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

Anal Intraepithelial Neoplasia (AIN) in HIV-infected Patients Clinical Trial

— TECAIN  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02615860
• Other study ID #: 01KG1425
• Status: Completed
• Phase: N/A
• Start date: November 2015
• Est. completion date: December 31, 2021

Study information

• Verified date: November 2022
• Source: University Hospital, Essen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 560
• Est. completion date: December 31, 2021
• Est. primary completion date: March 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Anal Intraepithelial Neoplasia (AIN) in HIV-infected Patients
• Carcinoma in Situ
• Neoplasms

Intervention

Other:
• Topical 85% trichloroacetic acid (TCA)
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

Procedure:
• Surgical electrocautery (ECA)
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

Locations

Country	Name	City	State
Germany	Universitätsklinikum Essen, Klinik für Dermatologie	Essen	Nordrheinwestfalen

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Essen

Country where clinical trial is conducted

Germany, 

References & Publications (30)

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Kreuter A, Potthoff A, Brockmeyer NH, Gambichler T, Stücker M, Altmeyer P, Swoboda J, Pfister H, Wieland U; German Competence Network HIV/AIDS. Imiquimod leads to a decrease of human papillomavirus DNA and to a sustained clearance of anal intraepithelial neoplasia in HIV-infected men. J Invest Dermatol. 2008 Aug;128(8):2078-83. doi: 10.1038/jid.2008.24. Epub 2008 Feb 14. — View Citation

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Kreuter A, Wieland U. Human papillomavirus-associated diseases in HIV-infected men who have sex with men. Curr Opin Infect Dis. 2009 Apr;22(2):109-14. doi: 10.1097/QCO.0b013e3283229fc8. Review. — View Citation

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Legarth R, Helleberg M, Kronborg G, Larsen CS, Pedersen G, Pedersen C, Jensen J, Nielsen LN, Gerstoft J, Obel N. Anal carcinoma in HIV-infected patients in the period 1995-2009: a Danish nationwide cohort study. Scand J Infect Dis. 2013 Jun;45(6):453-9. doi: 10.3109/00365548.2012.737476. Epub 2013 Jan 7. — View Citation

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Palefsky JM, Holly EA, Efirdc JT, Da Costa M, Jay N, Berry JM, Darragh TM. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS. 2005 Sep 2;19(13):1407-14. — View Citation

Palefsky JM. Anal cancer prevention in HIV-positive men and women. Curr Opin Oncol. 2009 Sep;21(5):433-8. doi: 10.1097/CCO.0b013e32832f511a. Review. — View Citation

Piketty C, Selinger-Leneman H, Bouvier AM, Belot A, Mary-Krause M, Duvivier C, Bonmarchand M, Abramowitz L, Costagliola D, Grabar S. Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV. J Clin Oncol. 2012 Dec 10;30(35):4360-6. doi: 10.1200/JCO.2012.44.5486. Epub 2012 Oct 22. — View Citation

Richel O, de Vries HJ, van Noesel CJ, Dijkgraaf MG, Prins JM. Comparison of imiquimod, topical fluorouracil, and electrocautery for the treatment of anal intraepithelial neoplasia in HIV-positive men who have sex with men: an open-label, randomised controlled trial. Lancet Oncol. 2013 Apr;14(4):346-53. doi: 10.1016/S1470-2045(13)70067-6. Epub 2013 Mar 15. — View Citation

Richel O, Wieland U, de Vries HJ, Brockmeyer NH, van Noesel C, Potthoff A, Prins JM, Kreuter A. Topical 5-fluorouracil treatment of anal intraepithelial neoplasia in human immunodeficiency virus-positive men. Br J Dermatol. 2010 Dec;163(6):1301-7. doi: 10.1111/j.1365-2133.2010.09982.x. Epub 2010 Nov 4. — View Citation

Sanclemente G, Herrera S, Tyring SK, Rady PL, Zuleta JJ, Correa LA, He Q, Wolff JC. Human papillomavirus (HPV) viral load and HPV type in the clinical outcome of HIV-positive patients treated with imiquimod for anogenital warts and anal intraepithelial neoplasia. J Eur Acad Dermatol Venereol. 2007 Sep;21(8):1054-60. — View Citation

Silling S, Kreuter A, Hellmich M, Swoboda J, Pfister H, Wieland U. Human papillomavirus oncogene mRNA testing for the detection of anal dysplasia in HIV-positive men who have sex with men. J Clin Virol. 2012 Apr;53(4):325-31. doi: 10.1016/j.jcv.2011.12.029. Epub 2012 Jan 18. — View Citation

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Singh JC, Kuohung V, Palefsky JM. Efficacy of trichloroacetic acid in the treatment of anal intraepithelial neoplasia in HIV-positive and HIV-negative men who have sex with men. J Acquir Immune Defic Syndr. 2009 Dec 1;52(4):474-9. doi: 10.1097/QAI.0b013e3181bc0f10. Erratum in: J Acquir Immune Defic Syndr. 2012 Jul 1;60(3):e105-6. — View Citation

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* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Recurrence of AIN at the previously treated sites		24 weeks after the end of TECAIN treatment
Secondary	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
Secondary	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
Secondary	Anal HPV types, HPV multiplicity, HPV DNA load and HPV oncogene mRNA		Baseline, 4 and 24 weeks after the end of TECAIN treatment
Secondary	Recurrence of AIN or new lesions		6 months after completion of TECAIN treatment in previously treated areas
Secondary	Duration of treatment phase		24 weeks after the end of TECAIN treatment
Secondary	Adverse events		During the whole study up to 36 weeks
Secondary	Treatment costs		24 weeks after the end of TECAIN treatment

External Links

•   Condylamata accuminata, description of the german STI-foundation