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Trial registered on ANZCTR


Registration number
ACTRN12617000467336
Ethics application status
Approved
Date submitted
13/03/2017
Date registered
31/03/2017
Date last updated
14/12/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Randomized, double-blind, placebo-controlled, single-dose, dose escalation study in healthy participants to evaluate safety, tolerability and pharmacokinetics of intra-vaginal ABI-1968
Scientific title
A Randomized, double-blind, placebo-controlled, single-dose, dose escalation study in healthy participants to evaluate safety, tolerability and pharmacokinetics of intra-vaginal ABI-1968
Secondary ID [1] 290740 0
ABI-1968-101
Universal Trial Number (UTN)
U1111-1190-8896
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cervical intraepithelial neoplasia (CIN) 301320 0
Cervical high-grade squamous intraepithelial lesions (HSIL) 301999 0
Condition category
Condition code
Reproductive Health and Childbirth 301691 301691 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase 1 study in healthy female volunteers involving 5 Cohorts
ABI-1968
Single dose topical cream delivered topically to the cervix by intra-vaginal application via a single-use graduated applicator which delivers an approximate 2g dose.
Cohort 1: 0.01%, Cohort 2: 0.03%, Cohort 3: 0.1%, Cohort 4: 0.3%, Cohort 5: 1.0% - by weight
The study drug (or placebo) will be administered as a topical cream to the cervix by intra-vaginal application by the Gynecologist.
This study is a dose escalation study meaning that the first cohort will receive the lowest dose of study drug. The dose of study drug will increase with each subsequent cohort. Results will be reviewed by a safety monitoring committee after each dose strength has been tested to make sure that it is safe to continue with testing in the next cohort. The next cohort will not be enrolled until the safety monitoring committee have confirmed it is safe to do so. The study can be stopped at any time, based on evaluation of the side effects of the study drug.
During this study, it is possible that the strengths may
be reduced, repeated or increased; however, 1.0 % is the highest dose that will be given.
Participants will not have a choice as to which cohort or dose level they are assigned (randomised) to,
with each cohort enrolled on a rst eligible basis. The participant and the study sta will not know if the
they are assigned to receive the active study drug or the placebo, although in an emergency the study staff can find out. The first cohort will have 2 ‘sentinel’ volunteers; one will receive the active drug, the other the placebo. These individuals will receive the study drug (or placebo) approximately 24 hours before the rest of the cohort. Participants will be told if they are assigned to the sentinel cohort.
Intervention code [1] 296765 0
Treatment: Drugs
Comparator / control treatment
Placebo topical cream containing Carbopol 974, Tefose 63, propylene glycol, light mineral oil, EDTA, methyl parabens, propyl parabens, sodium hydroxide and water, will be administered intra-vaginally by a designated Gynaecologist.
Control group
Placebo

Outcomes
Primary outcome [1] 300651 0
Safety and tolerability will be measured by the frequency and severity of Adverse events, relationship of Adverse events to study drug, safety laboratory, vital signs and physical abnormalities and other safety parameters.

In studies performed in rats and rabbits, multiple doses of topical cream at high dose strength caused inflammation and tissue irritation in the vagina and cervix.
In humans, irritation could possibly include vaginal itch, vaginal discharge, pain during or after intercourse, or pain on passing urine.
In studies where ABI-1968 was administered systemically at levels multiple logs higher than what should be achieved after topical administration, high concentrations of ABI-1968 resulted in some genotoxicity (damage to the genetic information within a cell causing a mutation). It is expected that the genotoxicity profile of topically applied ABI-1968 to be comparable to metronidazole, a vaginal gel used to treat vaginal bacterial infections.

Participants will be monitored for genitourinary signs and symptoms, including evidence of vaginal and/or cervical irritation, erythema and oedema. Adverse events and concomitant medications and information regarding coital history and any local adverse reactions in her partner will be collected. Vital signs, electrocardiograms (ECGs), clinical chemistry, haematology and urinalysis results will be obtained periodically.
Timepoint [1] 300651 0
1. Adverse Event Assessment: at Screening, Baseline, Day 1-pre dose and post dose, and at Days 2, 3, 4, 8, 15 and 29 (EOS)
2. Concomitant Medication information: at Screening, Baseline, Day 1-pre dose and ,post dose, and at Days 2, 3, 4, 8, 15 and 29
3. Physical Examination: at Screening and Day 29
4. Pelvic Exam for Urogenital AE Assessment: at Screening, Baseline, 12 hours post dose, and at Days 2, 8, 15 and 29
5. Cervical Image Acquisition: at Baseline and Days 8 and 29
6. Collection of Cytology Specimens: at Day 8 (Cohorts 1 and 2 only)
7. Safety Laboratory Evaluations: at Screening, Baseline, Days 2, 8 and 29
8. Vital Signs Assessments: at Screening, Baseline, Treatment Day 1-pre dose and 12 hours post dose, and at Days 2, 8, 15 and 29
9. ECG Parameters: at Screening, Baseline, Treatment Day 1and at 2 hours post dose and 8 hours post dose and Day 29
Secondary outcome [1] 330510 0
Plasma concentrations of ABI-1968 will be determined at various intervals following ABI-1968 dosing, and PK parameters will be calculated, if measured concentrations allow.
Individual ABI-1968 concentration data will be listed and summarized by treatment group with descriptive statistics.
Plasma ABI-1968 parameters will be determined using a non-compartmental analysis (NCA) approach.
The PK parameters time to maximum observed drug concentration (tmax), maximum observed drug concentration (Cmax), area under the curve (AUC) from time zero to last measurable concentration (AUC0-last), AUC from time zero to infinity (AUC8), apparent elimination half-life (t1/2), apparent terminal elimination rate constant (Kel), apparent clearance (CL/F) and apparent volume of distribution at the terminal phase (Vz/F) (where data are sufficient for parameter determination) will be determined.
Pharmacokinetic parameters will be listed for each participant and summarized by treatment group using descriptive statistics (N, arithmetic mean, SD, coefficient of variation [CV%], median, minimum, maximum, geometric mean and geometric CV%).
Additional statistical analysis will be performed if deemed appropriate.
Timepoint [1] 330510 0
PK Blood Collection: at Treatment Day 1-pre dose and 1, 6 and 12 hours post dose and Days 2, 3, 4, 8 and 29.

Eligibility
Key inclusion criteria
1. Women, 18 to 50 years old, with an intact uterus.
2. Generally, in good health with no clinically significant pulmonary, cardiac, gastro-enterologic, neurologic, renal, musculoskeletal, rheumatologic, metabolic, neoplastic, or endocrine disease.
3. Able and willing to use stringent methods of contraception after required abstinence period (up to Day 7) through to Day 28, including the use of a non-latex condom (for partner protection) and a second acceptable contraception method such as a vasectomy, contraceptive pill or IUDs are allowed. IUDs should be inserted at least 3 months prior to enrolment. The use of contraception methods such as a diaphragm, cervical caps, or Nuvaring - Registered Trademark, will not be allowed.
4. Agree to provide coital history at study visits, and any local adverse reactions for sexual partner.
5. Expect to have same sexual partner for duration of the study.
6. Agree to abstain from activities such as sexual intercourse, vaginal douching or insertion of any vaginal products other than the study drug for at least 48 hours prior to enrolment through 7 days after dosing.
7. Generally regular menstrual cycles.
8. Able and willing to return to the clinic for all study procedures.
9. Able and willing to provide informed consent.
10. Negative Pap test at screening or within 3 months of enrolment, and no history of cervical intraepithelial lesions at any time.
Minimum age
18 Years
Maximum age
50 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Women who are pregnant, plan to become pregnant in the next 3 months, or lactating females.
2. History of cancer, except basal cell or squamous cell carcinoma of the skin.
3. History of genital herpes with >3 outbreaks per year, or active non-HPV vaginal infection.
4. Have an active pelvic infection (positive urine screen for gonorrhea or chlamydial infection, positive bedside testing criteria for bacterial vaginosis, candida vaginitis or trichomonal vaginitis, positive bimanual exam consistent with pelvic inflammatory disease).
5. Current or recent abnormal vaginal discharge and /or abnormal vaginal bleeding, within the 3 months prior to randomization.
6. Had an abortion or miscarriage within the 3 months prior to randomization.
7. Any clinically significant immune suppressing condition.
8. Subjects with a significant acute condition or any other condition that in the opinion of the Investigator might interfere with the evaluation of the study objectives.
9. Currently taking any of the following medications: inhaled or oral corticosteroids, 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, within 2 weeks of enrolment.
10. Hypersensitivity to any component of the placebo formulation excipients or other nucleoside analogues (such as cidofovir, etc.).
11. Participation in any clinical study with an experimental medication or device within 30 days or 5 half-lives (whichever is longer) of enrolment.
12. Menses expected to start within 7 days of enrolment.
13. Current alcohol or substance abuse as assessed by the Principal Investigator.
14. An employee, or family member of an employee, of the Sponsor, the CRO, or the Clinical Research Unit (CRU).

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)
Electronic allocation schedule provided to un-blinded pharmacist
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The sample size for this study is approximately 40 participants.
The study is not intended to show statistical differences between treatment groups.
Sufficient numbers of participants will be enrolled to assess safety at a given dose level such that decisions can be made to escalate to the next dose level.
Safety Analysis Set: All participants who receive any amount of study drug or placebo.
PK Analysis Set: All participants who receive study drug and have sufficient PK data for analysis.
Frequencies and percentages will be presented for the categorical variable and descriptive statistics (arithmetic mean, standard deviation [SD], median, minimum and maximum) will be presented for continuous variables. Summary results will be presented by treatment group (i.e., pooled placebo group, ABI-1968 dose groups, and combined ABI-1968 group).
Safety and Tolerability:
Adverse events (AEs) will be coded using the most current Medical Dictionary for Regulatory Actvities (MedDRA - Registered Trademark) .
A by-participant AE data listing, including verbatim term, preferred term, system organ class, treatment, severity, and relationship to study drug, will be provided. The number of participants experiencing treatment emergent AEs (TEAE) and number of individual TEAE will be summarized by treatment group, system organ class and preferred term. TEAEs will also be summarized by severity and by relationship to study drug.
Laboratory evaluations, vital signs assessments and ECG parameters will be summarized by treatment group and protocol specified collection time-point. A summary of change from baseline at each protocol specified time-point will also be presented.
Changes in physical examination will be listed for each participant and described in the text of the final report.
Concomitant medications will be listed by participant and coded using the most current World Health Organization (WHO) drug dictionary available at CNS.
Medical history will be listed by participant.
Pharmacokinetics:
Individual ABI-1968 concentration data will be listed and summarized by treatment group with descriptive statistics (sample size [N], arithmetic mean, SD, median, minimum, maximum and geometric mean). Individual and mean ABI-1968 concentration-time profiles for each treatment group will also be presented graphically.
Plasma ABI-1968 parameters will be determined using a non-compartmental analysis (NCA) approach.
Pharmacokinetic parameters will be listed for each participant and summarized by treatment group using descriptive statistics (N, arithmetic mean, SD, coefficient of variation [CV%], median, minimum, maximum, geometric mean and geometric CV%).
Additional statistical analysis will be performed if deemed appropriate.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
23/03/2017
Date of last participant enrolment
Anticipated
19/05/2017
Actual
9/06/2017
Date of last data collection
Anticipated
20/06/2017
Actual
6/07/2017
Sample size
Target
40
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 7403 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 15205 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 295485 0
Commercial sector/Industry
Name [1] 295485 0
Antiva Australia Pty Ltd.
Country [1] 295485 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services, Pty Ltd.
Address
Level 4,
88 Jephson St,
TOOWONG
QLD 4066,

Country
Australia
Secondary sponsor category [1] 294304 0
None
Name [1] 294304 0
Address [1] 294304 0
Country [1] 294304 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296825 0
Alfred Health Human Research Ethics Committee
Ethics committee address [1] 296825 0
55 Commercial Rd,
Melbourne VIC 3004
Ethics committee country [1] 296825 0
Australia
Date submitted for ethics approval [1] 296825 0
11/01/2017
Approval date [1] 296825 0
10/03/2017
Ethics approval number [1] 296825 0

Summary
Brief summary
This research study is testing the safety, tolerability and pharmacokinetics (looking at the amount of drug in your blood to evaluate the way the body processes the drug) of ABI-1968 Topical cream delivered to the cervix by intra-vaginal application.
In this study, a total of 40 participants will be enrolled over 5 dosing groups/cohorts with each cohort consisting of 8 people – 6 will receive the active drug, and 2 will get placebo. Participants will be randomly assigned to receive either the active drug or placebo (a ‘dummy’ topical cream that looks identical, but contains no active drug). Participants will have a 75% chance of receiving study drug and 25% chance of receiving placebo. The study drug (or placebo) will be administered as a topical cream to the cervix by intra-vaginal application by the Gynecologist. No participant will be a member of more than one cohort.
This study is a dose escalation study meaning that the first cohort will receive the lowest dose of study drug. The dose of study drug will increase with each subsequent cohort. Results will be reviewed by a safety monitoring committee after each dose strength has been tested to make sure that it is safe to continue with testing in the next cohort. The next cohort will not be enrolled until the safety monitoring committee have confirmed it is safe to do so. The study can be stopped at any time, based on evaluation of the side effects of the study drug. The five different dose strengths planned for this study are 0.01, 0.03, 0.1, 0.3 and 1.0 % by weight, applied as a topical cream via a single-use graduated applicator which delivers an approximate 2g dose. During this study, it is possible that the strengths may be reduced, repeated or increased; however, 1.0 % is the highest dose that will be given.
Participants will not have a choice as to which cohort or dose level they are assigned (randomised) to, with each cohort enrolled on a first eligible basis. The participant and the study staff will not know if the they are assigned to receive the active study drug or the placebo, although in an emergency the study staff can find out. The first cohort will have 2 ‘sentinel’ volunteers; one will receive the active drug, the other the placebo. These individuals will receive the study drug (or placebo) approximately 24 hours before the rest of the cohort. Participants will be told if they are assigned to the sentinel cohort.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71138 0
Dr Jason Lickliter
Address 71138 0
Centre for Clinical Studies, Nucleus Network Ltd
5th Floor, Burnet Building, AMREP Precinct,
89 Commercial Rd, Melbourne, VIC, 3004
Country 71138 0
Australia
Phone 71138 0
+61 3 9076 8960
Fax 71138 0
Email 71138 0
[email protected]
Contact person for public queries
Name 71139 0
Jessica Faggian
Address 71139 0
Centre for Clinical Studies, Nucleus Network Ltd
5th Floor, Burnet Building, AMREP Precinct,
89 Commercial Rd, Melbourne VIC 3004
Country 71139 0
Australia
Phone 71139 0
+61 3 9076 8958
Fax 71139 0
Email 71139 0
[email protected]
Contact person for scientific queries
Name 71140 0
Jason Lickliter
Address 71140 0
Centre for Clinical Studies, Nucleus Network Ltd
5th Floor, Burnet Building, AMREP Precinct,
89 Commercial Rd, Melbourne, VIC, 3004
Country 71140 0
Australia
Phone 71140 0
+61 3 9076 8960
Fax 71140 0
Email 71140 0
[email protected]

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