Long-Term Follow-up Study of Cantharidin (YCANTH [VP-102/TO-208]) in Patients With Common Warts (Verruca Vulgaris)

COVE-4: A Phase 3, Open-Label, Long-Term Follow-Up Study to Evaluate the Safety and Efficacy of YCANTH (VP-102/TO-208) in Subjects With Common Warts (Verruca Vulgaris)

People who participated in either the COVE-2 or COVE-3 study for common warts, may be eligible to enroll into this Long Term Follow Up (LTFU) study COVE-4. The main question(s) to answer in this LTFU study are:

• To assess the safety of YCANTH (also known as VP-102 in the United Sates or TO-208 in Japan) by assessing concomitant medication use, and adverse events (AEs), including expected local skin reactions (LSRs).
• To evaluate the efficacy of continued skin application of YCANTH (VP-102/TO-208) when applied to each common wart once every 21 days for a maximum of 4 additional treatments.

Participants with eligible common warts present will receive YCANTH (VP-102/TO-208) with an interval of 21 (± 4) days between applications until there is a wart count of zero (ie, completed clearance has been achieved) or a maximum of 4 additional treatments. Participants with complete clearance will attend Observation Visits at intervals of 42 (± 4) days without treatment. Participants who develop a new wart after having a wart count of zero will resume Treatment Visits every 21 (± 4) days for a maximum of 4 additional treatments. All subjects will attend visits until the End-of-Study (EOS) Visit, which is on Day 378 (0/+ 8 days).

If participants still have warts present after 4 additional treatments of YCANTH (VP-102/TO-208) the wart(s) will be discontinued from study and participants will be allowed to seek treatment but should be limited to destructive therapy such as cryosurgery and warts cannot be within 10 mm of any warts that receive(d) study drug treatment . The exact interval of Treatment Visits will be determined by evaluation of the treatment site, taking into account any ongoing local skin reactions (LSRs), which are defined as temporary application site:

vesiculation, pain, pruritus, scabbing, erythema, discoloration, dryness, edema and erosion that is expected and consistent with historical treatment with YCANTH (VP-102/TO-208). Participants may receive treatment until all treatable common warts are clear, up to a maximum of 4 treatment sessions, or until Day 357, whichever occurs first.

Treatment:

For participants with warts present at the time of study entry, the first treatment application may occur on the same day as transition from the parent study. All required parent study assessments must be complete, including the final evaluation of response to treatment (ERT; as defined in Assessments and procedures).

In addition, eligibility for participation in the LTFU study must have been determined, and informed consent/assent for participation in this LTFU study obtained. YCANTH (VP-102/TO-208) will be applied by the Investigator or qualified member of the research team to treatable common warts, including an approximate 1 to 2 mm margin of healthy, surrounding skin. After YCANTH (VP-102/TO- 208) is applied, warts are to be covered with occlusive tape (occlusive tape with similar properties should be used across all clinical sites) that will remain in place overnight and should be removed 24 hours after application of study drug and just before a 24-hour ERT. Before application of study drug, wart paring, if necessary, will be completed with a sharp surgical instrument (eg, scalpel or flexible medical blade) to remove any adherent thick scale from a treatable common wart. Wart paring is required to be performed at any treatment visit when adherent thick scale is present, and the Investigator feels paring can be safely performed. Paring should be conducted by a trained practitioner and in compliance with any local regulations and should be discontinued if it results in punctate bleeding or significant pain. Not all treatable common warts may require paring. If adherent scale is not present, study drug can be applied without paring. The assessment for complete clearance may be made once all treatable common warts are evaluable and not obscured by an ongoing LSR. If the Investigator is unable to evaluate or treat 1 or more warts due to ongoing LSRs, no warts should be treated, and the visit will be documented as an Unscheduled Visit. The timing of the next treatment visit will be determined by resolution of the LSRs. The research team will be in contact with the Participant until all LSRs are resolved. Once LSRs have resolved, a Treatment Visit will be scheduled within 21 (± 4) days of the previous treatment application, noting it may be longer than 21 (± 4) days depending on the length of time until LSR resolution. All treatable common warts that are not completely clear should undergo treatment with study drug. Study duration from Days 84, 105, or 147 of the parent study (COVE-2 or COVE-3) through the final EOS visit of this LTFU study (Day 378) is approximately 294 days.

Inclusion Criteria:

Candidates will be included in the study if they:

1. Meet ≥ 1 of the following criteria:

   1. Completed the Day 84 visit in the parent study and have ≥ 1 treatable common warts.
   2. Completed the Day 105 visit in the parent study and have ≥ 1 treatable common warts.
   3. Completed the Day 147 visit in the parent study.

2. Provide written informed consent or assent in a manner approved by the Institutional Review Board (IRB) and/or have a parent/guardian provide written informed consent as evidenced by the signature on an IRB approved assent/consent form. Subjects who turn 18 years of age (or legal age per state or country) during the study may be required to re consent to remain on the study (follow the state or country regulatory requirements).

3. Agree to refrain from swimming, bathing, or prolonged immersion in water or any liquids until the study drug is removed after each treatment.

4. Have the ability, or have a parent/guardian with the ability, to follow study instructions and the willingness to complete all study requirements.

5. Agree not to use any wart-removing product (prescription or over-the-counter) other than the study drug during the course of the study with the exception of circumstances for excluded wart types. Excluded warts include common warts located in excluded areas that will not be treated or evaluated during the study as well as genital, plantar, or anal warts:

   a. If treatment of these excluded wart types is required during the study, it should be limited to destructive therapy such as cryosurgery and warts cannot be within 10mm of any warts that are under study.

6. Provide written authorization for use and disclosure of protected health information (per state and/or country requirements).

7. If participating in the optional photographic assessment, agree to allow photographs of treatable common warts to be taken at selected visits by the research team.

Exclusion Criteria:

Candidates will be excluded from the study if they:

1. Are unable to cooperate with the requirements or visits of the study, as determined by the Investigator.
2. Have any warts present at study entry in an allowed anatomic location that the subject, parent/guardian, or Investigator is unwilling to treat.
3. Are systemically immunosuppressed or have taken required systemic immunosuppressive or immunomodulatory medication (including oral or parenteral corticosteroids) within 30 days before enrollment or such treatment is planned to be required during the course of the study. Routine use of local (eg, topical, inhaled, intranasal) corticosteroids and episodic use of systemic medications to treat conditions arising during the study is allowed.
4. Have any chronic or acute medical condition that, in the opinion of the Investigator, may interfere with the study results or place the subject at undue risk (eg, human immunodeficiency virus, systemic lupus erythematosus, viral hepatitis, uncontrolled diabetes).
5. Have had any previous treatment (including an investigational agent in a clinical trial) of common warts, including but not limited to the use of cantharidin, imiquimod, antivirals, retinoids, topical salicylic acid, lactic acid, hydrogen peroxide, trichloroacetic acid, pulse dye laser, iodine-based or nitric oxide-based therapies, oral cimetidine, coix seed, intralesional immunotherapy, curettage, or freezing of warts in the 30 days before treatment.
6. Immunizations (eg, flu shots) may be administered throughout the study, but not within 5 days before or after any treatment with study drug.
7. Have received any investigational product as part of a clinical trial NOT related to the treatment of common warts within 30 days before the first application of the study drug.
8. Have epidermodysplasia verruciformis.
9. Have an active malignancy or are undergoing treatment for any malignancy.
10. Have a clinically significant medical, psychiatric, emotional condition, or abnormality that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data.
11. Have a hypersensitivity or an idiosyncratic reaction to YCANTH (VP-102/TO-208) or related compounds, or drug product excipients (acetone, ethyl alcohol, nitrocellulose, hydroxypropyl cellulose, castor oil, camphor, gentian violet, and denatonium benzoate).
12. Have a condition or situation that may interfere significantly with the subject's participation in the study (eg, subjects who require hospitalization for an acute or chronic condition including alcohol or drug abuse), at the determination of the Investigator.
13. Are sexually active or may become sexually active and are unwilling to practice responsible birth control methods (eg., combination of condoms and foam, birth control pills, intrauterine device, patch, shot and vaginal ring). Withdrawal is not an acceptable method of birth control. Females who have reached menarche must have a negative urine pregnancy test at each visit before treatment with YCANTH (VP-102/TO-208).
14. Are pregnant or breastfeeding.