Study of the Gut Hormone Analogue Y14 in Adult Subjects

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

Detailed Description
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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, enteropancreatic hormone changes and glucose tolerance in overweight/obese male subjects with normal glucose tolerance, Type 2 diabetes or prediabetes.

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

Conditions
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Diabetes Mellitus, Obesity

Intervention / Treatment
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* Drug: Y14
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 glucorticoids 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.0 mg<br>Y14 single dose, subcutaneous | Drug: Y14<br>* Gut hormone analogue<br>|
| Experimental: 2.0 mg<br>Y14 single dose, subcutaneous | Drug: Y14<br>* Gut hormone analogue<br>|
| Experimental: 6.0 mg<br>Y14 single dose, subcutaneous | Drug: Y14<br>* Gut hormone analogue<br>|
| Experimental: 9.0 mg<br>Y14 single dose, subcutaneous | Drug: Y14<br>* Gut hormone analogue<br>|
| Experimental: 18.0 mg<br>Y14 single dose, subcutaneous | Drug: Y14<br>* Gut hormone analogue<br>|
| Experimental: 36.0 mg<br>Y14 single dose, subcutaneous | Drug: Y14<br>* Gut hormone analogue<br>|
| Placebo Comparator: Placebo<br>0.9% saline | Drug: Placebo<br>* 0.9% saline<br>|
| Experimental: 26.0 mg (B1)<br>Y14 multiple dose, subcutaneous 5 doses over a 4 week treatment period: 9mg on day 1, 12mg on day 8, 16mg on day 15, 20mg on day 22 and 26mg on day 29. | Drug: Y14<br>* Gut hormone analogue<br>|
| Experimental: 36mg (B2)<br>Y14 multiple dose, subcutaneous 5 doses over a 4 week treatment period: 9mg on day 1, 24mg on day 8, 36mg on day 15, no dose on day 22 and 36mg on day 29. | Drug: Y14<br>* Gut hormone analogue<br>|
| Experimental: 36mg (B3)<br>Y14 multiple dose, subcutaneous 5 doses over a 4 week treatment period: 12mg on day 1, 24mg on day 8, 36mg on day 15, no dose on day 22 and 36mg on day 29. | Drug: Y14<br>* Gut hormone analogue<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (safety and tolerability) | Count of events | Up to 73 days after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed drug concentrations | (Cmax) | Up to 4 days (72h) after dosing and follow-up | 
| Time of occurrence of Cmax | (tmax) | Up to 4 days (72h) after dosing and follow-up | 
| Area under the plasma concentration -time curves | (AUC) | Up to 4 days (72h) after dosing and follow-up | 
| Apparent terminal rate constant | ʎz | Up to 4 days (72h) after dosing and follow-up | 
| Apparent terminal half-life (t1/2) | t½ | Up to 4 days (72h) after dosing and follow-up | 
| Visual analogue scale scoring as measures of satiety and nausea | % change from baseline | Up to 4 days (72h) after dosing | 
| Food intake | Assessed by measurement of weight of food eaten during meals supplied during in-patient phase of study | Up to 4 days (72h) after dosing | 
| Body weight | (kg) | Up to 73 days after dosing |