Obesity
Conditions
Keywords
Obesity, Peptide YY, Food intake, Safety, Pharmacokinetics
Brief summary
Obesity causes 600 premature deaths per week in the UK and existing treatments are not effective. When humans eat, the bowels naturally secrete chemicals into the bloodstream which make people feel full and which stop eating. One of these chemicals is known as Peptide YY (PYY). The investigators have previously shown that injections of PYY reduce appetite and food intake in human volunteers. The investigators have now developed a very similar chemical, Y242, as a treatment for obesity. Y242 has been tested in animals and has been shown to be safe, to reduce their appetite, and to last for much longer than PYY itself. This study will test Y242 to ensure that it is well tolerated in humans, and to see how long it lasts in the blood stream after being injected under the skin. It will also look for any effects on appetite.
Detailed description
Obesity causes 600 premature deaths per week in the UK and existing treatments are less than ideal. Intravenous infusion of a hormone called PYY reduces food intake but its effects only last for a few hours and it can cause nausea. Y242 is a longacting analogue of PYY. Given subcutaneously in rodents, it has a profile of action of at least 72 hours and strongly inhibits food intake. It causes weight loss without behavioural effects. With MRC funding, Y242 has passed Good Laboratory Practice toxicology testing and the present proposal is a first in human study to investigate its safety, tolerability and pharmacokinetics in overweight but otherwise healthy men. The study is a combined single ascending dose (part A) and multiple ascending dose (part B) Phase 1 investigation. The primary objective is to investigate safety and tolerability. The secondary objective is to assess Y242's pharmacokinetic (PK) profile. Possible effects on food consumption will be explored. For part A up to 48 subjects are planned, with up to 40 subjects for part B. In each part subjects are divided into groups, each of which is dosed with the same level, starting with a single dose (part A) much lower than is expected to cause an effect. Subjects are admitted to a Unit so they can be closely observed for adverse effects and safety tests, blood concentrations of the drug and food and liquid intake and output will be monitored. Subjects are allocated at random (like tossing a coin) to receive Y242 or placebo (dummy). Safety, tolerability and pharmacokinetic data will be summarised and available results considered in deciding dose escalation, with stopping rules designed to enable us to explore the relationship between dose and adverse effect (eg nausea) without causing unacceptable nausea or other symptoms in the volunteers.
Interventions
DRUGY242
Single ascending dose: subcutaneous injection of 2, 7.5, 15, 30, 60 and 90 mg Y242 (Part A); Multiple ascending dose: Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B)
DRUG0.9% saline
Identical volume to that of Y242
Sponsors
Medical Research Council
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Part A: Treatments were administered single-blind; subjects were blinded with regard to treatment and clinical staff remained blinded with regard to treatment until the Safety Committee meeting. Part B was double blind.
Intervention model description
Part A was a single blind, randomised, placebo controlled, single ascending dose (SAD) study. Part B was a double blind, randomised, placebo controlled, multiple ascending dose (MAD) study
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Adult males aged 18 to 50 years inclusive with BMI between 23.0 and 30.0 kg/m\^2 inclusive; * Subjects who are healthy 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 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 have a clinically relevant family history; * Subjects who have a history of relevant atopy; * Subjects who have a history of relevant drug hypersensitivity; * Subjects who have a history of alcoholism; * Subjects who have a history of drug abuse; * Subjects who have a history of migraine; * 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 4 weeks of first dosing; * 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 or blood products within 3 months of Day -2 (admission); * Subjects who have used any investigational drug in any clinical trial within 3 months of Day -2 (admission); * 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 Y242; * Subjects who are vegans or have any dietary restrictions; * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Up to 73 days | A treatment-emergent AE (TEAE) as defined as an AE that started after administration of IMP; in Part B this was an AE that started after the first dose of IMP. Adverse events with onset prior to dosing were considered as pre-treatment AEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body Weight | up to 32 day | Summary of Time-Matched % Change from Baseline in Body Weight (Baseline = Day -1) following multiple dose of Y242 (Part B) |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 2mg Y242 Y242 single dose, subcutaneous (Part A) | 3 |
| 7.5mg Y242 Y242 single dose, subcutaneous (Part A) | 3 |
| 15mg Y242 Y242 single dose, subcutaneous (Part A) | 6 |
| 30mg Y242 Y242 single dose, subcutaneous (Part A) | 6 |
| 60mg Y242 Y242 single dose, subcutaneous (Part A) | 6 |
| 90mg Y242 Y242 single dose, subcutaneous (Part A) | 6 |
| Placebo - Part A 0.9% saline
0.9% saline: Identical volume to that of Y242 | 10 |
| 60mg Y242 (B1) Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B) | 6 |
| 90mg Y242 (B2-B4) Y242 single subcutaneous dose, administered once a week for 5 weeks (Part B) | 14 |
| Placebo - Part B 0.9% saline
0.9% saline: Identical volume to that of Y242 | 8 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 7.5mg Y242 | 15mg Y242 | 30mg Y242 | 60mg Y242 | 90mg Y242 | 2mg Y242 | Placebo - Part A | 60mg Y242 (B1) | 90mg Y242 (B2-B4) | Placebo - Part B | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 39.7 years STANDARD_DEVIATION 5.51 | 25.5 years STANDARD_DEVIATION 5.79 | 28.7 years STANDARD_DEVIATION 9.2 | 31.5 years STANDARD_DEVIATION 11.47 | 34.3 years STANDARD_DEVIATION 7.5 | 30.7 years STANDARD_DEVIATION 2.52 | 31.3 years STANDARD_DEVIATION 6.04 | 35.7 years STANDARD_DEVIATION 6.62 | 29.4 years STANDARD_DEVIATION 7.1 | 34.6 years STANDARD_DEVIATION 6.76 | 31.6 years STANDARD_DEVIATION 7.61 |
| BMI (kg/m^2) | 26.37 kg/m^2 STANDARD_DEVIATION 0.929 | 26.88 kg/m^2 STANDARD_DEVIATION 1.148 | 25.55 kg/m^2 STANDARD_DEVIATION 2.128 | 26.05 kg/m^2 STANDARD_DEVIATION 2.595 | 25.93 kg/m^2 STANDARD_DEVIATION 2.325 | 26.13 kg/m^2 STANDARD_DEVIATION 1.845 | 25.94 kg/m^2 STANDARD_DEVIATION 1.731 | 25.03 kg/m^2 STANDARD_DEVIATION 1.462 | 26.07 kg/m^2 STANDARD_DEVIATION 1.92 | 27.46 kg/m^2 STANDARD_DEVIATION 1.431 | 26.2 kg/m^2 STANDARD_DEVIATION 1.84 |
| Height (cm) | 174.3 cm STANDARD_DEVIATION 5.69 | 177.2 cm STANDARD_DEVIATION 5.71 | 180.8 cm STANDARD_DEVIATION 9.99 | 177.7 cm STANDARD_DEVIATION 4.97 | 179.0 cm STANDARD_DEVIATION 4.29 | 183.3 cm STANDARD_DEVIATION 8.39 | 176.5 cm STANDARD_DEVIATION 6.82 | 174.3 cm STANDARD_DEVIATION 7.09 | 179.9 cm STANDARD_DEVIATION 6.32 | 180.9 cm STANDARD_DEVIATION 6.58 | 178.3 cm STANDARD_DEVIATION 6.55 |
| Race/Ethnicity, Customized Ethnic Origin Hispanic Or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Ethnic Origin Not Hispanic Or Latino | 3 Participants | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 3 Participants | 8 Participants | 5 Participants | 14 Participants | 8 Participants | 64 Participants |
| 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 |
| Race (NIH/OMB) Asian | 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) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 3 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 |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 3 Participants | 6 Participants | 5 Participants | 2 Participants | 6 Participants | 6 Participants | 9 Participants | 7 Participants | 51 Participants |
| Region of Enrollment United Kingdom | 3 participants | 6 participants | 6 participants | 6 participants | 6 participants | 3 participants | 10 participants | 6 participants | 14 participants | 8 participants | 68 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 |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 3 Participants | 10 Participants | 6 Participants | 14 Participants | 8 Participants | 68 Participants |
| Weight (kg) | 80.27 kg STANDARD_DEVIATION 7.199 | 84.58 kg STANDARD_DEVIATION 7.618 | 83.63 kg STANDARD_DEVIATION 10.723 | 82.52 kg STANDARD_DEVIATION 11.618 | 83.28 kg STANDARD_DEVIATION 9.781 | 87.5 kg STANDARD_DEVIATION 2.893 | 81.10 kg STANDARD_DEVIATION 10.363 | 76.18 kg STANDARD_DEVIATION 7.537 | 84.37 kg STANDARD_DEVIATION 7.846 | 89.89 kg STANDARD_DEVIATION 7.906 | 83.5 kg STANDARD_DEVIATION 9.01 |
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 |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 | 0 / 6 | 0 / 14 | 0 / 8 |
| other Total, other adverse events | 0 / 3 | 3 / 3 | 6 / 6 | 6 / 6 | 6 / 6 | 6 / 6 | 6 / 10 | 6 / 6 | 14 / 14 | 7 / 8 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 | 0 / 6 | 0 / 14 | 0 / 8 |
Outcome results
Primary
Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs)
A treatment-emergent AE (TEAE) as defined as an AE that started after administration of IMP; in Part B this was an AE that started after the first dose of IMP. Adverse events with onset prior to dosing were considered as pre-treatment AEs.
Time frame: Up to 73 days
Population: Summary statistics included number of subjects, arithmetic mean and standard deviation.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 2mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 0 Participants |
| 2mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| 2mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 0 Participants |
| 2mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| 7.5mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| 7.5mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 3 Participants |
| 7.5mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| 7.5mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 0 Participants |
| 15mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| 15mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 6 Participants |
| 15mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 0 Participants |
| 15mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| 30mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 6 Participants |
| 30mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| 30mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 0 Participants |
| 30mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| 60mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 0 Participants |
| 60mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| 60mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 6 Participants |
| 60mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| 90mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 0 Participants |
| 90mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| 90mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 6 Participants |
| 90mg Y242 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Placebo - Part A | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| Placebo - Part A | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 0 Participants |
| Placebo - Part A | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Placebo - Part A | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 6 Participants |
| 60mg Y242 (B1) | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 6 Participants |
| 60mg Y242 (B1) | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| 60mg Y242 (B1) | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| 60mg Y242 (B1) | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 0 Participants |
| 90mg Y242 (B2-B4) | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 3 Participants |
| 90mg Y242 (B2-B4) | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| 90mg Y242 (B2-B4) | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 14 Participants |
| 90mg Y242 (B2-B4) | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| Placebo - Part B | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Placebo - Part B | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Total number of AEs | 7 Participants |
| Placebo - Part B | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| Placebo - Part B | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation | 0 Participants |
Secondary
Body Weight
Summary of Time-Matched % Change from Baseline in Body Weight (Baseline = Day -1) following multiple dose of Y242 (Part B)
Time frame: up to 32 day
Population: Part B - Body weight change from baseline (%) following 5 weekly doses of Y242
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 60mg Y242 (B1) | Body Weight | -1.2 Percentage change in Body weight | Standard Deviation 1.9 |
| 90mg Y242 (B2-B4) | Body Weight | -1.0 Percentage change in Body weight | Standard Deviation 1.8 |
| Placebo - Part B | Body Weight | 1.8 Percentage change in Body weight | Standard Deviation 3.4 |