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Safety and Efficacy of Diacerein 1% Ointment Topical Formulation Compared to Placebo for Subjects With Epidermolysis Bullosa Simplex (EBS)

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ClinicalTrials.gov Identifier: NCT03154333
Recruitment Status : Recruiting
First Posted : May 16, 2017
Last Update Posted : April 18, 2018
Sponsor:
Information provided by (Responsible Party):
Castle Creek Pharmaceuticals, LLC

Brief Summary:
Epidermolysis bullosa simplex (EBS) is a rare genetic skin disease characterized by fragility of the skin and mucous membranes resulting in painful blisters and erosions after minor trauma. The simplex form is classified by skin blister development in the basal epidermis. Diacerein 1% Ointment is a topical ointment that is being developed for the treatment of EBS. Diacerein in the topical formulation is hydrolyzed to rhein in the epidermis and dermis following administration. Diacerein and rhein have been shown to inhibit the in vitro and in vivo production and activity of interleukin-1β (IL-1β) and other pro-inflammatory cytokines.The purpose of this study is to compare the efficacy of Diacerein 1% Ointment to Control Ointment when applied once-daily for 8 weeks in subjects with EBS.

Condition or disease Intervention/treatment Phase
Epidermolysis Bullosa Simplex Drug: Diacerein 1% Ointment Topical Formulation Drug: Vehicle Phase 2

Detailed Description:

The proposed study is an international, multicenter, randomized, double-blind, vehicle-controlled, parallel group study to evaluate the safety and efficacy of topical Diacerein 1% Ointment for the treatment of subjects with EBS. Subject randomization will be stratified by genotype (KRT5 and/or KRT14 versus other genotypes) and age group (<8 and ≥8 years old). Participants will be subject to up to 6-week screening period, then be assigned to treat EBS lesions once daily with either Diacerein 1% ointment topical formulation or placebo control ointment for 8 weeks, followed by an 8 week follow-up period. Approximately 80 subjects are planned to be randomized to one of the 2 treatment groups in this study at approximately 20 international investigational centers.

The primary objective of this study is to compare the efficacy of Diacerein 1% Ointment to Control Ointment based on reduction in body surface area (BSA) of EBS lesions being treated when applied once-daily for 8 weeks in subjects with EBS. The secondary objectives are to compare the effects of Diacerein 1% Ointment to Control Ointment in subjects with EBS in changes in Investigator Global Assessment (IGA) scores, pain, pruritus, mobility, and safety and tolerability.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An International, Multicenter, Randomized, Double-Blind, Parallel-Group Phase 2 Study Evaluating the Safety and Efficacy of Diacerein 1% Ointment Topical Formulation in Subjects With Epidermolysis Bullosa Simplex (EBS) [DELIVERS Study]
Actual Study Start Date : June 1, 2017
Estimated Primary Completion Date : November 2018
Estimated Study Completion Date : January 2019


Arm Intervention/treatment
Experimental: Diacerein 1% ointment
Diacerein 1% ointment topical formulation will be used for 8 weeks
Drug: Diacerein 1% Ointment Topical Formulation
Diacerein 1% Ointment administered topically

Placebo Comparator: A placebo topical ointment
Placebo topical ointment will be used for 8 weeks
Drug: Vehicle
Place ointment administered topically




Primary Outcome Measures :
  1. Efficacy of Diacerein 1% Ointment compared to Control Ointment based on Reduction in BSA of EBS lesions from Visit 2 (Week 0) to Visit 8 (Week 16) [ Time Frame: Change from Visit 2 (Week 0) to Visit 8 (Week 16) ]
    The primary endpoint is the proportion of subjects who achieve ≥40% reduction in BSA of EBS lesions from Visit 2 (Week 0) to Visit 8 (Week 16) to compare the efficacy of Diacerein 1% Ointment to Control Ointment based on reduction in body surface area (BSA) of EBS lesions being treated when applied once-daily for 8 weeks in subjects with EBS.The BSA will be determined by the investigator and the palmer method will be used to determine BSA of EBS lesion. 1% BSA is defined as the area of the subject's hand held flat, including the thumb and fingers held together.


Secondary Outcome Measures :
  1. Efficacy of Diacerein 1% Ointment compared to Control Ointment from Visit 2 (Week 0) to Visit 8 (Week 16) [ Time Frame: Change from Visit 2 (Week 0) compared to Visit 8 (Week 16) ]
    Statistically significant difference between Diacerein 1% ointment and Control ointment in terms of the proportion of subject who achieve treatment success defined as an Investigator's Global Assessment (IGA) grade 0 or 1 at Visit 2 (Week 0) compared to Visit 8 (Week 16) with at least a 2-point reduction in the IGA score.

  2. Efficacy of Diacerein 1% Ointment compared to Control Ointment based on Reduction in BSA of EBS lesions from Visit 2 (Week 0) to Visit 6 (Week 8) [ Time Frame: Change from Visit 2 (Week 0) compared to Visit 6 (Week 8) ]
    Determine the proportion of subjects who achieve ≥40% reduction in BSA of EBS lesions from Visit 2 (Week 0) to Visit 6 (Week 8) to compare the efficacy of Diacerein 1% Ointment to Control Ointment based on reduction in body surface area (BSA) of EBS lesions being treated when applied once-daily for 8 weeks in subjects with EBS.The BSA will be determined by the investigator and the palmer method will be used to determine BSA of EBS lesion. 1% BSA is defined as the area of the subject's hand held flat, including the thumb and fingers held together.

  3. Efficacy of Diacerein 1% Ointment compared to Control Ointment from Visit 2 (Week 0) to Visit 6 (Week 8) [ Time Frame: Change from Visit 2 (Week 0) compared to Visit 6 (Week 8) ]
    Statistically significant difference between Diacerein 1% ointment and Control ointment in terms of the proportion of subject who achieve treatment success defined as an Investigator's Global Assessment (IGA) grade 0 or 1 at Visit 2 (Week 0) compared to Visit 6 (Week 8) with at least a 2-point reduction in the IGA score.

  4. Pain Intensity assessed using the Numeric Rating Scale [ Time Frame: Change from Visit 2 (Week 0) compared to Visit 6 (Week 8) ]
    Pain Intensity will be assessed using the Numeric Rating Scale to describe the pain intensity.The Pain Intensity Assessment is the subject's assessment of pain at its worst experienced over the previous 24 hours on all EBS lesions.

  5. Pruritus Intensity assessed using the Numeric Rating Scale [ Time Frame: Change from Visit 2 (Week 0) compared to Visit 6 (Week 8) ]
    Pruritus Intensity will be assessed using the Numeric Rating Scale. The Pruritus Intensity is the subject's, or caregiver's if appropriate, assessment of the average overall intensity of pruritus experienced by the subject over the previous 24 hours on all EBS lesions

  6. Mobility Assessment using a series of age-appropriate questions in the eDiary [ Time Frame: Change from Visit 2 (Week 0) compared to Visit 8 (Week 16) ]
    The Mobility Assessment is the subject/caregiver's assessment of the subject's degree of mobility over the previous 24 hours. The subject/caregiver will report the degree of mobility by answering a series of age-appropriate questions in the eDiary.

  7. Number of patients with adverse events based on assessment of safety measures [ Time Frame: Change from Visit 8 (Week 16) compared to Visit 2 (Week 0) ]
    Number of patients with adverse events using the following safety measure assessments: demographics\medical history, adverse events and SAEs, vital signs, physical examination, clinical laboratory, and urine pregnancy tests.



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Ages Eligible for Study:   4 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject is male or female at least 4 years of age at Visit 1
  • Subject has a documented genetic mutation consistent with EBS. A blood or saliva sample will be collected for genetic confirmation if no documented gene mutation data is available. Gene mutations acceptable for inclusion are as follows: KRT5, KRT14, PLEC1, TGM5, PKP1, DSP, FERMT1, EXPH5, DST, KLHL24.
  • Subject has an Assessment Area of EBS lesions to be treated, that is ≥2% body surface area (BSA) and the EBS lesions are in one or both of the following body areas:

    • Localized: plantar and/or palmar areas (plantar areas where >25% of the area has hyperkeratosis that has been present for greater than 12 weeks cannot be included as part of the Assessment Area
    • Generalized: arms, legs, torso, hands and feet (scalp, groin and areas where, in the investigator's opinion, the study medication might become occluded cannot be included as part of the Assessment Area)
  • Subject's EBS lesions in the Assessment Area have an Investigator's Global Assessment (IGA) score of ≥3
  • Subject/caregiver agrees to not use any topical therapies other than the study medication that might influence the status of the EBS lesions during the duration of the study (e.g., medicated cleansers, CBD oil, MediHoney, Silvadine cream 1%, the Investigator should consult the Medical Monitor regarding therapies not specified in the protocol
  • Subject/caregiver agrees to follow topical product application instructions during the treatment period
  • If the subject is a woman of childbearing potential, she has a negative urine pregnancy test and agrees to use an approved effective method of birth control, as defined by this protocol, for the duration of the study.
  • Subject is non-pregnant, non-lactating and is not planning for pregnancy during the study period
  • Subject is in good general health and free of any known disease state or physical condition which, in the investigator's opinion, might impair evaluation of the EBS lesions or which exposes the subject to an unacceptable risk by study participation
  • Subject is willing and able to follow all study instructions and to attend all study visits
  • Subject/caregiver is able to comprehend and willing to sign an Informed Consent and/or Assent Form.

Exclusion Criteria:

  • Subject has EBS lesions to be treated that are infected (i.e., EBS lesions that require therapy to treat an infection)
  • Subject has used any diacerein containing product within 6 months prior to Visit 1
  • Subject has used systemic immunotherapy or cytotoxic chemotherapy within 60 days prior to Visit 1
  • Subject has used systemic steroidal therapy or has used topical steroidal therapy on the EBS lesions to be treated within 30 days prior to Visit 2 (Note: inhaled and ophthalmic products containing steroids are allowed)
  • Subject has evidence of a systemic infection or has used systemic antibiotics within 7 days prior to Visit 1
  • Subject is currently using systemic analgesics and/or anti-histamine therapy, for treatment of EBS lesions unless on a stable regimen (i.e., the same dosing regimen) for at least 4 weeks prior to Visit 1. Note: As needed (PRN) use of acetaminophen/paracetamol or NSAIDs within the 4 weeks prior to Visit 1 are permitted provided the treatment was unrelated to EBS symptom relief.
  • Subject has used any systemic diuretics or cardiac glycosides or any systemic product that, in the opinion of the investigator, might put the subject at undue risk by study participation or interferes with the study medication application or the study assessments within 30 days prior to Visit 1
  • Subject has used any topical product containing allantoin on the EBS lesions to be treated within 30 days prior to Visit 1
  • Subject has a current malignancy, or a history of treatment for a malignancy within 2 years prior to Visit 1 (Note: does not include non-melanoma skin cancer)
  • Subject currently has diabetes mellitus (HbA1c ≥6.5%); Note: controlled diabetes (HbA1c < 6.5%) is also considered exclusionary
  • Subject has a history of cardiac, hepatic (ALT and or AST >2x ULN, Total bilirubin >1.5x ULN at Visit 1), or renal disease (eGFR<30 ml/min/1.73 m^2) that, in the opinion of the investigator, might put the subject at undue risk by study participation or interferes with the study medication application or the study assessments
  • Subject has a non-EBS skin disease (e.g., psoriasis, atopic dermatitis, eczema, sun damage, etc.), or condition (e.g., sunburn) that, in the opinion of the investigator, might put the subject at undue risk by study participation or interferes with the study medication application or the study assessments
  • Subject has a history of sensitivity to any of the ingredients in the study medications
  • Subject has participated in an investigational drug trial/device in which administration of an investigational study medication occurred within 30 days prior to Visit 1.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03154333


  Hide Study Locations
Locations
United States, Arizona
Phoenix Childrens Hospital Recruiting
Phoenix, Arizona, United States, 85016
Contact: Kellie Badger    602-933-2053    kbadger@phoenixchildrens.com   
Principal Investigator: Harper Price         
United States, California
Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Elidia Tafoya    650-743-8520    etafoya@stanford.edu   
Principal Investigator: Joyce Teng, MD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Kathleen Peoples    720-777-4708    Kathleen.Peoples@childrenscolorado.org   
Principal Investigator: Anna Bruckner, MD         
United States, Illinois
Ann and Robert H. Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Rema Zebda, PhD    312-227-6484    rema.zebda@northwestern.edu   
Principal Investigator: Amy Paller, MD         
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Rema Zebda    312-227-6484    rema.zebda@northwestern.edu   
Principal Investigator: Amy Paller, MD         
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Amy Hanson    612-626-4424    Amhanson@umn.edu   
Principal Investigator: Kristen Hook, MD         
United States, Missouri
University of Missouri Healthcare Recruiting
Columbia, Missouri, United States, 65212
Contact: Hope Gole    573-882-8030    golehk@health.missouri.edu   
Principal Investigator: Jonathan Dyer, MD         
United States, North Carolina
University of North Carolina - Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27516
Contact: Laura Keck    984-974-3682    laura_mcleod@med.unc.edu   
Principal Investigator: Aida Lugo-Somolinos, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Melissa Reed    513-803-0053    Melissa.Reed1@cchmc.org   
Principal Investigator: Anne Lucky, MD         
United States, Texas
Children's Hospital of San Antonio ; Texas Dermatology and Laser Specialists Recruiting
San Antonio, Texas, United States, 78218
Contact: Jenna Encina    210-852-2779    jenna@texasdls.com   
Principal Investigator: John Browning, MD         
Australia, New South Wales
Premier Specialists Pty Ltd; The Church Recruiting
Kogarah, New South Wales, Australia, 2217
Contact: Helen Dickenson-Panas    0295985800    premierspecialiststrials@gmail.com   
Principal Investigator: Deirdre Murrell, MD         
Austria
EB House Austria Recruiting
Salzburg, Austria, A-5020
Contact: Sophie Kitzmueller    +43 (0) 55 7255 57052    s.kitzmueller@salk.at   
Principal Investigator: Martin Laimer, MD         
France
Hopital Saint Louis Recruiting
Paris, Cedex, France, 75010
Contact: Douniazed Chabane    +33 (0)1 42 49 90 90    douniazed.chabane@gmail.com   
Principal Investigator: Emmanuelle Bourrat, MD         
Hopital Necker-Enfants Malades Recruiting
Paris, Cedex, France, 75015
Contact: Wiam Bhia    33 0 6 79 97 59 94    wiam.bhia-ext@aphp.fr   
Principal Investigator: Christine Bodemer, MD         
CHU de NICE - Hopital de l'Archet II - Service de Dermatologie Recruiting
Nice, France, 06202
Contact: Marie-Claude Durpes    +33(0)4 92 03 54 84    durpes.mc@chu-nice.fr   
Principal Investigator: Christine Chiaverini, MD         
Germany
University Medical Center Freiburg Recruiting
Freiburg, Germany, 79104
Contact: Aurelia Winter    +49 (0) 761 270-67141    aurelia.winter@uniklinik-freiburg.de   
Principal Investigator: Cristina Has, MD         
Israel
Tel Aviv Sourasky Medical Center Recruiting
Tel Aviv, Israel, 6423906
Contact: Udi Ben Dor    +972-3-6973768    udibd@tlvmc.gov.il   
Principal Investigator: Eli Sprecher, MD         
Netherlands
University Medical Center Groningen Recruiting
Groningen, Netherlands, AB20;30,001
Contact: Rita Bozoglan    +33 (0) 657 3366 89    r.bozoglan@umcg.nl   
Principal Investigator: Marcel Jonkman, MD         
United Kingdom
Great Ormond Street Hospital Recruiting
London, England, United Kingdom, WC1N 3JH
Contact: Jakub Wyszynski    020-7188-6399    jakub.wyszynski@gosh.nhs.uk   
Principal Investigator: Jemima Mellerio         
St. Thomas' Hospital - St Johns Institute of Dermatology Recruiting
London, United Kingdom, SE1 7EH
Contact: Socha O'Sullivan    020 7188 7188    Sorcha.L.Osullivan@gstt.nhs.uk   
Principal Investigator: Jemima Mellerio, MD         
Sponsors and Collaborators
Castle Creek Pharmaceuticals, LLC
Investigators
Study Director: Amir Tavakkol, MD Castle Creek Pharmaceuticals

Additional Information:
Responsible Party: Castle Creek Pharmaceuticals, LLC
ClinicalTrials.gov Identifier: NCT03154333     History of Changes
Other Study ID Numbers: CCP-020-301
First Posted: May 16, 2017    Key Record Dates
Last Update Posted: April 18, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
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 Castle Creek Pharmaceuticals, LLC:
Epidermolysis
bullosa
simplex
blister
EBS
topical
ointment
lesion

Additional relevant MeSH terms:
Epidermolysis Bullosa
Epidermolysis Bullosa Simplex
Skin Abnormalities
Congenital Abnormalities
Skin Diseases, Genetic
Genetic Diseases, Inborn
Skin Diseases
Skin Diseases, Vesiculobullous
Diacetylrhein
Anti-Inflammatory Agents