Primary Imiquimod Treatment Versus Surgery for Vulvar Intraepithelial Neoplasia (PITVIN)

To evaluate the efficacy (defined as complete clinical response at 6 months) of imiquimod vs. standard treatment (surgery) for vulvar intraepithelial neoplasia (VIN).

Study Overview

• Status: Completed
• Conditions: Vulvar Intraepithelial Neoplasia
• Intervention / Treatment: Procedure: Surgery; Drug: Imiquimod

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Department of Obstetrics and Gynecology/ Medical University of Graz
  • Innsbruck, Austria, 6020
    • Department of Gynecology and Obstetrics, Medical University of Innsbruck
  • Klagenfurt, Austria
    • Dep. of Gynecology and Obstetrics, Klinikum Klagenfurt
  • Leoben, Austria
    • Dep. of Gynecology and Obstetrics
  • Linz, Austria, 4010
    • Dep. of Gynecology, Krankenhaus Barmherzige Schwestern Linz
  • Salzburg, Austria, 5020
    • Dep. of Gynecology and Obstetrics, Landeskrankenhaus Salzburg
  • Vienna, Austria, 1090
    • Department of General Gynecology and Gynecology Oncology, Medical University of Vienna
  • Oberösterreich
    • Linz, Oberösterreich, Austria, 4020
      • Dep. of Gynecology and Obstetrics, Landes Frauen- und Kinderklinik Linz
  • Styria
    • Graz, Styria, Austria, 8020
      • Dep. of Gynecology, Krankenhaus Barmherzige Brüder Graz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Histologically confirmed VIN (only usual type, formerly VIN 2-3)
• Visible, measurable lesion(s)
• Contraception (for premenopausal women)

Exclusion Criteria:

• Evidence of invasion
• History of cancer or severe inflammatory dermatosis of the vulva
• Pregnancy, lactation
• Immunodeficiency
• Any treatment for VIN within the previous three months
• Known hypersensitivity to imiquimod

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Primary Imiquimod; Treatment with imiquimod will be patient self-administered for a period of 4 months with possible extension to 6 months. A thin layer of imiquimod cream should be applied to the lesion and remain overnight without a cover. Application will be once a week for 2 weeks, then twice a week the following 2 weeks and, if tolerated, 3 times a week for the last weeks. In case of severe side-effects the number of applications can be reduced; a treatment-free period of no more than 1 week is permitted	Drug: Imiquimod; Other Names: Aldara
Active Comparator: Primary surgery; The type of surgery (excision or ablation) will be based on clinical findings and surgeon's judgement. After excision the specimen will be histologically analyzed to assess resection margins and rule out invasion.	Procedure: Surgery; Other Names: Excision; Ablation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete clinical response	No clinical evidence of vulvar lesion, i.e. 100% reduction of primary lesion size	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical response/ lesion size	Vulvar lesions will be described, measured with calipers, mapped and photographed. The digital photos will be analyzed with a computer program (ImageJ) to calculate the total lesion size in cm². Results will be classified as: no response (NR, reduction in lesion size of 25% or less), weak partial response (wPR, 26-75% reduction), strong partial response (stPR, 76%-99% reduction) and Complete response (CR, 100% reduction).	6 months
Histologic response	At baseline punch biopsies will be taken from the affected areas. The site of the initial biopsy will be photodocumented to ensure that the follow-up biopsy at 6 months is taken from the same site. Histologic results will be classified as response (R): complete disappearance of usual type VIN or reduction to VIN1,or no response (NR). All biopsy samples will be analysed independently by two experienced gynecologic pathologists unaware of the treatment allocation	6 months
Extent of surgery	The number, types and extent of surgical procedures will be recorded. The extent of surgery will be recorded as total operated lesion size (in cm², as measured on pre-operative photograph) and relative operated lesion size (percentage of operated lesion size compared with the original pretreatment lesion size)	6 months
HPV status	HPV status will be measured with the qualitative cobas® HPV Test, Roche, and the the APTIMA ® HPV assay, Gen-Probe.	6 months
Clinical response/lesion size	Vulvar lesions will be described, measured with calipers, mapped and photographed. The digital photos will be analyzed with a computer program (ImageJ) to calculate the total lesion size in cm². Results will be classified as: no response (NR, reduction in lesion size of 25% or less), weak partial response (wPR, 26-75% reduction), strong partial response (stPR, 76%-99% reduction) and Complete response (CR, 100% reduction).	12 months
Extent of surgery	The number, types and extent of surgical procedures will be recorded. The extent of surgery will be recorded as total operated lesion size (in cm², as measured on pre-operative photograph) and relative operated lesion size (percentage of operated lesion size compared with the original pretreatment lesion size)	12 months
HPV status	HPV status will be measured with the qualitative cobas® HPV Test, Roche, and the the APTIMA ® HPV assay, Gen-Probe.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
"Cervical Dysplasia Distress" Questionnaire	Change from baseline in "Cervical Dysplasia Distress" score at 6 months	6 months
"Cervical Dysplasia Distress" questionnaire	Change from Baseline in "Cervical Dysplasia Distress" score at 12 months	12 months
"Fear of Progression" Questionnaire	Change from Baseline "Fear of Progression" score at 6 months.	6 months
"Fear of Progression" questionnaire	Change from Baseline "Fear of Progression" score at 12 months.	12 months
"Sexual activity" Questionnaire	Change from baseline "Sexual activity" score at 6 months	6 months
"Sexual activity" questionnaire	Change from baseline "Sexual activity" score at 12 months	12 months
Immune cells in the epidermis	Histochemical analysis of immune cells from vulvar biopsy samples will be performed at baseline and at 6 months. Frozen sections will be prepared and stained with corresponding cell markers. Immune cell populations will be quantified as number of cells per square millimetre and will be compared between the two treatment groups. The following markers and their primary antibodies will be analysed: CD1a, marker for Langerhans cells, CD94, marker for natural killer cells, CD4, marker for T-helper cells, CD8, marker for cytotoxic T-cells and CD207, marker for immature dendritic cells expressing Langerin.	6 months
Aesthetic results	Detailed photos of the overall vulva will be taken. Photos will be compared to photos taken at baseline and judged by 4 independent, blinded observers for aesthetic results.	6 months
Aesthetic results	Detailed photos of the overall vulva will be taken. Photos will be compared to photos at baseline and judged by 4 independent, blinded observers for aesthetic results.	12 months
Visual analogue scale (VAS) for assessment of pain and pruritus	Change of VAS score for pain and pruritus from baseline to 6 months. VAS will be assessed at baseline, 1,2 ,3,4,5 and 6 months.	6 months

Collaborators and Investigators

• Sponsor: Medical University of Graz
• Collaborators: Austrian Science Fund (FWF)
• Investigators: Principal Investigator: Gerda Trutnovsky, MD, Medical University of Graz; Study Director: Karl Tamussino, MD, Medical University of Graz

Publications and helpful links

General Publications

• Trutnovsky G, Reich O, Joura EA, Holter M, Ciresa-Konig A, Widschwendter A, Schauer C, Bogner G, Jan Z, Boandl A, Kalteis MS, Regauer S, Tamussino K. Topical imiquimod versus surgery for vulvar intraepithelial neoplasia: a multicentre, randomised, phase 3, non-inferiority trial. Lancet. 2022 May 7;399(10337):1790-1798. doi: 10.1016/S0140-6736(22)00469-X. Epub 2022 Apr 25. Erratum In: Lancet. 2022 Oct 8;400(10359):1194.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): February 1, 2021
• Study Completion (Actual): February 1, 2021

Study Registration Dates

• First Submitted: May 6, 2013
• First Submitted That Met QC Criteria: May 21, 2013
• First Posted (Estimate): May 23, 2013

Study Record Updates

• Last Update Posted (Actual): April 14, 2021
• Last Update Submitted That Met QC Criteria: April 13, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Patient satisfaction; Surgery; HPV; VIN; Imiquimod
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms; Carcinoma in Situ; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Adjuvants, Immunologic; Interferon Inducers; Imiquimod
• Other Study ID Numbers: KLI293