A Randomized, Double-blind, Placebo-controlled, Phase 1 Study to Assess the Safety, Tolerability, and Pharmacokinetics of Ascending, Subcutaneous, Single and Multiple Doses of SHP681 (GLP-2 Analog-Fc Fusion) in Healthy Adult Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Shire
- 入组人数
- 104
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Based on Severity to SHP681 in Multiple Ascending Dose (MAD)
研究概览
简要总结
The purpose of the study is to assess the safety and tolerability of single and multiple ascending subcutaneous (SC) doses of SHP681 in healthy adult participants.
详细描述
The study consists of a single ascending dose (SAD) portion and a multiple ascending dose (MAD) portion.
The study duration for the SAD portion of the study consists of a screening period of up to 28 days and 1 treatment period of 29 days. SAD portion of the study contains 5 cohorts and dose escalation will proceed sequentially to assess the following single SC doses of SHP681 or SHP681 matched placebo: 0.2 milligram per kilogram (mg/kg), 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg.
The study duration of the MAD portion comprises of a screening period up to 28 days and a treatment period of 57 days for each cohort. MAD portion of the study contains 6 cohorts and dose escalation will proceed sequentially to assess the following SC doses of SHP681 or SHP681 matched placebo: 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg once weekly for 5 weeks till 5 cohorts and the 6th cohort will receive 4 mg/kg SHP681 or matched placebo every 2 weeks over a 6-week period (3 doses).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Ability to voluntarily provide written, signed, and dated informed consent to participate in the study.
- •An understanding, ability, and willingness to fully comply with study procedures and restrictions.
- •Age 18-50 inclusive at the time of consent. The date of signature of the informed consent is defined as the beginning of the screening period. This inclusion criterion will only be assessed at the first screening visit.
- •Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive requirements of the protocol or females of non-childbearing potential.
- •Considered "healthy" by the investigator. Healthy status is defined by absence of evidence of any active or chronic disease or condition based on a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead electrocardiogram (ECG), hematology, blood chemistry, and urinalysis.
- •Body mass index between 18.0 kilograms per square meter (kg/m^2) and 30.0 kg/m^2 inclusive with a body weight 50-100 kg (110-220 pounds [lbs]). This inclusion criterion will only be assessed at the first screening visit.
排除标准
- •History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or psychiatric disease, gall bladder removal, or current or recurrent disease that could affect the action, absorption, or disposition of the investigational product, or clinical or laboratory assessments.
- •Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment or render the participant unlikely to fully complete the study, or any condition that presents undue risk from the investigational product or procedures.
- •Known or suspected intolerance or hypersensitivity to the investigational product(s), closely-related compounds, or any of the stated ingredients.
- •Significant illness, as judged by the investigator, within 2 weeks of the first dose of investigational product.
- •Known history of alcohol or other substance abuse within the last year.
- •Donation of blood or blood products (example [eg], plasma or platelets) within 60 days prior to receiving the first dose of investigational product.
- •Within 30 days prior to the first dose of investigational product:
- •Have used an investigational product (if elimination half-life is less than (<) 6 days, otherwise 5 half-lives).
- •Have been enrolled in a clinical study.
- •Have had any substantial changes in eating habits, as assessed by the investigator.
- •Use of dipeptidyl peptidase (DPP)-4 inhibitors within 30 days or 5 half-lives, whichever is greater, prior to administration of the investigational product.
- •Confirmed systolic blood pressure greater than (>) 139 millimeters of mercury (mmHg) or <89mmHg, and diastolic blood pressure > 89mmHg or <49 mmHg.
- •Twelve-lead ECG demonstrating corrected QT interval by Fredericia (QTcF) >450 millisecond (msec) at screening. If QTcF exceeds 450 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF values should be used to determine the participant's eligibility.
- •Positive screen for alcohol or illicit drugs at screening or Day -
- •Male participants who consume more than 21 units of alcohol per week or 3 units per day. Female participants who consume more than 14 units of alcohol per week or 2 units per day.
- •(1 alcohol unit equal to [=] 1 beer or 1 wine (5 ounce [oz] per 150 milliliter [mL]) or 1 liquor (1.5 oz/40 mL) or 0.75 oz alcohol).
- •Positive human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody screen.
- •Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products in any form (eg, gum, patch). Ex-users must report that they have stopped using tobacco for at least 30 days prior to receiving the first dose of investigational product.
- •Routine consumption of more than 2 units of caffeine per day or participants who experience headaches associated with caffeine withdrawal. (1 caffeine unit is contained in the following items: one 6 oz (180 mL) cup of coffee, two 12 oz (360 mL) cans of cola, one 12 oz cup of tea, three 1 oz (85 g) chocolate bars. Decaffeinated coffee, tea, or cola are not considered to contain caffeine).
- •Prior screen failure (unless Sponsor approval is given), randomization, participation, or enrollment in this study or prior exposure to any GLP-2 analogs.
- •Unresected gastrointestinal (GI) polyp, known polyposis condition, or premalignant changes in the GI tract.
- •Any history of malignancy in the GI tract or treatment for any other malignancy in the previous 5 years.
- •Current use of any medication (including over-the-counter, herbal, or homeopathic preparations; with the exception of hormonal replacement therapy or hormonal contraceptives and occasional use of ibuprofen or acetaminophen and pre-approved medication for sedation or other medications required during or after the endoscopy). Current use is defined as use within 14 days of the first dose of investigational product.
- •Findings of subclinical hepatobiliary disease, such as gallstones, on abdominal ultrasound at screening as determined by the Investigator in consultation with the Medical Monitor.
研究组 & 干预措施
Single Ascending Dose (SAD): 0.2 mg/kg
Participants will receive single subcutaneous (SC) injection of 0.2 mg/kg SHP681 in the abdomen.
干预措施: SHP681 (Drug)
Single Ascending Dose (SAD): 0.5 mg/kg
Participants will receive single SC injection of 0.5 mg/kg SHP681 in the abdomen.
干预措施: SHP681 (Drug)
Single Ascending Dose (SAD): 1 mg/kg
Participants will receive single SC injection of 1 mg/kg SHP681 in the abdomen.
干预措施: SHP681 (Drug)
Single Ascending Dose (SAD): 2 mg/kg
Participants will receive single SC injection of 2 mg/kg SHP681 in the abdomen.
干预措施: SHP681 (Drug)
Single Ascending Dose (SAD): 4 mg/kg
Participants will receive single SC injection of 4 mg/kg SHP681 in the abdomen.
干预措施: SHP681 (Drug)
Single Ascending Dose (SAD): Placebo
Participants will receive single SC injection of placebo matched to SHP681 in the abdomen.
干预措施: Placebo (Other)
Multiple Ascending Dose (MAD): 0.2 mg/kg
Participants will receive SC injection of 0.2 mg/kg SHP681 once weekly for 5 weeks in the abdomen.
干预措施: SHP681 (Drug)
Multiple Ascending Dose (MAD): 0.5 mg/kg
Participants will receive SC injection of 0.5 mg/kg SHP681 once weekly for 5 weeks in the abdomen.
干预措施: SHP681 (Drug)
Multiple Ascending Dose (MAD): 1 mg/kg
Participants will receive SC injection of 1 mg/kg SHP681 once weekly for 5 weeks in the abdomen.
干预措施: SHP681 (Drug)
Multiple Ascending Dose (MAD): 2 mg/kg
Participants will receive SC injection of 2 mg/kg SHP681 once weekly for 5 weeks in the abdomen.
干预措施: SHP681 (Drug)
Multiple Ascending Dose (MAD): 4 mg/kg
Participants will receive SC injection of 4 mg/kg SHP681 once weekly for 5 weeks in the abdomen.
干预措施: SHP681 (Drug)
Multiple Ascending Dose (MAD): Placebo
Participants will receive SC injection of placebo matched to SHP681 once weekly for 5 weeks in the abdomen.
干预措施: Placebo (Other)
结局指标
主要结局
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Based on Severity to SHP681 in Multiple Ascending Dose (MAD)
时间窗: From start of study drug administration up to follow-up (Day 57 for MAD)
AE was any unfavorable and unintended sign, symptom, or disease temporally associated with study or use of investigational drug product (IP), whether or not the AE was considered related to IP. TEAEs: AEs occurring or worsening at or after first dose of IP or ongoing at time of enrollment. SAE :untoward medical occurrence that at any dose met one, more of the following criteria: results in death, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent, significant disability/incapacity, a congenital abnormality/birth defect, an important medical event. Severity: Mild: event that does not generally interfere with usual activities of daily living; Moderate: event that interferes with usual activities of daily living, causing discomfort, permanent risk of harm; Severe: AE that interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention.
Number of Participants With Anti-drug Antibody (ADA) to SHP681 in Single Ascending Dose (SAD) at Day 29
时间窗: Day 29
Antibody testing was conducted using an electro chemiluminescent signal method. Number of participants with ADA to SHP681 in SAD at Day 29 were reported.
Number of Participants With Anti-drug Antibody (ADA) to SHP681 in Multiple Ascending Dose (MAD) at Day 36
时间窗: Day 36
Antibody testing was conducted using an electro chemiluminescent signal method. Number of participants with ADA to SHP681 in MAD at Day 36 were reported.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Based on Severity to SHP681 in Single Ascending Dose (SAD)
时间窗: From start of study drug administration up to follow-up (Day 29 for SAD)
Adverse event (AE) was any unfavorable and unintended sign, symptom, or disease temporally associated with study or use of investigational drug product (IP), whether or not the AE was considered related to IP. TEAEs: AEs occurring or worsening at or after first dose of IP or ongoing at time of enrollment. SAE :untoward medical occurrence that at any dose met one, more of the following criteria: results in death, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent, significant disability/incapacity, a congenital abnormality/birth defect, an important medical event. Severity: Mild: event that does not generally interfere with usual activities of daily living; Moderate: event that interferes with usual activities of daily living, causing discomfort, permanent risk of harm; Severe: AE that interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention.
Number of Participants With Anti-drug Antibody (ADA) to SHP681 in Multiple Ascending Dose (MAD) at Day 57
时间窗: Day 57
Antibody testing was conducted using an electro chemiluminescent signal method. Number of participants with ADA to SHP681 in MAD at Day 57 were reported.
次要结局
- Average Concentration From Time Zero to 24 Hours Post Dose (Cavg,0-24) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24 hours post-dose)
- First Order Rate Constant Associated With the Terminal (Log-linear) Portion of the Curve (Lambda z) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose)
- Apparent Volume of Distribution Following Extravascular Administration Divided by the Fraction of Dose Absorbed Calculated as CL/F Divided by Lambda z (Vz/F) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose)
- Maximum Concentration During the Dosing Interval Occurring at Tmax (Cmax) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- Time of Maximum Observed Concentration Sampled During a Dosing Interval (Tmax) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- Average Concentration From Time Zero to 24 Hours Post Dose (Cavg,0-24) of SHP681 During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- Apparent Total Body Clearance Following Extravascular Administration Divided by the Fraction of Dose Absorbed Calculated as Dose Divided by AUCtau (CL/F) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- Time of the Last Measurable Concentration (Tlast) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose)
- Maximum Observed Plasma Concentration (Cmax) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose)
- Time of Maximum Observed Concentration Sampled During a Dosing Interval (Tmax) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose)
- Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-last) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose)
- Area Under the Curve Extrapolated to Infinity (AUC0-inf) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose)
- Terminal Half-life (t1/2) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose)
- Observed Concentration at the End of Each Dosing Interval (Immediately Before Next Dose) (Ctrough) of SHP681 for the First 5 Cohorts and Immediately Before 2nd and 3rd Dose of the 6th MAD Cohort During Multiple Ascending Dose (MAD)(Pre-dose on Days 8, 15, 22 and 29)
- Terminal Half-life (t1/2) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- First Order Rate Constant Associated With the Terminal (Log-linear) Portion of the Curve (Lambda z) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- Apparent Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed Calculated as Dose Divided by AUC0-inf (CL/F) of SHP681 During Single Ascending Dose (SAD)(Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose)
- Average Concentration From Time Zero to 24 Hours Post First Dose (Cavg,0-24) of SHP681 Post First Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24 hours post-dose on Day 1)
- Time of the Last Measurable Concentration (Tlast) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- Area Under the Curve for the Defined Interval Between Doses (Only Calculated if Interpretable) (AUC0-tau) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- Area Under the Curve Extrapolated to Infinity (AUC0-inf) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-last) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)
- Apparent Volume of Distribution Following Extravascular Administration Divided by the Fraction of Dose Absorbed Calculated as CL/F Divided by Lambda z (Vz/F) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD)(3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 and up to 768 hours post--dose on Day 29)