Human papillomavirus infection: a randomised controlled trial of Imiquimod cream (5%) versus Podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts

Plain English Summary

Background and study aims
Genital warts are a very common sexually transmitted disease and are caused in over 90% of cases by human papillomavirus (HPV) types 6 or 11. Podophyllotoxin (as a cream or solution) and imiquimod cream are the most frequently used topical treatments for genital warts, but they have never been adequately compared to determine their relative effectiveness with respect to the clearance or recurrence rate. A vaccine is available to prevent HPV 6 and 11 (as well as HPV 16 and 18, the viruses that cause most cervical cancer), but it is not known whether it will increase the rate of clearance of genital warts if it is given at the same time as topical treatment, or whether it can prevent recurrences. The aim of this study is to find out whether imiquimod or podophyllotoxin is more effective at clearing and preventing recurrence of genital warts, and whether the addition of HPV vaccination provides additional benefits.

Who can participate?
Patients aged 18 or over with genital warts

What does the study involve?
Participants are randomly allocated to be treated with either imiquimod cream or podophyllotoxin cream, and to be treated with either a course of quadrivalent HPV vaccine (active against HPV types 6/11/16/18) or a placebo (dummy injection). This results in four treatment groups: imiquimod cream plus HPV vaccine; podophyllotoxin cream plus HPV vaccine; imiquimod cream plus placebo vaccine; and podophyllotoxin cream plus placebo vaccine. Successful treatment is defined as clearance of warts after 16 weeks and no relapse between 16 and 48 weeks. The study also compares the time taken for warts to be cleared with each treatment, the number of patients switching treatment because of non-response to treatment or side-effects, and the patients’ quality of life. An analysis is also conducted to compare the cost effectiveness of each treatment. Imiquimod is currently more expensive than podophyllotoxin (although the cost difference is expected to reduce). The economic benefit of HPV vaccination is also studied.

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
University College London (UK)

When is the study starting and how long is it expected to run for?
June 2014 to March 2017

Who is funding the study?
Health Technology Assessment Programme (UK)

Who is the main contact?
Dr Macey Murray
macey.murray@ucl.ac.uk

Study website

Type

Scientific

Contact name

Dr Macey Murray

ORCID ID

Contact details

Comprehensive Clinical Trials Unit at UCL
Institute of Clinical Trials and Methodology
London
WC1E 6BT
United Kingdom
+44 (0)20 3549 5013 (Int Ext: 65013)
macey.murray@ucl.ac.uk

EudraCT/CTIS number

2013-002951-14

IRAS number

ClinicalTrials.gov number

Protocol/serial number

16857; HTA 11/129/187

Scientific title

Human papillomavirus infection: a randomised controlled trial of Imiquimod cream (5%) versus Podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac Trial)

Acronym

HIPvac

Study hypothesis

The HIPvac trial will address two questions regarding the management of patients with genital warts. The first is which of the two most frequently used creams used to treat warts, imiquimod or podophyllotoxin, is most effective at clearing genital warts, and preventing recurrence. The second is whether a course of human papillomavirus (HPV) vaccine started at the time of initiating topical treatment, increases the effectiveness of the cream in either clearing the warts or preventing recurrence. The HPV vaccine used is licensed for the prevention of infection caused by HPV 6 and 11 (which cause 90% genital warts) and HPV 16 and 18 (cause 70% cervical cancer). The vaccine is used in the national vaccination programme in the UK for girls aged 12-13; it is not licensed for the treatment of genital warts.

More details can be found at: http://www.nets.nihr.ac.uk/projects/hta/11129187
Protocol can be found at: http://www.nets.nihr.ac.uk/__data/assets/pdf_file/0007/94642/PRO-11-129-187.pdf

Ethics approval(s)

13/SC/0638; First MREC approval date 03/02/2014

Study design

Randomised; Interventional; Design type: Not specified, Treatment

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Study setting(s)

Hospital

Study type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Topic: Infectious diseases and microbiology; Subtopic: Infection (all Subtopics); Disease: Infectious diseases and microbiology

Intervention

The trial will follow participants for 48 weeks (6 visits). They will be randomly assigned to one of the creams (imiquimod 5% or podophyllotoxin 0.15%). Patients will know which cream they have been given as the creams have different dosing schedules. The creams will be used per standard care. The vaccine will be randomly assigned at the same time. Participants will receive either HPV vaccine (Gardasil) or placebo (saline injection). Patients will receive three doses of vaccine, the first at their baseline visit, then at week 8 and 24.

Intervention type

Mixed

Primary outcome measure

Wart clearance within 16 weeks of starting treatment and remaining wart-free between 16 and 48 weeks

Secondary outcome measures

1. Proportion wart-free at the end of the assigned treatment course; Timepoint(s): 4 or 16 weeks
2. Proportion experiencing wart recurrence/relapse after complete wart clearance; Timepoint(s): Up to 48 weeks
3. Time from complete wart clearance to recurrence/relapse; Timepoint(s): Up to 48 weeks
4. Adverse events; Timepoint(s): As required
5. Health-related quality of life, as measured by the Area Under the Curve for EQ-5D; Timepoint(s): At all visits
6. Symptom scores; Timepoint(s): At all review of treatment visits
7. Total costs of treatment including prescribed agents and clinic visits; Timepoint(s): 48 weeks
8. Proportion wart-free at 16 weeks, with use of additional treatment as required; Timepoint(s): 16 weeks
9. Quantity of additional treatment required to achieve clearance by 16 weeks; Timepoint(s): 16 weeks
10. Proportion wart-free at 24 weeks; Timepoint(s): 24 weeks
11. Proportion wart-free at 24 weeks with use of additional treatment as required; Timepoint(s): 24 weeks
12. Qantitiy of additional treatment required to achieve clearance by 24 weeks; Timepoint(s): 24 weeks
13. Proportion experiencing wart recurrence/relapse at 48 weeks after wart clearance at 24 weeks; Timepoint(s): 24, 48 weeks
14. Proportion experiencing complete wart clearance; Timepoint(s): 48 weeks
15. Time to complete wart clearance; Timepoint(s): Point of wart clearance

Overall study start date

30/06/2014

Overall study end date

31/03/2017

Reason abandoned (if study stopped)

Participant inclusion criteria

1. Age 18 years or over
2. Males and females
3. First episode or repeat episode of anogenital warts diagnosed clinically
4. External anogenital warts considered, in the opinion of the investigator, to be suitable for self-administered topical wart treatment (patients with concurrent internal anogenital warts are still eligible to participate)
5. Able to provide informed consent to participate in the trial

Participant type(s)

Patient

Age group

Adult

Lower age limit

18 Years

Sex

Both

Target number of participants

Planned Sample Size: 1000; UK Sample Size: 1000

Total final enrolment

503

Participant exclusion criteria

1. Previous wart treatment in the last 3 months
2. Previous quadrivalent HPV vaccine (previous bivalent HPV vaccine is not an exclusion criterion)
3. Previous intolerance to either of the topical treatments, vaccines or their constituents
4. Known HIV-positivity (HIV testing is not required for the trial)
5. Pregnancy or lactation (current, or planned in the next 6 months)
6. Women of child bearing potential not willing to use effective contraception for the duration and 30 days post completion of trial treatment: see above
7. Unable or unwilling to complete follow-up procedures
8. Lesion area greater than 4 cm2, requiring treatment under direct supervision of medical staff (in accordance with
podophyllotoxin cream Summary of Product Characteristics)
9. Patients who have had topical steroids applied to the target area, or systemic steroids or other immunosuppressive agents, within 1 month prior to randomisation
10. Patients enrolled in any other trial of an Investigational Medicinal Product, without the permission of the Chief Investigator
11. Any clinical condition which the investigator considers would make the patient unsuitable for the trial, including immunodeficiency conditions

Recruitment start date

30/06/2014

Recruitment end date

31/03/2017

Countries of recruitment

England, United Kingdom

Study participating centre

University College London
London
WC1E 6BT
United Kingdom

Organisation

University College London (UK)

Sponsor details

Gower Street
London
WC1E 6BT
England
United Kingdom

Sponsor type

University/education

Website

ROR

https://ror.org/02jx3x895

Funder type

Government

Funder name

Health Technology Assessment Programme

Alternative name(s)

NIHR Health Technology Assessment Programme, HTA

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

01/04/2020

Individual participant data (IPD) sharing plan

The data sharing plans for the current study are unknown and will be made available at a later date

IPD sharing plan summary

Data sharing statement to be made available at a later date

Study outputs