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Immune Response and General Immune Health in Subjects Infected With Herpes Simplex Virus Type 1 (HSV-1)

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ClinicalTrials.gov Identifier: NCT03661541
Recruitment Status : Completed
First Posted : September 7, 2018
Last Update Posted : September 7, 2018
Sponsor:
Information provided by (Responsible Party):
Squarex, LLC

Tracking Information
First Submitted Date  ICMJE May 1, 2018
First Posted Date  ICMJE September 7, 2018
Last Update Posted Date September 7, 2018
Actual Study Start Date  ICMJE March 2, 2017
Actual Primary Completion Date June 17, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 5, 2018)
  • Immune Monitoring - Cell Counts [ Time Frame: 8 weeks from Day 0 (Initial visit) +/- 7 days ]
    Cell Counts (Lymphocyte, T cell, B call, CD4, CD8, natural killer cells counts)
  • Immune Monitoring - Serum Cytokine Levels (pg/ml) [ Time Frame: 8 weeks from Day 0 (Initial visit) +/- 7 days ]
    Serum Cytokine Levels ( IL2R, IL12, INFG, IL4, IL5, IL10, IL13, IL1B, IL6, IL8, TNFA, IL2, IL17) in pg/mL
  • Immune Monitoring - RNA gene expression [ Time Frame: 8 weeks from Day 0 (Initial visit) +/- 7 days ]
    RNA gene expression arrays for 42 cytokine and immune related genes, expressed as ratio of absolute gene expression in PBMCs for each group (A, B, C, those with 0, few, or 6 or more herpes labialis outbreaks in the prior 12 months) on Day 0,1 and 2 and a each test condition (no stimulus, HSV-1, HSV-infected cell extracts, or Candida).
  • Immune Monitoring - PBMC proliferation [ Time Frame: 8 weeks from Day 0 (Initial visit) +/- 7 days ]
    PBMC proliferation in response to 3 stimuli: HSV-1 virus, HSV-1-infected cell extracts, and Candida albicans extract.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immune Response and General Immune Health in Subjects Infected With Herpes Simplex Virus Type 1 (HSV-1)
Official Title  ICMJE A Phase I Study of the Immune Response to Herpes Simplex Virus Type 1 (HSV-1) and General Immune Health in Subjects Infected With HSV-1
Brief Summary 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." 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. 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. SADBE has been reported to cause eczema, lymphadenopathy, blistering, allergic contact dermatitis, skin hypopigmentation, a burning sensation after application, and systemic reactions including fever and arthralgias. It is hoped that SADBE will offer subjects a safe and effective therapeutic option to decrease the frequency and severity of future herpes labialis outbreaks through these mechanisms. 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.
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. SADBE has also been used with some success in the treatment of alopecia areata. In a review of the literature, Rokhsar et al noted a 50% to 60% success rate of SADBE in use for hair re-growth in this population. SADBE has been reported to cause eczema, lymphadenopathy, blistering, allergic contact dermatitis, skin hypopigmentation, a burning sensation after application, and systemic reactions including fever and arthralgias. A study completed by Oglio et al of eight patients treated with SADBE for warts noted only mild and well tolerated side effects of erythema, desquamation, cutaneous edema, pruritus, burning, and pain. SADBE induces a delayed-type hypersensitivity response which in warts, is believed to induce the killing of virally infected cells by cytotoxic lymphocytes. This influx of lymphocytes into lesional Page 4 of 14 tissue may also enhance the recognition and processing of viral antigens, leading to clonal expansion of effector cells. It is hoped that SADBE will offer subjects a safe and effective therapeutic option to decrease the frequency and severity of future herpes labialis outbreaks through these mechanisms. 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Subjects will be recruited in three groups, all of whom are infected with HSV-1, as shown by having IgG against HSV-1:

x Group A: 12 subjects with 6 or more herpes labialis outbreaks in the past 12 months x Group B: 12 subjects with 1 to 2 outbreaks in the past 12 months x Group C: 12 subjects with zero outbreaks in the past 12 months Subjects in group A will receive 2% SADBE dose on the arm after their initial blood samples are obtained. Group A subjects will have blood collected and tests repeated 2 and 8 weeks later.

Subjects in Groups B and C will be matched to the subjects in Group A so that demographic characteristics (i.e., gender distribution, age and weight) are within broadly similar ranges.

Masking: None (Open Label)
Primary Purpose: Screening
Condition  ICMJE
  • HSV
  • Herpes Labialis
Intervention  ICMJE Drug: Squaric Acid Dibutyl Ester
2% squaric acid dibutyl ester (SADBE) (Supplied by Squarex) is topically applied to the inner aspect of the upper arm of the subject and covered with Tegaderm. Subject is advised to wash it off after 3 hours.
Other Name: SADBE
Study Arms  ICMJE
  • Experimental: Group A

    Subjects will be recruited in three groups, all of whom are infected with HSV-1, as shown by having IgG against HSV-1:

    Group A: 12 subjects with 6 or more herpes labialis outbreaks in the past 12 months.

    Subjects in group A will receive 2% Squaric Acid Dibutyl Ester (SADBE) dose on the arm after their initial blood samples are obtained. Group A subjects will have blood collected and tests repeated 2 and 8 weeks later.

    Subjects in Groups B and C will be matched to the subjects in Group A so that demographic characteristics (i.e., gender distribution, age and weight) are within broadly similar ranges.

    Intervention: Drug: Squaric Acid Dibutyl Ester
  • No Intervention: Group B

    Subjects will be recruited in three groups, all of whom are infected with HSV-1, as shown by having IgG against HSV-1:

    Group B: 12 subjects with 1 to 2 outbreaks in the past 12 months. Subjects in Groups B and C will be matched to the subjects in Group A so that demographic characteristics (i.e., gender distribution, age and weight) are within broadly similar ranges. Invite these back for a further blood draw on Day 0.

  • No Intervention: Group C

    Subjects will be recruited in three groups, all of whom are infected with HSV-1, as shown by having IgG against HSV-1:

    Group C: 12 subjects with zero outbreaks in the past 12 months. Subjects in Groups B and C will be matched to the subjects in Group A so that demographic characteristics (i.e., gender distribution, age and weight) are within broadly similar ranges. Invite these back for a further blood draw on Day 0.

Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 5, 2018)
36
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 25, 2017
Actual Primary Completion Date June 17, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age ≥18 and <65
  2. Positive test for IgG against herpes simplex virus type 1 (HSV-1).
  3. Groups A and B only: 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 criteria.
  4. Group A only: Self report having six or more episodes of herpes labialis in the past 12 months. Subjects will NOT be told that six-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 six or more and excluded from Group A if they give an answer of five or fewer.
  5. Group A only: 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.
  6. Group B only: Self report having exactly 1 or 2 episodes of herpes labialis in the past 12 months. Subjects will NOT be told that one or two 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 one or two and excluded from Group B if they give a different answer.
  7. Group C only: Self report having zero episodes of herpes labialis in the past 12 months. Subjects will NOT be told that zero 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 zero and excluded from Group C if they give an answer of one or more.

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 (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 (diabetes mellitus requiring insulin, CHF (NYHA class II or worse) MI, CVA or TIA within 3 months of screening visit, unstable angina pectoris, 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 baseline 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 had a vaccine for either HSV-1 or HSV-2.
  14. Group A only: People that have had treatment with anti viral therapy within 2 weeks before sensitization dose of SADBE.
  15. Groups B and C only: People that have had treatment with anti-viral therapy any time in the past 12 months.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03661541
Other Study ID Numbers  ICMJE 2017-SQ-Prism
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Squarex, LLC
Study Sponsor  ICMJE Squarex, LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Squarex, LLC
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP