Trial Title:
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
Condition:
Papilloma Viral Infection
CIN1
LSIL, Low Grade Squamous Intraepithelial Lesion
Conditions: Official terms:
Virus Diseases
Papillomavirus Infections
Papilloma
Conditions: Keywords:
Glycyrrhizinic Acid
LSIL/CIN1
Cervical adenocarcinoma
Immunomodulation
Study type:
Interventional
Study phase:
Phase 4
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Intervention:
Intervention type:
Dietary Supplement
Intervention name:
Glizigen
Description:
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.
Arm group label:
Glizigen Group
Intervention type:
Other
Intervention name:
Placebo
Description:
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.
Arm group label:
Placebo Group
Summary:
HPV infection can lead to cancer, especially when precancerous lesions have developed and
high-risk HPV is present.
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.
Detailed description:
Human Papillomaviruses are double-stranded DNA viruses characterised by their lack of a
lipid envelope. To date, more than 100 different types of HPV have been identified. They
can be divided into cutaneous or mucosal depending on the tissues they usually infect 1.
In parallel, HPVs can be classified as low-risk (HR-HPV) or high-risk (HR-HPV) viruses,
depending on the risk of developing cancer due to their persistence of infection 2.
Fifteen HPV types are considered high-risk (16, 18, 31, 33, 35, 35, 39, 45, 51, 52, 56,
58, 59, 68, 73 and 82) while three other types are classified as probable high-risk (26,
53 and 66).
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Women between 30 and 65 years of age.
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.
Exclusion Criteria:
1. Failure to meet any of the inclusion criteria.
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.
Gender:
Female
Gender based:
Yes
Minimum age:
30 Years
Maximum age:
65 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Hospital Ruber Internacional
Address:
City:
Madrid
Zip:
28034
Country:
Spain
Status:
Not yet recruiting
Contact:
Last name:
Alfonso Duque Frischcorn, Dr.
Investigator:
Last name:
Alfonso Duque Frischcorn, Dr.
Email:
Principal Investigator
Facility:
Name:
Hospital Clinico San Carlos
Address:
City:
Madrid
Zip:
28040
Country:
Spain
Status:
Recruiting
Contact:
Last name:
César A. Gómez Derch, D.
Investigator:
Last name:
Pluvio J. Coronado Martín, Dr.
Email:
Principal Investigator
Facility:
Name:
Hospital Universitario 12 de Octubre
Address:
City:
Madrid
Zip:
28041
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Carmen Martínez de de Pancorbo González, Dra.
Investigator:
Last name:
Victoria Bravo Violeta, Dra.
Email:
Principal Investigator
Facility:
Name:
Hospital Universitario La Paz
Address:
City:
Madrid
Zip:
28046
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Rafael Pérez-Santamaría Feijóo, Dr.
Investigator:
Last name:
María Serrano Velasco, Dra.
Email:
Principal Investigator
Start date:
June 7, 2023
Completion date:
January 8, 2025
Lead sponsor:
Agency:
Catalysis SL
Agency class:
Industry
Collaborator:
Agency:
Atika Pharma S.L.
Agency class:
Other
Source:
Catalysis SL
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05916911
