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Trial registered on ANZCTR


Registration number
ACTRN12621001487808
Ethics application status
Approved
Date submitted
16/09/2021
Date registered
1/11/2021
Date last updated
23/03/2022
Date data sharing statement initially provided
1/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A single centre, double blind, randomised, parallel group, single and multiple dose, safety and tolerability, pharmacokinetic study of R131-2 vaginal soft gel capsule in healthy women volunteers
Scientific title
Study assessing the single and multiple dose, safety and tolerability of an intravaginal soft gel capsule containing R131-2 in healthy women volunteers.
Secondary ID [1] 304957 0
None
Universal Trial Number (UTN)
U1111-1268-3335
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cervical neoplasia 323104 0
Condyloma acuminatum 323105 0
Condition category
Condition code
Infection 320681 320681 0 0
Sexually transmitted infections

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A study to investigate the safety, tolerability and pharmacokinetics of R131-2 vaginal soft gel capsule in healthy women volunteers after single and multiple doses of 300mg 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate / 25mg (2S)-N-[(2S,4S,5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide and observe the rates of side effects reported by women using R131-2 vaginal soft gel capsule compared to placebo.

This study comprises of one cohort. It involves a first period comprising a single 300 mg/25 mg dose on Day 1 of R131-2 or placebo vaginal soft gel capsule with Pharmacokinetic blood sampling during confinement up to 48 hours after dosing. Washout of one day and then a multiple dose second period (Day 3-23) comprising 20 daily doses x 300 mg/25 mg of R131-2 or placebo vaginal soft gel capsule administration followed by Pharmacokinetic blood sampling during confinement up to 36 hours post dosing.

The confinement days are Days 1-2 (27 hours) and Days 23-24 (27 hours).

The soft gel capsule will be self-administered into the vagina. Full instructions will be given as to its application. Participants will also be asked to provide a vaginal swabs at various intervals throughout the study. The capsule will be given to participants to take home along with the study questionnaires. A diary will also be completed by each participant.

To monitor adherence to the intervention product each participant will be given a diary to complete daily with vaginal swabs performed on Day 1, 8, 15, 23 and exit.

Pre and post study laboratory tests will be completed to assess the health of participants.
The intervention for this study is the soft gel capsule formulation of R131.
Intervention code [1] 321351 0
Treatment: Drugs
Comparator / control treatment
A placebo that is a Identical vaginal soft shell capsule containing Oleic acid, Polysorbate 20, Glycerol monooleate, Polyoxyl 35 castor oil and Butylated hydroxytoluene and does not contain R131-2.
Control group
Placebo

Outcomes
Primary outcome [1] 328635 0
To evaluate the pharmacokinetics of 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate (as summarised by Cmax and AUC) for the formulation. All plasma samples will be assayed for 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate using one fully validated LC/MS/MS method. Validation will be conducted to comply with FDA guidelines.
Timepoint [1] 328635 0
Day 1-3: 0, 1, 2, 4, 8, 12, 16, 20, 24, 36 and 48 hours after dosing.
Day 23-25: 0, 1, 2, 4, 8, 12, 16, 20, 24 and 36 hours after dosing
Primary outcome [2] 328639 0
To evaluate the pharmacokinetics of (2S)-N-[(2S,4S,5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide (as summarised by Cmax and AUC) for the formulation. All plasma samples will be assayed for (2S)-N-[(2S,4S,5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide using one fully validated LC/MS/MS method. Validation will be conducted to comply with FDA guidelines.
Timepoint [2] 328639 0
Day 1-3: 0, 1, 2, 4, 8, 12, 16, 20, 24, 36 and 48 hours after dosing.
Day 23-25: 0, 1, 2, 4, 8, 12, 16, 20, 24 and 36 hours after dosing
Primary outcome [3] 328640 0
To evaluate the safety (as summarised by adverse events and vital signs)

Vital Signs are assessed by a self assessment Vaginal Questionnaire using a 3 point rating scale daily and an Electronic Blood Pressure Monitor will be used to monitor Blood Pressure.
Timepoint [3] 328640 0
Adverse events will be assessed continuously from consent until study exit

Vital signs will be complete by self assessment daily and at every clinical visit :
Screening
Period 1 - Day 1 baseline, Day 2 at 12 and 24 hours and Day 3 at 36 and 48 hours after dosing
Period 2 - Day 8, Day 15, Day 23, Day 24 at 12 and 24 hours and Day 25 at 36 hours after dosing
Secondary outcome [1] 399786 0
Time to maximum peak concentration (Tmax) of (2S)-N-[(2S,4S,5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide;1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate will be determined by plasma sample analysis. Tmax will be the time where the maximum concentration occurred in the sample points.

For those participants receiving the placebo, only samples around the expected Tmax i.e. 2-3 hours will be assayed with the pre-dosing samples.
Timepoint [1] 399786 0
Day 1-3: 0, 1, 2, 4, 8, 12, 16, 20, 24, 36 and 48 hours after dosing.
Day 23-25: 0, 1, 2, 4, 8, 12, 16, 20, 24 and 36 hours after dosing
Secondary outcome [2] 399795 0
Additional Primary Outcome: To evaluate tolerability (as summarised by participant questionnaires (vaginal irritation questionnaire))
Timepoint [2] 399795 0
The Daily Diary and vaginal irritation questionnaire will be completed each morning following the previous evening dose. This will occur at each visit to the clinical site (Days 1-2 and 23-25), at each participants home and at each visit to Zenith Technology during the study (Days 8 and 15) for a total of 25 days. In addition to answering specific questions concerning irritation, participants will use a rating scale to evaluate discomfort and severity.

Eligibility
Key inclusion criteria
a) Women, 20 to 45 years old, with an intact uterus and vagina.
b) Generally, in good health with no clinically significant pulmonary, cardiac, gastroenterological, pancreatic, neurologic, renal, musculoskeletal, rheumatologic, metabolic, neoplastic, or endocrine disease.
c) BMI of greater than or equal to 19 and less than or equal to 30.0
d) ECG and vital signs within normal ranges
e) Agree to no Alcohol from 48 hours prior to dosing in period 1 until 7 days after receiving the final dose in period 2.
f) Abstain from food or beverages containing grapefruit, starfruit, pomegranate, pineapple, or pomelo for the entire study
g) Able and willing to abstain from sexual intercourse +/– 6 hours around dosing within Periods 1 and 2
h) Able and willing to use stringent methods of contraception after required abstinence period through to Day 29 (7 days after receiving the final dose in period 2), including the use of a non-latex condom (for partner protection) and a second acceptable contraception method.
i) Agree to abstain from activities such as vaginal douching or insertion of any vaginal products other than the study drug for at least 48 hours prior to enrolment and throughout the study.
j) Negative Pap test at screening or within 3 years of enrolment and no history of cervical intraepithelial lesions within the previous 3 years
k) Able and willing to return to the clinic for all study procedures.
l) Able and willing to provide informed consent.
Minimum age
20 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
a) Women who are pregnant, plan to become pregnant in the next 3 months, or lactating females.
b) History of genital herpes with >3 outbreaks per year, or active non-HPV vaginal infection
c) Positive result for Hep B, Hep C or HIV.
d) Have an active pelvic infection (positive urine screen for gonorrhoea or chlamydial infection, positive test and symptoms for bacterial vaginosis, candida vaginitis or trichomonal vaginitis)
e) Current or recent abnormal vaginal discharge and /or abnormal vaginal bleeding, within the 3 months prior to randomization as accessed by Investigator.
f) Had an abortion or miscarriage within the 3 months prior to randomization
g) Currently taking any of the following medications: oral corticosteroids, inhaled salmeterol and fluticasone; immunomodulatory treatments, over the counter (OTC) intra-vaginal preparation, or any prescription that in the opinion of the Investigator could interfere with the interpretation of the results.
h) Currently taking any of the medications listed here - Alfuzosin, Amiodarone, dronedarone, Ranolazine, Fusidic Acid, Colchicine, Astemizole, terfenadine, Lurasidone, Pimozide, Quetiapine, Dihydroergotamine, ergonovine, ergotamine, methylergonovine, Cisapride, Lovastatin, simvastatin, Avanafil, Sildenafil, Vardenafil, Oral midazolam, triazolam, St. John's wort.
i) Recent history (within previous 3 months) of Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema, deep vein thrombosis, tinnitus, vertigo, blood glucose disorders, pancreatitis, haemophilia.
j) Hypersensitivity to any component of R131-2 vaginal ointment excipients
k) Participation in any clinical study with an experimental medication or device within 30 days or 5 half-lives (whichever is longer) of enrolment.
l) Current alcohol or substance abuse as assessed by the Investigator.
m) An employee or first degree family member of an employee, the Sponsor, the CRO or study site.
n) Not having a GP

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)
The subject ID will be used to randomise each participant onto the study. Allocation concealment will be completed by the pharmacy staff who are independent of subject recruitment and who are unaware of the identity of each subject.

All staff obtaining consent and confirming eligibility will remain blinded as to what formulation each subject ID has been allocated. Individual randomisation envelopes will be provided in case the identity of study drug administered to a participant needs to be known.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization by computer
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
6/11/2021
Actual
6/11/2021
Date of last participant enrolment
Anticipated
Actual
6/11/2021
Date of last data collection
Anticipated
Actual
29/11/2021
Sample size
Target
12
Accrual to date
Final
12
Recruitment outside Australia
Country [1] 24047 0
New Zealand
State/province [1] 24047 0
Otago

Funding & Sponsors
Funding source category [1] 309342 0
Commercial sector/Industry
Name [1] 309342 0
Douglas Pharmaceuticals Ltd
Country [1] 309342 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
Zenith Technology Corporation Limited
Address
PO Box 1777
156 Frederick St
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 310310 0
None
Name [1] 310310 0
Address [1] 310310 0
Country [1] 310310 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309161 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 309161 0
Ethics committee country [1] 309161 0
New Zealand
Date submitted for ethics approval [1] 309161 0
01/07/2021
Approval date [1] 309161 0
16/08/2021
Ethics approval number [1] 309161 0
21/CEN/179

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113194 0
Dr Noelyn Hung
Address 113194 0
Zenith Technology Corp Ltd
PO Box 1777
156 Frederick St
Dunedin 9054
Country 113194 0
New Zealand
Phone 113194 0
+64 21 482 148
Fax 113194 0
+64 3 477 9605
Email 113194 0
noelyn.hung@otago.ac.nz
Contact person for public queries
Name 113195 0
Linda Folland
Address 113195 0
Zenith Technology Corp Ltd
PO Box 1777
156 Frederick St
Dunedin 9054
Country 113195 0
New Zealand
Phone 113195 0
+64 3 477 9669
Fax 113195 0
+64 3 477 9605
Email 113195 0
linda.folland@zenithtechnology.co.nz
Contact person for scientific queries
Name 113196 0
Tak Hung
Address 113196 0
Zenith Technology Corp Ltd
PO Box 1777
156 Frederick St
Dunedin 9054
Country 113196 0
New Zealand
Phone 113196 0
+64 3 477 9669
Fax 113196 0
+64 3 477 9605
Email 113196 0
tak.hung@zenithtechnology.co.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All data will be compiled into a final report that is the property of the sponsor company


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.