Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001562167
Ethics application status
Approved
Date submitted
30/10/2019
Date registered
13/11/2019
Date last updated
5/07/2021
Date data sharing statement initially provided
13/11/2019
Date results information initially provided
5/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Multi-Cohort, Single Dose Study to Assess The Relative Bioavailability, Performance, and Safety of Two Novel Formulations of CRN00808
Scientific title
A Phase 1, Multi-Cohort, Single Dose Study to Assess The Relative Bioavailability, Performance, and Safety of Two Novel Formulations of CRN00808
Secondary ID [1] 299579 0
CRN00808-07
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acromegaly 314853 0
Condition category
Condition code
Metabolic and Endocrine 313193 313193 0 0
Other endocrine disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
CRN00808 will be supplied as 10 mg capsules (Reference Formulation) or tablets (Novel Formulation 1 and Novel Formulation 2) for oral administration once daily as described below. Novel formulation 2 will also be supplied as a 20 mg tablet (Cohort 5 only). CRN00808, an investigational drug, is an orally bioavailable small molecule somatostatin receptor 2 (sst2) agonist that lowers growth hormone levels in acromegaly patients.

Lansoprazole, a marketed (TGA-approved) proton pump inhibitor, will be supplied as 15 mg tablets for oral administration twice daily (BID) for part of the study as described below.

The study will consist of 3 cohorts with 4 periods each, and 2 cohort of 3 periods. Enrolled participants will be assigned to Cohort 1, 2, 3, 4 or 5 and are expected to complete all periods; each period is separated by at least 7 days for Cohort 1, 2 and 3, and at least 10 days for Cohort 4 and 5.
Cohort 1 and 2 will be the same except the formulation used: Cohort 1 will receive CRN00808 Novel Formulation 1, and Cohort 2 will receive CRN00808 Novel Formulation 2.
Period 1. Subjects will take 15 mg twice daily lansoprazole at least 30 min prior to a meal. Beginning on Day -4, subjects will take the last dose of 15 mg lansoprazole in the morning prior to a single fasting dose of 20 mg CRN00808.
Period 2. Fasted subjects will take a single dose of 20 mg CRN00808
Period 3. Fasted subjects will take a single dose of 20 mg CRN00808 with a high-fat, high-calorie meal
Period 4. Fasted subjects will take a single dose of CRN00808 at a dose determined from previous pharmacokinetic data. The dose determination will be based on area under the plasma concentration (AUC), maximum plasma concentration (Cmax), and variability comparison of the novel formulation with existing data for the reference formulation (previous clinical experience), provided the selected dose will result in predicted Cmax and AUC that are below the No Observable Adverse Level Cmax and AUC observed in nonclinical toxicity studies.
A standard meal will be provided 2 hours after CRN00808 administration for Period 1, 2 and 4 of Cohort 1 and 2. The standard meal will provide a total of approximately 500 calories such that 36% of the calories are derived from fat, 14% from protein, and 50% from carbohydrates. An example meal is 1 slice of toast (wholemeal), 1 butter or margarine, 1 condiment, 1 cup of cereal/ 2 Weet-Bix with 250 mL milk, and 1 sugar sachet.
A high-fat, high-calorie meal provided in period 3 of cohort 1 and 2 will provide a total of 800-1000 calories such that 50-60% of the calories are derived from fat, 15-19% from protein and 25-31% from carbohydrates. An example meal is 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes and 8 ounces of whole milk.

Cohort 3 will consist of 4 periods. Period 1 will receive the CRN00808 Reference Formulation. Period 2 through Period 4 will receive CRN00808 Novel Formulation 2.

Period 1. Fasted subjects will take a single dose of 20 mg CRN00808 and remain fasting for 2 hours after drug administration
Period 2. Fasted subjects will take a single dose of 20 mg CRN00808 and remain fasting for 2 hours after drug administration
Period 3. Fasted subjects will take a single dose of 20 mg CRN00808 and remain fasting for 1 hour after drug administration
Period 4. Fasted subjects will take a single dose of 20 mg CRN00808 remain fasting for 0.5 hour after drug administration
A low-fat meal will be provided after CRN00808 administration for all periods of Cohort 3. The low-fat meal will provide a total of 400-500 calories such that 25% of the calories (11-14 grams) are derived from fat. An example meal is 8 oz of milk, one boiled egg, and one packet flavored instant oatmeal made with water.

Cohort 4 will consist of 3 periods. Subjects will receive a single dose of CRN00808 Novel Formulation 2 in each period.
Period 1. Fasted subjects will take a single dose of 40 mg CRN00808 and remain fasting for 1 hour after drug administration
Period 2. Fasted subjects will take a single dose of 80 mg CRN00808 and remain fasting for 1 hour after drug administration.
Period 3. Fasted subjects will take a single dose 80 mg CRN00808 with 4 hours fasting after drug administration.

A standard meal will be provided after CRN00808 administration for Cohort 4. The standard meal will provide a total of approximately 500 calories such that 36% of the calories are derived from fat, 14% from protein, and 50% from carbohydrates. An example meal is 1 slice of toast (wholemeal), 1 butter or margarine, 1 condiment, 1 cup of cereal/ 2 Weet-Bix with 250 mL milk, and 1 sugar sachet.

Cohort 5 will consist of 3 periods. In each period, a single dose of CRN00808 Novel Formulation 2 (60 mg) will be administered orally (3x20 mg tablets).
Period 1. Fasted subjects will take a single dose of 60 mg CRN00808 and remain fasting for 1 hour after drug administration
Period 2. Subjects will take 15 mg twice daily lansoprazole at least 30 min prior to a meal, beginning three days prior to CRN00808 administration. Subjects will take the last dose of 15 mg lansoprazole in the morning prior to a single fasting dose of 60 mg CRN00808. Subjects will then remain fasting for 1 hour after drug administration.
Period 3. Subjects will receive a single dose of 60 mg CRN00808 within 30 minutes of taking a low-fat meal.
For all Cohort 5 periods, subjects will receive their next meal after 4 hours post dosing.

A low-fat meal will be provided in Cohort 5. The low-fat meal will provide a total of 400-500 calories such that 25% of the calories (11-14 grams) are derived from fat. An example meal is 8 oz of milk, one boiled egg, and one packet flavored instant oatmeal made with water.

For all the periods of each cohort, subjects are expected to stay in the research unit the day before the dosing of each period to ensure the fasting requirement is met. Subjects are required to fast overnight (at least 10 hours; water is permitted until 1 hour before CRN00808 administration) prior to the CRN00808 dosing. All the dosing will be administered by the study personnel at the research unit. An accountability records will be maintained by the study personnel to ensure compliance.
Intervention code [1] 315836 0
Treatment: Drugs
Comparator / control treatment
CRN00808 Capsules (Reference Formulation) is the active control.
Control group
Active

Outcomes
Primary outcome [1] 321748 0
Characterize the pharmacokinetic parameters (including AUC, Cmax, Time to achieve maximum (Tmax), and apparent terminal half-life (t1/2))of the 10 mg CRN00808 Novel Formulation 1 in Cohort 1, and CRN00808 Novel Formulation 2 in Cohort 2 as measured from blood plasma concentrations of CRN00808.
Timepoint [1] 321748 0
Cohort 1 or 2, Periods 1 to 3: 15 minutes (min) pre-dose, 15 min post dose, 30 min, 45 min, 1 hour (hr), 1.25 hrs, 1.5 hrs, 2.0 hrs, 3.0 hrs, 4.0 hrs, 6.0 hrs, 8.0 hrs, 10 hrs, 12 hrs, 24 hrs
Cohort 1 or 2, Period 4: All the above plus 48 hrs, 120 hrs and 196 hrs post dose
Primary outcome [2] 321749 0
Compare the pharmacokinetic parameters (including AUC,Cmax, Tmax, and t1/2) of CRN00808 Reference Formulation to CRN00808 Novel Formulation 2 as measured from blood plasma concentrations of CRN00808; and to evaluate effect of timing of food administration on pharmacokinetics of low-dose CRN00808 Novel Formulation 2 as
measured from blood plasma concentrations of CRN00808. Pharmacokinetic parameters include AUC, Cmax, Tmax, and t1/2.
Timepoint [2] 321749 0
Cohort 3, Periods 1 to 4:
15 min pre dose, 15 min post dose, 30 min, 45 min, 1 hr, 1.25 hrs, 1.5 hrs, 2.0 hrs, 3.0 hrs, 4.0 hrs, 6.0 hrs, 8.0 hrs, 10 hrs, 12 hrs, 24 hrs, 72 hrs (Periods 1 and 2 only), and 168 hrs (Periods 1 and 2 only).
Primary outcome [3] 321752 0
Effect of timing of food administration on pharmacokinetics of higher doses of CRN00808 Novel Formulation 2 as measured from blood plasma concentrations of CRN00808; and to determine the optimal dosing regimen that results in high systemic exposure with low post-dose fasting duration. Pharmacokinetic parameters include AUC, Cmax, Tmax, and t1/2.
Timepoint [3] 321752 0
Cohort 4, Period 1 and 2: 15min pre dose, 15min post dose, 30 min, 45 min, 1 hr, 1.25 hrs, 1.5 hrs, 2.0hrs, 3.0hrs, 4.0hrs, 6.0hrs, 8.0hrs, 10hrs, 12hrs, 24 hours
Cohort 4, Period 3: 15min pre dose, 15min post dose, 30 min, 45 min, 1 hr, 1.25 hrs, 1.5 hrs, 2.0hrs, 3.0hrs, 4.0hrs, 6.0hrs, 8.0hrs, 10hrs, 12hrs, 24 hours, 48hrs, 96hrs, 144hrs and 192hrs,
Secondary outcome [1] 376125 0
Safety and tolerability of CRN00808 as assessed by vital sign measurements, cardiac monitoring, safety laboratory tests, physical examinations and adverse event assessments.
Timepoint [1] 376125 0
Vital sign and 12 lead ECG assessments will be completed as follows in Cohorts 1, 2 and 3: Day-1, Day 1 Predose, 3hrs post dose, Day 2 24hrs post dose in each period, plus at the final study visit after Period 4 (Day 30 for C1 and 2, Day 29 for C3). Assessment in Cohort 4 will be completed as follows: Day-1, Day 1 Predose, 3hrs post dose, Day 2 24hrs, Day 4 72hrs post dose in Period 1 and 2, In Period 3, assessment will be performed on Day-1, Day 1 Predose, 3hrs post dose, Day 2 24hrs, Day 3 48hrs post dose and at the study follow up visits on Days 25, 27 and 29 (final study visit). Assessment in Cohort 5 will be completed as follows: Day-1, Day 1 Predose, 3hrs post dose, Day 2 24hrs, Day 4 72hrs post dose and Day 7 144hrs post dose for each period.

Safety Laboratory testing for Serum Chemistry, Haematology and urinalysis, will be completed at the following time points in Cohort 1 and 2: Day-1, and 24hrs post dose in each period. Additional testing will be completed in period 4 at the following timepoints; 48hrs post dose, 120 hrs post dose and 196hrs post dose, and at the final follow up visit (8 days post dose). Testing will be completed at the following timepoints in Cohort 3: Day-1, and 24hrs post dose in each period. Additional testing will be completed in Period 4 at the final follow up visit (Day 29). Testing will be completed at the following timepoints in Cohort 4: Day-1, 24hrs and 72hrs post dose in period 1 and 2, Day-1, 24hrs and 48hrs post dose in period 3, and additional testing will be completed at the follow up visits on Day 25, Day 27 and Day 29 (final visit). Testing will be completed at the following timepoints in Cohort 5: Day-1, 24hrs, 72hrs and 144hrs post dose in all periods.

Physical examinations will be completed on Day -1 in period 1, and at the final follow up visit (Day 30 in C1/2, Day 29 C3/4, Day 27 C5) in each cohort.

Adverse events will be recorded from the time that a subject signs consent until the final follow up visit. Site staff will question subjects on their health when conducting other assessments throughout the trial. Adverse events will be assessed by study investigators. Adverse events known to be associated with somatostatin receptor agonists include abdominal pain, diarrhea, and nausea
Secondary outcome [2] 397841 0
Primary Outcome: Characterize the effect of the proton-pump inhibitor, lansoprazole, on the pharmacokinetics
of a 60 mg dose of CRN00808 Novel Formulation 2 tablets. Pharmacokinetic parameters include AUC, Cmax, Tmax, and t1/2.
Timepoint [2] 397841 0
Cohort 5 Period 1, 2 and 3 : 15min pre dose, 15min post dose, 30 min, 45 min, 1 hr, 1.25 hrs, 1.5 hrs, 2.0hrs, 3.0hrs, 4.0hrs, 6.0hrs, 8.0hrs, 10hrs, 12hrs, 24 hrs, 72hrs and 144hrs post dose.
Secondary outcome [3] 397842 0
Primary Outcome: Effect of a low fat meal on pharmacokinetics of a 60mg CRN00808 Novel Formulation 2 as measured from blood plasma concentrations of CRN00808 Pharmacokinetic parameters include AUC, Cmax, Tmax, and t1/2.
Timepoint [3] 397842 0
Cohort 5 Period 1, 2 and 3 : 15min pre dose, 15min post dose, 30 min, 45 min, 1 hr, 1.25 hrs, 1.5 hrs, 2.0hrs, 3.0hrs, 4.0hrs, 6.0hrs, 8.0hrs, 10hrs, 12hrs, 24 hrs, 72hrs and 144hrs post dose.

Eligibility
Key inclusion criteria
- Male and female subjects 18 to 55 years of age (Cohorts 1, 2 and 4)
- Male and Female subjects 18 to 65 years of age (Cohort 3 and 5)
- BMI 18 to 30 kg/m2
- Females must be non-pregnant and non-lactating, and either surgically sterile, post- menopausal, or using effective method(s) of birth control
- male subjects must use a condom, or his female partner of childbearing potential must use an effective form of contraception. Male subjects must also agree to not donate sperm for the duration of the study and until at least 3 months after the last dose of study drug.
- Willing to provide signed informed consent
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Prior treatment with CRN00808
- Any uncontrolled or active major systemic disease
- History or presence of malignancy except adequately treated basal cell and squamous cell carcinomas of the skin within the past 5 years.
- Active acute or chronic infection
- Use of any investigational drug within the past 60 days
- Had an unstable psychological disorder less than or equal to 1 year before screening based on the subject’s medical history.
- Had a medically significant illness within 30 days of admission.
- Use of any investigational drug within the past 60 days or 5 half-lives, whichever is longer prior to the first dosing of study drug.
- Use of any prior medication without approval of the Investigator within 14 days prior to admission.
- History of or current alcohol abuse
- Taking moderate or strong CYP3A4 inhibitors or inducers.
- Any condition that in the opinion of the investigator would jeopardize the subject's appropriate participation in the study

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
15/11/2019
Actual
15/11/2019
Date of last participant enrolment
Anticipated
1/02/2021
Actual
9/03/2021
Date of last data collection
Anticipated
1/03/2021
Actual
21/05/2021
Sample size
Target
60
Accrual to date
Final
57
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 14999 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 28284 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 304063 0
Commercial sector/Industry
Name [1] 304063 0
Crinetics Australia Pty Ltd
Country [1] 304063 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Crinetics Australia Pty Ltd
Address
17 Praeger Street
Chapel Hill, QLD 4069
Australia
Country
Australia
Secondary sponsor category [1] 304258 0
Commercial sector/Industry
Name [1] 304258 0
Avance Clinical Pty Ltd
Address [1] 304258 0
Level 1, 2 Ann Nelson Drive
Thebarton, SA, 5043
Australia
Country [1] 304258 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304554 0
Bellberry Human Research Ethics Committee A, (TGA Code: EC00372)
Ethics committee address [1] 304554 0
123 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [1] 304554 0
Australia
Date submitted for ethics approval [1] 304554 0
04/09/2019
Approval date [1] 304554 0
01/10/2019
Ethics approval number [1] 304554 0
2019-09-764-A-1

Summary
Brief summary
CRN00808 is an oral somatostain receptor 2 agonist (sst2) being developed for the treatment of acromegaly. This multi cohort single dose study will assess the relative bioavailability, performance and safety of two novel oral formulations of CRN00808.
Cohort 1 and Cohort 2 are identical in their design except for the CRN00808 formulation used. CRN00808 Novel Formulation 1 and CRN00808 Novel Formulation 2 will be evaluated in Cohorts 1 and 2 respectively, over 4 periods.
For Cohort 3 the test formulation used will be based on data and performance of the two test formulations evaluated in Cohorts 1 and/or 2. The cohort will consist of 4 periods. In Period 1, subjects will be administered the CRN00808 Reference Formulation. In the remaining periods, a single dose of CRN00808 Novel Formulation 2 will be administered orally after fasting to determine the food effect of CRN00808.
Cohort 4 will consist of 3 periods, with subjects being administered a single dose of CRN00808 Novel Formulation 2 in each after fasting to determine the optimal dose of CRN00808 and optimal post dose fasting. Dose level and post dose fasting Period 2 and 3 was based on the data obtained in Cohort 4 Period 1 and 2 respectively.
Cohort 5 will consist of 3 periods, with subjects being administered a single dose of CRN00808 Novel Formulation 2 in each period. In Period 1 and 2 CRN00808 will be administered after an overnight fast, and will be followed by the consumption of a low fat meal. In Period 3 the low fat meal will be consumed within 30 minutes prior to the administration of CRN00808.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97366 0
Prof Sepher Shakib
Address 97366 0
CMAX Clinical Research Pty Ltd
Level 5, 18 a North Terrace
Adelaide, SA, 5000
Australia
Country 97366 0
Australia
Phone 97366 0
+61 411 100 278
Fax 97366 0
Email 97366 0
[email protected]
Contact person for public queries
Name 97367 0
Prof Sepher Shakib
Address 97367 0
CMAX Clinical Research Pty Ltd
Level 5, 18 a North Terrace
Adelaide, SA, 5000
Australia
Country 97367 0
Australia
Phone 97367 0
+61 411 100 278
Fax 97367 0
Email 97367 0
[email protected]
Contact person for scientific queries
Name 97368 0
Prof Sepher Shakib
Address 97368 0
CMAX Clinical Research Pty Ltd
Level 5, 18 a North Terrace
Adelaide, SA, 5000
Australia
Country 97368 0
Australia
Phone 97368 0
+61 411 100 278
Fax 97368 0
Email 97368 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No plan to share individual participant data


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbasePharmacokinetics and Safety of an Improved Oral Formulation of Paltusotine, a Selective, Non-Peptide Somatostatin Receptor 2 (SST2) Agonist for the Treatment of Acromegaly.2021https://dx.doi.org/10.1210/jendso/bvab048.1068
Dimensions AIPituitary Diseases Registry Study in Latvia. Part 12021https://doi.org/10.1210/jendso/bvab048.1069
N.B. These documents automatically identified may not have been verified by the study sponsor.