Study of the Gut Hormone Analogue Y14 in Adult Subjects

Phase 1

Completed

Conditions: Diabetes Mellitus
Obesity

Interventions: Drug: Y14
Drug: Placebo

Registration Number: NCT03673111

Lead Sponsor: Imperial College London

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

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 77

Inclusion Criteria

Adult males aged 18 to 65 years inclusive with BMI between 25.0 and 38.0 kg/m2 inclusive;
(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;
Subjects who are otherwise healthy enough to participate, as determined by pre-study medical history, physical examination and 12-lead ECG;
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;
Subjects who are negative for hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) I and II tests at screening;
Subjects who are negative for drugs of abuse and alcohol tests at screening and admissions;
Subjects who are non-smokers for at least 3 months preceding screening;
Subjects who agree to use medically acceptable methods of contraception for at least 3 months after study drug administration;
Subjects who agree not to donate sperm for at least 3 months after study drug administration;
Subjects who are able and willing to give written informed consent.

Exclusion Criteria

Subjects who do not conform to the above inclusion criteria;
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;
Subjects who have a clinically relevant surgical history;
Subjects who are currently taking any of the following classes of diabetes medications: thiazolidinediones, dipeptidyl peptidase IV inhibitors ('gliptins'), GLP-1 analogues, and insulin;
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);
Subjects who have a history of relevant drug hypersensitivity;
Subjects who have a history of alcohol abuse or alcohol dependence according to DSMIV criteria within the last 2 years;
Subjects who have a history of drug or substance abuse according to DSM-IV criteria within the last 2 years;
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;
Subjects with a history of pancreatitis or pancreatic cancer;
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);
Subjects who have a significant infection or known inflammatory process on screening;
Subjects who have acute gastrointestinal symptoms at the time of screening or admission (e.g. nausea, vomiting, diarrhoea, heartburn);
Subjects who have an acute infection such as influenza at the time of screening or admission;
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.
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;
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
Subjects who have used any investigational drug in any clinical trial within 3 months of their first admission date;
Subjects who have received the last dose of investigational drug greater than 3 months ago but who are on extended follow-up;
Subjects who have previously received Y14;
Subjects who are vegans, vegetarian or have any dietary restriction (unless agreed as not clinically relevant by the PI and Sponsors);
Subjects who cannot communicate reliably with the Investigator;
Subjects who are unlikely to co-operate with the requirements of the study;
History or evidence of abnormal eating behaviour, as observed through the Dutch Eating Behaviour (DEBQ) and SCOFF questionnaires at screening.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability)	Up to 73 days after dosing	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

Secondary Outcome Measures

Name	Time	Method
Cmax	For Part A, Cohorts A3 to A9 - up to 840 hour post dose. For Part B - up to day 70 post 1st dose	The maximum observed concentration
AUC 0-72h	Up to 72hr after dosing	The area under the concentration versus time curve from time zero to 72 h postdose, calculated by the mixed linear/log trapezoidal rule
AUC 0-τ	Up to 168h after dosing	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).
T 1/2	For Part A, Cohorts A3 to A9 - up to 840 hour post dose. For Part B - up to day 70 post 1st dose	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.