Healthy
Conditions
Keywords
First in Human, Single Ascending Dose
Brief summary
A Phase 1, first in human, three-part, single centre study to assess the safety, tolerability, PK and PD of single ascending subcutaneous doses of HTL0030310 in healthy subjects
Detailed description
This is a first in human, three part study with the objective to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of single ascending subcutaneous doses of HTL0030310 in healthy subjects. Part 1 is a double-blind, placebo-controlled, randomised study assessing single ascending doses of HTL0030310. Part 2 is a site-blind (sponsor unblinded), placebo-controlled, part-randomised, fixed-sequence, single-dose, 4-period study assessing the PD of a positive control, pasireotide, following administration of challenge agents. Part 3 is a double-blind, placebo-controlled, part-randomised, fixed-sequence, single-dose, HTL0030310 proof of pharmacological effect study, where PD effects of HTL0030310 will be investigated following administration of challenge agents. The challenge agents administered in this study will be: oral glucose tolerance test (OGTT), Growth hormone-releasing hormone (GHRH), and corticotrophin releasing hormone (CRH) combined with desmopressin.
Interventions
DRUGHTL0030310
Solution for Subcutaneous injection
DRUGPasireotide
Pasireotide 600 μg for subcutaneous injection
DRUGPlacebo
Matching placebo Solution
Sponsors
Nxera Pharma UK Limited
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males or healthy a woman is considered of childbearing potentiaL (WONCBP); a WONCBP unless she is permanently sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum follicle-stimulating hormone \[FSH\] concentration ≥40 IU/L). 2. Age 18 to 50 years of age 3. A BMI of 20.0 to 30.0 kg/m2, with a minimum weight of 45 kg 4. Must be willing and able to communicate and participate in the whole study 5. Must provide written informed consent 6. Must agree to adhere to the contraception requirements defined in the protocol (Section 9.4)
Exclusion criteria
1. Subjects who have received any IMP in a clinical research study within the previous 3 months of screening 2. Subjects who are study site employees, or immediate family members of a study site or sponsor employee 3. Subjects who have previously been enrolled in this study. Subjects who have taken part in Part 1/Part 2 are not permitted to take part in Part 2/Part 3 4. History of any drug or alcohol abuse in the past 2 years 5. Regular alcohol consumption in males \>21 units per week and females \>14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type) 6. Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission 7. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months 8. Females of childbearing potential. A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum FSH concentration ≥40 IU/L). All female subjects must have a negative urine pregnancy test 9. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening 10. Subjects with vital signs outside the normal range for healthy volunteers (HR \< 50 or \>90 bpm; Systolic BP \> 140 mmHg; Diastolic BP \> 90 mmHg) 11. Clinically significant abnormal biochemistry, haematology, coagulation or urinalysis as judged by the investigator (laboratory parameters are listed in Appendix 1 of the protocol) 12. Fasting blood glucose at screening above the upper limit of normal (3.9 to 5.8 mM) 13. HbA1c at screening above the upper limit of normal (\>6%) 14. Abnormal renal function - defined as creatinine clearance \< 70mL/min using the Cockcroft-Gault equation at screening 15. Abnormal hepatic function - defined as ALT, AST and total bilirubin \> 1.5 x upper limit of normal at screening 16. Positive drugs of abuse test result (drugs of abuse tests are listed in Appendix 1 of the protocol) 17. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results 18. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or GI disease, neurological or psychiatric disorder, as judged by the investigator 19. Family history of long QT syndrome or sudden cardiac death in a young adult where a cause of arrhythmia cannot be excluded 20. QTcF at screening \>450 msec in males or \>470 msec in females 21. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients, including glucose/fructose intolerance for the standard OGTT 22. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active 23. Donation or loss of greater than 400 mL of blood within the previous 3 months 24. Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than up to 4 g per day paracetamol) or herbal remedies (including St. John's Wort) in the 21 days before IMP administration (See Section 11.4 of protocol). Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the PI and sponsor's medical monitor 25. Subjects with tattoos or scars on the abdomen which may interfere with injection site assessments or pharmacodynamic measurements, as determined by the PI or delegate at screening 26. Failure to satisfy the investigator of fitness to participate for any other reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of treatment related adverse events (as determined by abnormal clinical laboratory tests, vitals signs, ECG parameters, Holter ECG parameters and injection site reactions) | Admission up to 8 days post dose | Safety and Tolerability |
| Part 2 and Part 3 Area under the effect time curve (EAUC) 1) for insulin, glucose, glucagon, GLP1, C-peptide and GIP level 2) for GH 3) ACTH and cortisol | Predose up to 4 hours post dose | Pharmacodynamics |
| Part 2 and Part 3 Maximum observed effect (EMax) 1) for insulin, glucose, glucagon, GLP1, C-peptide and GIP level 2) for GH 3) ACTH and cortisol | Predose up to 4 hours post dose | Pharmacodynamics |
| Part 2 and Part 3 Time to reach Maximum observed effect (TEMax) 1) for insulin, glucose, glucagon, GLP1, C-peptide and GIP level 2) for GH 3) ACTH and cortisol | Predose up to 4 hours post dose | Pharmacodynamics |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2 Time to reach Maximum observed plasma concentration (Tmax) of single subcutaneous doses of pasireotide | Predose to 24 hours postdose | Pharmacokinetics |
| Part 2 Area under the curve (AUC) of single subcutaneous doses of pasireotide | Predose to 24 hours postdose | Pharmacokinetics |
| Part 3: Number of treatment related adverse events (as determined by abnormal clinical laboratory tests, vitals signs, ECG parameters and injection site reactions) | Admission up to 8 to 10 days post final dose | Safety and Tolerability |
| Part 1 Maximum observed plasma concentration (Cmax) of single subcutaneous doses of HTL0030310 | Pre dose to 144 hours post dose | Pharmacokinetics |
| Part 3 Time to reach Maximum observed plasma concentration (Tmax) of single subcutaneous doses of HTL0030310 | Predose to 96 hours postdose | Pharmacokinetics |
| Part 3 Area under the curve (AUC) of single subcutaneous doses of HTL0030310 | Predose to 96 hours postdose | Pharmacokinetics |
| Part 3 Maximum observed plasma concentration (Cmax) of single subcutaneous doses of HTL0030310 | Predose to 96 hours postdose | Pharmacokinetics |
| Part 1 Time to reach Maximum observed plasma concentration (Tmax) of single subcutaneous doses of HTL0030310 | Pre dose to 144 hours post dose | Pharmacokinetics |
| Part 1 Area under the curve (AUC) of single subcutaneous doses of HTL0030310 | Pre dose to 144 hours post dose | Pharmacokinetics |
| Part 2 Maximum observed plasma concentration (Cmax) of single subcutaneous doses of pasireotide | Predose to 24 hours postdose | Pharmacokinetics |
Countries
United Kingdom
Outcome results
None listed