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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: CRN00808
* Drug: Placebo Oral Solution
* Drug: Midazolam oral solution
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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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

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: Parallel Assignment
Interventional Model Description: Single and multiple-dose cohorts are placebo-controlled. The midazolam cohort does not have placebo.
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 |