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Trial registered on ANZCTR


Registration number
ACTRN12620001187932
Ethics application status
Approved
Date submitted
22/09/2020
Date registered
10/11/2020
Date last updated
9/04/2021
Date data sharing statement initially provided
10/11/2020
Date results information initially provided
9/04/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
An Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Dapagliflozin 70 mg Extended Release Capsules in Healthy Volunteers
Scientific title
An Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Dapagliflozin 70 mg Extended Release Capsules in Healthy Volunteers
Secondary ID [1] 302304 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes Mellitus 319057 0
Condition category
Condition code
Metabolic and Endocrine 317010 317010 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Extended release (ER) Dapagliflozin (LYN-045)
Administration: oral (capsules)

A total of 10 subjects are planned to be enrolled, 2 in the sentinel group and 8 in the main group. All subjects will receive 3 doses of Immediate release (IR) dapagliflozin 10 mg in the inpatient unit, Dose 1 on Day -3, Dose 2 on Day -2, and Dose 3 on Day -1. Following that, all subjects will receive 2 doses of LYN-045 70 mg. Dose 1 will be administered in the inpatient unit on Day 1, dose 2 of LYN-045 will be administered on Day 8. The mouth cavity is inspected after administration of the capsule.

A review of safety information will be performed after the 2 sentinel subjects complete 2 days of observation after dosing with the initial dose of LYN-045. The safety data will be reviewed by the Investigator to determine whether enrollment of subjects in the main group may proceed.
Intervention code [1] 318594 0
Treatment: Drugs
Comparator / control treatment
No control group; open label
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325119 0
Safety and tolerability of LYN-045 assessed from the incidence of treatment-emergent adverse events (TEAEs) and laboratory, vital sign, and electrocardiogram assessments.
Timepoint [1] 325119 0
Adverse events (AE): Screening, Day -4, Day -3, Day -2, Day -1, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 14, Day 15 and Day 21 (EOS).
Vital signs: Vitals will be obtained at Screening, Day -2, Day -1, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 14, Day 15 and Day 21 (EOS).
ECG: ECGs will be recorded at Screening, Day 1, Day 8, Day 10 and Day 15.
Biochemistry, coagulation, hematology: Blood samples will be taken at Screening, Day -4, Day 1, Day 9, Day 15 and Day 21 (EOS).
Physical Examination (PE): General PE will will occur at Screening, Day -4 and Day 21 (EOS), A directed PE will occur at Day 1, Day 8, Day 10 and Day 15.
Primary outcome [2] 325120 0
PK of ER dapagliflozin following administration of LYN-045 to include where possible and appropriate: Cmax, Cmin, Tmax, Tlast, Kel, AUC0-24, AUC0-t, AUC0-168, and AUC0-8.
Timepoint [2] 325120 0
PK samples: Blood samples will be collected on Day 1 (pre-dose, 1, 2, 4, 6, 8 and 12 hours post-dose), Day 2 (24 and 36 hours post-dose), Day 3 (48 and 60 hours post-dose), Day 4 (72 and 84 hours post-dose), Day 5 (96 and 108 hours post-dose), and Day 6 (120 hours post-dose)
Secondary outcome [1] 386929 0
GI transit and exit properties of LYN-045 capsules by X-ray imaging assessments and fecal recovery by the following:
- Visualization and localization to the stomach of LYN-045 formulation components.
- Visualization and localization to the GIT of LYN-045 formulation components.
- Assessment of GI tract exit of LYN-045 formulation components by fecal recovery.
Timepoint [1] 386929 0
X-ray imaging: an Abdominal X-ray is performed at Day 7, Day 8, Day 10 and Day 14.
Fecal recovery: Bowel movements will be collected on Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9 and Day 10.
Secondary outcome [2] 386930 0
PK of dapagliflozin after oral administration of IR 10 mg to include where possible and appropriate: Cmax, Cmin, Tmax, Kel, AUC0-24, and AUC0-t.
Timepoint [2] 386930 0
PK samples: Blood samples will be collected on Day -2 (8 hours post-dose) and Day -1 (pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 8, 12, and 24 hours post-dose).
Secondary outcome [3] 386931 0
Urinary glucose after LYN-045 administration.
Timepoint [3] 386931 0
Urine glucose analysis: Urine samples will be taken at Screening, Day -4, Day -3, Day -2, Day -1, Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 8, Day 9, Day 10, Day 14, Day 15 and Day 21 (EOS)

Eligibility
Key inclusion criteria
To be eligible to participate in the study, individuals must meet all the following inclusion criteria at Screening (and at other timepoints, where specified):
1. Men and women aged 18 to 64 years of age.
2. Individuals in good current health, in the Investigator’s opinion, as evidenced on review of medical history that includes no significant GI abnormalities, physical examination, concomitant medications, and other safety assessments.
3. Body mass index equal or greater18.5 kg/m2 and smaller than35 kg/m2.
4. Able to read and understand study procedures and provide written informed consent before the initiation of any protocol-specific procedures.
5. Willing to comply with all protocol-specified procedures and availability for the duration of the study.
Minimum age
18 Years
Maximum age
64 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
To be eligible to participate in the study, individuals must meet NONE of the following exclusion criteria at Screening (and at other timepoints, where specified):
1. Individuals with known clinically significant esophageal or GI disease, including but not limited to:
a. Known strictures such as esophageal web, pyloric stenosis, or small intestinal stricture, or individuals with high risk of stricture, i.e., Crohn's disease.
b. Diagnosis of a condition known to elevate or lower gastric pH, e.g., achlorhydria or hypochlorhydria.
c. Prior varices or small or large bowel obstructions.
d. Prior abdominal or upper GI surgery. (Prior uncomplicated laparoscopic procedures are permitted.)
e. History of dysphagia or aspiration in the last 5 years.
f. History of an esophageal motility disorder or undergoing treatment for a gastric motility disorder.
g. Multiple episodes of abdominal pain, chronic constipation, or diarrhea in the prior 3 months.
h. Moderate or severe dysmenorrhea or menorrhagia (with use of pain medication) in the prior 3 months.
i. History of moderate to severe acid reflux disease or a score of equal and greater than 2 on the Acid Reflux Severity Scale (ARSS), indicating moderate to severe symptoms. The ARSS scale is as follows:
None = 0 no symptoms.
Mild = 1 awareness of symptom, but easily tolerated.
Moderate = 2 discomfort sufficient to cause interference with normal activities.
Severe = 3 incapacitating, with inability to perform normal activities.
2. Individuals with PILL-5 questionnaire score of 5 or greater.
3. Medical history or current diagnoses indicating the presence of any of the following conditions:
a. Presence of an uncontrolled, unstable, clinically significant medical condition that could put the subject at risk because of participation in the study, interfere with the subject’s ability to participate in the study or influence the interpretation of safety or PK evaluations.
b. History of a major cardiovascular event (myocardial infarction, cardiac surgery or revascularization, unstable angina, stroke, or transient ischemic attack) or a hospitalization for heart failure within 6 months of Screening.
c. Any clinically significant illness, medical or surgical procedure, or trauma within 4 weeks of Screening.
d. Known immunocompromised status, including individuals who have undergone organ transplantation, are on immunosuppression therapy for an immune mediated disease, or are positive for HIV.
e. Positive test for active hepatitis B or C at Screening. Individuals with successfully treated hepatitis B infection which has been resolved for greater than 1 year or successfully treated hepatitis C infection will not be excluded.
f. Donated more than 250 mL of blood within 4 weeks of Screening.
g. Difficulties with venipuncture/cannulation, including difficulty accessing veins for blood sampling and/or history of coagulopathy or endocarditis.
h. Active SARS-CoV-2 infection, as defined in the SARS-CoV-2 risk management plan.
i. Chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year).
j. Individuals who are contraindicated to taking dapagliflozin (FORXIGA®, FARXIGA®), e.g., severe renal impairment, end-stage renal disease, or patients on dialysis.
4. Use of the following medications/treatments in the 2 weeks before enrollment, including:
a. Proton pump inhibitors (PPIs).
b. H2 blockers.
c. Non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA).
d. Prokinetic agents.
e. Medications that may interfere with the absorption, metabolism, or excretion of LYN-045.
f. Concomitant medications, natural remedies, supplements or vitamins. Use of antacids is permissible, except within 2 hours of dosing with LYN-045.
g. Use of blood products within 3 months of Screening.
h. Loop diuretic medications, such as furosemide, ethacrynic acid, bumetanide, or torsemide.
5. Individuals with clinically significant abnormal safety (e.g., physical examination, vital signs) or laboratory assessments at Screening, specifically:
a. Presence of a clinically significant abnormal laboratory result on blood or urine safety tests.
b. Anemia (hemoglobin below the lower limit of normal reference range).
c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal and greater than3.0 × the upper limit of normal (ULN) or total bilirubin equal and greater than1.5 × ULN.
d. Moderate or severe renal insufficiency (glomerular filtration rate smaller than60 mL/min, as determined using the Cockcroft-Gault formula).
e. Heart rate of smaller 50 beats per minute (bpm).
f. Systolic blood pressure equal and greater than150 mmHg and/or diastolic blood pressure equal and greater100 mmHg.
g. Glycated hemoglobin (HbA1c) equal and greater than7.0 % at Screening.
h. Positive fecal occult blood test at Screening in subjects who are greater than45 years unless they have had a normal colonoscopy within the past 5 years.
i. Creatine kinase >2 × ULN.
j. Thrombocytopenia (platelet count under 150×109/L) or bleeding diathesis (international normalized ratio [INR] greater1.4).
6. Individuals with a history of any drug or alcohol use disorder in the past 2 years. Positive results for drugs of abuse or positive ethanol breathalyzer screen finding will exclude individuals, unless the positive finding can be accounted for by documented prescription use. Exclusions include:
a. History of alcohol consumption exceeding moderate use; in males exceeding 21 units per week and in females exceeding 14 units per week (1 unit = 360 ml beer, 25 mL of 40% spirit or a 125 mL glass of wine) over the past month. Subjects are not permitted to consume alcohol during the inpatient stay nor 12 hours before any clinic visit while an outpatient.
b. Current smokers, users of e-cigarettes, vaping products, or nicotine replacement products and individuals who have smoked within the last 12 months. Positive results for cotinine are exclusionary.
7. Individuals of reproductive potential who are (hetero) sexually active but unwilling to use acceptable means of contraception through the End of Study. For clarity, individuals who are at least 1 year post-menopausal are not of reproductive potential. Acceptable means of contraception include:
a. Individuals who have been surgically sterilized.
b. Females of reproductive potential: diaphragm, injectable, oral/patch contraceptives for a minimum of 6 weeks, contraceptive sponge, implant, or intrauterine device in use prior to enrollment, with use of condom for their male partners.
c. Males: condom in combination with any of the above means of contraception for their female partners.
d. All individuals: abstinence may be an acceptable means of contraception as long as the individual consents to initiate immediate use of double barrier protection for the duration of the study should (hetero) sexual intercourse occur.
8. Individuals who are nursing or who have a positive or indeterminate pregnancy test at either Screening (serum test) or enrollment (urine test).
9. Use of any experimental agent within 3 months or 5 half-lives of Screening, whichever is longer.
10. Employee or immediate family member of employee of the site, Sponsor, or study-related vendors.
11. History of a serious allergic or hypersensitivity reaction to dapagliflozin or LYN-045 excipients (refer to Investigator’s Brochure).
12. Individuals with history of X-ray, computed tomography (CT) scan or angiogram of the abdomen within one year of 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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
This study is exploratory in nature and therefore is not designed to test hypotheses.

Recruitment
Recruitment status
Completed
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 in Australia
Recruitment state(s)
SA
Recruitment postcode(s) [1] 31264 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 306729 0
Commercial sector/Industry
Name [1] 306729 0
Lyndra® Therapeutics, Inc.
Address [1] 306729 0
65 Grove Street, Suite 301
Watertown
MA 02472
Country [1] 306729 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Novotech (Australia) Pty Limited
Address
Level 3, 235 Pyrmont St,
Pyrmont NSW 2009
Country
Australia
Secondary sponsor category [1] 307280 0
None
Name [1] 307280 0
Address [1] 307280 0
Country [1] 307280 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306902 0
Bellberry Limited
Ethics committee address [1] 306902 0
123 Glen Osmond Road
Eastwood, South Australia 5063
Ethics committee country [1] 306902 0
Australia
Date submitted for ethics approval [1] 306902 0
30/09/2020
Approval date [1] 306902 0
08/10/2020
Ethics approval number [1] 306902 0

Summary
Brief summary
Lyndra Therapeutics is currently developing extended release (ER) capsules for weekly administration across therapeutic areas with certain medications for which consistent pharmacokinetics (PK) or enhanced adherence may translate to improved efficacy, and possibly better safety. LYN-045 (Lyndra code for dapagliflozin) ER capsules are intended to provide comparable dapagliflozin exposure to daily treatment affording better accessibility and tolerability for the treatment of type 2 diabetes mellitus (T2DM).

This Phase 1 study is intended for execution in healthy individuals due to its exploratory nature. Data from this study will be a key indicator of feasibility of the product concept and will inform formulation optimization and dose selection for further development.
This study will be conducted in up to 10 healthy volunteers (including 2 sentinels) who meet all of the inclusion criteria and none of the exclusion criteria.

This is a single-center, open-label study of dapagliflozin 70 mg ER capsules (LYN-045) to evaluate its safety, tolerability, and PK administered as 2 weekly doses in healthy male and female volunteers.
All subjects will receive 3 doses of IR dapagliflozin 10 mg in the inpatient unit, Dose 1 on Day -3, Dose 2 on Day -2, and Dose 3 on Day -1. Following that, all subjects will receive 2 doses of LYN-045 70 mg; on Day 1 and Day 8. After completion of Day 10 assessments, subjects will be discharged from the inpatient unit. Thereafter, subjects will attend study center visits on an outpatient basis on Days 14 and 15. All subjects will attend an End-of-Study (EOS) visit on Day 21 for final study assessments.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105394 0
Prof Sepehr Shakib
Address 105394 0
CMAX Clinical Research
Level 5, 18a North Terrace
Adelaide, South Australia 5000
Country 105394 0
Australia
Phone 105394 0
+61 0411 100 278
Fax 105394 0
Email 105394 0
sepehr.shakib@sa.gov.au
Contact person for public queries
Name 105395 0
Prof Sepehr Shakib
Address 105395 0
CMAX Clinical Research
Level 5, 18a North Terrace
Adelaide, South Australia 5000
Country 105395 0
Australia
Phone 105395 0
+61 0411 100 278
Fax 105395 0
Email 105395 0
sepehr.shakib@sa.gov.au
Contact person for scientific queries
Name 105396 0
Dr Patrick G Boen
Address 105396 0
VP, Clinical Development
Lyndra Therapeutics, Inc.
65 Grove Street
Suite 301
Watertown, MA 02472
Country 105396 0
United States of America
Phone 105396 0
+1 862 251 1544
Fax 105396 0
Email 105396 0
pgoen@lyndra.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a healthy volunteer study and the individual participant results are not useful to the participants or to others outside of the sponsor and the Sponsors authorized representatives.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary