Primary Objective* To explore the pharmacodynamics of ICVT comprised of digoxin and furosemide (dual agent), digoxin (single agent), furosemide (single agent) in patients with AK. * To evaluate clinical efficacy of ICVT comprised of digoxin and…
ID
Source
Brief title
Condition
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Complete clinical clearance (CCC) per field
* Change in AK-FAS (AK field assessment scale)
* Change in lesion count per field
* Investigator global score of each field (IGS, using a 7 point scale from -2
(significantly worse) to +4 (completely cured), according to Nelson et al.
2013)
* Evolution of one assigned target lesion in the field, assessed by dermoscopy
(assessing erythema, scaling, pigmentation, and follicular plug, using a 5
point score)
* Standardized photography with Canfield VISIA or 2D photography (depending on
the location of the field)
* Biopsy biomarkers (where validated assays available at the time of study
completion: IFN-a. IFN-g, Ki-67, p53, MCM7 (minichromosome maintenance protein
7), putrescene, spermidine, beta HPV types 5,8,15,20,24,38)
* Skin swab markers (where validated assays available at the time of study
completion: beta HPV types 5,8,15,20,24,38 by luminex, qPCR for HPV DNA)
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 at screening and EOS. 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) as well as for treatment compliance and daily
facial photography (*selfies*).
Background summary
Actinic keratosis (AK) are common skin lesions which appear clinically as
erythematous, scaly plaques on sun-exposed skin. As UV radiation has been
recognized the main risk factor, they are typically located on the face, scalp,
neck and extremities. The prevalence of AK lesions in adults increases with
age: less than 10 percent for 20- to 29-year-olds, approximately 80 percent for
60- to 69-year-olds, and more than 80 percent for 70-year-olds and older. On
histology examination AK is a proliferation of neoplastic keratinocytes in the
epidermis, characterized by architectural disorder, with features of abnormal
shape and size of keratinocytes, nuclear atypia and hyperkeratosis. AK may
enter spontaneous remission or remain stable. However, importantly, AK are also
known as precursor lesions of squamous cell carcinoma (SCC). Furthermore, the
annual burden for the treatment of AK has been estimated at around 900 million
dollars in the USA alone. (Dodds A et al, 2014, Berlin JM, 2010).
Investigations have suggested a role for human papilloma virus (HPV) and the
development of AK into SCC. In 2005, Weissenborn and colleagues determined
viral DNA loads of six frequent HPV types (5, 8, 15, 20, 24 and 36) by qPCR in
AK, NMSC and perilesional tissue. HPV viral load was highest in AK compared
with non-melanoma skin cancer (NMSC) and perilesional tissue. It was suggested
that active HPV replication and presumably enhanced gene expression may
stimulate keratinocyte proliferation and contribute to carcinogenesis in early
stages of NMSC development. (Weissenborn et. al. 2005).
In 2006 the association between HPV infection and SCC development was further
explored. Presence of HPVL1 and E6 seroreactivity and viral DNA were determined
for HPV types 5, 8, 15, 16, 20, 24, and 38 in three study groups: SCC patients,
AK patients and controls without any history of skin tumors. After recruitment,
the response rate was between 75% and 85% in all groups. Eyebrow hair was
collected from 57 controls, 126 AK, and 63 SCC cases, and blood from 53
controls, 118 AK, and 55 SCC cases.HPV DNA positivity was most prevalent in the
AK cases (54%) compared with the SCC (44%) or tumor-free controls (40%).
(Struijk et. al 2006).
An additional study from 2009 published similar results for a long-term
persistence of betapapillomavirus (betaHPV). Eyebrow hairs were collected from
171 participants and tested for 25 different betaHPV types in 1996 and 2003. Of
the total betaHPV infections detected, 30% were found to persist. After
accounting for AK at baseline, persistence of betaHPV DNA resulted in a 1.4
fold increase in risk of having AK on the face in 2007. (Plasmeijer E et. al.
2009)
Cutanea Life Sciences (CLS, former sponsor) is investigating ICVT, comprised of
digoxin (0.125%) and furosemide (0.125%) as a potential treatment for
HPV-mediated and associated diseases including cutaneous warts, anogentical
warts (AGWs), and high-grade squamous intraepithelial neoplasion (HSIL), the
later formerly referred to as usual type vulvar intraepithelial neoplasia
(uVIN). This study will be the first study of ICVT in AK. The ionic properties
of digoxin and furosemide interact with the cell membrane ion cotransporters
Na+/K+-ATPase and Na+-K+-2Cl- co-transporter-1 and thereby inhibit the K+
influx on which DNA viruses rely for replication. In an in vitro study,
published in 2006, digoxin and furosemide inhibited replication in DNA viruses,
herpes simplex virus, varicella zoster virus, human cytomegalovirus and
adenovirus. Both drugs prompted antiviral effects by extracellular K+; these
effects were most potent when digoxin and furosemide were used in combination
(Hartley C, 2006). In two exploratory clinical studies of CLS003 in patients
with cutaneous warts tolerability and short-term safety was established as well
as efficacy in terms of viral load reduction and dimensional changes of the
lesions.
Based on the scientific literature on the potential association of HPV with AK,
the study results to date with ICVT support the concept of an investigation of
ICVT in the therapeutic management of AK. This study is intended to assess the
clinical efficacy and pharmacodynamics of ICVT as a potential new treatment for
AK. Clinical efficacy by means of clinical outcomes (i.e. clearance of the
lesions, AK-FAS) and sub-clinical parameters / biomarkers on the skin and
systemic ones will be assessed.
Study objective
Primary Objective
* To explore the pharmacodynamics of ICVT comprised of digoxin and furosemide
(dual agent), digoxin (single agent), furosemide (single agent) in patients
with AK.
* To evaluate clinical efficacy of ICVT comprised of digoxin and furosemide
(dual agent), digoxin (single agent), furosemide (single agent), and vehicle
gel.
Secondary Objectives
* To evaluate the safety and tolerability of ICVT comprised of digoxin and
furosemide (dual agent), digoxin (single agent), furosemide (single agent)
Study design
This study is a phase 2, double-blind, vehicle-controlled, parallel group,
efficacy and pharmacodynamic study of ICVT in AK.
Intervention
Treatment
8 subjects : ICVT comprised of Digoxin and Furosemide (0.125%) QD during six
weeks
8 subjects : Furosemide (0.125%) QD during six weeks.
8 subjects : Digoxin (0.125%) QD during six weeks.
8 subjects : Placebo (Vehicle Gel) QD daily during six weeks.
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 in a topical formulation.
Potential beneficial effects on AK are to be explored in this study. Careful
observation and medical management will minimize any associated risk in this
study.
Chudoji Awatacho 93
Shimogyo-ku, Kyoto 600-8815
JP
Chudoji Awatacho 93
Shimogyo-ku, Kyoto 600-8815
JP
Listed location countries
Age
Inclusion criteria
For enrollment of subjects the following criteria must be met:
1. Male and female subjects *18 years with a condition of general good health
(with the exception of AK). The health status is verified by absence of
evidence of any clinical significant active or uncontrolled chronic disease
other than AK following a detailed medical history, a complete physical
examination including vital signs, 12-lead ECG, hematology, blood chemistry,
virology and urinalysis;
2. Confirmed clinical AK diagnosis by dermatologist (biopsy proven after end of
study, in untreated part of the AK field)
3. At least 2 facial fields of at least 25 cm2 (but preferably >35 cm2) present
at screening and baseline visit where at least 2 AK lesions are visible in each
field (preferably the forehead, temple or cheek)
4. Able to participate and willing to give written informed consent and to
comply with the study restrictions.
5. Ability to communicate well with the investigator in Dutch.
6. Willing to refrain from using other topical products in the treatment area,
or prohibited medications for the duration of the study.
7. Willing to limit sun exposure of the involved skin to the extent
vocationally possible.
8. Subjects and their partners of childbearing potential must use effective
contraception, for the duration of the study and for 3 months after the last
dose.
Exclusion criteria
Eligible subjects must meet none of the following exclusion criteria:
1. Have used or received any treatment for AK in the treatment area within 28
days prior to enrollment (including topical medications, immunosuppressive or
immunomodulating agents, phototherapy, oral retinoids, or other therapies for
AKs)
2. Have any current pathologically relevant skin conditions in the field area
other than AK (e.g. squamous cell carcinoma or basal cell carcinoma).
3. Have a known hypersensitivity to any of the investigational product
ingredients, including digoxin and furosemide.
4. Current use of systemic digoxin or furosemide.
5. Participation in an investigational drug or device study within 3 months
prior to screening or more than 4 times a year
6. Loss or donation of blood over 500 mL within three months (males) or four
months (females) prior to screening or intention to donate blood or blood
products during the study.
7. If a woman of childbearing potential, pregnant, or breast-feeding, or
planning to become pregnant during the study.
Design
Recruitment
Medical products/devices used
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 | EUCTR2018-000034-36-NL |
| CCMO | NL64613.056.18 |