A Study to Assess the Safety, Tolerability, and Pharmacokinetics of Ascending, Subcutaneous, Single and Multiple Doses of SHP681 (Glucagon-like Peptide-2 [GLP-2] Analog-Fc Fusion) in Healthy Adult Participants

• ClinicalTrials.gov Identifier: NCT03859323
• Recruitment Status: Completed
• First Posted: March 1, 2019
• Last Update Posted: February 17, 2020
• Sponsor: Shire
• Information provided by (Responsible Party): Shire

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers	Drug: SHP681; Other: Placebo	Phase 1

Detailed Description:

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 102 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 26, 2019
• Actual Primary Completion Date: January 6, 2020
• Actual Study Completion Date: January 6, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Single Ascending Dose (SAD): 0.2 mg/kg; Participants will receive single subcutaneous (SC) injection of 0.2 mg/kg SHP681 in the abdomen.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Experimental: Single Ascending Dose (SAD): 0.5 mg/kg; Participants will receive single SC injection of 0.5 mg/kg SHP681 in the abdomen.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Experimental: Single Ascending Dose (SAD): 1 mg/kg; Participants will receive single SC injection of 1 mg/kg SHP681 in the abdomen.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Experimental: Single Ascending Dose (SAD): 2 mg/kg; Participants will receive single SC injection of 2 mg/kg SHP681 in the abdomen.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Experimental: Single Ascending Dose (SAD): 4 mg/kg; Participants will receive single SC injection of 4 mg/kg SHP681 in the abdomen.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Placebo Comparator: Single Ascending Dose (SAD): Placebo; Participants will receive single SC injection of placebo matched to SHP681 in the abdomen.	Other: Placebo; Participants will receive SC injection of placebo matched to SHP681 in the abdomen.
Experimental: 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.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Experimental: 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.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Experimental: 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.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Experimental: 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.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Experimental: 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.	Drug: SHP681; Participants will receive SC injection of SHP681 in the abdomen.
Placebo Comparator: Multiple Ascending Dose (MAD): Placebo; Participants will receive SC injection of placebo matched to SHP681 once weekly for 5 weeks in the abdomen.	Other: Placebo; Participants will receive SC injection of placebo matched to SHP681 in the abdomen.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) to SHP681 in Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: From start of study drug administration up to follow-up (Day 29 for SAD / Day 57 for MAD) ]
   An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. TEAEs are defined as all AEs occurring or worsening at or after the first dose of investigational drug product in SHP681-101 or ongoing from SHP681-101 at the time of enrollment into SHP681-101 will be summarized.
2. Number of Participants With Anti-drug Antibody (ADA) to SHP681 in Single Ascending Dose (SAD) Portion of the Study [ Time Frame: Day 29 ]
   ADA of SHP681 will be assessed.
3. Number of Participants With Anti-drug Antibody (ADA) to SHP681 in Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: Day 36 ]
   ADA of SHP681 will be assessed.
4. Number of Participants With Anti-drug Antibody (ADA) to SHP681 in Multiple Ascending Dose (MAD) Portion of the Study Day [ Time Frame: Day 57 ]
   ADA of SHP681 will be assessed.
5. Number of Participants With Neutralizing Anti-drug Antibody (nADA) to SHP681 in Single Ascending Dose (SAD) Portion of the Study [ Time Frame: Day 29 ]
   nADA of SHP681 will be assessed.
6. Number of Participants With Neutralizing Anti-drug Antibody (nADA) to SHP681 in Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: Day 36 ]
   nADA of SHP681 will be assessed.
7. Number of Participants With Neutralizing Anti-drug Antibody (nADA) to SHP681 in Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: Day 57 ]
   nADA of SHP681 will be assessed.

Secondary Outcome Measures :

1. Maximum Observed Plasma Concentration (Cmax) of SHP681 During Single Ascending Dose (SAD) Portion of the Study [ Time Frame: Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose ]
   Cmax of SHP681 will be assessed.
2. Time of the Last Measurable Concentration (tlast) of SHP681 During Single Ascending Dose (SAD) Portion of the Study [ Time Frame: Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose ]
   tlast of SHP681 will be assessed.
3. Time of Maximum Observed Concentration Sampled During a Dosing Interval (tmax) of SHP681 During Single Ascending Dose (SAD) Portion of the Study [ Time Frame: Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose ]
   tmax of SHP681 will be assessed.
4. Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-last) of SHP681 During Single Ascending Dose (SAD) Portion of the Study [ Time Frame: Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose ]
   AUC0-last of SHP681 will be assessed.
5. Area Under the Curve Extrapolated to Infinity (AUC0-inf) of SHP681 During Single Ascending Dose (SAD) Portion of the Study [ Time Frame: Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose ]
   AUC0-inf of SHP681 will be assessed.
6. Terminal Half-life (t1/2) of SHP681 During Single Ascending Dose (SAD) Portion of the Study [ Time Frame: Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose ]
   t1/2 of SHP681 will be assessed.
7. First Order Rate Constant Associated With the Terminal (log-linear) Portion of the Curve (Lambda z) of SHP681 During Single Ascending Dose (SAD) Portion of the Study [ Time Frame: Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose ]
   Lambda z of SHP681 will be assessed.
8. 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) Portion of the Study [ Time Frame: Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose ]
   CL/F of SHP681 will be assessed.
9. 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) Portion of the Study [ Time Frame: Pre-dose, 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504, 672 hours post-dose ]
   Vz/F of SHP681 will be assessed.
10. Area Under the Curve From the Time of Dosing to the 24 hours Post First Dose(AUC0-24) of SHP681 Post First Dose During Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: 3, 6, 12, 24 hours post-dose on Day 1 ]
    AUC0-24 of SHP681 post first dose during MAD portion of the study will be assessed.
11. Maximum Concentration Occurring During 24 hours After First Dose (Cmax,24) of SHP681 Post First Dose During Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: 3, 6, 12, 24 hours post-dose on Day 1 ]
    Cmax,24 of SHP681 post first dose during MAD portion of the study will be assessed.
12. Time of Maximum Observed Concentration During 24 hours After First Dose (tmax,24) of SHP681 Post First Dose During Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: 3, 6, 12, 24 hours post-dose on Day 1 ]
    tmax,24 of SHP681 post first dose during MAD portion of the study will be assessed.
13. 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) Portion of the Study [ Time Frame: 3, 6, 12, 24 hours post-dose on Day 1; pre-dose on Days 8, 15, 22 and 29 ]
    Ctrough of SHP681 for the First 5 cohorts and immediately before 2nd and 3rd dose of the 6th MAD cohort during MAD portion of the study will be assessed.
14. Maximum Concentration During the Dosing Interval Occurring at tmax (Cmax) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    Cmax of SHP681 post fifth dose during MAD portion of the study will be assessed.
15. Time of the Last Measurable Concentration (Tlast) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    Tlast of SHP681 post fifth dose during MAD portion of the study will be assessed.
16. Time of Maximum Observed Concentration Sampled During a Dosing Interval (tmax) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    tmax of SHP681 post fifth dose during MAD portion of the study will be assessed.
17. Area Under the Curve for the Defined Interval Between Doses (Only Calculated if Interpretable) (AUCtau) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    AUCtau of SHP681 post fifth dose during MAD portion of the study will be assessed.
18. 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) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    AUC0-last of SHP681 post fifth dose during MAD portion of the study will be assessed.
19. Area Under the Curve Extrapolated to Infinity (AUC0-inf) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    AUC0-inf of SHP681 post fifth dose during MAD portion of the study will be assessed.
20. Terminal Half-life (t1/2) of SHP681 Post Fifth Dose During Multiple Ascending Dose (MAD) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    t1/2 of SHP681 post fifth dose during MAD portion of the study will be assessed.
21. 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) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    Lambda z of SHP681 post fifth dose during MAD portion of the study will be assessed.
22. 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) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    CL/F of SHP681 post fifth dose during MAD portion of the study will be assessed.
23. 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) Portion of the Study [ Time Frame: 3, 6, 12, 24, 48, 72, 96, 120, 168, 240, 336, 504 and 672 hours post-dose on Day 29 ]
    Vz/F of SHP681 post fifth dose during MAD portion of the study will be assessed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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:

  1. Have used an investigational product (if elimination half-life is less than (<) 6 days, otherwise 5 half-lives).
  2. Have been enrolled in a clinical study.
  3. 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 -1.

• 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.

Contacts and Locations

Locations

United States, Tennessee

New Orleans Center for Clinical Research

Knoxville, Tennessee, United States, 37920

Sponsors and Collaborators

Shire

Investigators

• Study Director: Study Director; Shire

More Information

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT03859323
• Other Study ID Numbers: SHP681-101
• First Posted: March 1, 2019
• Last Update Posted: February 17, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No