Primary Objective• To explore the pharmacodynamics of the ionic contra-viral therapy CLS003 in immunocompromised and immunocompetent patients with benign and premalignant HPV-induced genital lesions.• To evaluate clinical efficacy of CLS003 compared…
ID
Source
Brief title
Condition
- Vulvovaginal disorders (excl infections and inflammations)
- Cutaneous neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacodynamic / efficacy endpoints
- For both cohorts:
• Lesion (vulvar HSIL or wart) size reduction as absolute and percent reduction
in lesion diameter as measured by caliper and 3D photography
• Change in patient-reported outcomes (QoL and patient-reported clearance)
• HPV viral load assessment (quantitative PCR including HPV genotyping in swabs
and biopsies)
• Change in the HPV viral load (nominal, natural log transformed, and natural
log of viral load per DNA copies) as determined by qPCR in swabs and biopsies
• Mean HPV viral load (nominal, natural log transformed, and natural log of
viral load per DNA copies) in swabs and biopsies
• Histology (regression of vulvar HSIL or AGWs, HPV genotyping)
• Local immunity status (Histological changes in immune cells in the
mucosa/submucosa)
- For vulvar HSIL cohort
• Vulvar HSIL, size and reduction in lesion size (clinical assessment of
lesions by RECIST, absolute reduction in lesion size, lesion size reduction
(percentage) as measured by caliper and 3D photograpy
• Percentage clearance of vulvar HSIL lesions
• Proportion of subjects with all vulvar HSIL lesions cleared
• Histology (regression of high grade dysplasia to no dysplasia)
• Histological recurrence (progression of no dysplasia to high grade dysplasia)
in the Part 1 follow-up period
- For genital wart cohort:
• Wart size and reduction in wart size of the target wart (absolute reduction
in lesion size, lesion size reduction (percentage)) as measured by caliper and
3D photography
• Percentage clearance of genital warts
• Proportion of subjects with all genital warts cleared
• Clinical recurrence in the Part 1 follow-up period
Secondary outcome
Adverse events (AE) will be collected throughout the study, at every study
visit. Laboratory safety testing, 12-Lead ECGs and vital signs will be
performed and measured multiple times during the course the study according to
the Visit and Assessment Schedule. Plasma digoxin levels will be determined by
therapeutic drug monitoring (TDM) at the end week 3 (day 21) and 6 (day 42).
Patients will fill in a daily questionnaire (numeric rating scale pain/itch)
about local tolerance (e-diary).
Background summary
Human papillomavirus (HPV) infection is the most common sexually transmitted
disease worldwide and can result in benign, premalignant and malignant lesions
of the genital skin and genital mucosal surfaces. Among immunosuppressed
patients, the prevalence of low as well as high risk HPV-infections is higher
than in the immune competent population, and therefore HPV-induced genital
lesions are more common in this group of patients[1;2].
Current surgical therapies for HPV-induced genital lesions are not directed at
clearance of the HPV infection, but at physical removal of the lesions and
stimulating the host immune system. Recurrence rate is high and often the
currently available treatments cause a high physical and psychosocial burden
[2;3].
Cutanea Life Sciences (CLS) is investigating various formulations with digoxin
and furosemide as a potential treatment for HPV infections of skin and other
similar tissue. In a published in vitro study in 2006 [4], the cardiac
glycoside digoxin and loop diuretic furosemide inhibited replication in DNA
viruses, herpes simplex virus, varicella zoster virus, human cytomegalovirus
and adenovirus. The effects were most potent when digoxin and furosemide were
used in combination as the topical formulation CLS003. This new approach,
described as Ionic Contra-Viral Therapy (ICVT), is suggested to be most
effective via topical application.
One potential viral target of ICVT is human papillomavirus (HPV) in associated
cutaneous and mucosal lesions. Specifically, the ionic properties of digoxin
and furosemide were noted to inhibit the K+ influx on which DNA viruses rely
for replication. These drugs interact with the cell membrane ion
co-transporters Na+/K+-ATPase and Na+-K+-2Cl- co-transporter. A previous study
was conducted with a group of 80 patients with cutaneous warts, which
demonstrated ICVT to be effective, safe and well tolerated.
Study objective
Primary Objective
• To explore the pharmacodynamics of the ionic contra-viral therapy CLS003 in
immunocompromised and immunocompetent patients with benign and premalignant
HPV-induced genital lesions.
• To evaluate clinical efficacy of CLS003 compared to vehicle in
immunocompromised and immunocompetent patients with benign and premalignant
HPV-induced genital lesions
Secondary Objectives
• To evaluate the safety and tolerability of CLS003 in immunocompromised and
immunocompetent patients with benign and premalignant HPV-induced genital
lesions
Study design
A phase 2 efficacy and pharmacodynamic study of digoxin / furosemide ICVT in
immunocompromised and immunocompetent patients with benign and premalignant
HPV-induced genital lesions.
Intervention
Investigational drug
- CLS003: topical formulation (gel) containing digoxin (0.125% w/w) and
furosemide (0.125%).
Comparative treatment
- Vehicle topical formulation (placebo)
During the treatment period topical formulation will be applied once daily.
Study burden and risks
CLS003 consists of a combination of the active substances digoxin and
furosemide. The cardiac glycoside digoxin and the loop diuretic furosemide are
currently market registered drugs for various indications e.g. heart failure /
atrium fibrillation and hypertension, respectively. The formulations on the
market comprise oral and parenteral route of administration leading to high
systemic exposure to both drugs. Consequently, there is a vast amount of
pre-clinical and clinical experience with these mechanisms of action.
Therefore, drugs of this class can be administered safely to healthy volunteers
and patients with a topical formulation.
Potential beneficial effects on AGWs and vulvar HSIL are to be explored in this
study. Therefore, providing the protocol is adhered to, careful observation and
medical management will minimize any associated risk in this study.
Liberty Ridge Drive, Suite 3000 1500
Wayne 19087
US
Liberty Ridge Drive, Suite 3000 1500
Wayne 19087
US
Listed location countries
Age
Inclusion criteria
For enrollment of subjects the following criteria must be met:
1. Vulvar HSIL or AGW patients, >= 18 years of age, in general, stable good health (with the exception of the immunocompromised disorder) as per judgment of the investigator based upon the results of a medical history, physical examination, ECG, chemistry, hematology.
2. In case of the immunocompromised patient group(s): having an immunosuppressive disease or receiving immunosuppressive therapy for any reason including but not limited to; patients with auto-immune disease, HIV patients, transplantation patients
3. In case of genital warts: have at least 3 genital warts (only applicable for study part 1)
4. In case of vulvar HSIL: at least one lesion that can be accurately measured (using RECIST criteria) in at least one dimension with longest diameter >=20 mm OR in 2 perpendicular dimensions that when multiplied together give a surface area >=120 mm² (only applicable for study part 1)
5. If female of childbearing potential, have a negative urine pregnancy test at Screening and Day 0, and is willing to use effective contraception during the study and 3 months afterwards (i.e. oral, implanted, injectable, IUD, diaphragm, condom, tubal ligation, abstinence, or are in a monogamous relationship with a partner who has had a vasectomy)
6. Able to participate and willing to give written informed consent and to comply with the study restrictions
7. Ability to communicate well with the investigator in the Dutch language
8. Willing to refrain from using other topical products in the treatment area, or prohibited medications for the duration of the study
Exclusion criteria
Eligible subjects must meet none of the following exclusion criteria:
1. Significant, uncontrolled or unstable disease in any organ system as per judgment of the investigator (regardless of association with the immunosuppressing disorder/therapy), including but not limited to: psychiatric, neurologic, cardiovascular, pulmonary, gastrointestinal, hepatic, renal, endocrine, hematologic or respiratory disease
2. Have used or received any topical genital wart treatment, cryotherapy, electrocoagulation, surgery in the treatment area within 28 days prior to enrolment
3. Have used or received any topical vulvar HSIL treatment, laser therapy or surgery in the treatment area within 28 days prior to enrolment
4. Have any current relevant skin infections in the treatment area other than genital warts (inclusively, but not limited to atopic dermatitis, lichen sclerosis, lichen planus or psoriasis)
5. Have a known sensitivity to any of the investigational product ingredients, including digoxin and furosemide
6. Participation in an investigational drug or device study within 3 months prior to screening or more than 4 times in the past year
7. Loss or donation of blood over 500 mL within three months prior to screening.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-000870-39-NL |
| CCMO | NL57025.056.17 |