of the Investigator.
- •Current or chronic history of GI disorders or conditions interfering with normal GI anatomy or motility, with the exception of pancreatic insufficiency due to pancreatectomy, including pancreaticoduodenectomy, or CP
- •Use of any prescribed or nonprescribed medication potentially interfering with gastric pH, intestinal motility, or fat absorption, including herbal and dietary supplements and antacids; these medications shall be stopped for a minimum of 5 times their half-life before IP administration if, in the opinion of the Investigator, this does not represent a risk for the subject's wellbeing. EXCEPTIONS:
- •Histamine H2 receptor antagonists, PPI, insulin, analgesics, and chronic pain medications.
- •Oral contraceptives, paracetamol, or multivitamins. Subjects who have received approved vaccines (including approved COVID-19 vaccines) may be allowed if these vaccines are taken no less than 72 hours prior to the IP dose at the discretion of the Investigator.
- •Use of antibiotics within 8 days before the Pancreo-Lip breath test at Screening or Day 1.
研究组 & 干预措施
CDX-7108
CDX-7108, an oral recombinant lipase. It is a modified version of a triacylglycerol lipase enzyme derived from the bacteria Bacillus thermoamylovans (btLIP) and produced by fermentation of recombinant Escherichia coli.7
干预措施: Part A (Drug)
CDX-7108
CDX-7108, an oral recombinant lipase. It is a modified version of a triacylglycerol lipase enzyme derived from the bacteria Bacillus thermoamylovans (btLIP) and produced by fermentation of recombinant Escherichia coli.7
干预措施: Part B (Drug)
CDX-7108
CDX-7108, an oral recombinant lipase. It is a modified version of a triacylglycerol lipase enzyme derived from the bacteria Bacillus thermoamylovans (btLIP) and produced by fermentation of recombinant Escherichia coli.7
干预措施: Part C (Drug)
Placebo
Excipients only
干预措施: Part A (Drug)
Placebo
Excipients only
干预措施: Part B (Drug)
Placebo
Excipients only
干预措施: Part C (Drug)
结局指标
主要结局
Changes in physical examination from baseline: General Appearance
时间窗: Up to 5 weeks
Changes in general appearance of the skin from baseline
Changes in coagulation tests from baseline
时间窗: Up to 5 weeks
Number of participants with changes in coagulation factors (INR, prothrombin time, fibrogen, red blood cell indices and leukocyte count) using immunoassays.
Changes in Pulse Rate vital signs from baseline
时间窗: Up to 5 weeks
Changes in pulse rate from baseline
Changes in 12-lead electrocardiogram (ECG) PR Interval from baseline
时间窗: Up to 5 weeks
Changes in ECG PR interval from baseline
Changes in 12-lead electrocardiogram (ECG) QT Interval from baseline
时间窗: Up to 5 weeks
Changes in ECG QT interval from baseline
Changes in physical examination from baseline: Musculoskeletal system
时间窗: Up to 5 weeks
Changes in musculoskeletal system from baseline
Changes in physical examination from baseline: Lymph nodes
时间窗: Up to 5 weeks
Changes in lymph nodes from baseline
Changes in physical examination from baseline: Eyes
时间窗: Up to 5 weeks
Changes in general appearance of the eyes from baseline
Adverse events
时间窗: Up to 9 weeks
Number and severity of adverse events
Changes in Systolic Blood Pressure from baseline
时间窗: Up to 5 weeks
Changes in Systolic Blood Pressure from baseline
Changes in Body Temperature vital signs from baseline
时间窗: Up to 5 weeks
Changes in body temperature from baseline
Changes in 12-lead electrocardiogram (ECG) QRS duration from baseline
时间窗: Up to 5 weeks
Changes in electrocardiogram QRS duration interval from baseline
Changes in physical examination from baseline: Nose
时间窗: Up to 5 weeks
Changes in general appearance of the nose from baseline
Changes in haematology from baseline
时间窗: Up to 5 weeks
Number of participants with changes in haematology measurements (erythrocyte count, thrombocyte count, haemoglobin, haematocrit, mean cell hemoglobin concertation) using immunoassays.
Changes in Diastolic Blood Pressure from baseline
时间窗: Up to 5 weeks
Changes in Diastolic Blood Pressure from baseline
Changes in 12-lead electrocardiogram (ECG) Heart Rate from baseline
时间窗: Up to 5 weeks
Changes in ECG Heart rate from baseline
Changes in physical examination from baseline: Head
时间窗: Up to 5 weeks
Changes in general appearance of the head from baseline
Changes in physical examination from baseline: Throat
时间窗: Up to 5 weeks
Changes in general appearance of the throat from baseline
Changes in physical examination from baseline: Cardiovascular system
时间窗: Up to 5 weeks
Changes in cardiovascular system from baseline
Changes in physical examination from baseline: Respiratory system
时间窗: Up to 5 weeks
Changes in respiratory system from baseline
Changes in urinalysis from baseline
时间窗: Up to 5 weeks
Number of participants with changes in leucocyte esterase, protein, urobilinogen, ketones, bilirubin, microscopy, blood, pH, nitrate, specific gravity, urobilinogen and glucose) using immunoassays.
Changes in physical examination from baseline: Ears
时间窗: Up to 5 weeks
Changes in general appearance of the ears from baseline
Changes in clinical chemistry from baseline
时间窗: Up to 5 weeks
Number of participants with changes in clinical chemistry (bicarbonate, albumin, total protein, blood glucose, sodium, potassium, phosphate, calcium, urea creatine, chloride, creatine kinase, urate, AST, ALT, ALP, GGT, triglycerides, total cholesterol, lactate dehydrogenase, c-reactive protein, total bilirubin) using immunoassays.
Changes in Respiratory Rate vital signs from baseline
时间窗: Up to 5 weeks
Changes in respiratory rate from baseline
Changes in 12-lead electrocardiogram (ECG) QTcF Interval from baseline
时间窗: Up to 5 weeks
Changes in ECG QTcF interval from baseline
Changes in physical examination from baseline: Neck
时间窗: Up to 5 weeks
Changes in general appearance of the neck (including thyroid) from baseline
Changes in physical examination from baseline: GI system
时间窗: Up to 5 weeks
Changes in GI system from baseline
Changes in physical examination from baseline: Nervous system
时间窗: Up to 5 weeks
Changes in nervous system from baseline
次要结局
- Concentration-time profile of CDX-7108(Up to 7 days)
- CO2 excretion rate(Up to 43 days)
- Lipase activity(Day 1)