A Study in Healthy Subjects to Assess the Safety, Tolerability, PK and PD of HTL0030310

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Three-Part Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Subcutaneous Doses of HTL0030310 in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: HTL0030310
* Drug: Pasireotide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Healthy males or healthy WONCBP; 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 follicle-stimulating hormone [FSH] concentration ≥40 IU/L). Age 18 to 50 years of age A BMI of 20.0 to 30.0 kg/m2, with a minimum weight of 45 kg Must be willing and able to communicate and participate in the whole study Must provide written informed consent Must agree to adhere to the contraception requirements defined in the protocol (Section 9.4) Inclusion criteria 4 and 6 from the list above will be re-assessed at admission/pre-dose. Exclusion Criteria Subjects who have received any IMP in a clinical research study within the previous 3 months of screening Subjects who are study site employees, or immediate family members of a study site or sponsor employee 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 History of any drug or alcohol abuse in the past 2 years 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) 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 Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months 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 Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening Subjects with vital signs outside the normal range for healthy volunteers (HR < 50 or >90 bpm; Systolic BP > 140 mmHg; Diastolic BP > 90 mmHg) Clinically significant abnormal biochemistry, haematology, coagulation or urinalysis as judged by the investigator (laboratory parameters are listed in Appendix 1 of the protocol) Fasting blood glucose at screening above the upper limit of normal (3.9 to 5.8 mM) HbA1c at screening above the upper limit of normal (>6%) Abnormal renal function - defined as creatinine clearance < 70mL/min using the Cockcroft-Gault equation at screening Abnormal hepatic function - defined as ALT, AST and total bilirubin > 1.5 x upper limit of normal at screening Positive drugs of abuse test result (drugs of abuse tests are listed in Appendix 1 of the protocol) Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or GI disease, neurological or psychiatric disorder, as judged by the investigator Family history of long QT syndrome or sudden cardiac death in a young adult where a cause of arrhythmia cannot be excluded QTcF at screening >450 msec in males or >470 msec in females Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients, including glucose/fructose intolerance for the standard OGTT Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active Donation or loss of greater than 400 mL of blood within the previous 3 months 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 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 Failure to satisfy the investigator of fitness to participate for any other reason Exclusion criteria 11, 16, 22, 24 and 26 from the list above will be re-assessed at admission/pre-dose.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Single Ascending Dose<br>Eight subjects in up to 8 cohorts will be dosed. A single subcutaneous injection of HTL0030310 or placebo will be administered. In each cohort, 6 subjects will receive HTL0030310 and 2 subjects will receive placebo. | Drug: HTL0030310<br>* Solution for Subcutaneous injection<br>Drug: Placebo<br>* Matching placebo Solution<br>|
| Experimental: Part 2 Pasireotide PD Assessment<br>Sixteen subjects in 2 cohorts (8 subjects per cohort) will be dosed on 4 occasions. Within each cohort, 4 subjects will be randomised to active dosing with CRH with desmopressin, GHRH and OGTT challenge and 4 subjects will be randomised to placebo dosing with CRH with desmopressin, GHRH and OGTT challenge. | Drug: Pasireotide<br>* Pasireotide 600 μg for subcutaneous injection<br>Drug: Placebo<br>* Matching placebo Solution<br>|
| Experimental: Part 3 Proof of Pharmacological Effect<br>Up to 80 subjects in 4 cohorts (up to 20 subjects per cohort) will be dosed in up to 3 study periods. In each period, subjects will receive active drug or placebo with GHRH, OGTT and CRH with desmopressin (optional). | Drug: HTL0030310<br>* Solution for Subcutaneous injection<br>Drug: Placebo<br>* Matching placebo Solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Safety and Tolerability | Admission up to 8 days post dose | 
| 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 | Pharmacodynamics | Predose up to 4 hours post dose | 
| 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 | Pharmacodynamics | Predose up to 4 hours post dose | 
| 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 | Pharmacodynamics | Predose up to 4 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 Maximum observed plasma concentration (Cmax) of single subcutaneous doses of HTL0030310 | Pharmacokinetics | Pre dose to 144 hours post dose | 
| Part 1 Time to reach Maximum observed plasma concentration (Tmax) of single subcutaneous doses of HTL0030310 | Pharmacokinetics | Pre dose to 144 hours post dose | 
| Part 1 Area under the curve (AUC) of single subcutaneous doses of HTL0030310 | Pharmacokinetics | Pre dose to 144 hours post dose | 
| Part 2 Maximum observed plasma concentration (Cmax) of single subcutaneous doses of pasireotide | Pharmacokinetics | Predose to 24 hours postdose | 
| Part 2 Time to reach Maximum observed plasma concentration (Tmax) of single subcutaneous doses of pasireotide | Pharmacokinetics | Predose to 24 hours postdose | 
| Part 2 Area under the curve (AUC) of single subcutaneous doses of pasireotide | Pharmacokinetics | Predose to 24 hours postdose | 
| Part 3: Number of treatment related adverse events (as determined by abnormal clinical laboratory tests, vitals signs, ECG parameters and injection site reactions) | Safety and Tolerability | Admission up to 8 to 10 days post final dose | 
| Part 3 Maximum observed plasma concentration (Cmax) of single subcutaneous doses of HTL0030310 | Pharmacokinetics | Predose to 96 hours postdose | 
| Part 3 Time to reach Maximum observed plasma concentration (Tmax) of single subcutaneous doses of HTL0030310 | Pharmacokinetics | Predose to 96 hours postdose | 
| Part 3 Area under the curve (AUC) of single subcutaneous doses of HTL0030310 | Pharmacokinetics | Predose to 96 hours postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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First in Human, Single Ascending Dose