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

• ClinicalTrials.gov Identifier: NCT01861535
• Recruitment Status: Completed
• First Posted: May 23, 2013
• Last Update Posted: April 14, 2021
• Sponsor: Medical University of Graz
• Collaborator: Austrian Science Fund (FWF)
• Information provided by (Responsible Party): Medical University of Graz

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Vulvar Intraepithelial Neoplasia	Drug: Imiquimod; Procedure: Surgery	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 110 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Primary Imiquimod Treatment Versus Surgery for Vulvar Intraepithelial Neoplasia
• Study Start Date: June 2013
• Actual Primary Completion Date: February 2021
• Actual Study Completion Date: February 2021

Arms and Interventions

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 Name: 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

Outcome Measures

Primary Outcome Measures :

1. Complete clinical response [ Time Frame: 6 months ]
   No clinical evidence of vulvar lesion, i.e. 100% reduction of primary lesion size

Secondary Outcome Measures :

1. Clinical response/ lesion size [ Time Frame: 6 months ]
   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).
2. Histologic response [ Time Frame: 6 months ]
   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
3. Extent of surgery [ Time Frame: 6 months ]
   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)
4. HPV status [ Time Frame: 6 months ]
   HPV status will be measured with the qualitative cobas® HPV Test, Roche, and the the APTIMA ® HPV assay, Gen-Probe.
5. Clinical response/lesion size [ Time Frame: 12 months ]
   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. Extent of surgery [ Time Frame: 12 months ]
   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)
7. HPV status [ Time Frame: 12 months ]
   HPV status will be measured with the qualitative cobas® HPV Test, Roche, and the the APTIMA ® HPV assay, Gen-Probe.

Other Outcome Measures:

1. "Cervical Dysplasia Distress" Questionnaire [ Time Frame: 6 months ]
   Change from baseline in "Cervical Dysplasia Distress" score at 6 months
2. "Cervical Dysplasia Distress" questionnaire [ Time Frame: 12 months ]
   Change from Baseline in "Cervical Dysplasia Distress" score at 12 months
3. "Fear of Progression" Questionnaire [ Time Frame: 6 months ]
   Change from Baseline "Fear of Progression" score at 6 months.
4. "Fear of Progression" questionnaire [ Time Frame: 12 months ]
   Change from Baseline "Fear of Progression" score at 12 months.
5. "Sexual activity" Questionnaire [ Time Frame: 6 months ]
   Change from baseline "Sexual activity" score at 6 months
6. "Sexual activity" questionnaire [ Time Frame: 12 months ]
   Change from baseline "Sexual activity" score at 12 months
7. Immune cells in the epidermis [ Time Frame: 6 months ]
   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.
8. Aesthetic results [ Time Frame: 6 months ]
   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.
9. Aesthetic results [ Time Frame: 12 months ]
   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.
10. Visual analogue scale (VAS) for assessment of pain and pruritus [ Time Frame: 6 months ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Austria

Dep. of Gynecology and Obstetrics, Landes Frauen- und Kinderklinik Linz

Linz, Oberösterreich, Austria, 4020

Dep. of Gynecology, Krankenhaus Barmherzige Brüder Graz

Graz, Styria, Austria, 8020

Department of Obstetrics and Gynecology/ Medical University of Graz

Graz, Austria, 8036

Department of Gynecology and Obstetrics, Medical University of Innsbruck

Innsbruck, Austria, 6020

Dep. of Gynecology and Obstetrics, Klinikum Klagenfurt

Klagenfurt, Austria

Dep. of Gynecology and Obstetrics

Leoben, Austria

Dep. of Gynecology, Krankenhaus Barmherzige Schwestern Linz

Linz, Austria, 4010

Dep. of Gynecology and Obstetrics, Landeskrankenhaus Salzburg

Salzburg, Austria, 5020

Department of General Gynecology and Gynecology Oncology, Medical University of Vienna

Vienna, Austria, 1090

Sponsors and Collaborators

Medical University of Graz

Austrian Science Fund (FWF)

Investigators

• Principal Investigator: Gerda Trutnovsky, MD; Medical University of Graz
• Study Director: Karl Tamussino, MD; Medical University of Graz

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Medical University of Graz
• ClinicalTrials.gov Identifier: NCT01861535
• Other Study ID Numbers: KLI293
• First Posted: May 23, 2013
• Last Update Posted: April 14, 2021
• Last Verified: April 2021

Keywords provided by Medical University of Graz:

VIN; Imiquimod; Surgery; HPV; Patient satisfaction

Additional relevant MeSH terms:

Neoplasms; Carcinoma in Situ; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Imiquimod; Toll-Like Receptor Agonists; Molecular Mechanisms of Pharmacological Action; Immunomodulating Agents; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic; Antineoplastic Agents; Interferon Inducers