Efficacy and Safety of TCA vs. ECA for the Treatment of AIN in HIV-positive Patients

Study Overview
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Brief Summary
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Comparative evaluation of efficacy and safety of high-resolution anoscopy (HRA)-guided topical treatment (trichloroacetic acid, TCA) vs. surgical treatment (electrocautery, ECA) in HIV-positive patients for human papillomavirus (HPV)- induced AIN, an anal cancer precursor. The primary hypothesis is that cost-saving and simple TCA treatment is non-inferior to the current best option therapy with ECA. TCA treatment would also be possible in the normal setting of a doctor´s office without extensive specialization and without complex technical equipment.

Detailed Description
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Anal human papillomavirus (HPV)-infection and HPV-induced AIN, an anal cancer precursor, are very frequent in HIV-positive patients (HIV+), especially in men who have sex with men (MSM), but also in women. Consequently, HIV+ have a strongly increased risk for anal cancer. Screening for and treatment of AIN are recommended in HIV+, although only two RCT on AIN treatment have been published. We plan a multicenter, unblinded, non-inferiority RCT that evaluates the efficacy and safety of 2 high-resolution anoscopy (HRA)-guided treatment options for AIN: topical application of trichloroacetic acid (TCA) and surgical treatment with electrocautery (ECA). ECA was the best option for intra-anal AIN in a recent randomized controlled trial (RCT). TCA, an inexpensive and established therapy for genital warts, has been evaluated for AIN only in a retrospective pilot study that showed clearance rates comparable to those found for ECA, with possibly less adverse events (AE). Our primary hypothesis is that cost-saving and simple TCA is non-inferior to ECA. 2800 HIV+ will be screened by HRA in 9 proctological centers and 560 HIV+ with histologically confirmed intra-anal AIN will be randomized (1:1) to receive up to 4 treatments with TCA or ECA within 12 weeks. The primary efficacy endpoint is clinical (HRA) and histological resolution of AIN 4 weeks after the last treatment. Secondary endpoints comprise recurrence of AIN 24 weeks after end of therapy, the number of interventions, AE, and the influence of HPV parameters such as anal HPV-types, viral load and HPV-oncogene-mRNA.

Official Title
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Efficacy and Safety of Topical Trichloroacetic Acid vs. Electrocautery for the Treatment of Anal Intraepithelial Neoplasia in HIV-positive Patients (TECAIN) - a Randomized Controlled Trial

Conditions
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Anal Intraepithelial Neoplasia (AIN) in HIV-infected Patients

Intervention / Treatment
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* Other: Topical 85% trichloroacetic acid (TCA)
* Procedure: Surgical electrocautery (ECA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV positive patients Legally eligible patients and age ≥ 18 years Sufficient knowledge of the German language, spoken and written Patient is willing and able to appear regularly to the treatment- and follow-up appointments Clinically visible AIN-lesion, which was confirmed by histopathology (findings not older than 2 weeks after the date of collection and removal date no longer than 16 weeks prior to baseline) Written informed consent Exclusion Criteria: Currently diagnosed anal cancer or anal cancer in anamnesis (within the last 5 years) Acute life-threatening disease Participation in a proctologic study within the last 30 days Participation in this study at an earlier date Simultaneous participation in another clinical trial, which excludes the participation in this study Simultaneous topical and systemic treatments wtih medications that affect the study outcome, such as immunomodulatory substances: Interferone, imiquimod or systemic glucocorticosteroids lactation Pregnancy: In patients of childbearing age, a pregnancy has to be ruled out by pregnancy test or other suitable methods. Women of childbearing potential without adequate contraceptive protection. Contraindication for using trichloroacetic acid or electrocautery Patients in whom general anesthesia in the treatment of AIN is necessary already at study start Other serious intra-anal and proctologic disorders, which make additional proctologic or systemic treatments necessary, which influence the study result, such as an active Crohn's disease, which must be treated locally and systemically with immunosuppressives or an active proctitis. Patients who have been vaccinated before baseline against HPV

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topical 85% trichloroacetic acid (TCA)<br>AIN lesions are treated with trichloric acid | Other: Topical 85% trichloroacetic acid (TCA)<br>* In the experimental intervention arm, all visible lesions are treated with 85% TCA by dipping the wooden stick end of a cotton swab into a cup containing TCA. The stick end is saturated with TCA and is inserted through the anoscope and directed to the lesion under HRA guidance. TCA is applied to the lesion repeatedly until the lesion changes to a dense white colour. Each TCA application session is followed by another appointment four weeks later, where the clinician re-evaluates the lesions of the patient and determines whether a next TCA application is necessary up to a maximum of four times<br>* Other names: Topical treatment with trichloroacetic acid (TCA);|
| Active Comparator: Surgical electrocautery (ECA)<br>AIN lesions are treated with electrocautery | Procedure: Surgical electrocautery (ECA)<br>* In the control arm, HRA-guided ECA, is performed every 4 weeks up to a maximum of four times. All visible lesions are ablated at every visit. Bleeding from small vessels can be stopped by ECA. Patients undergo local anaesthesia if necessary<br>* Other names: Device: Electrocauter;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Therapeutic success (success rate) defined as clinically (HRA) and histologically confirmed resolution (normal histology) or regression (from AIN2/3 to AIN1) of AIN | The primary endpoint is therapeutic success (success rate) defined as clinically (HRA) and histologically confirmed resolution (normal histology) or regression (from AIN 2/3 to AIN1) of AIN four weeks after the last treatment within TECAIN. Patients not showing up at this mandatory follow-up appointment will be counted as treatment failure. Histologically confirmed resolution/regression 4 (to 8) weeks after therapy has been the primary endpoint in the two published RCTs and in several pilot studies. Clearance of AIN after treatment is the most relevant endpoint for patients, since AIN can rapidly progress to AC in HIV+ patients. | Four weeks after the last treatment within TECAIN | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence of AIN at the previously treated sites |  | 24 weeks after the end of TECAIN treatment | 
| Number of interventions needed during the 12 weeks TECAIN treatment period. | Additional treatments are possible after baseline, but they are not mandatory, if the lesions are cleared. So 4 weeks after each treatment the investigator checks, if the lesions are cleared and decides if he does another treatment or if the patient can progress to the follow up | 4 weeks after the end of TECAIN treatment | 
| Pain of the proctologic AIN treatments | Additional treatments are possible after baseline, but they are not mandatory, if the lesions are cleared. So 4 weeks after each treatment the investigator checks, if the lesions are cleared and decides if he does another treatment or if the patient can progress to the follow up | Up to 16 weeks after study start | 
| Anal HPV types, HPV multiplicity, HPV DNA load and HPV oncogene mRNA |  | Baseline, 4 and 24 weeks after the end of TECAIN treatment | 
| Recurrence of AIN or new lesions |  | 6 months after completion of TECAIN treatment in previously treated areas | 
| Duration of treatment phase |  | 24 weeks after the end of TECAIN treatment | 
| Adverse events |  | During the whole study up to 36 weeks | 
| Treatment costs |  | 24 weeks after the end of TECAIN treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-infection, anal cancer (AC), anal cancer prevention, anal dysplasia, anal intraepithelial neoplasia (AIN), human papillomavirus (HPV), HPV-induced anal cancer precursor lesions, electrocautery (ECA), topical trichloroacetic acid (TCA) treatment.