A Phase 2, Muti-Center Study of Repeat Dosing of Squaric Acid Dibutyl Ester in Subjects With Herpes Labialis

• Sponsor: Squarex, LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03521479
• Collaborator: (none)
• Enrollment: 40
• Locations: 2
• Arms: 4
• Actual Duration (Months): 18.8
• Patients Per Site: 20
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

Primary Objective: To assess local and generalized adverse events with repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).

Secondary Objective: To assess efficacy of repeat topical application of 2% and 0.5% SADBE in the prevention of herpes labialis episodes.

Condition or Disease	Intervention/Treatment	Phase
Herpes Labialis; HSV	Drug: Squaric Acid Dibutyl Ester	Phase 2

Detailed Description

Primary oral infection with the herpes simplex virus (HSV) typically occurs at a young age, is asymptomatic, and is not associated with significant morbidity. After primary oral infection, HSV may persist in a latent state in the trigeminal ganglion and later reactivate as the more common herpes labialis, or "cold sores." Common triggers for reactivation are well known and include ultraviolet light, trauma, fatigue, stress, fever, inflammation, and menstruation. These lesions affect up to 45 percent of the U.S. population. They classically manifest as a well-localized cluster of small vesicles along the vermilion border of the lip or adjacent skin. The vesicles subsequently rupture, ulcerate, and crust within 24 to 48 hours. Spontaneous healing occurs over seven to 10 days.

In immunocompetent patients, herpes labialis usually is mild and self-limited. However, pain, swelling, and cosmetic concerns may prompt physician consultation. Orally administered antiviral agents, such as acyclovir (Zovirax) or valacyclovir (Valtrex), have a modest clinical benefit if initiated during the prodrome. Topical treatment with 1% penciclovir cream (Denavir) may reduce healing time and pain slightly, even if initiated after the prodrome. However, reduction in healing time with systemic or topical agents is modest.

Squaric acid dibutyl ester (SADBE) is a topical immunotherapeutic agent used in the treatment of verruca vulgaris and alopecia areata. During a recent FDA Compounding Advisory Committee Meeting, it was recommended that squaric acid dibutylester be included on the list of bulk drug substances allowed for use in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act. And SADBE has now been so listed under section 503A.

A study completed by Lee et al of 29 patients with recalcitrant warts demonstrated complete clearance in 69% of patients with application every 2-4 weeks. Silverberg et al showed a complete clearance in 58% of patients (n=61) when SADBE was applied 3 times weekly. A placebo-controlled clinical study completed at Massachusetts General Hospital showed that squaric acid prevented recurrence of herpetic lesions. The effect of SADBE of delaying new herpes labialis outbreaks was highly significant (p<0.01) as compared to placebo.

Primary Objective: To assess local and generalized adverse events with repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).

Secondary Objective: To assess efficacy of repeat topical application of 2% and 0.5% SADBE in the prevention of herpes labialis episodes.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects will receive on a double blind basis one of two treatment regimens: Group A: 15 subjects, treated with 2% SADBE on day 0 and with 2% SADBE on the visits at week 3, week 6, week 9, and month 8. Group B: 15 subjects, treated with 2% SADBE on day 0 and with 0.5% SADBE on the visits at week 3, week 6, week 9, and month 8. And subjects will be recruited on an open label basis to two other treatment regimens: Group C: 15 subjects, treated with 2% SADBE on day 0, month 3, and month 6. Group D: 15 subjects, treated with 2% SADBE on day 0 and month 6.Subjects will receive on a double blind basis one of two treatment regimens:Group A: 15 subjects, treated with 2% SADBE on day 0 and with 2% SADBE on the visits at week 3, week 6, week 9, and month 8. Group B: 15 subjects, treated with 2% SADBE on day 0 and with 0.5% SADBE on the visits at week 3, week 6, week 9, and month 8.And subjects will be recruited on an open label basis to two other treatment regimens:Group C: 15 subjects, treated with 2% SADBE on day 0, month 3, and month 6. Group D: 15 subjects, treated with 2% SADBE on day 0 and month 6.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The double-blinding only applies between groups A and B. Subjects for groups C and D will be recruited on an open label basis.
• Primary Purpose: Prevention
• Official Title: A Phase 2, Muti-Center Study of Repeat Dosing of Squaric Acid Dibutyl Ester in Subjects With Herpes Labialis
• Actual Study Start Date: Mar 12, 2018
• Actual Primary Completion Date: Oct 5, 2018
• Actual Study Completion Date: Oct 5, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 2% SADBE on the visits at week 3, week 6, week 9, and month 8.	Drug: Squaric Acid Dibutyl Ester; Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).; Other Names: Repeat Dosing
Experimental: Group B Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 0.5% SADBE on the visits at week 3, week 6, week 9, and month 8.	Drug: Squaric Acid Dibutyl Ester; Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).; Other Names: Repeat Dosing
Active Comparator: Group C Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0, month 3, and month 6.	Drug: Squaric Acid Dibutyl Ester; Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).; Other Names: Repeat Dosing
Active Comparator: Group D Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and month 6.	Drug: Squaric Acid Dibutyl Ester; Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).; Other Names: Repeat Dosing

Outcome Measures

Primary Outcome Measures

1. Local and Generalized Adverse Events [9 months]

   Local and generalized adverse events with repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age ≥ 18 and ≤ 65

2. Clinical diagnosis of herpes labialis, which may be made at the screening visit based on the patient's self-reported history of symptoms. An active herpes labialis outbreak at the time of entry into the clinical trial will neither be required nor will be an exclusion criterion.

3. Self report having four (4) or more episodes of herpes labialis in the past 12 months.

Subjects will NOT be told that four-or-more episodes in the previous 12 months is the entry criterion. Subjects will be asked "How many separate episodes of cold sores have you had in the previous 12 months?" They will be included if they give an answer of four or more and excluded if they give an answer of three or fewer.

1. At least half of the subject's episodes of the previous 12 months should be vesicular in nature and at least half preceded by prodromal symptoms. Prodromal symptoms may include tingling, itching, burning or pain before the development of a herpetic lesion.

Exclusion Criteria:

1. Pregnant or lactating females.

2. Current or recurrent non-herpetic infection or any underlying condition that may predispose to infection or anyone who has been admitted to the hospital due to bacteremia, pneumonia or any other serious infection in the last 12 months.

3. Therapy with glucocorticoid or immunosuppressants at time of recruitment or within past 4 weeks prior to the screening visit, or at any time during the study (including inhaled corticosteroids for asthma), except for topical steroids in sites other than face.

4. History of malignancy (except patients with surgically cured basal cell or squamous cell skin cancers).

5. History of organ transplantation.

6. HIV-positive status determined by history at screening or known history of any other immunosuppressive disease.

7. Severe co-morbidities (CHF [NYHA class II or worse], MI, CVA or TIA) within 3 months of screening visit, current unstable angina pectoris or oxygen-dependent severe pulmonary disease.

8. Known hypersensitivity to Dimethyl sulfoxide (DMSO).

9. Any condition judged by the investigator to cause this clinical trial to be detrimental to the patient.

10. Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of the screening visit.

11. Previous exposure to SADBE (squaric acid or squaric acid dibutyl ester).

12. Subject has an abnormal skin condition (e.g., acne, eczema, rosacea, psoriasis, albinism, or chronic vesiculo-bullous disorder) that occurs in the area ordinarily affected by herpes labialis

13. Subject has an abnormal skin condition (e.g., eczema, rosacea, psoriasis, albinism, or chronic vesiculo-bullous disorder) that occurs in the inner aspect of either upper arm (the area where drug will be applied).

14. Subject has had a vaccine for either HSV-1 or HSV-2.

15. Subject has had treatment with anti-viral therapy (including ABREVA) within 2 weeks before first dose of SADBE or at any time during the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	International Research Partners, LLC	Doral	Florida	United States	33166
2	Prism Clinical Research, LLC	Saint Paul	Minnesota	United States	55114

Sponsors and Collaborators

• Squarex, LLC

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 19, 2017

More Information

Publications

None provided.

• Responsible Party: Squarex, LLC
• ClinicalTrials.gov Identifier: NCT03521479
• Other Study ID Numbers: P2c
• First Posted: May 11, 2018
• Last Update Posted: Aug 6, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Squarex, LLC: Squaric Acid; SADBE; Squaric acid dibutyl ester
• Additional relevant MeSH terms: Herpes Simplex; Herpes Labialis; Squaric acid dibutyl ester

Study Results

Participant Flow

Arm/Group Title	Group A	Group B	Group C	Group D
Arm/Group Description	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 2% SADBE on the visits at week 3, week 6, week 9, and month 8. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 0.5% SADBE on the visits at week 3, week 6, week 9, and month 8. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0, month 3, and month 6. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and month 6. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).
Period Title: Overall Study
STARTED	10	10	10	10
COMPLETED	10	10	10	10
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Group A	Group B	Group C	Group D	Total
Arm/Group Description	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 2% SADBE on the visits at week 3, week 6, week 9, and month 8. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 0.5% SADBE on the visits at week 3, week 6, week 9, and month 8. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0, month 3, and month 6. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and month 6. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Total of all reporting groups
Overall Participants	10	10	10	10	40
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	10 100%	10 100%	10 100%	10 100%	40 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.3 (11.3)	39.2 (10.1)	47.1 (12.4)	47.2 (13.1)	43.94 (11.83)
Sex: Female, Male (Count of Participants)
Female	7 70%	5 50%	5 50%	6 60%	23 57.5%
Male	3 30%	5 50%	5 50%	4 40%	17 42.5%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 10%	1 10%	0 0%	0 0%	2 5%
African American or Black	0 0%	0 0%	1 10%	1 10%	2 5%
White	8 80%	9 90%	7 70%	8 80%	32 80%
Hispanic or Latino	1 10%	0 0%	2 20%	1 10%	4 10%
Region of Enrollment (participants) [Number]
United States	10 100%	10 100%	10 100%	10 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Local and Generalized Adverse Events
Description	Local and generalized adverse events with repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group A	Group B	Group C	Group D
Arm/Group Description	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 2% SADBE on the visits at week 3, week 6, week 9, and month 8. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 0.5% SADBE on the visits at week 3, week 6, week 9, and month 8. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0, month 3, and month 6. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and month 6. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).
Measure Participants	10	10	10	10
Localized reaction (rash, erythema, itching/pruritus, warmth/burning) at application site	24	14	17	6
Generalized adverse events (related, possible or greater)	2	3	1	0
Generalized adverse event (unrelated)	4	7	6	4

Adverse Events

Time Frame	172 days
Adverse Event Reporting Description	At risk participants listed below as 30 because the 10 participants in each group was counted on 3 separate occasions.
Arm/Group Title	Group A		Group B		Group C		Group D
Arm/Group Description	Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 2% SADBE on the visits at week 3, week 6, week 9, and month 8. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).		Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and with 0.5% SADBE on the visits at week 3, week 6, week 9, and month 8. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).		Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0, month 3, and month 6. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).		Treated with 2% Squaric Acid Dibutyl Ester (SADBE) on day 0 and month 6. Squaric Acid Dibutyl Ester: Repeat topical application of 2% and 0.5% squaric acid dibutyl ester (SADBE) in subjects with frequent herpes labialis (4 or more episodes in the previous 12 months).
All Cause Mortality
	Group A		Group B		Group C		Group D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Group A		Group B		Group C		Group D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Group A		Group B		Group C		Group D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/30 (43.3%)		12/30 (40%)		6/30 (20%)		4/30 (13.3%)
Skin and subcutaneous tissue disorders
Rash	3/10 (30%)		6/10 (60%)		6/10 (60%)		4/10 (40%)
Rash	6/10 (60%)		6/10 (60%)		0/10 (0%)		0/10 (0%)
Rash	4/10 (40%)		0/10 (0%)		0/10 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.