Ixekizumab in the Treatment of Bullous Pemphigoid

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT03099538
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 4
• Location: 1
• Arm: 1
• Actual Duration (Months): 21.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Recently, Interleukin (IL)-17 has been identified as a key driver of chronic inflammation in Bullous Pemphigoid (BP). Ixekizumab is a recombinant high-affinity fully human monoclonal antibody that targets IL-17A Immunoglobulin gamma-1 (IgG1)/kappa-class. The purpose of this study is to determine the effect of Ixekizumab on BP patients.

Condition or Disease	Intervention/Treatment	Phase
Bullous Pemphigoid; Pemphigoid	Drug: Ixekizumab	Phase 2

Detailed Description

BP is the most common auto-immune blistering disease of the skin and causes significant morbidity. BP disproportionally affects the elderly population and the current, non-specific immunosuppressive therapies, in addition to patient comorbidities, are associated with a high risk of infection related mortality. Neutrophils and their proteases have been shown to play a major role in the cleavage of Bullous Pemphigoid 180 Antigen (BP180) in BP. Mast cells and other cellular mediators also contribute to the pro-inflammatory environment within and surrounding blisters of BP. However, the prior targeting of mast cells and basophils has resulted in unpredictable disease control. Recently, IL-17 has been identified as a key driver of chronic inflammation in BP. With the increasing aged population in the United States, BP will increase in prevalence and the development of a more targeted approach will be necessary to decrease morbidity and mortality. IL-17 inhibition with Ixekizumab may have targeted, disease-modifying effects on BP. The primary objective is to test the effect of Ixekizumab in the treatment of the autoimmune blistering disease, BP.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: This is a single center, exploratory, open-label, single-arm design study of 12 patients with BP. Treatment naïve and treatment refractory patients with BP will be treated with Ixekizumab. Patients who are non-responders, to physician choice standard of care, will undergo a washout period and will be enrolled in the study.This is a single center, exploratory, open-label, single-arm design study of 12 patients with BP. Treatment naïve and treatment refractory patients with BP will be treated with Ixekizumab. Patients who are non-responders, to physician choice standard of care, will undergo a washout period and will be enrolled in the study.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Ixekizumab in the Treatment of Bullous Pemphigoid
• Actual Study Start Date: Aug 15, 2017
• Actual Primary Completion Date: Jun 6, 2019
• Actual Study Completion Date: Jun 6, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ixekizumab Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12.	Drug: Ixekizumab; Subcutaneous injection; Other Names: Taltz

Outcome Measures

Primary Outcome Measures

1. Cessation of Blister Formation [Up to 12 weeks]

   Median time to cessation of blister formation during the 12 weeks of therapy.

Secondary Outcome Measures

1. Change in Bullous Pemphigoid Disease Activity Index (BPDAI) [Week 0 and week 12]

   The change in Bullous Pemphigoid Disease Activity Index (BPDAI) from week 0 to 12 of treatment will be measured.The BPDAI is a standard scoring system for cutaneous disease activity and pruritus in BP. BPDAI is predictive of the likelihood of a subsequent flare. The BPDAI consists of scoring various types of lesions and creates a score ranging from 0 to 120. A score of greater than 56 is considered severe disease.

2. Prednisone Dose (mg) [Epoch 1 (washout- up to 4 weeks) Epoch 2 (week 0 to week 12) Epoch 3 (week 12 to week 16)]

   Average daily prednisone dose (mg) will be calculated for each Epoch.

3. Number of Participants With Treatment-related Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). [weeks 0 to 18]

   The clinical safety of Ixekizumab will be monitored with collection of vital signs, clinical examination, and clinical laboratory studies. Adverse events (AE) will be reported per the Common Terminology Criteria for Adverse Events (CTCAEv4.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE Grade refers to the severity of the AE. The CTCAE displays Grades 1-5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

4. Decrease in Immunoglobulin G Anti-Bullous Pemphigoid 180 and 230 Antibody (Anti-BP180 & 230 IgG) [week 0, 4, 8, 12]

   We will measure the anti-BP180&230 antibodies through out treatment. These assays will be completed using and ELISA assay. Mayo medical labs references for anti-BP180&230 (<9.0 Units negative, > or = 9.0 Units positive)

5. Decrease in Neutrophil and Eosinophil Counts [week 0, 4, 8, 12]

   Neutrophil and eosinophil counts will be monitored throughout therapy. Mayo medical labs reports normal neutrophil levels (1.70-7.00X10(9)/L) and normal eosinophil levels (0.05-0.5X10(9)/L)

6. Change in Multiplex Cytokine Analysis [week 0, 4, 8, 12]

   Multiplex cytokine analysis will be performed throughout therapy on Interleukin (IL)- 6, 17, 22, 23, Transforming growth factor beta (TGFb), and matrix-metalloprotease-9 (MMP9).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Subjects eligible for inclusion in this study have to fulfill all of the following

Inclusion criteria:

• Subjects must be able to understand and comply with the requirements of the study and communicate with the investigator. Subjects must give written, signed, and dated informed consent before any study related activity is performed. When appropriate, a legal representative will sign the informed consent according to local laws and regulation

• Both men and women must be at least 18 years of age at the time of screening

• Subjects must have clinical, histological, and serological features of BP

• Urticarial plaques and/or vesicles and bullae

• Characteristic eosinophilic spongiosis and/or subepidermal separation of the skin

• Positive direct immunofluorescence (IgG and or C3 at the basement membrane zone) or indirect immunofluorescence (IgG on the roof of salt- split skin) or positive serologies on ELISA for BPAG1 or BPAG2

• Subjects must have treatment naive BP or treatment refractory disease, as defined by failure of at least one established treatment for BP

• Candidate for systemic therapy, defined by

• involvement of greater than 5 percent body surface area or moderate to extensive disease as defined by: the mean number of new bullae and urticarial plaques that have appeared over the course of 3 days as determined by the investigator or referring physician (moderate disease defined by greater than 1 and less than 10 new bullae and greater than 5 urticarial plaques and extensive disease by greater than 10 new bullae)

• Failure of prior therapy

• Topical treatment

• Systemic immunosuppressant

• Oral antibiotics and/or niacinamide

Exclusion Criteria:

Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. In order to ensure the recruitment of a representative sample of all eligible subjects, the investigator may apply no additional exclusions.

• Forms of BP other than classic BP (e.g. mucous membrane BP, Brunsting-Perry BP, p200 BP, p105 BP, or BP with concomitant pemphigus vulgaris Drug-induced BP (e.g., new onset or current exacerbation from angiotensin converting enzyme inhibitors, penicillamine, furosemide, phenacetin)

• Subjects who are receiving treatments known to worsen BP and use of penicillamine or phenacetin and those on angiotensin converting enzyme inhibitors or furosemide who have not been on a stable dose at least 4 weeks prior to enrollment.

• Ongoing use of prohibited treatments.

• Previous exposure to Ixekizumab or any other biologic drug directly targeting IL-17A or IL-17 (receptor A)RA

• Use of any other investigational drugs within 5 half-lives of the investigational treatment before study drug initiation or until the pharmacodynamics effect has returned to baseline, whichever is longer

• Previous use of IL-20 monoclonal antibody

• Pregnant or nursing (lactating) women (pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test)

• Women of childbearing potential [Post-menopausal or not of child-bearing potential is defined by: 1 year of natural (spontaneous) amenorrhea or Surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks ago. Oophorectomy alone must confirmed by follow up hormone level assessment to be considered not of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception which includes:

• Total abstinence (Periodic abstinence and withdrawal are not acceptable methods of contraception)

• Female sterilization (bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. Oophorectomy alone requires follow up hormone level assessment for fertility.

• Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject.

• Barrier methods of contraception: condom or occlusive cap. Use of oral, injected or implanted hormonal methods of contraception or other forms or hormonal contraception that have complete efficacy (failure less than 1 percent). (The dose of the contraceptive should be stable for 3 months)

• Active ongoing inflammatory diseases of the skin other than BP that might confound the evaluation of the benefit of Ixekizumab

• Underlying condition (including, but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions) which, in the opinion of the investigator, significantly immunocompromises the subject and/or places the subject at unacceptable risk for receiving an immunomodulatory therapy Investigator discretion should be used for subjects with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders Significant medical problems, including but not limited to the following: uncontrolled hypertension, congestive heart failure (New York Heart Association (NYHA) status of class III or IV)

• Serum creatinine level exceeding 2.0 mg per dL (176.8 micro mol per L) at screening

• Total white blood cell (WBC) count less than 2,500 per microL, platelets less than 100,000 per microL, neutrophils less1500/microL or hemoglobin less than 8.5 g per dL, at screening

• Active systemic infections during the 2 weeks prior to randomization (common cold viruses not included) or any infection that reoccurs on a regular basis.

• Investigator discretion should be used regarding subjects who have traveled or resided in areas of endemic mycoses, such as histoplasmosis, coccidioidomycosis or blastomycosis and for subjects with underlying conditions that may predispose them to infection, such as advanced or inadequately controlled diabetes. Due to its endemic nature in Arizona, coccidioidomycosis screening is performed at baseline. A history of a disseminated coccidioidomycosis infection will exclude subjects.

• History of an ongoing, chronic or recurrent infectious disease, or evidence of tuberculosis infection as defined by a positive or indeterminate QuantiFERON Tuberculosis (TB)-Gold test (QFT) at screening.

• Subjects with a positive QFT test may participate in the study if a full tuberculosis work up (according to local practice/guidelines) is completed within 12 weeks prior to establishes conclusively that the subject has no evidence of active tuberculosis.

If the presence of latent tuberculosis is established, then treatment must have been initiated and maintained according to local country guidelines for at least 4 weeks prior to randomization.

• Past medical history of, or current infection with, human immunodeficiency virus (HIV), hepatitis B or hepatitis C prior to new diagnosis at screening

• History of lymphoproliferative disease and or any known malignancy and/or history of malignancy of any organ system within the past 5 years

Exceptions include:

For skin squamous cell carcinoma in situ and or well differentiate squamous cell carcinoma and/or basal cell carcinoma and or actinic keratosis and/or melanoma in situ that have been treated with no evidence of recurrence For the cervix carcinoma that has been removed For the colon non-invasive malignant colon polyps that have been removed

• Current severe progressive or uncontrolled disease which the investigator renders the subject unsuitable for the trial or puts the subject at increased risk Inability or unwillingness to undergo repeated venipuncture

• Any medical or psychiatric condition which, in the investigator's opinion, would keep the subject from adhering to the protocol or completing the study per protocol

• History or evidence of ongoing alcohol or drug abuse, within the last 6 months prior to the initiation of therapy

• Plans for administration of live vaccines during the study period or in the 12 weeks prior to the initiation of therapy

• Bacillus Calmette-Guerin (BCG) vaccination within 12 months of starting the study or with 12 months after completing the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Scottsdale	Arizona	United States	85259

Sponsors and Collaborators

• Mayo Clinic
• Eli Lilly and Company

Investigators

• Principal Investigator: Aaron Mangold, MD, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 26, 2018

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• Responsible Party: Aaron R. Mangold, Assistant Professor of Dermatology, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03099538
• Other Study ID Numbers: IRB#16-008302
• First Posted: Apr 4, 2017
• Last Update Posted: May 21, 2020
• Last Verified: May 1, 2020

• 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
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Aaron R. Mangold, Assistant Professor of Dermatology, Mayo Clinic: Ixekizumab; Bullous Pemphigoid; Pemphigoid; IL17; IL-17; Interleukin 17
• Additional relevant MeSH terms: Pemphigoid, Bullous; Ixekizumab

Study Results

Participant Flow

Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
Period Title: Overall Study
STARTED	4
COMPLETED	1
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
Overall Participants	4
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.8 (6.45)
Sex: Female, Male (Count of Participants)
Female	4 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 25%
Not Hispanic or Latino	3 75%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	4 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%

Outcome Measures

1. Primary Outcome

Title	Cessation of Blister Formation
Description	Median time to cessation of blister formation during the 12 weeks of therapy.
Time Frame	Up to 12 weeks

Outcome Measure Data

Analysis Population Description

Endpoint was not achieved as there was no cession of blisters.

Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
Measure Participants	4
Median (Standard Deviation) [days]	NA (NA)

2. Secondary Outcome

Title	Change in Bullous Pemphigoid Disease Activity Index (BPDAI)
Description	The change in Bullous Pemphigoid Disease Activity Index (BPDAI) from week 0 to 12 of treatment will be measured.The BPDAI is a standard scoring system for cutaneous disease activity and pruritus in BP. BPDAI is predictive of the likelihood of a subsequent flare. The BPDAI consists of scoring various types of lesions and creates a score ranging from 0 to 120. A score of greater than 56 is considered severe disease.
Time Frame	Week 0 and week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
Measure Participants	4
Week 0	24.8 (17.71)
Week 12	39 (24.48)

3. Secondary Outcome

Title	Prednisone Dose (mg)
Description	Average daily prednisone dose (mg) will be calculated for each Epoch.
Time Frame	Epoch 1 (washout- up to 4 weeks) Epoch 2 (week 0 to week 12) Epoch 3 (week 12 to week 16)

Outcome Measure Data

Analysis Population Description

Only one subject remained in the study by Epoch 3 timepoint (week 12 to 16)

Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
Measure Participants	4
Epoch 1	0 (0)
Epoch 2	15.42 (9.17)
Epoch 3	0 (0)

4. Secondary Outcome

Title	Number of Participants With Treatment-related Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).
Description	The clinical safety of Ixekizumab will be monitored with collection of vital signs, clinical examination, and clinical laboratory studies. Adverse events (AE) will be reported per the Common Terminology Criteria for Adverse Events (CTCAEv4.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE Grade refers to the severity of the AE. The CTCAE displays Grades 1-5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time Frame	weeks 0 to 18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
Measure Participants	4
Grade 1	1 25%
Grade 2	0 0%
Grade 3	0 0%
Grade 4	0 0%
Grade 5	0 0%

5. Secondary Outcome

Title	Decrease in Immunoglobulin G Anti-Bullous Pemphigoid 180 and 230 Antibody (Anti-BP180 & 230 IgG)
Description	We will measure the anti-BP180&230 antibodies through out treatment. These assays will be completed using and ELISA assay. Mayo medical labs references for anti-BP180&230 (<9.0 Units negative, > or = 9.0 Units positive)
Time Frame	week 0, 4, 8, 12

Outcome Measure Data

Analysis Population Description

This outcome measure was not achieved due to lack to sample to run assays.

Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
Measure Participants	0

6. Secondary Outcome

Title	Decrease in Neutrophil and Eosinophil Counts
Description	Neutrophil and eosinophil counts will be monitored throughout therapy. Mayo medical labs reports normal neutrophil levels (1.70-7.00X10(9)/L) and normal eosinophil levels (0.05-0.5X10(9)/L)
Time Frame	week 0, 4, 8, 12

Outcome Measure Data

Analysis Population Description

This outcome measure was not achieved due to lack of data.

Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
Measure Participants	0

7. Secondary Outcome

Title	Change in Multiplex Cytokine Analysis
Description	Multiplex cytokine analysis will be performed throughout therapy on Interleukin (IL)- 6, 17, 22, 23, Transforming growth factor beta (TGFb), and matrix-metalloprotease-9 (MMP9).
Time Frame	week 0, 4, 8, 12

Outcome Measure Data

Analysis Population Description

This outcome measure was not achieved due to lack of sample to run assays.

Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
Measure Participants	0

Adverse Events

Time Frame	Adverse events were collected for each subject from baseline until 30 days post-study participation, for a total of approximately four to five months.
Arm/Group Title	Ixekizumab
Arm/Group Description	Ixekizumab subcutaneous 160mg week 0, 80mg weeks 2, 4, 6, 8, 10, 12. Ixekizumab: Subcutaneous injection
All Cause Mortality
	Ixekizumab
	Affected / at Risk (%)	# Events
Total	0/4 (0%)
Serious Adverse Events
	Ixekizumab
	Affected / at Risk (%)	# Events
Total	0/4 (0%)
Other (Not Including Serious) Adverse Events
	Ixekizumab
	Affected / at Risk (%)	# Events
Total	4/4 (100%)
Eye disorders
Conjunctivitis	1/4 (25%)	1
Dry eyes	1/4 (25%)	1
General disorders
Rib pain	1/4 (25%)	1
Skin Pain	1/4 (25%)	1
Headache	1/4 (25%)	1
Facial swelling	1/4 (25%)	1
Infections and infestations
Staphylococcal overgrowth	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Shortness of breath	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Pruritus	2/4 (50%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.