Clinical trial NCT03276858: Single and Multiple-Ascending Dose Study of CRN00808 in Healthy Volunteers
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Lead sponsor: Crinetics Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2017-09-08
Enrollment: 99
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single and multiple-dose cohorts are placebo-controlled. The midazolam cohort does not have placebo.
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Day 1 through Day 10
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of CRN00808 multiple ascending doses using clinical assessments and subject self-reporting
timeFrame: Day 1 through Day 21
Secondary outcomes:
measure: AUC of CRN00808 single ascending doses
timeFrame: Day 1 through Day 7
measure: Cmax of CRN00808 single ascending doses
timeFrame: Day 1 through Day 7
measure: t1/2 of CRN00808 single ascending doses
timeFrame: Day 1 through Day 7
measure: Tmax of CRN00808 single ascending doses
timeFrame: Day 1 through Day 7
measure: AUC of CRN00808 multiple ascending doses
timeFrame: Day 1 through Day 20
measure: Cmax of CRN00808 multiple ascending doses
timeFrame: Day 1 through Day 20
measure: t1/2 of CRN00808 multiple ascending doses
timeFrame: Day 1 through Day 20
measure: Tmax of CRN00808 multiple ascending doses
timeFrame: Day 1 through Day 20
measure: Pharmacodynamics of CRN00808 in single ascending dose cohorts assessed by GHRH analog stimulated GH levels
timeFrame: Day -1 and Day 1
measure: Effect of CRN00808 on pharmacokinetics of midazolam
timeFrame: Day 1 through Day 10
measure: Effect of CRN00808 on Cmax of midazolam
timeFrame: Day 1 through Day 10
measure: Effect of CRN00808 on t1/2 of midazolam
timeFrame: Day 1 through Day 10
measure: Effect of CRN00808 on Tmax of midazolam
timeFrame: Day 1 through Day 10
measure: Relative bioavailability of capsule formulation
timeFrame: Day 1 to Day 7
measure: Effect of food on Cmax of CRN00808
timeFrame: Day 1 to Day 7
measure: Effect of food on AUC of CRN00808
timeFrame: Day 1 to Day 7
measure: Pharmacodynamics of CRN00808 in multiple ascending dose cohorts assessed by serum IGF-1 and GH
timeFrame: Day -1 to Day 21
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Nucleus Network
state: Victoria
Study officials:
affiliation: Nucleus Network
name: Jason Lickliter, MBBS PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.