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Citrate

Application of DEFLAGYN vaginal gel for 3x 28days (as per instructions provided by the manufacturer)

DEFLAGYN is a vaginal gel, classified as a medical device, containing silica and citric acid, which binds pathogens, inhibits their spread and exerts an antioxidant effect. It is applied intravaginally (through an applicator) and used for 3 months.

DEFLAGYN vaginal gel

Clemens B Tempfer, MD, MBA

Günther A Rezniczek, PhD

Human papillomaviruses (HPV) are the most common sexually transmitted pathogens worldwide and in most cases are causally associated with the development of cervical cancer, one of the most common cancers in women and one of the leading causes of death in women worldwide. Precancerous lesions (dysplasias) or the presence of a high-risk HPV subtype are detected by a screening smear test performed by a gynecologist. If precancerous lesions are detected, conization (= surgical removal of a cone of tissue from the cervix) is the method of choice for removing the diseased tissue. However, if the degree of dysplasia is correspondingly low or the smear is unclear, then the guideline-compliant non-surgical treatment provides for a wait-and-see approach with PAP and HPV smear control after 6-8 months.

This "wait-and-see" approach can be complemented by local therapy with an immunostimulant. For this purpose, DEFLAGYN® (a vaginal gel containing silica and citric acid) and Aldara® (imiquimod, a Toll-Like Re-ceptor 7 antagonist) are available. However, while the latter is not approved for the treatment of cervical dysplasia or HPV infection, DEFLAGYN® has CE marking and approval as a medical device for treatment in a number of indications, such as unclear cervical smears, HPV-induced cervical lesions, p16/Ki-67-positive cervical lesions or cervical erosions.

However, available studies on the efficacy of DEFLAGYN are limited. For example, there is only one prospective randomized trial (Major et al, 2021, Arch. Gynecol. Obstet. 303:501-511), which included 216 women with histologically confirmed CIN 1/2. A 3-month intravaginal application of DEFLAGYN® resulted in regression of CIN 1/2 in 72% versus 25% in the control arm (no intervention). Side effects of therapy with DEFLAGYN® were not observed in this study.

Due to the frequency of CIN and HPV infections in the female population and due to the high medical relevance of a conservative method of treating this disease, further methodologically high-quality studies on the efficacy of DEFLAGYN® should be performed.

1. HPV and dysplasia of the cervix uteri Human papillomaviruses (HPV) are the most common sexually transmitted pathogens worldwide. The prevalence in both male and female populations is high. Epidemiological estimates suggest that 85-91% of sexually active adults acquire at least one genital HPV infection by age 50, with approximately 95% of HPV infections being spontaneously eliminated within 2 years in terms of HPV immunologic clearance. HPV preferentially infects the epithelial cells of the anogenital area and, through incorporation of HPV DNA into the host genome of the basal cells of the squamous epithelium of the cervix and subsequent expression of viral components, causes dysplastic changes in the cervical epithelium that, if left untreated, can develop into invasive carcinoma of the cervix (cervical carcinoma).

   Cervical carcinoma is the fourth most common cancer as well as the fourth leading cause of cancer-related death in women worldwide, responsible for 6.6% (570,000) of all new cancer cases and 7.5% (311,000) of cancer-related deaths in women in 2018.

   The precursor of squamous cell carcinoma of the uterine cervix (approximately 80% of all cervical cancers) is cervical intraepithelial neoplasia (CIN), which has three grades of expression (CIN1, CIN 2, and CIN 3). Compared with invasive cervical carcinoma, the incidence and prevalence of precancerous lesions of the cervix uteri are much higher. It is estimated that approximately 100,00 w0omen in Germany develop high-grade dysplasia (CIN2/CIN3) each year.
2. Therapy Dysplasia of the cervix typically becomes conspicuous during gynecological screening examinations. Here, smears are taken from the ectocervix and endocervix and assessed cytologically for dysplastic cells and the quality of the smear after Papanicolaou staining. HPV infection diagnostics are also performed as part of the statutory cervical carcinoma screening (annually or every 3 years) in order to detect the presence of HPV high risk infections.

   In case of abnormalities in the cervical smear and/or HPV high risk infection with suspicion of cervical dysplasia, presentation to a specialized dysplasia consultation is recommended for further clarification of dysplastic changes. During the subsequent colposcopic examination, a histological tissue sample ('cervical biopsy') of conspicuous areas is taken. The histopathological processing of the tissue samples and the colposcopic image of the spread of the changes in the cervix then allow individualized therapy planning.
3. Conization as the standard of surgical treatment If precancerous lesions with the potential to develop into an invasive cervical tumor are detected, conization (= surgical removal of a cone of tissue from the cervix) is the method of choice for removing the diseased tissue. The worldwide standard surgical procedure for conization is LLETZ conization (="Large Loop Excision of the Transformation Zone"). In addition to the risk of local persistence of precancerous lesions if cervical dysplasia is incompletely removed, LLETZ also increases the risk of preterm delivery in subsequent pregnancy. This risk increases with increasing volume of removed tissue. To reduce or avoid the aforementioned complications, conization should be performed under colposcopic vision and as little healthy cervical tissue as possible should be removed.
4. Non-surgical treatment options Non-surgical methods for the treatment of CIN and/or HPV high risk infections are limited. According to the current S3 guideline, in case of CIN 1 and/or HPV high risk infection, a wait-and-see approach with PAP and HPV smear control in 6-8 months is possible. Alternatively, local therapy with an immunostimulant may be used. DEFLAGYN® and Aldara® are available for this purpose. Aldara® is imiquimod, a Toll-Like Receptor 7 (TLR 7) antagonist, which leads to a local immune response. However, Aldara® is not approved for the treatment of CIN or HPV infections. DEFLAGYN®, on the other hand, has a CE mark and medical device approval for the treatment of unclear cervical smears (ASC-US, ASC-H, LSIL, HSIL or PAP II-p, PAP III-p, PAP IIID1, PAP IIID2 or PAP III, PAP IIID) or HPV-induced cervical lesions or p16/Ki-67-positive cervical lesions or cervical erosions.
5. DEFLAGYN® - Mode of action and approval status DEFLAGYN® is a vaginal gel containing silica and citric acid, which binds pathogens, inhibits their spread and exerts an antioxidant effect. It is applied intravaginally and used for 3 months. In a prospective randomized study of 216 women with histologically confirmed CIN 1/2, 3 months of intravaginal application of DEFLAGYN® resulted in regression of CIN 1/2 in 72% versus 25% in the control arm (no intervention). The rate of HPV high risk infections decreased from 87% to 44% in the intervention arm. No other intervention studies on the efficacy of DEFLAGYN® can be found in the literature (PubMed search on 08/14/2022; search terms: dysplasia, deflagyn, HPV, silicon dioxide gel, randomized). Side effects of therapy with DEFLAGYN® were not observed in the study. Due to the frequency of CIN and HPV infections in the female population and due to the high medical relevance of a conservative method of this disease, further methodologically high-quality studies on the efficacy of DEFLAGYN® are useful.

1:1 randomization into a control arm (wait-and-see) and a treatment arm (vaginal gel)

DEFLAGYN® Vaginal Gel and Spontaneous Remission and Regression of Unclear Cervical Smears and HPV High-risk Infections

Data will be shared upon reasonable request made to the corresponding author. This includes individual participant data underlying the results presented here, after deidentification, as well as data dictionaries and the the study protocol. Data is available after publication, without a specific end date. Requesting investigators must show that their proposed use of the data has been approved by an independent review committee identified for this purpose.

General satisfaction of the patients with quality of care (100-mm-visual analog scale; 0 = very unsatisfied, 100=very satisfied)

The rate of hr-HPV-positive findings after 3 months.

The rate of hr-HPV-positive findings after 6 months.

The rate of progression (in case of mild dysplasia at start)

The rates of newly diagnosed (i.e. not present during initial examination at study start) dysplasia or malignancies

The number and kind of complications during the first 3 months

Ruhr University of Bochum

Director, Department of Obstetrics and Gynecologiy

Straight wire excision of transformation zone is an electrosurgical conization method, which uses a straight wire electrode.

LLETZ cone is a electrosurgical conization method, which is performed with a large loop electrode of 20 mm depth.

Straight wire excision of transformation zone is an electrosurgical conization method, which uses a straight wire electrode as a knife to remove the dysplastic epithelium of the cervix.

SWETZ

LLETZ cone is a electrosurgical conization method, which is performed with a large loop electrode of 20 mm depth. The loop is applied to the cervix outside the lateral margin of the transformation zone and brought slowly to the controlateral transformation zone margin.

LLETZ cone

Maria J Camargo, PHD

The purpose of this trial is to evaluate if Straight Wire Excision of the Transformation Zone (SWETZ) is superior to (Large Loop Excision of the Transformation Zone) LLETZ cone in reducing the incomplete excision of disease.

Cone biopsy is a surgical procedure which objectives the excision of endocervical pre-invasive disease located at transformation zone or glandular epithelium. Although cone biopsy is considered adequate for the treatment of endocervical dysplastic epithelium , using electrosurgery as opposed to the cold knife technique of cone biopsy has been criticized because of the perceived potential for incomplete excision of disease, thermal damage and surgical specimen fragmentation, which might increase the risk of missing early invasive cancer. Also, incomplete excision margin of disease exposes women to an increased risk of residual post-treatment disease.

The standard procedure, Large Loop Excision of the Transformation Zone (LLETZ-cone), is performed with a large loop electrode of 20-25 mm depth.

The experimental intervention is Straight Wire Excision of the Transformation Zone (SWETZ), a method of excision using a 1cm straight disposal of 0.20 wire to remove the endocervical transformation zone or glandular disease.

Both procedures were previously studied in another clinical trial(NCT00995020), but the histological analysis were inconclusive for many outcomes. SWETZ were superior to LLETZ cone to acquire complete excision of disease, with no statistical significance, probably due to the small sample size.

This study objectives a better histological analyses of the surgical specimens related to incomplete excision, thermal damage and fragmentation.

A Trial of Two Electrosurgical Conizations: Histopathological Analysis of Excision Margins

Large Loop Excision of Transformation Zone Cone Versus Straight Wire Excision of Transformation Zone : Histopathological Analysis of Excision Margins

Incomplete excision was considered when high-grade intraepithelial (CIN2-3) or microinvasive neoplasia was present in the endocervical limit of the excised specimen.

Oswaldo Cruz Foundation

Participants at risk: the ones originally included and who received one of the procedures, no matter who had been excluded from the primary outcome analysis.

Straight wire excision of transformation zone is an electrosurgical conization method, which uses a straight wire electrode.

SWETZ: Straight wire excision of transformation zone is an electrosurgical conization method, which uses a straight wire electrode as a knife to remove the dysplastic epithelium of the cervix.

LLETZ cone is a electrosurgical conization method, which is performed with a large loop electrode of 20 mm depth.

LLETZ cone: LLETZ cone is a electrosurgical conization method, which is performed with a large loop electrode of 20 mm depth. The loop is applied to the cervix outside the lateral margin of the transformation zone and brought slowly to the controlateral transformation zone margin.

LLETZ Cone

Straight wire excision of transformation zone (SWETZ) is an electrosurgical conization method, which uses a straight wire electrode as a knife to remove the dysplastic epithelium of the cervix.

Straight Wire Excision of Transformation Zone (SWETZ)

Large loop excision of the Transformation Zone (LLETZ-cone) is a electrosurgical conization method, which is performed with a large loop electrode of 20 mm depth. The loop is applied to the cervix outside the lateral margin of the transformation zone and brought slowly to the controlateral transformation zone margin.

Large Loop Excision of the Transformation Zone (LLETZ-cone)

Total

Age, Continuous

Female

Sex/Gender, Customized

Dr Fábio Russomano

The Prevalence of Incomplete Excision of Dysplasia at the Endocervical Excision Margin as Recognized Histologically.

Straight wire excision of transformation zone is an electrosurgical conization method, which uses a straight wire electrode to remove the dysplastic epithelium of the cervix.

Large Loop Excision of the Transformation Zone (LLETZ-cone) is a electrosurgical conization method, which is performed with a large loop electrode of 20 mm depth. The loop is applied to the cervix outside the lateral margin of the transformation zone and brought slowly to the controlateral transformation zone margin.

Overall Study

Immune System Diseases

Syndrome

Uterine Cervical Neoplasms

Acquired Immunodeficiency Syndrome

HIV Infections

Immunologic Deficiency Syndromes

AIDS-Related Complex

Blood-Borne Infections

Lentivirus Infections

Retroviridae Infections

RNA Virus Infections

Dermatologic Agents

Isotretinoin

Keratolytic Agents

William Robinson

Mitchell Maiman

The purpose of this study is to see if it is safe and effective to give isotretinoin to HIV-infected women with cervical tumors to prevent these tumors from becoming cancerous.

Cervical tumors are found in both HIV-infected and HIV-negative women. However, HIV-infected women are at a greater risk, and often their tumors become cancerous more quickly than those in HIV-negative women. Isotretinoin may be able to prevent this from happening. However, since these tumors tend to disappear over time, many doctors are hesitant to give their patients isotretinoin since this drug causes birth defects. This study looks at whether it is better to treat cervical tumors in HIV-infected women or to wait and see if they will disappear by themselves.

Cervical neoplasia is frequently seen in HIV-infected women, apparently resulting from immunosuppression and common risk factors, including sexual behavior patterns. In HIV seronegative women, progression of preinvasive neoplasia is relatively slow, and up to 40 percent of low grade squamous intraepithelial lesions (grade I CIN/HPV-associated changes) regress to a normal appearance over time. Many clinicians have opted not to treat CIN I/HPV-associated changes due to this high spontaneous regression rate. Currently, retinoids, principally isotretinoin, are the most consistently effective medical therapy for CIN/HPV-associated changes, but use of isotretinoin in HIV-infected patients has not been extensively documented. (AS PER AMENDMENT 6/10/97)

Patients are randomized to receive oral isotretinoin for 6 months or be observed only for 6 months, with 12 additional months of follow-up. \[AS PER AMENDMENT 7/23/99: Follow-up time has been decreased to 9 months from the last patient enrolled.\]

Safety and Effectiveness of Giving Isotretinoin to HIV-Infected Women to Treat Cervical Tumors

A Randomized Phase III Trial of Oral Isotretinoin Versus Observation for Low-Grade Squamous Intraepithelial Lesions in HIV-Infected Women

National Institute of Allergy and Infectious Diseases (NIAID)

Hyperplasia

Antineoplastic Agents

Fluorouracil

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Maiman M

Watts DH

To determine the efficacy and safety of intravaginal fluorouracil administered as prophylaxis in HIV-infected women who have received standard ablative therapy (surgery) for high-grade cervical dysplasia (pre-cancer of the cervix; cervical intraepithelial neoplasia). To correlate time to recurrence of cervical dysplasia with T-cell function.

Women with HIV infection are at greater risk for cervical dysplasia. Because of the likelihood that untreated or recurrent cervical dysplasia may progress to invasive cancer, there is an urgent need to develop appropriate therapies.

Women with HIV infection are at greater risk for cervical dysplasia. Because of the likelihood that untreated or recurrent cervical dysplasia may progress to invasive cancer, there is an urgent need to develop appropriate therapies.

Patients are randomized to receive either intravaginal fluorouracil or no treatment (observation only). Fluorouracil cream is self-administered via applicator at biweekly intervals for 6 months. Patients are evaluated for recurrent cervical dysplasia by cytology and colposcopy with or without biopsy.

A Phase III Randomized Trial of Topical Vaginal Fluorouracil (5-Fluorouracil, 5-FU) Maintenance Therapy Versus Observation After Standard Treatment for High-Grade Cervical Dysplasia in HIV-Infected Women

Hoffmann-La Roche

Diseases and Abnormalities at or Before Birth

Congenital Abnormalities

851B 0.15% formulation, gel, topically, twice a week for 2 cycles.

851B

Medical Director

The purpose of this study was to evaluate efficacy of 851B gel over a range of concentrations and dosing regimens on high-risk cervical human papillomavirus infection in women.

Cervical cancer is caused by infection with specific genotypes of the human papillomavirus referred to as oncogenic or high-risk human papillomavirus. Current epidemiologic evidence suggests that 80% of sexually active women will become infected during their lifetime with human papillomavirus and 50% of these infections will be due to high-risk human papillomavirus. With US annual rates of cervical cancer now in the range of 13,000/year, a very substantial number of women are left with uncertainty regarding whether their infection will clear spontaneously or progress to cancer.

Subjects participating in this study were required to visit the clinic for approximately 15 or 16 visits, and maintain a diary of self-dosing and menstruation cycles. The total time of participation in this study was approximately 27 months.

Efficacy of 851B Gel for Treating High-Risk Cervical Human Papillomavirus Infection in Women.

A Randomized, Double-blind, Placebo-Controlled, Dose Response Study to Evaluate 851B Gel Delivered Intravaginally Twice a Week for Two, Three-Week Cycles in Women Who Are Positive For High-Risk Genotypes of Human Papillomavirus and Have Mild Cytological Abnormalities

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
DEFLAGYN® Vaginal Gel and Spontaneous Remission and Regression of Unclear Cervical Smears and HPV High-risk Infections	NCT05509413	Cervix Dysplasi... HPV Infection	DEFLAGYN vagina...	18 Years -	Ruhr University of Bochum
A Trial of Two Electrosurgical Conizations: Histopathological Analysis of Excision Margins	NCT01929993	Cervical Intrae...	SWETZ LLETZ cone	-	Oswaldo Cruz Foundation
Safety and Effectiveness of Giving Isotretinoin to HIV-Infected Women to Treat Cervical Tumors	NCT00001073	HIV Infections Cervix, Dysplas...	Isotretinoin	13 Years -	National Institute of Allergy and Infectious Diseases (NIAID)
A Phase III Randomized Trial of Topical Vaginal Fluorouracil (5-Fluorouracil, 5-FU) Maintenance Therapy Versus Observation After Standard Treatment for High-Grade Cervical Dysplasia in HIV-Infected Women	NCT00000758	HIV Infections Cervix, Dysplas...	Fluorouracil	13 Years -	National Institute of Allergy and Infectious Diseases (NIAID)
Efficacy of 851B Gel for Treating High-Risk Cervical Human Papillomavirus Infection in Women.	NCT00117884	Papillomavirus ...	851B 851B 851B 851B 851B 851B 851B 851B 851B 851B 851B	18 Years - 40 Years	Takeda
DEFLAGYN® Vaginal Gel and Spontaneous Remission and Regression of Unclear Cervical Smears and HPV High-risk Infections	NCT05509413	Cervix Dysplasi... HPV Infection	DEFLAGYN vagina...	18 Years -	Ruhr University of Bochum
A Phase III Randomized Trial of Topical Vaginal Fluorouracil (5-Fluorouracil, 5-FU) Maintenance Therapy Versus Observation After Standard Treatment for High-Grade Cervical Dysplasia in HIV-Infected Women	NCT00000758	HIV Infections Cervix, Dysplas...	Fluorouracil	13 Years -	National Institute of Allergy and Infectious Diseases (NIAID)

Spots Global Cancer Trial Database for cervix dysplasia