A Four-Part Study to Assess the Safety, Tolerability, PK and PD of ONO-5788 in Healthy Adult Volunteers

A Randomized, Double-blind, Placebo-Controlled, Four- Part Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ONO-5788 in Healthy Adult Volunteers

This is a first in human study to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of ONO-5788 in healthy adult volunteers. This study will be conducted in 4 parts: a single-ascending dose part, a multiple-ascending dose part, an elderly part and a proof of principle part.

Study Overview

• Status: Terminated
• Conditions: Acromegaly
• Intervention / Treatment: Drug: ONO-5788; Drug: ONO-5788 Placebo; Drug: Octreotide

Detailed Description

This single centre study will be comprised of 4 parts, Part A (SAD; up to 7 cohorts, 8 subjects per cohort and including an assessment of food effect), a multiple-dose part (up to 4 doses, 10 subjects per cohort); an elderly cohort (8 subjects per gender) and a proof of principle part.

The single ascending dose part (Part A) comprises of increasing doses of an oral solution or capsule, with an investigation of the potential for food effects.

The multiple ascending dose part (Part B, MAD; 14 days dosing) will be initiated after the PK and safety data are available from the single ascending dose part. Subjects in Part B will have ultrasound scans of the gallbladder during the study and at screening a HIDA scan will be performed. An evaluation of the PK in the elderly and any potential gender differences will also be evaluated in Part C. Subjects in Part C will have an ultrasound of the gallbladder at screening.

Part D will be a proof of principle evaluation where the effects of ONO-5788 to inhibit the GHRH and arginine-stimulated GH release will be evaluated. Octreotide acetate is a reference arm in this part of the study.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85283
      • Celerion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy, adult, male and female (women of non-child bearing potential, surgically sterile) volunteers, 18-55 years of age, inclusive, at screening (Parts A & B only).
• Healthy, adult, males and female (women of non-child bearing potential), ≥65 years of age at screening (Part C only).
• Healthy, adult, male, 18-40 years of age, inclusive, at screening (Part D only).
• Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or ECG abnormalities (All Parts).
• Body mass index (BMI) of ≥18.5 to ≤30 kg/m2 at screening (Parts A, B & C).
• Body mass index (BMI) of ≥18.5 to <25 kg/m2 at screening (Part D only).

Exclusion Criteria:

• History of any illness that, in the opinion of the PI or designee, might confound the results of the study or poses an additional risk to the subject by their participation in the study.
• History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.
• History or presence of hypersensitivity or idiosyncratic reaction to the study drugs,excipients or related compounds.

• History or presence of:

  1. Gallstones, cholangitis, and/or cholecystitis or clinically significant findings on gallbladder ultrasound as determined by the Principal Investigator;
  2. Pancreatitis;
  3. Hypothyroidism;
  4. Known diabetes mellitus type 1 or type 2;
  5. Hypocalcaemia or hypokalemia;
  6. Hypoglycemia or hyperglycemia or fasting blood glucose outside normal local range;
  7. Thrombocytopenia or other clinically significant hematologic abnormalities;
  8. Inflammatory bowel disease, irritable bowel syndrome, or abdominal surgery;
  9. Known vitamin B12 deficiency.
  10. Abnormal gallbladder ejection fraction on hepatobiliary iminodiacetic acid (HIDA) scan at screening (Part B only)
• Positive urine drug, alcohol or cotinine results at screening or check in.
• Clinically significant serum electrolyte (sodium, potassium, chloride, bicarbonate) abnormalities at screening or each check-in, in the estimation and clinical judgment of the PI or designee.
• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV).
• Seated blood pressure is less than 90/40 millimeter of mercury (mmHg) or greater than 140/90 mmHg (160/95 mmHg for Part C) at screening.
• Has engaged in strenuous physical exercise in the 48 hours prior first dosing or intends to undergo strenuous physical exercise at any time throughout the study.
• Donation of blood or significant blood loss within 56 days prior to the first dosing.
• Plasma donation within 7 days prior to the first dosing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

11

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ONO-5788 Part A1; Single ascending doses of ONO-5788 or placebo in fasted healthy volunteers randomized 6 active : 2 placebo per group	Drug: ONO-5788; Investigational drug
Placebo Comparator: ONO-5788 Placebo Part A1; Single ascending doses of ONO-5788 or placebo in fasted healthy volunteers randomized 6 active : 2 placebo per group	Drug: ONO-5788 Placebo; Placebo Comparator
Experimental: ONO-5788 Part A2; Single dose (1-2 groups) of ONO-5788 or placebo in healthy volunteers under fed conditions randomized 6 active : 2 placebo per group	Drug: ONO-5788; Investigational drug
Placebo Comparator: ONO-5788 Placebo Part A2; Single dose (1-2 groups) of ONO-5788 or placebo in healthy volunteers under fed conditions randomized 6 active : 2 placebo per group	Drug: ONO-5788 Placebo; Placebo Comparator
Experimental: ONO-5788 Part B; Multiple ascending doses of ONO-5788 or placebo in healthy volunteers randomized 8 active : 2 placebo per group	Drug: ONO-5788; Investigational drug
Placebo Comparator: ONO-5788 Placebo Part B; Multiple ascending doses of ONO-5788 or placebo in healthy volunteers randomized 8 active : 2 placebo per group	Drug: ONO-5788 Placebo; Placebo Comparator
Experimental: ONO-5788 Part C; Single doses of ONO-5788 or placebo in elderly female or elderly male healthy volunteers randomized 6 active : 2 placebo per group	Drug: ONO-5788; Investigational drug
Placebo Comparator: ONO-5788 Placebo Part C; Single doses of ONO-5788 or placebo in elderly female or elderly male healthy volunteers randomized 6 active : 2 placebo per group	Drug: ONO-5788 Placebo; Placebo Comparator
Experimental: ONO-5788 Part D; Single doses of ONO-5788, octreotide or placebo in healthy volunteers stimulated with growth hormone release hormone (GHRH) and arginine	Drug: ONO-5788; Investigational drug
Placebo Comparator: ONO-5788 Placebo Part D; Single doses of ONO-5788, octreotide or placebo in healthy volunteers stimulated with growth hormone release hormone (GHRH) and arginine	Drug: ONO-5788 Placebo; Placebo Comparator
Active Comparator: Octreotide Part D; Single doses of ONO-5788, octreotide or placebo in healthy volunteers stimulated with growth hormone release hormone (GHRH) and arginine	Drug: Octreotide; Active Comparator in Part D; Other Names: Sandostatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment emergent adverse events by severity	An adverse event is any untoward medical occurrence in a participant who receive study drug without regard to possible causal relationship.	Part A - up to day 8; Part B - at least day 21; Part C - at least day 21; and Part D - up to day 28
Number of participants with serious adverse events (SAEs)	An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged hospitalization, life-threatening experience or persistent disability.	Part A - up to day 8; Part B - at least day 21; Part C - at least day 21; and Part D - up to day 28
Number of participants with clinically significant changes in vital signs	Number of participants with clinically significant changes in vital signs including pulse/heart rate, respiratory rate, and blood pressure will be reported.	Part A - up to day 8; Part B - at least day 21; Part C - at least day 21; and Part D - up to day 28
Number of participants with ECG abnormalities	Number of participants with ECG abnormalities will be reported	Part A - up to day 8; Part B - at least day 21; Part C - at least day 21; and Part D - up to day 28
Number of participants with clinical laboratory abnormalities	Number of participants with clinical laboratory abnormalities will be reported	Part A - up to day 8; Part B - at least day 21; Part C - at least day 21; and Part D - up to day 28
Number of participants with clinically significant change in ultrasound of gallbladder	Number of participants with clinically significant change in ultrasound of gallbladder will be reported	Part B - up to day 21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (AUC)	Assessment of the plasma area under the curve of ONO-5788 and metabolites (Parts A, B and C only)	Day 1 through Day 14
Pharmacokinetics (AUC) - food effect	Effect of food on the plasma area under the curve of ONO-5788 and metabolites (Parts A only)	Day 1
Pharmacokinetics (Cmax)	Assessment of the maximum observed plasma concentration of ONO-5788, metabolites (Parts A, B, C & D) and octreotide (Part D only)	Day 1 through Day 14
Pharmacokinetics (Cmax) - food effect	Effect of food on the maximum observed plasma concentration of ONO-5788, and metabolites (Part A only)	Day 1
Pharmacokinetics (Tmax)	Assessment of the time to reach Cmax for ONO-5788, metabolites (Parts A, B, C & D) and octreotide (Part D only)	Day 1 through Day 14
Pharmacokinetics (Tmax) - food effect	Effect of food on the time to reach Cmax for ONO-5788, metabolites (Part A only)	Day 1 through Day 14
Pharmacokinetics (Ctrough)	Assessment of trough levels for ONO-5788 and metabolites immediately before dosing (Part B only)	Day 1 through Day 14
Pharmacokinetics (T1/2)	Assessment of the elimination half-life of ONO-5788 and metabolites (Parts A, B and C only)	Day 1 through Day 14
Pharmacokinetics (T1/2) - food effect	Effect of food on the elimination half-life of ONO-5788 and metabolites (metabolite) (Part A only)	Day 1
Pharmacokinetics (CL/F)	Assessment of the apparent clearance rate of ONO-5788 (Parts A & C)	Day 1
Pharmacokinetics (CL/F) - food effect	Effect of food on the apparent clearance rate of ONO-5788 (Part A only)	Day 1
Pharmacokinetics (Cave)	Average concentration of ONO-5788/metabolites/Octreotide (Part D only)	Day 1
Pharmacodynamics (IGF-1)	Assessment of the effects of ONO-5788 on IGF-1 levels (Part B only)	Day 1 through Day 21
Pharmacodynamics (Growth Hormone)	Assessment of the effects of ONO-5788 on GH levels (Part B)	Day 1 through Day 21
Pharmacodynamics (Growth Hormone)	Assessment of the effects of ONO-5788 on GHRH & arginine stimulated GH levels (Part D)	Day 1
Pharmacodynamics (IGFBP3)	Assessment of the effects of ONO-5788 on IGFBP3 levels (Part B only)	Day 1 through Day 21

Collaborators and Investigators

• Sponsor: Ono Pharmaceutical Co. Ltd

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2018
• Primary Completion (Actual): May 16, 2019
• Study Completion (Actual): May 16, 2019

Study Registration Dates

• First Submitted: June 1, 2018
• First Submitted That Met QC Criteria: June 18, 2018
• First Posted (Actual): June 27, 2018

Study Record Updates

• Last Update Posted (Actual): June 5, 2019
• Last Update Submitted That Met QC Criteria: June 3, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Musculoskeletal Diseases; Hypothalamic Diseases; Bone Diseases; Bone Diseases, Endocrine; Hyperpituitarism; Pituitary Diseases; Acromegaly; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Octreotide
• Other Study ID Numbers: ONO-5788-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No