Diabetes Mellitus, Obesity
Conditions
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.
Interventions
DRUGY14
Gut hormone analogue
DRUGPlacebo
0.9% saline
Sponsors
Medical Research Council
Covance
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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 |
| 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. |
Countries
United Kingdom
Participant flow
Pre-assignment details
Single ascending dose - Part A: Cohort A1 comprised 4 subjects (3 active and 1 placebo): each volunteer was dosed in three treatment periods (TP) with three ascending dose levels (doses 1 mg, 2 mg, 6 mg Y14), with minimum washouts of 1 week between Day 1 of each TP. Within each TP three subjects were given the study drug and one placebo (sterile 0.9% \[w/v\] saline. Each volunteer in Cohort A2 onwards was dosed only once. Multiple ascending dose - Part B: Each participant received up to 5 doses
Participants by arm
| Arm | Count |
|---|---|
| SAD A1 Sequential cross-over group received either Saline or 1 mg dose Y14 (A1) single dose, subcutaneous injection in the first treatment period; Saline or 2 mg dose Y14 single dose, subcutaneous injection in the second period, Saline or 6 mg dose Y14 single dose, subcutaneous injection in the third treatment period. Treatment periods were 12-15 days apart. | 5 |
| 9.0 mg (A2) Y14 single dose, subcutaneous
Y14: Gut hormone analogue | 5 |
| 9 mg (A3) Y14 single dose, subcutaneous
Y14: Gut hormone analogue | 5 |
| 9 mg (A4) Y14 single dose, subcutaneous
Y14: Gut hormone analogue | 5 |
| 18.0 mg (A5) Y14 single dose, subcutaneous
Y14: Gut hormone analogue | 5 |
| 36.0 mg (A6) Y14 single dose, subcutaneous
Y14: Gut hormone analogue | 5 |
| 18 mg (A7) Y14 single dose, subcutaneous
Y14: Gut hormone analogue | 5 |
| 36 mg (A8) Y14 single dose, subcutaneous
Y14: Gut hormone analogue | 5 |
| 36 mg (A9) Y14 single dose, subcutaneous
Y14: Gut hormone analogue | 5 |
| Placebo SAD A2-A9 0.9% saline
Placebo: 0.9% saline | 8 |
| Placebo (Part B) 0.9% saline multiple subcutaneous injection:
5 injections over a 4 week treatment period | 6 |
| 9-26.0 mg (B1) Y14 multiple dose, subcutaneous 5 doses over a 4 week treatment period: escalating dose up to 26 mg
Y14: Gut hormone analogue | 6 |
| 9-36 mg (B2) Y14 multiple dose, subcutaneous 5 doses over a 4 week treatment period: escalating dose up to 36 mg
Y14: Gut hormone analogue | 6 |
| 12-36 mg (B3) Y14 multiple dose, subcutaneous 5 doses over a 4 week treatment period: escalating dose up to 36 mg.
Y14: Gut hormone analogue | 6 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 9.0 mg (A2) | 9 mg (A3) | 9 mg (A4) | SAD A1 | 18.0 mg (A5) | 36.0 mg (A6) | 18 mg (A7) | 36 mg (A8) | 36 mg (A9) | Placebo SAD A2-A9 | Placebo (Part B) | 9-26.0 mg (B1) | 9-36 mg (B2) | 12-36 mg (B3) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.2 years STANDARD_DEVIATION 5.02 | 47.8 years STANDARD_DEVIATION 10.8 | 41.2 years STANDARD_DEVIATION 13.3 | 49.2 years STANDARD_DEVIATION 13.44 | 45.6 years STANDARD_DEVIATION 14.9 | 47.8 years STANDARD_DEVIATION 1.5 | 40.4 years STANDARD_DEVIATION 13.3 | 44.2 years STANDARD_DEVIATION 12.5 | 37.0 years STANDARD_DEVIATION 12.2 | 44.8 years STANDARD_DEVIATION 11.5 | 49.5 years STANDARD_DEVIATION 11.9 | 36.7 years STANDARD_DEVIATION 10 | 42.3 years STANDARD_DEVIATION 9.6 | 40.8 years STANDARD_DEVIATION 9.7 | 42.6 years STANDARD_DEVIATION 11.6 |
| BMI (kg/m^2) | 30.0 kg/m^2 STANDARD_DEVIATION 2.7 | 30.8 kg/m^2 STANDARD_DEVIATION 1.9 | 27.6 kg/m^2 STANDARD_DEVIATION 2.4 | 29.2 kg/m^2 STANDARD_DEVIATION 2.05 | 30.6 kg/m^2 STANDARD_DEVIATION 1.8 | 28.8 kg/m^2 STANDARD_DEVIATION 1.87 | 27.0 kg/m^2 STANDARD_DEVIATION 2.9 | 30.6 kg/m^2 STANDARD_DEVIATION 4.2 | 26.6 kg/m^2 STANDARD_DEVIATION 0.9 | 30.1 kg/m^2 STANDARD_DEVIATION 2.9 | 29.7 kg/m^2 STANDARD_DEVIATION 3.1 | 30.2 kg/m^2 STANDARD_DEVIATION 3.9 | 30.2 kg/m^2 STANDARD_DEVIATION 2.9 | 29.5 kg/m^2 STANDARD_DEVIATION 2.1 | 29.3 kg/m^2 STANDARD_DEVIATION 2.7 |
| Body Weight (kg) | 101.6 kg STANDARD_DEVIATION 12.7 | 100.4 kg STANDARD_DEVIATION 11.3 | 86.2 kg STANDARD_DEVIATION 11.78 | 89.0 kg STANDARD_DEVIATION 12.41 | 101.6 kg STANDARD_DEVIATION 9.6 | 93.3 kg STANDARD_DEVIATION 5.6 | 87.4 kg STANDARD_DEVIATION 13.3 | 92.4 kg STANDARD_DEVIATION 16.47 | 88.6 kg STANDARD_DEVIATION 7.4 | 97.5 kg STANDARD_DEVIATION 14.9 | 93.2 kg STANDARD_DEVIATION 14.8 | 97.5 kg STANDARD_DEVIATION 14 | 95.2 kg STANDARD_DEVIATION 9.8 | 92.0 kg STANDARD_DEVIATION 8.1 | 92.0 kg STANDARD_DEVIATION 12.09 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 4 Participants | 5 Participants | 5 Participants | 5 Participants | 4 Participants | 4 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 6 Participants | 66 Participants |
| Region of Enrollment United Kingdom | 5 participants | 5 participants | 5 participants | 5 participants | 5 participants | 5 participants | 5 participants | 5 participants | 5 participants | 8 participants | 6 participants | 6 participants | 6 participants | 6 participants | 77 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 8 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk | EG020 affected / at risk | EG021 affected / at risk | EG022 affected / at risk | EG023 affected / at risk | EG024 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 8 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 2 / 3 | 1 / 3 | 1 / 3 | 3 / 3 | 3 / 8 | 5 / 5 | 4 / 5 | 1 / 5 | 5 / 5 | 5 / 5 | 4 / 5 | 5 / 5 | 5 / 5 | 3 / 6 | 5 / 6 | 4 / 6 | 6 / 6 | 5 / 6 | 6 / 6 | 6 / 6 | 6 / 6 | 5 / 6 | 6 / 6 | 5 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 8 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
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
Time frame: Up to 73 days after dosing
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (A1) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 2 Participants |
| 1.0 mg (A1) TP1 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 1 Participants |
| 2.0 mg (A1) TP2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 1 Participants |
| 6.0 mg (A1) TP3 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 3 Participants |
| 9 mg (A4) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 5 Participants |
| 9 mg (A3) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 4 Participants |
| 9.0 mg (A2) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 1 Participants |
| 18 mg (A7) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 5 Participants |
| 18.0 mg (A5) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 5 Participants |
| 36 mg (A8) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 4 Participants |
| 36.0 mg (A6) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 5 Participants |
| 36 mg (A9) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 5 Participants |
| Placebo SAD A2-A9 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 3 Participants |
| Placebo (Part B) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 3 Participants |
| 9 mg Y14 (B1) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 5 Participants |
| 9 mg Y14 (B2) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 4 Participants |
| 12 mg Y14 (B1) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 6 Participants |
| 12 mg Y14 (B3) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 5 Participants |
| 16 mg Y14 (B1) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 6 Participants |
| 20 mg Y14 (B1) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 6 Participants |
| 24 mg Y14 (B2) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 6 Participants |
| 24 mg Y14 (B3) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 5 Participants |
| 26 mg Y14 (B1) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 6 Participants |
| 36 mg Y14 (B2) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 5 Participants |
| 36 mg Y14 (B3) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Safety and Tolerability) | 6 Participants |
Secondary
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
Time frame: Up to 72hr after dosing
Population: PK Parameters: N/A = For the doses given to cohorts A1, A2, A3 and A5, Y14 was below the LLOQ(\<0.2 ng/mL) in most samples (BLQ=below the limit of quantification), so the data for cohort A4 and cohort A6 onwards are presented. Only subjects receiving Y14 were analysed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (A1) | AUC 0-72h | NA ng.h/mL | — |
| 1.0 mg (A1) TP1 | AUC 0-72h | NA ng.h/mL | — |
| 2.0 mg (A1) TP2 | AUC 0-72h | NA ng.h/mL | — |
| 6.0 mg (A1) TP3 | AUC 0-72h | NA ng.h/mL | — |
| 9 mg (A4) | AUC 0-72h | NA ng.h/mL | — |
| 9 mg (A3) | AUC 0-72h | NA ng.h/mL | — |
| 9.0 mg (A2) | AUC 0-72h | 16.4 ng.h/mL | Geometric Coefficient of Variation 83 |
| 18 mg (A7) | AUC 0-72h | NA ng.h/mL | — |
| 18.0 mg (A5) | AUC 0-72h | 24.4 ng.h/mL | Geometric Coefficient of Variation 21 |
| 36 mg (A8) | AUC 0-72h | 26.3 ng.h/mL | Geometric Coefficient of Variation 105 |
| 36.0 mg (A6) | AUC 0-72h | 34.0 ng.h/mL | Geometric Coefficient of Variation 50 |
| 36 mg (A9) | AUC 0-72h | 33.4 ng.h/mL | Geometric Coefficient of Variation 51 |
| Placebo SAD A2-A9 | AUC 0-72h | NA ng.h/mL | — |
| Placebo (Part B) | AUC 0-72h | NA ng.h/mL | — |
| 9 mg Y14 (B1) | AUC 0-72h | 19.7 ng.h/mL | Geometric Coefficient of Variation 89.7 |
| 9 mg Y14 (B2) | AUC 0-72h | 53.2 ng.h/mL | Geometric Coefficient of Variation 21 |
| 12 mg Y14 (B1) | AUC 0-72h | 76.7 ng.h/mL | Geometric Coefficient of Variation 26 |
| 12 mg Y14 (B3) | AUC 0-72h | 89.6 ng.h/mL | Geometric Coefficient of Variation 17 |
| 16 mg Y14 (B1) | AUC 0-72h | 81.2 ng.h/mL | Geometric Coefficient of Variation 45 |
| 20 mg Y14 (B1) | AUC 0-72h | 10.1 ng.h/mL | Geometric Coefficient of Variation 303 |
| 24 mg Y14 (B2) | AUC 0-72h | 38.1 ng.h/mL | Geometric Coefficient of Variation 34 |
| 24 mg Y14 (B3) | AUC 0-72h | 82.1 ng.h/mL | Geometric Coefficient of Variation 21 |
| 26 mg Y14 (B1) | AUC 0-72h | 63.6 ng.h/mL | Geometric Coefficient of Variation 76 |
| 36 mg Y14 (B2) | AUC 0-72h | 9.67 ng.h/mL | Geometric Coefficient of Variation 165 |
| 36 mg Y14 (B3) | AUC 0-72h | 40.4 ng.h/mL | Geometric Coefficient of Variation 36 |
| 36 mg Y14 (B3) 1st Dose | AUC 0-72h | 86.6 ng.h/mL | Geometric Coefficient of Variation 22 |
| 36 mg Y14 (B3) 2nd Dose | AUC 0-72h | 87.2 ng.h/mL | Geometric Coefficient of Variation 34 |
Secondary
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).
Time frame: Up to 168h after dosing
Population: PK Parameters: N/A = For the doses given to cohorts A1, A2, A3 and A4, Y14 was below the LLOQ(\<0.2 ng/mL) in most samples (BLQ=below the limit of quantification), so the data for cohort A5 onwards are presented. Only subjects receiving Y14 were analysed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (A1) | AUC 0-τ | NA ng.h/mL | — |
| 1.0 mg (A1) TP1 | AUC 0-τ | NA ng.h/mL | — |
| 2.0 mg (A1) TP2 | AUC 0-τ | NA ng.h/mL | — |
| 6.0 mg (A1) TP3 | AUC 0-τ | NA ng.h/mL | — |
| 9 mg (A4) | AUC 0-τ | NA ng.h/mL | — |
| 9 mg (A3) | AUC 0-τ | NA ng.h/mL | — |
| 9.0 mg (A2) | AUC 0-τ | NA ng.h/mL | — |
| 18 mg (A7) | AUC 0-τ | 64.0 ng.h/mL | Geometric Coefficient of Variation 105 |
| 18.0 mg (A5) | AUC 0-τ | 164 ng.h/mL | Geometric Coefficient of Variation 199 |
| 36 mg (A8) | AUC 0-τ | 65.2 ng.h/mL | Geometric Coefficient of Variation 126 |
| 36.0 mg (A6) | AUC 0-τ | 78.2 ng.h/mL | Geometric Coefficient of Variation 47 |
| 36 mg (A9) | AUC 0-τ | 59.2 ng.h/mL | Geometric Coefficient of Variation 84.6 |
| Placebo SAD A2-A9 | AUC 0-τ | NA ng.h/mL | — |
| Placebo (Part B) | AUC 0-τ | NA ng.h/mL | — |
| 9 mg Y14 (B1) | AUC 0-τ | 24.8 ng.h/mL | Geometric Coefficient of Variation 127 |
| 9 mg Y14 (B2) | AUC 0-τ | 108 ng.h/mL | Geometric Coefficient of Variation 18.7 |
| 12 mg Y14 (B1) | AUC 0-τ | 139 ng.h/mL | Geometric Coefficient of Variation 17 |
| 12 mg Y14 (B3) | AUC 0-τ | 153 ng.h/mL | Geometric Coefficient of Variation 16 |
| 16 mg Y14 (B1) | AUC 0-τ | 144 ng.h/mL | Geometric Coefficient of Variation 53 |
| 20 mg Y14 (B1) | AUC 0-τ | 15.6 ng.h/mL | Geometric Coefficient of Variation 598 |
| 24 mg Y14 (B2) | AUC 0-τ | 107 ng.h/mL | Geometric Coefficient of Variation 31 |
| 24 mg Y14 (B3) | AUC 0-τ | 159 ng.h/mL | Geometric Coefficient of Variation 25 |
| 26 mg Y14 (B1) | AUC 0-τ | 154 ng.h/mL | Geometric Coefficient of Variation 76 |
| 36 mg Y14 (B2) | AUC 0-τ | 17.0 ng.h/mL | Geometric Coefficient of Variation 298 |
| 36 mg Y14 (B3) | AUC 0-τ | 106 ng.h/mL | Geometric Coefficient of Variation 28 |
| 36 mg Y14 (B3) 1st Dose | AUC 0-τ | 193 ng.h/mL | Geometric Coefficient of Variation 19 |
| 36 mg Y14 (B3) 2nd Dose | AUC 0-τ | 225 ng.h/mL | Geometric Coefficient of Variation 48 |
Secondary
Cmax
The maximum observed concentration
Time frame: For Part A, Cohorts A3 to A9 - up to 840 hour post dose. For Part B - up to day 70 post 1st dose
Population: PK Parameters: N/A= For the doses given to cohorts A1, A2 and A3, Y14 was below the LLOQ(\<0.2 ng/mL) in most samples (BLQ=below the limit of quantification), so the data for cohort A4 onwards are presented. Only subjects receiving Y14 were analysed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (A1) | Cmax | NA ng/mL | — |
| 1.0 mg (A1) TP1 | Cmax | NA ng/mL | — |
| 2.0 mg (A1) TP2 | Cmax | NA ng/mL | — |
| 6.0 mg (A1) TP3 | Cmax | NA ng/mL | — |
| 9 mg (A4) | Cmax | NA ng/mL | — |
| 9 mg (A3) | Cmax | NA ng/mL | — |
| 9.0 mg (A2) | Cmax | 0.459 ng/mL | Geometric Coefficient of Variation 44 |
| 18 mg (A7) | Cmax | 0.383 ng/mL | Geometric Coefficient of Variation 46 |
| 18.0 mg (A5) | Cmax | 0.607 ng/mL | Geometric Coefficient of Variation 111 |
| 36 mg (A8) | Cmax | 0.677 ng/mL | Geometric Coefficient of Variation 66 |
| 36.0 mg (A6) | Cmax | 0.908 ng/mL | Geometric Coefficient of Variation 81 |
| 36 mg (A9) | Cmax | 0.704 ng/mL | Geometric Coefficient of Variation 59 |
| Placebo SAD A2-A9 | Cmax | NA ng/mL | — |
| Placebo (Part B) | Cmax | NA ng/mL | — |
| 9 mg Y14 (B1) | Cmax | 0.640 ng/mL | Geometric Coefficient of Variation 39 |
| 9 mg Y14 (B2) | Cmax | 0.870 ng/mL | Geometric Coefficient of Variation 26 |
| 12 mg Y14 (B1) | Cmax | 1.32 ng/mL | Geometric Coefficient of Variation 35 |
| 12 mg Y14 (B3) | Cmax | 1.64 ng/mL | Geometric Coefficient of Variation 19 |
| 16 mg Y14 (B1) | Cmax | 1.48 ng/mL | Geometric Coefficient of Variation 49 |
| 20 mg Y14 (B1) | Cmax | 0.389 ng/mL | Geometric Coefficient of Variation 41 |
| 24 mg Y14 (B2) | Cmax | 0.702 ng/mL | Geometric Coefficient of Variation 52 |
| 24 mg Y14 (B3) | Cmax | 1.4 ng/mL | Geometric Coefficient of Variation 21 |
| 26 mg Y14 (B1) | Cmax | 1.1 ng/mL | Geometric Coefficient of Variation 66 |
| 36 mg Y14 (B2) | Cmax | 0.355 ng/mL | Geometric Coefficient of Variation 37 |
| 36 mg Y14 (B3) | Cmax | 0.787 ng/mL | Geometric Coefficient of Variation 35 |
| 36 mg Y14 (B3) 1st Dose | Cmax | 1.35 ng/mL | Geometric Coefficient of Variation 20 |
| 36 mg Y14 (B3) 2nd Dose | Cmax | 1.54 ng/mL | Geometric Coefficient of Variation 41 |
Secondary
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.
Time frame: For Part A, Cohorts A3 to A9 - up to 840 hour post dose. For Part B - up to day 70 post 1st dose
Population: PK Parameters:~NA= Values below the limit of quantification (BLQ) For the doses given to cohorts in Part A, Y14 was below the lower limit of quantification (\<0.2 ng/mL) in most samples and it was not possible to estimate an unambiguous Tmax or T1/2 due to the extended PK profile of Y14. Therefore the data for Part B only are presented.~Participants who received placebo were not assessed for this measure, therefore only subjects receiving Y14 were analysed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1.0 mg (A1) TP1 | T 1/2 | NA hours | — |
| 2.0 mg (A1) TP2 | T 1/2 | NA hours | — |
| 6.0 mg (A1) TP3 | T 1/2 | NA hours | — |
| 9 mg (A4) | T 1/2 | NA hours | — |
| 9 mg (A3) | T 1/2 | NA hours | — |
| 9.0 mg (A2) | T 1/2 | NA hours | — |
| 18 mg (A7) | T 1/2 | NA hours | — |
| 18.0 mg (A5) | T 1/2 | NA hours | — |
| 36 mg (A8) | T 1/2 | NA hours | — |
| 36.0 mg (A6) | T 1/2 | NA hours | — |
| 36 mg (A9) | T 1/2 | NA hours | — |
| 9 mg Y14 (B1) | T 1/2 | 277 hours | Geometric Coefficient of Variation 106 |
| 9 mg Y14 (B2) | T 1/2 | 294 hours | Geometric Coefficient of Variation 46 |
| 12 mg Y14 (B1) | T 1/2 | 190 hours | Geometric Coefficient of Variation 28 |