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Trial registered on ANZCTR


Registration number
ACTRN12618001726246
Ethics application status
Approved
Date submitted
9/10/2018
Date registered
19/10/2018
Date last updated
13/06/2019
Date data sharing statement initially provided
13/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1b, Multicentre, Open Label, Study of the Efficacy, Safety and Tolerability of R131 Vaginal Ointment in Women with Cytological Abnormalities of the Uterine Cervix
Scientific title
A Phase 1b, Multicentre, Open Label, Study of the Efficacy, Safety and Tolerability of R131 Vaginal Ointment in Women with Cytological Abnormalities of the Uterine Cervix
Secondary ID [1] 296280 0
R131-C103
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cervical intraepithelial neoplasia caused by Human papilloma virus 309952 0
Condition category
Condition code
Cancer 308727 308727 0 0
Cervical (cervix)
Reproductive Health and Childbirth 308747 308747 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
R131 Vaginal Ointment 2.5 g, applied daily for 21 days up to 3 cycles, with a 7 day wash out period between the cycles. The duration of treatment will depend on patients' response to it: patients who don't respond to treatment after the first cycle, will continue receiving the intervention for another cycle. Patients who don't respond to the second cycle of treatment, will continue to the third cycle of treatment.
Patients will be completing a drug diary on a daily basis in order for the researcher to monitor drug adherence. Medication tubes will also be weighed upon return.
Intervention code [1] 312610 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307707 0
• Changes from baseline to Colposcopic biopsy

Timepoint [1] 307707 0
6 weeks after last dose of R131
Primary outcome [2] 307784 0
• Changes from baseline to the colposcopic appearance of disease
Timepoint [2] 307784 0
6 weeks after last dose of R131
Primary outcome [3] 307785 0
• Changes from baseline to the presence/absence of HPV genotypes (cervical swab)
Timepoint [3] 307785 0
6 weeks after last dose of R131
Secondary outcome [1] 352592 0
• Incidence of adverse events.

Possible adverse events:
Vulvovaginal candidiasis
Bacterial vaginosis
Timepoint [1] 352592 0
6 weeks after last dose of R131
Secondary outcome [2] 352924 0
• Changes from baseline in blood pressure (assessed using a blood pressure monitor),
Timepoint [2] 352924 0
6 weeks after last dose of R131
Secondary outcome [3] 352925 0
• Changes from baseline in heart rate (assessed using a blood pressure monitor),
Timepoint [3] 352925 0
6 weeks after last dose of R131
Secondary outcome [4] 352926 0
• Changes from baseline in temperature (assessed using a tympanic thermometer),
Timepoint [4] 352926 0
6 weeks after last dose of R131
Secondary outcome [5] 352927 0
• Changes from baseline in laboratory assessments (haematology).
Timepoint [5] 352927 0
6 weeks after last dose of R131
Secondary outcome [6] 352928 0
• Changes from baseline in safety clinical laboratory assessments (biochemistry).
Timepoint [6] 352928 0
6 weeks after last dose of R131
Secondary outcome [7] 352929 0
• Changes from baseline in: safety clinical laboratory assessments (urinalysis).
Timepoint [7] 352929 0
6 weeks after last dose of R131

Eligibility
Key inclusion criteria
1. Provision of written informed consent prior to any study specific procedures;
2. Female participants aged 25-45 years inclusive at the time of screening visit;
3. Positive result for cervical high-risk HPV;
4. Screening biopsy proven high-grade cytological abnormality of the uterine cervix defined as CIN 2 and above OR low-grade cytological abnormality of the uterine cervix defined as CIN 1/LSIL, as demonstrated by colposcopic biopsy within 6 months of screening. Participants will be stratified according to their grade of cytological abnormality;
5. Transformation zone needs to be fully visible
6. Generally, in good health with no clinically significant disease as determined by the
investigator;
7. Regular menstruation with an approximate 28-day cycle;
8. Agree to abstain from activities such as vaginal douching or insertion of any vaginal
products (including tampons, and intravaginal contraceptives such as contraceptive
cap and spermicide) other than the study drug for at least 48 hours prior to enrolment
and throughout the study (with the exception of tampons which may be used during
the participants menstrual cycle);
9. Women of childbearing potential (WOCBP) must use a highly effective form of birth control (confirmed by the Investigator). Rhythm methods will not be considered as highly effective methods of birth control. Highly effective forms of birth control include:
• True sexual abstinence (defined as refraining from heterosexual intercourse for the duration of the study and a minimum of 30 days following the last dose of study drug);
• Vasectomised partner (provided that the partner is the sole sexual partner of the female participant with childbearing potential and that the vasectomised partner has received medical assessment of the surgical success);
• Oral or transdermal combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation;
• Oral, injectable or implantable progestogen-only hormone contraception
associated with inhibition of ovulation (Depo-Provera™, Implanon);
• Any effective intrauterine device/levonorgestrel intrauterine system;
• Female sterilisation by tubal occlusion;
• Evra Patch ™.
WOCBP must agree to use a highly effective method of birth control, as defined
above, from enrolment, throughout the study duration and for 30 days after the last
dose of IMP.
WOCBP are defined as women who are neither permanently sterilised (hysterectomy,
bilateral oophorectomy, or bilateral salpingectomy),
10. Male partners of female participants must agree to use condoms during sexual
intercourse from the first dose of investigational product until 30 days after the
participants last dose to avoid potential transfer of investigational product.
11. Able and willing to abstain from sexual intercourse from 6 hours prior to dosing until
6 hours after dosing;
12. Ability and willingness to attend the necessary visits to the study centre;
13. Ability to read and write;
14. Be willing and able to adhere to the prohibitions and restrictions specified in the protocol.
Minimum age
25 Years
Maximum age
45 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any significant disease or disorder (e.g. cardiovascular, pulmonary, gastrointestinal,
hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or may influence
the results of the study, or the participant’s ability to participate in the study;
2. Any clinically significant abnormal findings in physical examination, vital signs,
haematology, clinical chemistry, or urinalysis during screening and at baseline, which
in the opinion of the investigator, may put the participant at risk because of her participation in the study, or may influence the results of the study, or the participant’s
ability to complete entire duration of the study;
3. Pregnant, breastfeeding, or lactating women (WOCBP must have a negative serum
pregnancy test at screening and a negative urine pregnancy test at the start of each
treatment period [i.e. Day 1, Day 28, Day 56]);
4. Women who plan to become pregnant in the next 6 months;
5. History of genital herpes with >3 outbreaks per year, or active non-HPV vaginal infection;
6. Active pelvic infection (positive for gonorrhoea or chlamydial infection, positive test
for bacterial vaginosis, candida vaginitis or trichomonal vaginitis). Participants with positive results can be re-tested once during screening;
7. Positive bimanual exam consistent with pelvic inflammatory disease;
8. Positive result for hepatitis B, hepatitis C or human immunodeficiency virus;
9. Current or recent abnormal vaginal discharge and /or abnormal vaginal bleeding, within the 3 months prior to randomisation as assessed by the investigator;
10. Had an abortion or miscarriage or taken the morning-after pill within the 3 months
prior to enrolment;
11. Currently taking immunosuppressants, intra-vaginal preparations, or any prescription
that in the opinion of the investigator could interfere with the interpretation of the results;
12. Previous exposure to lopinavir/ritonavir (within 3 months prior to screening),
contraindication to the use of lopinavir/ritonavir or known allergy, hypersensitivity, or
intolerance to any component of lopinavir/ritonavir vaginal ointment excipients;
13. Previous HPV vaccination;
14. Recent history (within 3 months prior to screening) of Stevens-Johnson syndrome,
erythema multiforme, urticaria, angioedema, deep vein thrombosis, tinnitus, vertigo,
blood glucose disorders, pancreatitis, haemophilia;
15. Receipt of any investigational product within 30 days or 5 half-lives prior to dosing;
16. Employees of the clinical study centre or family members (first-degree relatives) of
such individuals or anyone involved in the planning and/or conduct of the study;
17. Participants who, in the opinion of the Investigator, do not understand the information
and procedures of the study, or would not be compliant with them (in particular the
study restrictions and risks involved).

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)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
A Statistical Analysis Plan (SAP) will be written after finalising the protocol and prior to
database lock. The SAP will detail the implementation of all the planned statistical analysis in accordance with the principal features stated in the protocol. Any deviations from the SAP will be presented in the final clinical study report.
In general, data will be summarised using descriptive statistics (mean, median, standard
deviation, minimum and maximum) or frequency counts and percentages, as appropriate to the type of data. Baseline will be defined as the last available, valid, non-missing assessment prior to dosing.
Only data from protocol scheduled visits/time points will be included in the summary tables. Data from unscheduled visits/time points will not be included in the summary tables but will be included in the figures and listings.

Recruitment
Recruitment status
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] 20906 0
New Zealand
State/province [1] 20906 0

Funding & Sponsors
Funding source category [1] 300870 0
Commercial sector/Industry
Name [1] 300870 0
Douglas Pharmaceuticals Ltd
Address [1] 300870 0
Central Park Drive, Linkoln.
Auckland, 0610
Country [1] 300870 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
Douglas Pharmaceuticals Ltd
Address
Central Park Drive, Linkoln.
Auckland, 0610
Country
New Zealand
Secondary sponsor category [1] 300429 0
Commercial sector/Industry
Name [1] 300429 0
Pharmaceutical Solutions Ltd
Address [1] 300429 0
Level 1, The Levy Building, 20 Customs Street East, Auckland 1010
Country [1] 300429 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301645 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 301645 0
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 301645 0
New Zealand
Date submitted for ethics approval [1] 301645 0
10/10/2018
Approval date [1] 301645 0
13/12/2018
Ethics approval number [1] 301645 0

Summary
Brief summary
This study aims to investigate efficacy, safety and tolerability of R131 vaginal ointment in women with low grade and high grade cervical intraepithelial neoplasia (CIN) who have been diagnosed with Human papilloma virus (HPV). R131 ointment will be self-applied to the vagina once a day for 21 days in up to 3 treatment cycles. There will be a 7 day wash out at the end of each treatment cycle.
The total duration of participation of each subject will depend on their response to the treatment. If they do not respond to treatment after the first cycle, they will continue treatment for another cycle. If they do not respond after the second cycle, they will have a third cycle of treatment. Response will be assessed by colposcopy which will be performed at screening, baseline, at the end of each treatment cycle and 6 weeks after the end of treatment.
Each subject will attend a screening visit, a baseline visit, a visit at the end of each treatment cycle, up to 3 cycles, and an end of study visit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87650 0
Dr Amanda Tristram
Address 87650 0
Level 4, Women's Health
Wellington Regional Hospital
Riddiford Street
Newtown
Wellington 6021
Country 87650 0
New Zealand
Phone 87650 0
+6443855999
Fax 87650 0
Email 87650 0
Amanda.Tristram@ccdhb.org.nz
Contact person for public queries
Name 87651 0
Dr Amanda Tristram
Address 87651 0
Level 4, Women's Health
Wellington Regional Hospital
Riddiford Street
Newtown
Wellington 6021
Country 87651 0
New Zealand
Phone 87651 0
+6443855999
Fax 87651 0
Email 87651 0
Amanda.Tristram@ccdhb.org.nz
Contact person for scientific queries
Name 87652 0
Dr Amanda Tristram
Address 87652 0
Level 4, Women's Health
Wellington Regional Hospital
Riddiford Street
Newtown
Wellington 6021
Country 87652 0
New Zealand
Phone 87652 0
+6443855999
Fax 87652 0
Email 87652 0
Amanda.Tristram@ccdhb.org.nz

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