Baricitinib in the Treatment of Adults With Pyoderma Gangrenosum (PG)

• ClinicalTrials.gov Identifier: NCT04901325
• Recruitment Status: Recruiting
• First Posted: May 25, 2021
• Last Update Posted: September 10, 2021
• Sponsor: Oregon Health and Science University
• Information provided by (Responsible Party): Alex Ortega Loayza, Oregon Health and Science University

Study Description

Brief Summary:

An Open-Label, Proof-Of-Concept, Study of Baricitinib for the Treatment of Pyoderma Gangrenosum

Condition or disease	Intervention/treatment	Phase
Pyoderma Gangrenosum; Skin Diseases; Wound Heal; Pyoderma; Skin Ulcer	Drug: Baricitinib	Phase 2

Detailed Description:

This is a Phase II study that will be open label and include a total of 20 patients who will receive the investigational product. PG will be defined by the investigator and a second reviewer on the basis of results from clinical, histological and laboratory assessments. These patients will undergo 24 weeks of baricitinib dosed daily and stable dose of prednisone dosed daily with follow-up until week 36.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Baricitinib in the Treatment of Adults With Pyoderma Gangrenosum (PG)
• Estimated Study Start Date: September 29, 2021
• Estimated Primary Completion Date: July 5, 2023
• Estimated Study Completion Date: December 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Baricitinib for PG; Subjects with PG will be treated with 4 mg once daily of baricitinib for 24 weeks in addition to starting stable dose (at least 2 weeks) of prednisone at 30 mg daily. Prednisone will be tapered based on a pre-established algorithm assessed by investigator.	Drug: Baricitinib; Subjects with PG will be treated with 4 mg once daily of baricitinib for 24 weeks.; Other Name: Olumiant

Outcome Measures

Primary Outcome Measures :

1. Change in lesion surface area [ Time Frame: Measured at week 0, 2, 6, 8, 12, 24. ]
   Mean and percentage change in surface area of target lesion of PG (two-dimensional surface in mm²) using digital photography (eKare). The largest lesion on a single plane will designated at the beginning of the study as the target ulcer.

Secondary Outcome Measures :

1. Physician Global Assessment (PGA) [ Time Frame: Weeks 2, 6, 8 16, 24, 28 and 36 ]

   Physician Global Assessment (PGA) 5-point scale and proportion of patients achieving PGA between 0 and 2 at the target lesion after treatment with baricitinib at weeks 2, 6, 8, 16, 24, 28, and 36. This scale has been used in previous trials:

   0 = total resolution of target ulcer with no signs of active PG; 1= almost completely healed target ulcer with only minimal signs of active PG; 2 = evidence of target ulcer healing which involves at least 50 percent of ulcer/ulcer margin; 3 = evidence of target ulcer healing which involves less than 50 percent of ulcer/margin; 4 = no evidence of target healing ulcer

2. Participants receiving ≤8mg prednisone per day [ Time Frame: Over 24-week period of study. ]
   Percentage of participants who receive prednisone at a dose of 8 mg or less per day (physiological dose).
3. Sustained remission [ Time Frame: Subjects will be monitored at 28 and 36 weeks to assess for sustained remission. ]

   Sustained remission at weeks 28 and 36, as measured by the subject remaining between 0 and 2 in the Physician Global Assessment (PGA) scale and/or decrease in ulcer area size of at least 50 percent after treatment has been completed.

   PGA Scale (0-4):

   0 = total resolution of target ulcer with no signs of active PG; 1= almost completely healed target ulcer with only minimal signs of active PG; 2 = evidence of target ulcer healing which involves at least 50 percent of ulcer/ulcer margin; 3 = evidence of target ulcer healing which involves less than 50 percent of ulcer/margin; 4 = no evidence of target healing ulcer

4. Time to healing [ Time Frame: Recorded at week 24 ]
   Time to which sterile dressings are not required.
5. Time to recurrence (weeks) [ Time Frame: 36 weeks ]
   Interval between target lesion healing and further episodes of PG at any site through the study.
6. Number of treatment failures [ Time Frame: By week 24 ]
   Treatment intolerance, number of patients switching into standard of care or target lesion unhealed.
7. Adverse reactions to medications [ Time Frame: 36 weeks ]
   Possibly-, probably- or related throughout the study.
8. Quality of life change (as measured by the Dermatology Life Quality Index) [ Time Frame: Weeks 2, 6,8 ,16,24, 28 and 36 ]
   Proportion of subjects achieving a 4-point change in quality of life measured by the Dermatology Life Quality Index (DLQI) at week 24, and mean change in DLQI score at week 24. The DLQI is a validated tool for inflammatory skin conditions. It is a 10-question survey, scored 0 - 30 points. For inflammatory skin conditions, a 4-point change in DLQI score is considered clinically important.
9. Skin pain scale [ Time Frame: Week 2, 6, 8, 16, 24, 28 and 36 ]
   Mean percentage in improvement in pain related to PG target ulcer measured by 0 - 10-point numeric pain rating scale (NRS) at week 0 and week-24. The pain NRS is a subject-administered, 11-point horizontal scale anchored at 0 and 10, with 0 representing "no pain" and 10 representing "worst pain imaginable."
10. Correlation of improvement [ Time Frame: Week 0-24 ]
    Correlation of improvement with cytokine gene expression in skin and blood. before and after treatment

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Willingness to comply with study procedures/requirements
• Capable of giving informed consent
• Diagnosis of at least one PG ulcer by clinical, histological and laboratory assessments with a minimum wound size of 4 cm2.
• Male age 18-99 who agree to not father a child or donate sperm while on study and at least 1 week following last dose of the study drug. If subject is a sexually active male and could cause a pregnancy, subject must be sure that female partner(s) are using birth control that works well or not have sex.
• Female age 18-99; either of non-childbearing potential or of childbearing potential who test negative for pregnancy and agree to use at least two reliable methods of birth control or remain abstinent during the study and for at least 1 week following the last dose of baricitinib.
• Classic PG defined as deep ulceration with undermining violaceous borders.
• Are candidate for systemic therapy. All participants will be taking and clinically stable 30 mg (same ulcer size) of prednisone fort least two weeks at the start of the study. Patients must have discontinued immunosuppressive therapies (cyclosporine, azathioprine, mycophenolate mofetil, methotrexate, apremilast, dapsone) due to inadequate response or intolerance for at least 4 weeks prior to beginning the study drug.
• Undergoing at least once a week standard of care wound care at home or wound care facility.
• Willingness to travel to Oregon Health and Science University (OHSU) for all study visits, or living >30 miles from OHSU and willing/able to participate in remote videoconferencing visits with access to a computer with internet and webcam capabilities.

Exclusion Criteria:

• Have history of malignancy or lymphoproliferative disease; or have signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly; or have active primary or recurrent malignant disease; or have been in remission from clinically significant malignancy for < 5years.
• Patients with cervical carcinoma in situ, basal cell carcinoma or squamous cell carcinomas who have had active disease within 3 years of screening for this study. Active, untreated, acute or chronic infection (such as untreated tuberculosis), or immunocompromised to an extent that such that participation in the study would pose an unacceptable risk to the subject. (Treated infections such as latent tuberculosis after completion of the appropriate therapy are not excluded.)
• Clinically serious infection or received intravenous antibiotics for an infection, within 4 weeks of randomization.
• Active viral infection that, based on the investigator's clinical assessment, makes the subject and unsuitable candidate for the study.
• Positive for human immunodeficiency virus, hepatitis B virus, or hepatitis C virus.
• Symptomatic herpes zoster infection within 12 weeks of screening or recurrent or disseminated (even a single episode) herpes zoster.
• Symptomatic herpes simplex at the time of randomization or disseminated (even a single episode) herpes simplex
• History of disseminated opportunistic infections (e.g., listeriosis and histoplasmosis).

• Have a history of venous thromboembolism (VTE), or are considered at high risk for VTE as deemed by the investigator, or have 2 or more of the following risk factors for VTE:

  1. Aged >65 years.
  2. Body mass index (BMI) >35 kg/m2.
  3. Oral contraceptive use and current smoker.
• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration equation Creatinine 2009 equation).
• Wound care debridement of any PG ulcer within 2 weeks.
• Intralesional corticosteroids within 4 weeks of screening.
• Previous exposure to a Janus kinase (JAK) inhibitor (ruxolitinib, tofacitinib, upadacitinib, filgotinib). For biologic therapies, the specific washout periods used will at least 4 weeks for anakinra, etanercept, infliximab, adalimumab, alefacept, golimumab, secukinumab, ixekizumab, risankizumab, guselkumab, tildrakizumab, canakinumab, ustekinumab and at least 24 weeks for rituximab or efalizumab.
• Patients who are currently on immunosuppressive therapies or have not discontinued them for at least 4 weeks.
• Clinically significant (per investigator's judgement) drug or alcohol abuse within the last 6 months preceding the Baseline Visit.
• Have a live vaccine within 12 weeks prior to baseline or intend to have a live vaccine during the course of study.
• Had any major surgery within 8 weeks prior to baseline or will require major surgery during the study, which in the opinion of the investigator would pose an unacceptable risk to the subject.
• Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting. Uncontrolled hypertension - confirmed systolic blood pressure >160 mmHg or diastolic blood pressure >100 mm Hg.
• Gastrointestinal (GI) perforation (other than appendicitis or penetrating injury), diverticulitis or significantly increased for GI perforation (within past 6 months) per investigator judgement; any condition could interfere with drug absorption including but not limited to short bowel syndrome.
• Presence of significant uncontrolled respiratory, hepatic, renal, endocrine, hematologic, neurologic, or neuropsychiatric disorders, or abnormal laboratory screening values that, in the opinion of the investigator, pose an unacceptable risk to the subject if participating in the study or of interfering with the interpretation of the data.
• Have clinical laboratory test results at screening that are outside the normal reference range of the population and are considered clinically significant, or have any of the following specific abnormalities: Neutrophil count <1500 cells/µL, lymphocyte count <500 cells/µL, platelet count <100,000 cells/µL, aspartate transaminase (AST) or alanine aminotransferase (ALT) > 2 times the upper limit of normal, hemoglobin <10 g/dL for male and female subjects, eGFR>60.
• Women who are lactating or breastfeeding.
• Have any other condition that precludes the subject from following and completing the protocol, in the opinion of the investigator.
• Are investigator site personnel directly affiliated with this study and/or their immediate families (spouse, parent, child, or sibling).
• Are currently enrolled in, or discontinued from a clinical trial involving an investigational product or non-approved use of a drug or device within the last 4 weeks or a period of at least 5 half-lives of the last administration of the drug, whichever is longer, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

Contacts and Locations

Contacts

Contact: Alex G Ortega- Loayza, MD, MCR; 503-418-3376; ortegalo@ohsu.edu

Contact: Morgan Vague, BA; 713-628-4926; vague@ohsu.edu

Locations

United States, Oregon

Oregon Health and Science University; Recruiting

Portland, Oregon, United States, 97239

Contact: Alex Ortega, MD, MCR 503-418-3376 ortegalo@ohsu.edu

Contact: Morgan Vague, BA 7136284926 vague@ohsu.edu

Sponsors and Collaborators

Oregon Health and Science University

Investigators

• Principal Investigator: Alex G Ortega-Loayza, MD, MCR; Oregon Health & Science University, Department of Dermatology

More Information

Publications:

Braswell SF, Kostopoulos TC, Ortega-Loayza AG. Pathophysiology of pyoderma gangrenosum (PG): an updated review. J Am Acad Dermatol. 2015 Oct;73(4):691-8. doi: 10.1016/j.jaad.2015.06.021. Epub 2015 Aug 5. Review.

Alves de Medeiros AK, Speeckaert R, Desmet E, Van Gele M, De Schepper S, Lambert J. JAK3 as an Emerging Target for Topical Treatment of Inflammatory Skin Diseases. PLoS One. 2016 Oct 6;11(10):e0164080. doi: 10.1371/journal.pone.0164080. eCollection 2016.

Shanmugam VK, McNish S, Shara N, Hubley KJ, Kallakury B, Dunning DM, Attinger CE, Steinberg JS. Chronic leg ulceration associated with polycythemia vera responding to ruxolitinib (Jakafi(®)). J Foot Ankle Surg. 2013 Nov-Dec;52(6):781-5. doi: 10.1053/j.jfas.2013.07.003. Epub 2013 Aug 14.

Nasifoglu S, Heinrich B, Welzel J. Successful therapy for pyoderma gangrenosum with a Janus kinase 2 inhibitor. Br J Dermatol. 2018 Aug;179(2):504-505. doi: 10.1111/bjd.16468. Epub 2018 May 21.

Kochar B, Herfarth N, Mamie C, Navarini AA, Scharl M, Herfarth HH. Tofacitinib for the Treatment of Pyoderma Gangrenosum. Clin Gastroenterol Hepatol. 2019 Apr;17(5):991-993. doi: 10.1016/j.cgh.2018.10.047. Epub 2018 Nov 4.

Palanivel JA, Macbeth AE, Levell NJ. Pyoderma gangrenosum in association with Janus kinase 2 (JAK2V617F) mutation. Clin Exp Dermatol. 2013 Jan;38(1):44-6. doi: 10.1111/j.1365-2230.2012.04375.x. Epub 2012 May 21.

Ortega-Loayza AG, Nugent WH, Lucero OM, Washington SL, Nunley JR, Walsh SW. Dysregulation of inflammatory gene expression in lesional and nonlesional skin of patients with pyoderma gangrenosum. Br J Dermatol. 2018 Jan;178(1):e35-e36. doi: 10.1111/bjd.15837. Epub 2017 Dec 5.

Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, Brown JP, Cohen A, Kim H. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013 Aug 15;9(1):30. doi: 10.1186/1710-1492-9-30.

Smolen JS, Genovese MC, Takeuchi T, Hyslop DL, Macias WL, Rooney T, Chen L, Dickson CL, Riddle Camp J, Cardillo TE, Ishii T, Winthrop KL. Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment. J Rheumatol. 2019 Jan;46(1):7-18. doi: 10.3899/jrheum.171361. Epub 2018 Sep 15. Erratum in: J Rheumatol. 2019 Dec;46(12):1648-1649.

• Responsible Party: Alex Ortega Loayza, Associate Professor of Dermatology, School of Medicine, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT04901325
• Other Study ID Numbers: Baricitinib for PG Treatment
• First Posted: May 25, 2021
• Last Update Posted: September 10, 2021
• Last Verified: September 2021

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 Alex Ortega Loayza, Oregon Health and Science University:

Baricitinib; JAK Kinase Inhibitors

Additional relevant MeSH terms:

Skin Diseases; Pyoderma; Pyoderma Gangrenosum; Skin Ulcer; Skin Diseases, Vascular