Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001577101
Ethics application status
Approved
Date submitted
4/11/2019
Date registered
15/11/2019
Date last updated
4/03/2022
Date data sharing statement initially provided
15/11/2019
Date results information initially provided
4/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Dapagliflozin Extended Release Capsules in Healthy Volunteers.
Scientific title
An Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Dapagliflozin Extended Release Capsules in Healthy Volunteers.
Secondary ID [1] 299692 0
LYN-045-C-001
Secondary ID [2] 299693 0
CM5619
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes 315046 0
Condition category
Condition code
Metabolic and Endocrine 313376 313376 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is LYN-045, an extended release (ER) oral capsule containing dapagliflozin 35 mg. The rationale for the development of this ER formulation is to reduce the frequency of dosing orally administered dapagliflozin once weekly or less and thereby improving the management of type 2 diabetes.
The study will consist of three cohorts, with each cohort receiving a different formulation of LYN-045.

In Cohort 1, 8 participants will receive the base formulation - LYN-045-B.
Each participant will receive:
On day 1, a single dose of immediate release (IR) dapagliflozin (FORXIGA®) 10 mg oral tablet that will be administered to facilitate characterisation of the dapagliflozin pharmacokinetics.
On day 4, the LYN-045-B will be administered as single dose ER oral capsule containing 35 mg dapagliflozin. On both days (1 and 4), the single oral dose of the IR dapagliflozin tablet or LYN-045-B ER oral capsule will be administered and directly observed by a trained nurse (at a minimum) in an inpatient unit.
Eligible healthy volunteers enrolled into the study should expect to participate in the study for up to 4 weeks, from the time of enrolment through the last study visit.

In Cohort 2, 16 participants will be dosed with the stiffer core formulation – LYN-045-SC – 8 with a stabilising ring and 8 without.
On day 1, the LYN-045-SC will be administered as single dose ER oral capsule containing 35 mg dapagliflozin. The single oral dose of LYN-045-SC ER oral capsule will be administered and directly observed by a trained nurse (at a minimum) in an inpatient unit. Eligible healthy volunteers enrolled into the study should expect to participate in the study for up to 4 weeks, from the time of enrolment through the last study visit.

In Cohort 3, 10 participants will be dosed with the flexible arm formulation – LYN-045-FA – once with a stabilising ring and once without (two total doses).
Each participant in Cohort 3 will receive:
On day -4, a single dose of immediate release (IR) dapagliflozin (FORXIGA®) 10 mg oral tablet that will be administered to facilitate characterisation of the dapagliflozin pharmacokinetics. On Day 1, the LYN-045-FA with or without the stabilising ring will be administered as single dose ER oral capsule containing 35 mg dapagliflozin. After confirmation of gastric emptying, on Day 10 a single oral dose of LYN-045-FA ER oral capsule will be administered. Participants will receive the formulation (with/without ring) not received on Day 1. All administration of LYN-045-FA will be directly observed by a trained nurse (at a minimum) in an inpatient unit.
Eligible healthy volunteers enrolled into the study should expect to participate in the study for up to 4 weeks, from the time of enrolment through the last study visit.
In Cohort 4, 16 participants will be dosed with the disintegrating matrix formulations – 1 dose of LYN-045-DM – with a short disintegrating matrix (SDM) and one dose with a Long disintegrating matrix (LDM).
On day -2 and Day -1, a single dose of immediate release (IR) dapagliflozin (FORXIGA®) 10 mg oral tablet will be administered to facilitate characterisation of the dapagliflozin pharmacokinetics. On day 1, the LYN-045-SDM will be administered as single dose oral capsule containing 35 mg dapagliflozin. On day 10, the LYN-045-LDM will be administered as single dose oral capsule containing 35 mg dapagliflozin. The oral doses of the LYN-045-DM oral capsules will be administered and directly observed by a trained nurse (at a minimum) in an inpatient unit. Eligible healthy volunteers enrolled into the study should expect to participate in the study for up to 4 weeks, from the time of enrolment through the last study visit.

In Cohort 5, 20 participants will be dosed with disintegrating matrix formulations LYN-045-DMR – 10 volunteers will receive 1 dose of LYN-045-DMR1, and 10 further volunteers will receive one dose of LYN-045-DMR2.
On Day 1 a single dose of LYN-045-DMR will be administered as single dose oral capsule containing 35 mg dapagliflozin. The oral dose of the LYN-045-DMR oral capsule will be administered and directly observed by a trained nurse (at a minimum) in an inpatient unit. Eligible healthy volunteers enrolled into the study should expect to participate in the study for up to 3 weeks, from the time of enrolment through the last study visit.
Intervention code [1] 315958 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321857 0
Safety and tolerability of LYN-045-B, LYN-045-SC and LYN-045-FA, assessed from adverse events (AEs).
Timepoint [1] 321857 0
Adverse events will be collected at screening visit, upon admission to the inpatient unit, and at dosing of IR dapagliflozin and the 3 days that follow up to LYN-045 dosing (C1,C3 and C4 only)). They will also be assessed upon dosing of LYN-045 at 0, 4, 6 and 12 hours post dose and daily on inpatient days as well as outpatient days (C1, C2 and C4). In C5, AEs will be assessed before dosing, and after dosing prior to checkout on Day 1. Further AE assessment will occur at all outpatient and Inpatient visits. Adverse events will be assessed by physical exam, electrocardiogram, vital signs, safety labs (serum assay), urine dipstick and participant self-report.
Directed physical exams will be performed on screening visit, upon admission to the inpatient unit and prior to dosing with LYN-045, upon discharge from the inpatient unit and on outpatient visit days (final outpatient visit on for C3 - Day 23). Full physical exams for C4 will be performed at screening, admission to the unit (Day -3) an at the end of study visit on Day 23. Directed physical exams will be performed on Day -1, Day 1 and Day 10 prior to dosing and check out from the unit on Day 6 and 15. Full physical exams for C5 will be performed at screening, admission to the unit (Day 1), check in for the inpatient stay (Day 7), clinic discharge (Day 10/11) and at the end of study visit (Day 20). Directed physical exams will be performed at outpatient visits on on Days 3, 4, 6 and 12.
Vital signs will be collected at the screening visit, upon admission to the inpatient unit, at dosing of IR dapagliflozin and the days that follow (C1, C3 and C4 only), upon dosing of LYN-045 at 0, 4 and 12 hours post dose, and daily on inpatient days and outpatient days for all cohorts.
Safety labs will be collected in C1 as follows; at screening visit, at dosing of IR dapagliflozin, dosing of LYN-045 (Day 4) and at study day 10. Safety labs will be collected in C2 as follows; at screening visit, at dosing of LYN-045 (Day 1) and at study Day 7 by serum assay. Safety labs will be collected in C3 as follows; at screening visit, at dosing of IR dapagliflozin, dosing of LYN-045 (Day 4) and at study day 10. Safety labs will be collected in C4 as follows; Screening, at initial check into the unit (Day -3) and 5 days post dosing of LYN-045 (Day 5 and Day 14). Safety labs will be collected in C5 as follows; Screening, pre dose of LYN-045 on Day 1, and during the inpatient stay on Day 8.
For Cohort 1 and 2; Electrocardiograms will be performed at screening visit, upon admission to the inpatient unit (day minus 1), at dosing of LYN-045 (pre-dose and 4 hours post dose) and at days 7 and 10 (C1) or days 4 and 7 (C2). For Cohort 3 Electrocardiograms will be performed at screening visit, 4 hours after dosing with LYN-045 on Day 1 and 10, and on Days 6 and 15 prior to discharge
For Cohort 4, Electrocardiograms will be performed at the screening visit, 4 hours after dosing with LYN-045 on Day 1 and 10, and additionally on Day 6 and 15 prior to discharge
For Cohort 5, Electrocardiograms will be performed at the screening visit, prior to dosing with LYN-045 on Day 1 and additionally on check into the unit on Day 7, and check out on Day 11.
Primary outcome [2] 321858 0
Pharmacokinetics of dapagliflozin following administration of LYN-045 ER formulations, as assessed by: e.g. Cmax, Cmin, Tmax, Tlast, Kel, AUC0-24, AUC0-t, AUC0-168, and AUC0-8 by validated serum assay.
Timepoint [2] 321858 0
C1 PK sampling will be completed as follows: Post IR dapagliflozin dosing at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, and 12 hours post-dose Day 1 through Day 4 at 24, 36, 48, 60, and 72 hours post-dose by validated serum assay. Post LYN-045 sampling at 0 hours (pre-dose; also 72-hour IR post-dose timepoint), 1, 2, 4, 6, 8, and 12 hours on Day 4 (C1) and twice-daily through to the morning of Day 11 (e.g. 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours post-dose) by validated serum assay.
C2 PK Sampling will completed as follows: LYN-045 PK sampling at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 12 hours on Day 1 and twice-daily through to the morning of D8 (C2 and 3) (e.g. 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours post-dose) by validated serum assay.
C3 PK sampling will be completed as follows: Post IR dapagliflozin dosing in the evening on Day -2, at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours and 24 hours post dose on Day -1 by validated serum assay. LYN-045 PK sampling at 0 hours (pre-dose; also 24-hour IR post-dose timepoint), 1, 2, 4, 6, 8, and 12 hours on Day 1 (dose 1) and 10 (dose 2), and twice daily through to the morning of Day 6 and Day 15 respectively for each dose (e.g. 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 hours post-dose) by validated serum assay. Single PK sample will also be collected in the morning at each outpatient clinic visit on Days 7 to 9, and 16, 17, 20, and 23.
C4 PK sampling will be completed as follows: evening prior to IR dapagliflozin on Day -2, Post IR dapagliflozin dosing on Day -1, at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12 hours and 24 hours post dose (Day 1 pre LYN-045 dose) by validated serum assay. Further Pk sampling will occur at 0 hours (pre-dose), 1, 2, 4, 6, 8, and 12 hours on Day 1 and 10 and twice-daily through the morning of Day 6 and 15 respectively for dose 1 and 2 of LYN-045 (e.g. 24, 36, 48, 60, 72, 84, 96, 108, and 120 hours post-dose).
Secondary outcome [1] 376496 0
Gastrointestinal transit of LYN-045 capsules by imaging assessments (MRI, Ultrasound, X ray), and Urine Glucose analysis.
Timepoint [1] 376496 0
Imaging:
MRI will be performed two days post dosing of LYN-045, 4 days post dosing of LYN-045 and 7 days post dosing of LYN-045/discharge from inpatient unit in cohort 1 and 2., Abdominal x-rays will be performed on days 15 and 18 (C1) or Days 12 and 15 (C2) outpatient visits.
Cohort 3 will be assessed by X-Ray, at the following time points: Day 4, 6, 13 and 15. X-Rays will also be performed on Days 9 and 23 if gastric emptying has not been confirmed before each respective day. Participants in Cohort 4 will have X-Ray completed in the same fashion as Cohort 3.
Cohort 4 Participants will also undergo ultrasound between 0.5 hours and 3 hours post dose of LYN-045 on days 1 and 10.
Cohort 5 Participants will undergo X-Ray at the following timepoints: Day 6, Day 8, Day 10, Day 14 and Day 20. Participants will also undergo ultrasound on Day 3, 6, 8, 10 and 12. If the stellate has been noted to pass at any point, no further imaging will be required.
Urine Glucose Analysis:
In Cohort 3 and 4 whilst inpatients, Participants will also collect pooled urine samples from midnight through to morning void at approximately 7am. While outpatients, participants are to continue to catch urine overnight and bring the pooled urine to the clinic. After checkout on Day 15, Participants are to continue to catch urine until the stellate has been confirmed to have passed the stomach, as per the PI. A urine glucose dipstick analysis is to be completed on a sample of each overnight urine pool, to aid in determining stellate position.
In Cohort 5, no overnight pooling is required. A urine dipstick to monitor urine glucose will be completed at the following timepoints: Day 1 predose, Day 4, 7, 8, 9, 10, 11 and 14.

Eligibility
Key inclusion criteria
1. Provision of signed and dated informed consent;
2. Stated willingness to comply with all protocol-specified procedures and availability for the duration of the study;
3. Good current health, in the opinion of the Investigator, as evidenced on review of medical history, no significant gastrointestinal abnormalities, physical examination, concomitant medications, and other safety assessments;
4. Body mass index (BMI) of greater than or equal to 18 kg/m2 and less than or equal to 30 kg/m2;
5. Body weight greater than or equal to 55 kg.
Minimum age
18 Years
Maximum age
49 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Any known clinically significant esophageal or gastrointestinal disease;
2. Unusual score for swallowing questionnaire.
3. Do not demonstrate normal swallowing and gastrointestinal passage for capsule, as assessed while undergoing imaging studies.
4. Symptoms suggestive of irritable bowel syndrome, functional constipation or functional diarrhea;
5. History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs;
6. Clinically significant abnormal safety (e.g., physical examination) or safety laboratory assessments;
7. Hepatitis B, hepatitis C, or H. pylori infection at Screening, unless there is a confirmed medical history of successful treatment;
8. Use of prescription medications, natural remedies, vitamins or non-prescription medicines associated with changes to gastric motility or pH or management of gastrointestinal symptoms within two weeks of study dosing;
9. Individuals who are contraindicated based on dapagliflozin;
10. History of any drug or alcohol use disorder in the past 2 years;
11. Individuals of reproductive potential who are (hetero) sexually active but unwilling to use acceptable means of contraception through the End of Study;
12. Individuals who are nursing or who have positive or indeterminate pregnancy tests at screening.

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
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Issues with IP manufacturing for C5 impacted by COVID.
Date of first participant enrolment
Anticipated
25/11/2019
Actual
3/12/2019
Date of last participant enrolment
Anticipated
Actual
5/03/2021
Date of last data collection
Anticipated
Actual
21/04/2021
Sample size
Target
70
Accrual to date
Final
44
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 15086 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 28382 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 304169 0
Commercial sector/Industry
Name [1] 304169 0
Lyndra Australia Pty Ltd
Country [1] 304169 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Lyndra Australia Pty Ltd
Address
Level 13 41 Exhibition Street
Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 304397 0
None
Name [1] 304397 0
Address [1] 304397 0
Country [1] 304397 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304643 0
Bellberry Limited HREC Committee D
Ethics committee address [1] 304643 0
123 Glen Osmond Rd
Eastwood SA 5063
Ethics committee country [1] 304643 0
Australia
Date submitted for ethics approval [1] 304643 0
02/10/2019
Approval date [1] 304643 0
28/10/2019
Ethics approval number [1] 304643 0
2019-09-755

Summary
Brief summary
An open-label study in healthy volunteers:
To evaluate the safety, tolerability and pharmacokinetics of dapagliflozin (35 mg) extended release capsules (LYN-045) in healthy volunteers

To characterize the pharmacokinetics (PK) of dapagliflozin (35 mg) extended release capsules (LYN-045).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97698 0
Prof Sepehr Shakib
Address 97698 0
CMAX
Level 5
18a North Terrace
Adelaide SA 5000
Country 97698 0
Australia
Phone 97698 0
+61 0870742823
Fax 97698 0
Email 97698 0
[email protected]
Contact person for public queries
Name 97699 0
Ms Jessica Ballinger
Address 97699 0
(Director)
Lyndra Australia Pty Ltd
Level 13
41 Exhibition Street
Melbourne VIC 3000
Country 97699 0
Australia
Phone 97699 0
+1 857 201 5322
Fax 97699 0
Email 97699 0
[email protected]
Contact person for scientific queries
Name 97700 0
Dr Bernard Silverman
Address 97700 0
Lyndra Therapeutics Inc
65 Grove Street
Suite 301
Watertown, MA 02472
Country 97700 0
United States of America
Phone 97700 0
+1 617 803 2445
Fax 97700 0
Email 97700 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only
When will data be available (start and end dates)?
3 moths following publication, 4 years following publication
Available to whom?
case by case basis at the discretion of Lyndra (primary sponsor)
Available for what types of analyses?
Only to achieve the aims in the approved proposal
How or where can data be obtained?
Required to sign data access agreement by emailing primary sponsor ([email protected]).


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
No additional documents have been identified.