Study of the Gut Hormone Analogue Y14 in Adult Subjects

A Randomised, Placebo Controlled First in Human Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Y14 in Adult Subjects

A randomised, placebo controlled Phase I study to investigate investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of Y14 in adult subjects.

Study Overview

• Status: Completed
• Conditions: Obesity; Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: Y14

Detailed Description

Objectives:

Primary Objective

• To investigate the safety and tolerability of single doses of Y14 in overweight/obese but otherwise healthy male subjects.
• To investigate the safety and tolerability of multiple doses of Y14 in overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or prediabetes.

Secondary Objectives

• To assess the pharmacokinetic (PK) profile of single doses of Y14 in overweight/obese but otherwise healthy male subjects.
• To assess the PK profile of multiple ascending doses of Y14 in overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or prediabetes.

Exploratory Objective

• To investigate the effects of multiple doses of Y14 on food consumption, body weight and glucose tolerance in overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or prediabetes.

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom, LS2 9LH
    • Covance Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Adult males aged 18 to 65 years inclusive with BMI between 25.0 and 38.0 kg/m2 inclusive;
2. (PART B only) Subjects who have normal glucose tolerance, Type 2 diabetes, impaired glucose tolerance or impaired fasting glucose according to WHO 2006 and 2011 criteria;
3. Subjects who are otherwise healthy enough to participate, as determined by pre-study medical history, physical examination and 12-lead ECG;
4. Subjects whose clinical laboratory test results are either within the normal range or if outside this range the abnormalities are judged to be not clinically relevant and are acceptable to the Investigator;
5. Subjects who are negative for hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) I and II tests at screening;
6. Subjects who are negative for drugs of abuse and alcohol tests at screening and admissions;
7. Subjects who are non-smokers for at least 3 months preceding screening;
8. Subjects who agree to use medically acceptable methods of contraception for at least 3 months after study drug administration;
9. Subjects who agree not to donate sperm for at least 3 months after study drug administration;
10. Subjects who are able and willing to give written informed consent.

Exclusion Criteria:

1. Subjects who do not conform to the above inclusion criteria;
2. Subjects who have a clinically relevant history or presence of gastrointestinal (especially associated with vomiting), respiratory, renal, hepatic, haematological, lymphatic, neurological (especially if associated with balance disorders or vomiting e.g. migraine or labyrinthitis), cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders;
3. Subjects who have a clinically relevant surgical history;
4. Subjects who are currently taking any of the following classes of diabetes medications: thiazolidinediones, dipeptidyl peptidase IV inhibitors ('gliptins'), GLP-1 analogues, and insulin;
5. Subjects who have a history of relevant and severe atopy e.g. asthma, angioedema requiring emergency treatment, severe hayfever requiring regular treatment (i.e. taking antihistamines and/or glucocorticoids more regularly than 3 times a week), severe eczema requiring regular treatment (i.e. taking antihistamines and/or glucocorticoids more regularly than 3 times a week);
6. Subjects who have a history of relevant drug hypersensitivity;
7. Subjects who have a history of alcohol abuse or alcohol dependence according to DSMIV criteria within the last 2 years;
8. Subjects who have a history of drug or substance abuse according to DSM-IV criteria within the last 2 years;
9. Subjects who have a history of clinically significant migraine as judged by the Investigator. Subjects can be included if they have not had a migraine for the last 3 years;
10. Subjects with a history of pancreatitis or pancreatic cancer;
11. Subjects who consume more than 21 units of alcohol a week (unit = 1 glass of wine (125 mL) = 1 measure of spirits = ½ pint of beer);
12. Subjects who have a significant infection or known inflammatory process on screening;
13. Subjects who have acute gastrointestinal symptoms at the time of screening or admission (e.g. nausea, vomiting, diarrhoea, heartburn);
14. Subjects who have an acute infection such as influenza at the time of screening or admission;
15. Subjects who have used prescription drugs within 2 weeks of first dosing. For Part B, patients are allowed to be treated for their diabetes with monotherapy with a sulphonylurea, metformin, or a SGLT-2 inhibitor, dual therapy with any two of the following drug types: a sulphonylurea, metformin, and/or a SGLT-2 inhibitor; triple therapy with a sulphonylurea, metformin, and a SGLT-2 inhibitor. In addition patients in Part B are allowed to take hypolipidaemic and/or antihypertensive treatments, provided that the doses have not been altered within the 4 weeks prior to entering the study. Other medications may be allowed if the Investigator and Sponsor both agree that they will not affect the outcome of the study or the safety of the subject.
16. Subjects who have used over the counter medication excluding routine vitamins and paracetamol but including megadose (intake of 20 to 600 times the recommended daily dose) vitamin therapy within 7 days of first dosing, unless agreed as not clinically relevant by the Principal Investigator and Sponsor;
17. Subjects who have donated blood within 3 months prior to screening; Subjects who have donated plasma within the 7 days prior to screening; Subjects who have donated platelets within the 6 weeks prior to screening
18. Subjects who have used any investigational drug in any clinical trial within 3 months of their first admission date;
19. Subjects who have received the last dose of investigational drug greater than 3 months ago but who are on extended follow-up;
20. Subjects who have previously received Y14;
21. Subjects who are vegans, vegetarian or have any dietary restriction (unless agreed as not clinically relevant by the PI and Sponsors);
22. Subjects who cannot communicate reliably with the Investigator;
23. Subjects who are unlikely to co-operate with the requirements of the study;
24. History or evidence of abnormal eating behaviour, as observed through the Dutch Eating Behaviour (DEBQ) and SCOFF questionnaires at screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

16

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1.0 mg Y14 (A1); Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 2.0 mg Y14 (A1); Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 6.0 mg Y14 (A1); Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 9.0 mg Y14 (A2) with varied formulation; Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 18.0 mg Y14 (A5) with varied formulation; Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 36.0 mg Y14 (A6) with varied formulation; Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Placebo Comparator: Placebo (B); 5 subcutaneous injections of 0.9% saline, over a 4 week treatment period	Drug: Placebo; 0.9% saline; Other Names: Saline
Experimental: 9-26.0 mg (B1); Y14 multiple dose, subcutaneous 5 doses over a 4 week treatment period: escalating doses to a max of 26 mg	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 9-36 mg (B2); Y14 multiple dose, subcutaneous 4 doses over a 4 week treatment period: escalating doses to a max of 36 mg	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 12-36 mg (B3); Y14 multiple dose, subcutaneous 4 doses over a 4 week treatment period: escalating doses to a max of 36 mg	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Placebo Comparator: Placebo (A); Single subcutaneous injection of 0.9% saline	Drug: Placebo; 0.9% saline; Other Names: Saline
Experimental: 9 mg Y14 (A3) with varied formulation; Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 9 mg Y14 (A4) with varied formulation; Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 18 mg Y14 (A7) with varied formulation; Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 36 mg Y14 (A8) with varied formulation; Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue
Experimental: 36 mg Y14 (A9) with varied formulation; Y14 single dose, subcutaneous	Drug: Y14; Gut hormone analogue; Other Names: Gut hormone analogue

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability)	As assessed by reporting of adverse events, vital signs, physical examination, clinical laboratory safety assessments, and ECG parameters. Possibly or definitely related to study drug	Up to 73 days after dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax	The maximum observed concentration	For Part A, Cohorts A3 to A9 - up to 840 hour post dose. For Part B - up to day 70 post 1st dose
AUC 0-72h	The area under the concentration versus time curve from time zero to 72 h postdose, calculated by the mixed linear/log trapezoidal rule	Up to 72hr after dosing
AUC 0-τ	The area under the concentration versus time curve within a (168 h) dosing interval, calculated by the mixed linear/log trapezoidal rule (equivalent to AUC0-168h, which was calculated as the area under the concentration versus time curve from time zero to 168 h post-dose after a single dose, calculated by the mixed linear/log trapezoidal rule).	Up to 168h after dosing
T 1/2	Drug Half-life (t1/2) is defined as the amount of time (hours) required for the drug concentration to be reduced to exactly half its initial concentration or amount in blood. The apparent terminal half-life, calculated from Loge 2 / λz: For Part A cohorts, it was not possible to estimate an unambiguous Tmax or T1/2 due to the extended PK profile of Y14. For Part B cohorts, no individual administered dose half-life data were collected for this outcome, but one half-life value was measured after all doses had been administered and these values were analysed only for the treated-arms that is B1, B2 and B3.	For Part A, Cohorts A3 to A9 - up to 840 hour post dose. For Part B - up to day 70 post 1st dose

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Medical Research Council; Covance
• Investigators: Study Director: Stephen Bloom, FMedSci, FRS, Sponsor Chief Investigator, Imperial College London

Publications and helpful links

General Publications

• Tan TM, Minnion J, Khoo B, Ball LJ, Malviya R, Day E, Fiorentino F, Brindley C, Bush J, Bloom SR. Safety and efficacy of an extended-release peptide YY analogue for obesity: A randomized, placebo-controlled, phase 1 trial. Diabetes Obes Metab. 2021 Jul;23(7):1471-1483. doi: 10.1111/dom.14358. Epub 2021 Mar 9.

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2017
• Primary Completion (Actual): February 13, 2019
• Study Completion (Actual): February 13, 2019

Study Registration Dates

• First Submitted: May 23, 2018
• First Submitted That Met QC Criteria: September 13, 2018
• First Posted (Actual): September 17, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 10, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormones
• Other Study ID Numbers: ICIM/2016/Y14/01; 2017-000380-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No