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Trial registered on ANZCTR


Registration number
ACTRN12620001214921p
Ethics application status
Not yet submitted
Date submitted
15/10/2020
Date registered
16/11/2020
Date last updated
16/11/2020
Date data sharing statement initially provided
16/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of ALP001E in Healthy Subjects and Patients with Type 2 Diabetes
Scientific title
A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of ALP001E in Healthy Subjects and Patients with Type 2 Diabetes
Secondary ID [1] 302388 0
None
Universal Trial Number (UTN)
U1111-1257-4918
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes Mellitus 319177 0
Condition category
Condition code
Metabolic and Endocrine 317147 317147 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1 – Single ascending doses and food-effect: Cohorts 1 to 5
Planned a single oral dose of ALP001E capsules under fasting conditions: 25 mg, 75 mg, 150 mg, 300 mg, 600 mg. Subjects from Cohort 3 will be administered the same dose in a second period after ingestion of a high-fat meal. Subjects will be served a high-fat, high-caloric meal of approximately 800 to 1000 calories (approximately 50% of total caloric content of the meal derived from fat). This test meal should derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively. An example would be a meal consisting of two eggs fried in butter, 2 slices of toast with butter, 2 strips of bacon, approximately 120 g of hash brown potatoes, and 240 mL of whole milk.

Part 2 – Formulation bridging cohort (if needed)
If needed, one dose level is planned for Part 2 after evaluation of bioavailability and safety data of Cohort 3 of Part 1 as determined by the SRC. In this bridging cohort, dose in suspension will be then repeated using a lower step down dose administered in previous cohort, final dose to be determined by dose escalation committee based on preceding safety and PK data. A single oral dose of ALP001E given by staff in the study unit.

Part 3 – Multiple ascending doses: Healthy Cohort 6 and type 2 diabetes (T2DM) Cohort 7 to 9
Planned dose of ALP001E capsules to healthy volunteers (Cohorts 6): 150 mg
Planned dose of ALP001E capsules to T2DM (Cohorts 7 to 9): 50 mg, 100 mg, and 150 mg
Oral given by staff in the study unit once daily for 14 days.

The strategies of adherence to the doses:
For Part 1, Study medication capsules will be administered to each subject with approximately 240 mL of water. For Part 2 (if needed), suspension formulation will be prepared and orally administered to study subjects. For Part 3, drug administration will be done at the same time every day.
A hand and mouth check will be performed to ensure consumption of the medication to all subjects.
Intervention code [1] 318673 0
Treatment: Drugs
Comparator / control treatment
Placebo for oral capsules/suspension will be administered to match the doses for the intervention active treatment with ALP001E.
The composition of the placebo hypromellose acetate succinate (92.74%), and macrogol (15)-hydroxystearate (7.26%).
Control group
Placebo

Outcomes
Primary outcome [1] 325225 0
Safety and tolerability will be assessed by reporting of adverse events (i.e., seriousness, severity, relationship to the study medication, outcome, duration), clinical laboratory tests (hematology, biochemistry), physical examination (System Organ Class examination), vital signs (systolic and diastolic blood pressure: manual sphygmomanometer, digital blood pressure cuff, heart rate (oxymeter), respiratory rate and body temperature: oral or aural) and 12-lead ECGs (semi-supine 12 lead-paper ECG).

As this is the first study of ALP001E in humans, adverse events are not yet known. Based on findings from the nonclinical testing program, and the experience with other GRAs that have undergone clinical testing potential risks include: hepatic steatosis; increases in blood pressure, cholesterol/lipids, weight, and AST/ALT; abnormal storage of glycogen; decreased blood sugars; increased number of alpha cells; and glucagonoma.
Timepoint [1] 325225 0
During Part 1 and 2, subjects will be confined to the study unit and assessed daily from Day -1 to Day 3 before being discharged. Subjects will return for follow up on Day 6 +/- 1. At the end of each dosing cohort a safety review committee will meet to review all available safety information to determine if it is safe to continue to the next dose level.
During Part 3, subjects will be confined to the study unit and assessed daily from Day -1 to Day 6 morning before being discharged. Subjects will return daily to the study unit every day from Day 7 until Day 11 when they will be re-confined again until Day 15. Subjects will be then discharged and will return for a follow up on Day 19 +/- 1.
Secondary outcome [1] 387267 0
In Part 1, Part 2 (SAD cohorts), and Part 3 (MAD cohorts) glycemic effect will be assessed: fasting plasma glucose will be measured
Timepoint [1] 387267 0
Part 1 and Part 2:
Blood samples will be collected:
-screening
-prior to dosing on Day 1
-samples will be collected at 12, 24, and 48 hours post-dose.

Part 3:
Blood samples will be collected at:
-Screening
-prior to dosing on Days 1, 2, 3, 4, 6, 8, 10, 12, and 14
Secondary outcome [2] 387275 0
In Part 3 (MAD cohorts) PD assessments will be assessed: fasting plasma insulin, glucagon, and active and total GLP-1 will be measured
Timepoint [2] 387275 0
Part 3
-prior to dosing on Day 1 and 14
Secondary outcome [3] 387276 0
In Part 3 MAD T2DM patient cohorts: 7-point glucose measurement will be measured
Timepoint [3] 387276 0
Blood samples will be collected on the following days:
- pre-breakfast, post-breakfast, pre-lunch, post-lunch, pre-dinner, post-dinner, bedtime on Day -1 (admission) and Day 14
Secondary outcome [4] 387277 0
In Part 3 T2DM patient cohorts: HbA1c measurement will be measured.
Timepoint [4] 387277 0
Blood samples will be collected on the following days:
-screening
-Day 19 +/- 1
Secondary outcome [5] 387321 0
The following pharmacokinetic parameters will be measured in plasma and urine: ALP001 concentration and Pharmacokinetic (PK) profile: AUC0-t, Cmax, Tmax, T½ el, Kel, Cl/F, and Vd/F. Ae0-t, Fe0-t and CLR
Timepoint [5] 387321 0
Part 1 and Part 2:
Blood PK samples will be collected:
-prior to dosing on Day 1
-samples will be collected at 10, 20, 30 minutes, and 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours post-dose.

Part 3 (blood and urine):
Blood PK samples will be collected at:
-prior to dosing on Day 1, 5, 10, 13, and 14.
-post-dose on Day 1 and Day 14: at 10, 20, 30 minutes, and 1, 1.5, 2, 4, 6, 8, 10, 12, 16 and 24 hours (pre-dose of Day 2 and 24 hours post-dose of Day 14).

Urine PK samples will be collected at:
-Day 1: prior to dosing (-12 to 0 hour) and 0-6, 6-12, and 12-24 hours after drug administration
-Day 14: prior to dosing (-12 to 0 hour) and 0-6, 6-12, and 12-24 hours after drug administration, plus 24-36 hours post-dose
Secondary outcome [6] 388827 0
Part 3 MAD T2DM patient 150 mg cohort only: change from baseline (Day-1) in fasting plasma glucose (FPG) measured during an oral glucose tolerance test (OGTT) on Day 14 of treatment.
Timepoint [6] 388827 0
Samples collect at 0.5, 1, 1.5, 2, 3, and 4 hours post glucose load on Day-1 and 14.
Secondary outcome [7] 388841 0
Part 3 MAD T2DM patient 150 mg cohort only: change from baseline (Day-1) in glucagon plasma level measured during an OGTT on Day 14 of treatment
Timepoint [7] 388841 0
Samples collect at 0.5, 1, 1.5, 2, 3, and 4 hours post glucose load on Day-1 and 14.
Secondary outcome [8] 388842 0
Part 3 MAD T2DM patient 150 mg cohort only: change from baseline (Day-1) in insulin plasma level measured during an OGTT on Day 14 of treatment.
Timepoint [8] 388842 0
Samples collect at 0.5, 1, 1.5, 2, 3, and 4 hours post glucose load on Day-1 and 14.
Secondary outcome [9] 388843 0
Part 3 MAD T2DM patient 150 mg cohort only: change from baseline (Day-1) in active GLP-1 plasma level measured during an OGTT on Day 14 of treatment.
Timepoint [9] 388843 0
Samples collect at 0.5, 1, 1.5, 2, 3, and 4 hours post glucose load on Day-1 and 14.
Secondary outcome [10] 388844 0
Part 3 MAD T2DM patient 150 mg cohort only: change from baseline (Day-1) in total GLP-1 plasma level measured during an OGTT on Day 14 of treatment.
Timepoint [10] 388844 0
Samples collect at 0.5, 1, 1.5, 2, 3, and 4 hours post glucose load on Day-1 and 14.

Eligibility
Key inclusion criteria
All study participates:
• body weight greater than or equal to 50.0 kg for males and greater than or equal to 45.0 kg for females
• non-smokers
• Females of childbearing potential and male subjects who are not vasectomized for at least 6 months who are sexually active must be willing to use acceptable contraceptive method throughout the study (from the screening) and for 30 days after the last study drug administration.

Healthy volunteers:
• Body mass index (BMI) > 18.5 and < 30.0 kg/m^2
• the absence of clinically significant illness and surgery within 4 weeks prior to first dosing
• the absence of significant history of biliary tract disease
• has FPG between 70 mg/dL and 110 mg/dL (3.9 to 6.1 mmol/L) (inclusive)

Type 2 Diabetics Patients:
• BMI between 20 and 42 kg/m^2;
• Subjects with established diagnosis of T2DM of at least 1 year duration at the time of screening;
• FPG greater than or equal to 6.94 mmol/L and less than or equal to 14.43 mmol/dL (260 mg/dL) at screening;
• Subjects must be on a stable dose of metformin for greater than or equal to 12 weeks without use of other antidiabetic medications for >3 weeks prior to randomization and maintain the dose until the end of the study;
• HbA1C greater than or equal to 6.5 and less than or equal to 10% at screening.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
All study participates:
• Any confirmed clinically significant abnormality at physical examination, clinically significant abnormal laboratory test results or positive test for hepatitis B, hepatitis C, or HIV found during medical screening.
• Evidence of clinically significant hepatic, biliary tract disease or renal impairment including ALT and AST > 10% × ULN; creatinine clearance levels (Cockcroft Gault of <60mL, min); serum triglyceride level > 4.52 mmol/L (>400 mg/dL), total bilirubin is above ULN.
• Use of medications, with the exception of hormonal contraceptives and medications exempted by the Investigator on a case-by-case basis because they are judged unlikely to affect the pharmacokinetic profile of the study drug or subject safety (e.g., topical drug products without significant systemic absorption).

Healthy volunteers:
• Clinically significant electrocardiogram (ECG) abnormalities or vital sign abnormalities (systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or heart rate less than 40 or over 100 bpm) at screening

Type 2 Diabetics Patients:
• Type 1 diabetes mellitus, maturity-onset diabetes of the young or any rare form of diabetes other than type 2, hyperglycemia due to secondary causes such as hyperadrenocorticalism caused by Cushing’s syndrome, pheochromocytoma, acromegaly or untreated hyperthyroidism
• Clinically significant ECG abnormalities or vital sign abnormalities (systolic blood pressure lower than 90 or over 150 mmHg, diastolic blood pressure lower than 50 or over 95 mmHg, or heart rate less than 40 or over 100 bpm) at screening.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 23015 0
New Zealand
State/province [1] 23015 0

Funding & Sponsors
Funding source category [1] 306812 0
Commercial sector/Industry
Name [1] 306812 0
CMC Magnetics Corporation
Address [1] 306812 0
No. 215, Wenhua 2nd Road, Guishan District, Taoyuan City 333, Taiwan (R.O.C.)
Country [1] 306812 0
Taiwan, Province Of China
Primary sponsor type
Commercial sector/Industry
Name
CMC Magnetics Corporation
Address
No. 215, Wenhua 2nd Road, Guishan District, Taoyuan City 333, Taiwan (R.O.C.)
Country
Taiwan, Province Of China
Secondary sponsor category [1] 307376 0
Commercial sector/Industry
Name [1] 307376 0
CMC Magnetics Corporation
Address [1] 307376 0
No. 215, Wenhua 2nd Road, Guishan District, Taoyuan City 333, Taiwan (R.O.C.)
Country [1] 307376 0
Taiwan, Province Of China

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 306976 0
Health and Disability Ethics Committees (HDECs)
Ethics committee address [1] 306976 0
Postal address:
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140

Street address:
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 306976 0
New Zealand
Date submitted for ethics approval [1] 306976 0
16/11/2020
Approval date [1] 306976 0
Ethics approval number [1] 306976 0

Summary
Brief summary
This study is the first clinical study conducted with ALP001E and is designed to assess the safety and tolerability, pharmacokinetics (how the drug is absorbed by the body) and pharmacodynamics (the effect the drug has on the body) of ALP001E when administered as single and multiple ascending doses in healthy participants and as multiple doses in patient with type 2 diabetes mellitus. The study will start with a low single dose and safety information will be reviewed by a safety review committee to confirm if higher doses can be given to sequential cohorts before giving multiple doses.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105622 0
Dr Christopher Wynne
Address 105622 0
Christchurch Clinical Studies Trust Ltd
Level 4/264 Antigua Street, Christchurch Central, Christchurch 8011, New Zealand
Country 105622 0
New Zealand
Phone 105622 0
+6433729477
Fax 105622 0
Email 105622 0
chris@ccst.co.nz
Contact person for public queries
Name 105623 0
Miss Jia Ling Hsu
Address 105623 0
CMC Magnetics Corporation
No. 215, Wenhua 2nd Road, Guishan District, Taoyuan City 333, Taiwan (R.O.C.)
Country 105623 0
Taiwan, Province Of China
Phone 105623 0
+88633978886
Fax 105623 0
Email 105623 0
j6698@cmcnet.com.tw
Contact person for scientific queries
Name 105624 0
Dr Gabriel Castro
Address 105624 0
CMC Magnetics Corporation
No. 215, Wenhua 2nd Road, Guishan District, Taoyuan City 333, Taiwan (R.O.C.)
Country 105624 0
Taiwan, Province Of China
Phone 105624 0
+88633978886
Fax 105624 0
Email 105624 0
j6695@cmcnet.com.tw

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results