Single and Multiple-Ascending Dose Study of CRN00808 in Healthy Volunteers

A Double-Blind, Randomized, Placebo-Controlled, Single- And-Multiple-Dose Study to Evaluate the Safety, PK, and PD of CRN00808 in Healthy Volunteers and to Determine the Effect of CRN00808 on Midazolam PK

This single-center study will be conducted in 3 phases: a single-ascending dose phase (up to 8 cohorts, 8 subjects/cohort), a multiple-dose phase (up to 5 cohorts, 9 subjects/cohort), and a midazolam drug-drug interaction phase (one cohort of 8 subjects).

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: CRN00808; Drug: Placebo oral capsule; Drug: Placebo Oral Solution; Drug: Midazolam oral solution

Detailed Description

The single-dose phase initiates with ascending doses of an oral solution followed by a 3-way crossover food effect and bioavailability (capsule formulation) cohort. Serum IGF-1 levels and GHRH-analog stimulated GH levels will be assessed as pharmacodynamics measures.

The first multiple-dose (7 days dosing) cohort will be initiated after the PK and safety data are available from the single-dose phase. Subsequent multiple-dose cohorts will have 10 days of dosing. Serum IGF-1 level and GH levels will be assessed as pharmacodynamics measures.

The last cohort in the study is midazolam drug-drug interaction study. The dose will be selected based on review of all pharmacokinetic and safety data for the single-dose and multiple-dose cohorts completed. On Day 1, 8 subjects will receive a single oral 2 mg dose of midazolam. Starting on Day 3 through Day 8, subjects will receive daily doses of CRN00808. On Day 9, subjects will be administered CRN00808 and 2 mg midazolam together.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia
      • Nucleus Network

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• BMI 18 to 30 kg/m2
• Females postmenopausal or surgically sterile

Exclusion Criteria:

• Any uncontrolled or active major systemic disease including, but not limited to: acromegaly (with or without pituitary surgery or radiation therapy), cardiac, pulmonary, gastrointestinal, metabolic, urogenital, neurological, immunological, psychiatric, or neoplastic disorder with metastatic potential
• History or presence of malignancy within the past 5 years. Subjects who have been successfully treated (for 3 months or longer) with no recurrence of basal or squamous cell carcinoma of the skin or carcinoma in-situ of the cervix may be enrolled.
• Use of any investigational drug within the past 60 days or 5 half-lives, whichever is longer
• Have a medically significant abnormality observed during screening or the admission physical examination or in any other baseline measurements
• Use of any prior medication without approval of the investigator within 14 days prior to admission
• Tested positive at screening for HIV, hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCV-Ab) or has a history of a positive result
• History of alcohol or substance abuse in the past 6 months
• Any condition that in the opinion of the investigator would jeopardize the subject's appropriate participation in this Phase 1 study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CRN00808 Oral Solution; CRN00808 oral solution, single-dose	Drug: CRN00808; Investigational drug
Experimental: CRN00808 Oral Capsule; CRN00808 oral capsule, single-dose and multiple-doses	Drug: CRN00808; Investigational drug
Placebo Comparator: Placebo Oral Solution; Placebo oral solution, single-dose	Drug: Placebo Oral Solution; Placebo
Placebo Comparator: Placebo Oral Capsule; Placebo oral capsule, single-dose and multiple doses	Drug: Placebo oral capsule; Placebo
Other: Midazolam Oral Solution; Midazolam oral solution, two single-doses as part of the drug-drug interaction arm of the study	Drug: CRN00808; Investigational drug; Drug: Midazolam oral solution; Midazolam as part of the drug-drug interaction arm of the study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of CRN00808 single ascending doses using clinical assessments, telemetry, and Holter monitoring and subject self-reporting	ECG, clinical laboratory parameters, vital signs, physical examinations, telemetry, Holter monitoring	Day 1 through Day 10
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of CRN00808 multiple ascending doses using clinical assessments and subject self-reporting	ECG, clinical laboratory parameters, vital signs, physical examinations	Day 1 through Day 21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC of CRN00808 single ascending doses	plasma AUC	Day 1 through Day 7
Cmax of CRN00808 single ascending doses	plasma Cmax	Day 1 through Day 7
t1/2 of CRN00808 single ascending doses	plasma t1/2	Day 1 through Day 7
Tmax of CRN00808 single ascending doses	plasma Tmax	Day 1 through Day 7
AUC of CRN00808 multiple ascending doses	plasma AUC	Day 1 through Day 20
Cmax of CRN00808 multiple ascending doses	plasma Cmax	Day 1 through Day 20
t1/2 of CRN00808 multiple ascending doses	plasma t1/2	Day 1 through Day 20
Tmax of CRN00808 multiple ascending doses	plasma Tmax	Day 1 through Day 20
Pharmacodynamics of CRN00808 in single ascending dose cohorts assessed by GHRH analog stimulated GH levels	Suppression of serum GH induced by a GH secretagogue	Day -1 and Day 1
Effect of CRN00808 on pharmacokinetics of midazolam	midazolam plasma AUC	Day 1 through Day 10
Effect of CRN00808 on Cmax of midazolam	midazolam plasma Cmax	Day 1 through Day 10
Effect of CRN00808 on t1/2 of midazolam	midazolam plasma t 1/2	Day 1 through Day 10
Effect of CRN00808 on Tmax of midazolam	midazolam plasma Tmax	Day 1 through Day 10
Relative bioavailability of capsule formulation	single-dose crossover arm only	Day 1 to Day 7
Effect of food on Cmax of CRN00808	plasma Cmax compared with and without food in single dose arm	Day 1 to Day 7
Effect of food on AUC of CRN00808	Plasma AUC compared with and without food in single dose arm	Day 1 to Day 7
Pharmacodynamics of CRN00808 in multiple ascending dose cohorts assessed by serum IGF-1 and GH	serum IGF-1 and GH	Day -1 to Day 21

Collaborators and Investigators

• Sponsor: Crinetics Pharmaceuticals Inc.
• Investigators: Principal Investigator: Jason Lickliter, MBBS PhD, Nucleus Network

Publications and helpful links

General Publications

• Madan A, Markison S, Betz SF, Krasner A, Luo R, Jochelson T, Lickliter J, Struthers RS. Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers. Pituitary. 2022 Apr;25(2):328-339. doi: 10.1007/s11102-021-01201-z. Epub 2022 Jan 9.

Study record dates

Study Major Dates

• Study Start (Actual): September 22, 2017
• Primary Completion (Actual): April 30, 2018
• Study Completion (Actual): April 30, 2018

Study Registration Dates

• First Submitted: September 5, 2017
• First Submitted That Met QC Criteria: September 7, 2017
• First Posted (Actual): September 8, 2017

Study Record Updates

• Last Update Posted (Actual): August 29, 2018
• Last Update Submitted That Met QC Criteria: August 27, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Pharmaceutical Solutions
• Other Study ID Numbers: CRN00808-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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