Evaluation Of The Efficacy Of The Combination Of GLIZIGEN® Oral Solution 1/Day And Vaginal Gel 1/Night For 2 Months In Patients With Cervical Intraepithelial Neoplasia Grade 1 (LSIL/CIN-1) Caused By High-Risk Human Papillomavirus (HPV-AR)
NCT ID: NCT05916911
Last Updated: 2024-02-07
Study Results
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Basic Information
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RECRUITING
PHASE4
120 participants
INTERVENTIONAL
2023-06-07
2025-01-08
Brief Summary
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Glizigen is an oral and intravaginal treatment based on activated glycyrrhizinic acid that has shown potential benefit in patients with HPV.
In order to improve the existing evidence, the present study consists of a randomized, double-blind, placebo-compared clinical trial to evaluate the efficacy of combined treatment with Glizigen Oral Solution and Glizigen Vaginal Gel for the resolution of biopsy-confirmed grade 1 cervical intraepithelial neoplasia (CIN-1) in patients with high-risk HPV.
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Detailed Description
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HPV infection occurs through direct contact with the skin or mucous membranes of an infected person, who may or may not have visible lesions. In the case of genital infection, vaginal or anal intercourse is the main route of transmission. HPV is very common, and it is estimated that, in the United States, approximately 80% of women will have acquired an infection by the age of 50.
Most HPV infections do not cause symptoms or disease and disappear 12-24 months after infection. The small proportion of these infections that persist result in precancerous lesions that may progress to cancer. HPV infection is associated with virtually 100% of cervical cancer cases and with a high rate of anogenital and oropharyngeal cancers.
According to the World Health Organisation, the approach to cervical cancer prevention consists of primary prevention through HPV vaccination to prevent HPV infection, and secondary prevention through screening programmes to achieve early detection of HPV infection. Screening programmes differ from country to country, but are mainly based on determination of the presence of the virus by viral DNA testing and determination of intraepithelial lesions by cytology (Pap smear). A positive HPV DNA test implies the presence of the virus in the sample, while positive cytology implies an alteration or lesion in the tissue.
The morphology of squamous intraepithelial lesions caused by HPV in the lower anogenital tract is identical in all locations and in both sexes. The LAST Terminology classifies HPV-associated histological squamous intraepithelial lesions into two grades, low-grade lesions (LSIL) and high-grade lesions (HSIL). The term LSIL also includes cervical intraepithelial neoplasia grade 1 (CIN1) of the Richart classification, adopted by WHO in 2004.
LSIL/CIN1 lesions are the histological manifestation of a self-limiting HPV infection that most often resolves spontaneously. Close follow-up of patients with LSIL lesions minimises the risk of developing cervical cancer by observing whether the lesions resolve or, conversely, detecting early if they progress to HSIL. CIN2 and CIN3 lesions are included in the term HSIL. HSIL/CIN2 lesions can still revert to L-SIL or progress to neoplasia. In contrast, HSIL/CIN3 lesions are considered true intraepithelial neoplasms with a high potential for progression and are the necessary precursor lesion to cervical cancer and should be treated by destructive or excisional methods.
Another relatively common cytological alteration is atypical squamous cells of undetermined significance (ASCUS). An ASCUS cytology result may be due to HPV infection or other causes, so when detected, HPV-DNA testing is recommended. ASCUS is usually associated with SIL lesions, mainly LSIL, although HSIL cannot be ruled out.
On the other hand, colposcopy is an essential examination in the secondary prevention of cervical cancer (CCU) as it is the only procedure that allows the identification of intraepithelial cervical lesions, their location, extension and characteristics, and directs the biopsy to obtain diagnostic confirmation.
As previously advanced, secondary prevention is useful for early diagnosis of HPV infections, allowing treatment of high-grade lesions (HSIL) before they progress to cervical cancer. At the same time, it allows close follow-up of patients with low-grade lesions (LSIL). However, there is currently no specific treatment for LSILs, so it is limited to "wait and see" or observation without treatment.
Adequate nutritional status of patients with HPV infections is essential for optimal immune system function. Therefore, maintaining an adequate diet, smoking cessation and regular exercise are recommended as part of observational management strategies for patients with HPV infections. In some cases, supplementation of relevant macro- and micronutrients may help to stimulate the immune system and accelerate HPV clearance and lesion resolution. Indeed, dietary deficiencies of nutrients such as folates, vitamin C, vitamin B12, zinc and others have been linked to increased persistence of HPV infections and progression of HPV-related lesions. Moreover, other bio-functional ingredients with immunomodulatory, antiviral or antiproliferative activity could be useful both orally and topically.
Glizigen® vaginal gel and Glizigen® oral solution contain glycyrrhizinic acid as a common ingredient. Glycyrrhizinic acid or glycyrrhizin is a natural triterpenoid from liquorice root (Glycyrrhiza glabra) whose topical and systemic use has been evaluated in a multitude of studies that have demonstrated its safety and efficacy against different viral processeS. Among its most studied properties are its antiviral, anticarcinogenic and immunomodulatory action, and it has also been shown to have re-epithelialising, antibacterial, anti-inflammatory and antioxidant properties.
The mechanisms of antiviral action described for glycyrrhizinic acid against different viruses include: direct inactivation of the virus, reduction of virus fusion with the cell membrane, inhibition of viral replication, modulation of the immune response and stimulation of apoptosis:
In addition, glycyrrhizinic acid has demonstrated antiproliferative action against different types of cell lines or animal models of cervical, skin, colon or ovarian cancer. Specifically, it has been shown to be able to induce apoptosis and arrest the cell cycle in the G0/G1 phase in cervical cancer cells. Furthermore, it has a synergistic effect with cisplatin and 5-fluorouracil (5-FU) when combined with them. However, unlike cisplatin and 5-FU, glycyrrhizinic acid has no cytotoxic action against non-cancerous cells. Therefore, all these properties described for glycyrrhizinic acid make it a perfect candidate to prevent the proliferation of HPV-associated precancerous lesions.
Topical and systemic use of glycyrrhizinic acid activated by a catalytic process (Glizigen®) has been evaluated in women with HPV infections of the cervix, vagina or vulva, as well as in women and men with anogenital condylomas. The use of these formulations with activated glycyrrhizinic acid has shown good efficacy in favouring HPV negativisation and resolution of low-grade lesions (LSIL). It has also demonstrated a good safety profile and significantly superior efficacy to placebo and slightly superior efficacy to podophyllotoxin in the treatment of anogenital condylomata.
Rationale for the study HR-HPV infection carries a risk of developing cervical cancer, especially when precancerous lesions have already developed. The current screening system allows us to identify these patients; however, there is still no clear therapeutic option to treat patients before they develop high-grade lesions, where the most common management is surgical treatment.
Previous studies with Glizigen® provide evidence of its potential benefit in patients with cervical HPV infections, but there are a number of limitations that need to be addressed. Among them, the main limitation is that they are open-label, uncontrolled studies. It is true that Glizigen® has been used in comparative studies against placebo or podophyllotoxin in patients with anogenital condylomas . On the other hand, these studies in patients with HPV in the cervix included patients with both high- and low-risk HPV infection, who may or may not have histological lesions.
Therefore, this study would be justified by the following points:
* There is a need to investigate new therapeutic options, as there is no approved treatment for CIN1 lesions caused by HPV. It is therefore of interest to evaluate the efficacy of Glizigen® in the group of patients with HR-HPV LSIL/CIN1.
* It is of interest to evaluate the efficacy of the topical and systemic combination of Glizigen® with the new topical formulation.
* There is a need to provide higher quality evidence on the efficacy of Glizigen® than is currently available.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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Glizigen Group
Patients will receive combined treatment with Glizigen® oral solution and Glizigen® vaginal gel for 2 months.
Glizigen
Treatment initiation: Treatment should be started simultaneously with the appropriate oral and intravaginal formulation after the last menstrual period or immediately in menopausal patients.
A total of 60 single doses of intravaginal use and 60 doses of oral solution should be given to each patient.
The intravaginal gel should be applied every night before going to sleep by inserting the cannula completely into the vagina and pressing the tube until the entire contents of the tube are poured into the vagina, then removing the cannula from the vagina while continuing to press the tube to avoid retrograde aspiration of the product. Application of the intravaginal gel should be discontinued during days of menstrual bleeding.
The oral solution should be administered by drinking 1 vial every morning without interruption for 60 days from the start of treatment. It can be taken either on an empty stomach or with food.
Placebo Group
Patients will receive combined treatment with Placebo oral solution and Placebo vaginal gel for 2 months.
Placebo
Treatment initiation: Treatment should be started simultaneously with the appropriate oral and intravaginal formulation after the last menstrual period or immediately in menopausal patients.
A total of 60 placebo single doses of intravaginal use and 60 placebo doses of oral solution should be given to each patient.
The placebo intravaginal gel should be applied every night before going to sleep by inserting the cannula completely into the vagina and pressing the tube until the entire contents of the tube are poured into the vagina, then removing the cannula from the vagina while continuing to press the tube to avoid retrograde aspiration of the product. Application of the intravaginal gel should be discontinued during days of menstrual bleeding.
The placebo oral solution should be administered by drinking 1 vial every morning without interruption for 60 days from the start of treatment. It can be taken either on an empty stomach or with food.
Interventions
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Glizigen
Treatment initiation: Treatment should be started simultaneously with the appropriate oral and intravaginal formulation after the last menstrual period or immediately in menopausal patients.
A total of 60 single doses of intravaginal use and 60 doses of oral solution should be given to each patient.
The intravaginal gel should be applied every night before going to sleep by inserting the cannula completely into the vagina and pressing the tube until the entire contents of the tube are poured into the vagina, then removing the cannula from the vagina while continuing to press the tube to avoid retrograde aspiration of the product. Application of the intravaginal gel should be discontinued during days of menstrual bleeding.
The oral solution should be administered by drinking 1 vial every morning without interruption for 60 days from the start of treatment. It can be taken either on an empty stomach or with food.
Placebo
Treatment initiation: Treatment should be started simultaneously with the appropriate oral and intravaginal formulation after the last menstrual period or immediately in menopausal patients.
A total of 60 placebo single doses of intravaginal use and 60 placebo doses of oral solution should be given to each patient.
The placebo intravaginal gel should be applied every night before going to sleep by inserting the cannula completely into the vagina and pressing the tube until the entire contents of the tube are poured into the vagina, then removing the cannula from the vagina while continuing to press the tube to avoid retrograde aspiration of the product. Application of the intravaginal gel should be discontinued during days of menstrual bleeding.
The placebo oral solution should be administered by drinking 1 vial every morning without interruption for 60 days from the start of treatment. It can be taken either on an empty stomach or with food.
Eligibility Criteria
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Inclusion Criteria
2. Diagnosed with infection with at least one high-risk HPV strain (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73 and 82) by PCR test and positive cytology with confirmation of LSIL/CIN-1 by colposcopy and biopsy.
3. Adequate cultural level and understanding of the clinical study.
4. Agree to participate voluntarily in the study and give written informed consent.
2. Patient receiving any other product aimed at favouring the resolution of HPV infection.
3. Women with polymenorrhoea or frequent bleeding that makes vaginal administration of the preparation impossible.
4. Patient with immunosuppressive treatment or with other infectious processes in the genitals (e.g. herpes, candida, etc.).
5. Pregnant patients.
6. Participation in a concomitant trial that conflicts with this study.
7. Women with HIV infection.
8. Patients allergic to any component of the investigational product.
Patients who have been vaccinated against HPV before or after the start of the study are eligible to participate in the study, and this should be correctly reflected in the Data Collection Notebook.
30 Years
65 Years
FEMALE
No
Sponsors
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Atika Pharma S.L.
UNKNOWN
Catalysis SL
INDUSTRY
Responsible Party
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Principal Investigators
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Pluvio J. Coronado Martín, Dr.
Role: PRINCIPAL_INVESTIGATOR
Hospital San Carlos, Madrid
Locations
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Hospital Ruber Internacional
Madrid, , Spain
Hospital Clinico San Carlos
Madrid, , Spain
Hospital Universitario 12 de Octubre
Madrid, , Spain
Hospital Universitario La Paz
Madrid, , Spain
Countries
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Central Contacts
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Facility Contacts
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Alfonso Duque Frischcorn, Dr.
Role: primary
César A. Gómez Derch, D.
Role: primary
Carmen Martínez de de Pancorbo González, Dra.
Role: primary
Rafael Pérez-Santamaría Feijóo, Dr.
Role: primary
References
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Jung WW, Chun T, Sul D, Hwang KW, Kang HS, Lee DJ, Han IK. Strategies against human papillomavirus infection and cervical cancer. J Microbiol. 2004 Dec;42(4):255-66.
Rositch AF, Koshiol J, Hudgens MG, Razzaghi H, Backes DM, Pimenta JM, Franco EL, Poole C, Smith JS. Patterns of persistent genital human papillomavirus infection among women worldwide: a literature review and meta-analysis. Int J Cancer. 2013 Sep 15;133(6):1271-85. doi: 10.1002/ijc.27828. Epub 2012 Oct 11.
Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003 Feb 6;348(6):518-27. doi: 10.1056/NEJMoa021641.
Baseman JG, Koutsky LA. The epidemiology of human papillomavirus infections. J Clin Virol. 2005 Mar;32 Suppl 1:S16-24. doi: 10.1016/j.jcv.2004.12.008.
Braaten KP, Laufer MR. Human Papillomavirus (HPV), HPV-Related Disease, and the HPV Vaccine. Rev Obstet Gynecol. 2008 Winter;1(1):2-10.
de Sanjose S, Brotons M, Pavon MA. The natural history of human papillomavirus infection. Best Pract Res Clin Obstet Gynaecol. 2018 Feb;47:2-13. doi: 10.1016/j.bpobgyn.2017.08.015. Epub 2017 Sep 6.
Bosch FX, Broker TR, Forman D, Moscicki AB, Gillison ML, Doorbar J, Stern PL, Stanley M, Arbyn M, Poljak M, Cuzick J, Castle PE, Schiller JT, Markowitz LE, Fisher WA, Canfell K, Denny LA, Franco EL, Steben M, Kane MA, Schiffman M, Meijer CJ, Sankaranarayanan R, Castellsague X, Kim JJ, Brotons M, Alemany L, Albero G, Diaz M, de Sanjose S; authors of ICO Monograph Comprehensive Control of HPV Infections and Related Diseases Vaccine Volume 30, Supplement 5, 2012. Comprehensive control of human papillomavirus infections and related diseases. Vaccine. 2013 Dec 31;31 Suppl 7(Suppl 7):H1-31. doi: 10.1016/j.vaccine.2013.10.003.
Comprehensive Cervical Cancer Control: A Guide to Essential Practice. 2nd edition. Geneva: World Health Organization; 2014. Available from http://www.ncbi.nlm.nih.gov/books/NBK269619/
Chan CK, Aimagambetova G, Ukybassova T, Kongrtay K, Azizan A. Human Papillomavirus Infection and Cervical Cancer: Epidemiology, Screening, and Vaccination-Review of Current Perspectives. J Oncol. 2019 Oct 10;2019:3257939. doi: 10.1155/2019/3257939. eCollection 2019.
Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, Wilkinson EJ, Zaino RJ, Wilbur DC; Members of LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med. 2012 Oct;136(10):1266-97. doi: 10.5858/arpa.LGT200570. Epub 2012 Jun 28.
Kaufman RH. Dysplasia and carcinoma in situ of the cervix. Clin Obstet Gynecol. 1967 Dec;10(4):748-84. No abstract available.
Other Identifiers
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GLI-112
Identifier Type: -
Identifier Source: org_study_id
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