A Phase 4 interventional study of Glizigen and Placebo in Papilloma Viral Infection, CIN1 and LSIL, Low Grade Squamous Intraepithelial Lesion, sponsored by Catalysis SL. Recruiting at 4 sites in Spain. Open to female participants aged 30 Years to 65 Years. Per ClinicalTrials.gov, last updated 2024-02-07.
Sponsored by Catalysis SL · Phase 4, Interventional, and Treatment
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.
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:
576 studies on the registry are indexed under Papillomavirus Infections; 132 are open to participants now.
This study's planned enrollment of 120 is below the median of 235 across 402 interventional studies indexed under Papillomavirus Infections.
Browse Papillomavirus Infections studies →Catalysis SL is the lead sponsor of 53 studies on the registry; 4 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
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.
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients will receive combined treatment with Glizigen® oral solution and Glizigen® vaginal gel for 2 months.
Dietary Supplement: Glizigen
Patients will receive combined treatment with Placebo oral solution and Placebo vaginal gel for 2 months.
Other: 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 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.
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.
Rate of resolution of cervical intraepithelial neoplasia grade 1 (CIN-1) caused by High Risk Human Papillomavirus (HR-HPV).
To assess whether nutritional supplementation with Glizigen® oral solution in combination with topical intravaginal use of Glizigen® vaginal gel promotes resolution of grade 1 cervical intraepithelial neoplasia (CIN-1) caused by High-Risk Human Papillomavirus (HR-HPV) compared to placebo after two months of treatment and 4 months after the end of treatment. It will be measured by biopsy.
Time frame: 6 months
Antiviral effectiveness of glizigen against high-risk HPV infection.
To evaluate the efficacy of Glizigen® in improving the negativation rate of high-risk HPV strains (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73 and 82) compared to placebo after two months of treatment and 4 months after the end of treatment by PCR.
Time frame: 2 and 6 months
Antiviral effectiveness of glizigen against multi high-risk HPV infection.
To assess the efficacy of Glizigen® in improving the negative rate of single or multiple high-risk HPV infections compared to placebo after two months of treatment and 4 months after the end of treatment by PCR.
Time frame: 2 and 6 months
Control of progression of Cervical intraepithelial neoplasia from CIN-1 to HSIL/CIN-2/3.
To evaluate the efficacy of Glizigen® in preventing the progression of cervical intraepithelial neoplasia from grade 1 (CIN-1) to grade 2 or 3 (HSIL/CIN-2/3) by colposcopy.
Time frame: 2 and 6 months
Grade of safety control
Assess safety at both systemic and local levels using treatment-related adverse effect monitoring questionnaires (YES/NO)
Time frame: 2 and 6 months
To Assess patient Tolerance of the study product.
To assess the patient's acceptance of the investigational product, questionnaires will be carried out during follow-up medical visits. Questionnaires are: - Tolerance questionnaire (YES/NO).
Time frame: 2 and 6 months
To Assess patient acceptance of the study product.
To assess the patient's acceptance of the investigational product, questionnaires will be carried out during follow-up medical visits. Questionnaires are: - Product acceptance questionnaire (YES/NO).
Time frame: 2 and 6 months
To Assess patient adherence of the study product.
To assess the patient's acceptance of the investigational product, questionnaires will be carried out during follow-up medical visits. Questionnaires are: - Treatment adherence questionnaire (YES/NO).
Time frame: 2 and 6 months
To Assess adherence to treatment
Assess adherence to treatment by following patients throughout the trial, calculating the average number of patients who stop treatment over the 6 months.
Time frame: 2 and 6 months
Plan to share: Yes
Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report, Analytic code
Started Jun 2023 (actual). Primary completion is estimated for Jun 2024, 11 months after the start.
Of 28 phase 4 interventional studies under Papillomavirus Infections, half reached primary completion within 62 months of starting (the median), counting those still running; a quarter within 20 and three quarters within 92. This study's planned 11 months is below that.
How these figures are worked out, and which studies are left out of them.
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Studies of the drug tested here: Glycyrrhizic Acid