Tofacitinib for Immune Skin Conditions in Down Syndrome

• ClinicalTrials.gov Identifier: NCT04246372
• Recruitment Status: Recruiting
• First Posted: January 29, 2020
• Last Update Posted: January 19, 2023
• Sponsor: University of Colorado, Denver
• Collaborator: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

People with Down syndrome (DS) display widespread immune dysregulation, including several immune skin conditions. This study hypothesizes that pharmacological inhibition of the increased interferon (IFN) signaling seen in DS is safe and could improve associated skin conditions.

The study evaluates the safety and efficacy treatment with Tofacitinib, an FDA-approved drug known to block IFN signaling, in adolescents and adults with DS and an autoimmune and/or autoinflammatory skin condition. Investigators will also measure the impact of interferon inhibition on a variety of molecular markers, as well as the cognitive abilities and quality of life of participants.

Condition or disease	Intervention/treatment	Phase
Down Syndrome; Alopecia Areata; Atopic Dermatitis / Eczema; Hidradenitis Suppurativa; Vitiligo; Psoriasis	Drug: Tofacitinib	Phase 2

Detailed Description:

Trisomy 21 (T21) is the most common human chromosomal disorder, occurring in ~1/700 live births, leading to the condition known as Down syndrome (DS). Importantly, people with DS display widespread immune dysregulation and over half of adults with T21 are affected by one or more autoimmune conditions, including several immune skin conditions. The driving hypothesis for this study is that hyperactivation of interferon (IFN) signaling leads to myriad immune-driven diseases and immunological phenotypes in people with DS, and that pharmacological inhibition of IFN signaling could have multidimensional therapeutic benefits in this population.

This study utilizes Tofacitinib, an FDA-approved drug known to block IFN signaling and several accompanying inflammatory pathways, to reduce IFN signaling in DS and to measure its effects via multidimensional endpoints. Previous studies and current clinical trials indicate that Janus kinase (JAK) inhibitors, such as Tofacitinib, can block inflammatory pathways and may have beneficial effects on immune skin conditions. Further, inhibition of chronically active IFN signaling in DS with Tofacitinib may attenuate other core drivers of immune dysregulation, leading to improvements in other immune diseases and conditions common to DS that are potentially driven by inflammation, such as cognitive deficits. Investigators will test these hypotheses using a battery of immune and molecular assessments, as well as cognitive testing and quality of life measures. This clinical trial evaluates adolescent and adult participants with DS during eight study visits over an approximate five month period.

Specific Aims:

1. To define the safety profile of JAK inhibition in people with DS,
2. To determine the impact of JAK inhibition on the immune dysregulation caused by trisomy 21,
3. To define the impact of JAK inhibition on immune skin conditions in DS, and
4. To characterize the impact of JAK inhibition on cognition and quality of life in DS.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: All participants will receive the investigational product, Tofacitinib.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety and Efficacy of Tofacitinib for Immune Skin Conditions in Down Syndrome
• Actual Study Start Date: October 21, 2020
• Estimated Primary Completion Date: August 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: On Treatment; Tofacitinib 5mg oral tablets twice daily for 16 weeks	Drug: Tofacitinib; Treatment with oral Tofacitinib for immune mediated skin conditions in adults with Down syndrome; Other Name: Xeljanz

Outcome Measures

Primary Outcome Measures :

1. Safety as Assessed by Number of Serious Adverse Events (SAE) [ Time Frame: Up to Week 18 ]
   Number of SAEs that are definitely related to Tofacitinib treatment
2. Change in Interferon (IFN) Scores in the Transcriptome of White Blood Cells [ Time Frame: Baseline and 16 weeks ]
   A composite score used to represent the change in activation of the interferon pathway. Possible scores increase from zero with higher scores indicating a more activated interferon pathway.

Secondary Outcome Measures :

1. Change in Investigator's Global Assessment (IGA) [ Time Frame: Baseline and 16 weeks ]
   The IGA will be used to assess overall changes in severity across five skin conditions (alopecia, atopic dermatitis, vitiligo, psoriasis and hidradenitis suppurativa) scored from 0 (clear) to 4 - 5 (very severe).
2. Change in Dermatology Life Quality Index (DLQI) [ Time Frame: Baseline and 16 weeks ]
   The DLQI will be used to assess participant-reported impact of skin conditions on self-image, relationships, and daily activities. Possible total scores range from 0-30, with higher scores indicating a more impaired quality of life.
3. Change in Eczema Area and Severity Index (EASI) Score in Participants with Atopic Dermatitis [ Time Frame: Baseline and 16 weeks ]
   The EASI will be used to assess changes in the extent (area) and severity of atopic dermatitis (eczema). Each of four sites (head, upper limbs, trunk, and lower limbs), are weighted by overall contribution to body surface area and separately scored by using four parameters (erythema, infiltration, excoriations, lichenification), each of which is graded on a severity scale of 0 (none) to 4 (severe), as well as degree of involvement. Possible total scores range from 0-72, with higher scores indicating a more severe involvement.
4. Change in Severity of Alopecia Tool (SALT) Score in Participants with Alopecia [ Time Frame: Baseline and 16 weeks ]
   The SALT will be used to assess changes in degree and extent (area) of hair loss due to alopecia on the head. Each of four scalp sites (left side, right side, top and back) are weighted by overall contribution to scalp surface area and rated for percent involvement. Possible total scores range from 0-72, with higher scores indicating a larger affected area.
5. Change in Modified Sartorius Score (MSS) Score in Participants with Hidradenitis Suppurativa [ Time Frame: Baseline and 16 weeks ]
   The MSS will be used to assess changes in areas affected by hidradenitis suppurativa. Each of seven sites (right/left axillae, right/left groin, right/left gluteal, other) are scored by number of lesions, distance between lesions, and presence of normal skin between lesions. Possible total scores range up from 0 with no maximum, with higher scores indicating a more severe involvement.
6. Change in Psoriasis Area and Severity Index (PASI) Score in Participants with Psoriasis [ Time Frame: Baseline and 16 weeks ]
   The PASI will be used to assess changes in extent (area) and severity of psoriasis. Each of four sites (head, upper limbs, trunk, and lower limbs) are weighted by overall contribution to body surface area and separately scored by degree of involvement and three additional parameters (erythema, induration and desquamation), each of which is graded on a severity scale of 0 (Not severe) to 4 (very severe). Possible total scores range from 0-72, with higher scores indicating a more severe involvement.
7. Change in Vitiligo Extent Tensity Index (VETI) in Participants with Vitiligo [ Time Frame: Baseline and 16 weeks ]
   The VETI will be used to assess changes in extent (area) of skin affected by vitiligo. Each of five sites (head, trunk, upper limbs, lower limbs, genitalia) are weighted by overall contribution to body surface area and rated for degree of de-pigmentation scale of Stage 0 (normal skin) to Stage 5 (complete de-pigmentation plus significant hair whitening) and percent involvement. Possible scores range from 0-55.5, with a higher score indicating a higher degree of involvement.
8. A composite score generated using the Meso Scale Discovery (MSD) platform used to assess inflammatory changes in plasma. [ Time Frame: Baseline and 16 weeks ]
   Possible total scores increase from zero, with higher scores indicating a higher inflammatory state.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 50 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Males or females with DS between 12 and 50 years of age who weigh at least 40 kg.

• Diagnosis of at least one active immune skin condition, including but not limited to:

  1. Moderate-to-severe atopic dermatitis
  2. Alopecia areata affecting at least 25% of the scalp
  3. Moderate-to-severe hidradenitis suppurativa
  4. Moderate-to-severe psoriasis
  5. Moderate-to-severe vitiligo.
• Be willing to avoid pregnancy or fathering children.
• Must present with a study partner or legal guardian who can complete, or assist with completing, study materials as appropriate.

Exclusion Criteria

• Weigh less than 40 kg.
• Pregnancy or breast feeding.
• No study partner or legal guardian.
• Vaccination with live attenuated virus within six weeks of inclusion in the study or planned during the study.
• Clinically significant chronic or active viral infection including but not limited to HIV, hepatitis, CMV, EBV, HSV.
• Severe renal impairment.
• History of malignant solid tumor cancer within five years prior to study entry or where there is current evidence of recurrent or metastatic disease.
• Poor venous access not allowing repeated blood tests or non-compliance with venipuncture requirements.
• Prior treatment with a JAK inhibitor or with an investigational agent, device, or procedure within 21 days of enrollment.
• Concomitant treatment with other immunosuppressants (e.g. corticosteroids, methotrexate) or strong CP3A4 or CYP2C19 inhibitors or inducers (e.g. ketoconazole, fluconazole).
• Known allergies, hypersensitivity, or intolerance to Tofacitinib.
• History of thrombotic disorder.
• Superficial skin infection within 2 weeks of inclusion in the study.
• History of disseminated herpes zoster, disseminated herpes simplex, or recurrent localized dermatomal herpes zoster.
• Intravenous antimicrobial therapy within 3 months of inclusion in the study.
• Oral antimicrobials within 2 weeks of inclusion in the study.
• Participants may be excluded for other unforeseen reasons at the study doctor's discretion.
• Unable to provide assent in cases where informed consent is obtained from other authorized representative.
• Kidney transplant within the last two years
• Any history of heart attack or stroke.
• Any history of lymphoma.
• Past or current smokers.
• Not fully vaccinated against COVID-19 in accordance with current CDC definition.

Contacts and Locations

Contacts

Contact: Angela Rachubinski, PhD; 303-724-7366; DSresearch@cuanschutz.edu

Contact: Belinda Enriquez Estrada, MS; 303-724-0491; DSresearch@cuanschutz.edu

Locations

United States, Colorado

Linda Crnic Institute for Down Syndrome; Recruiting

Aurora, Colorado, United States, 80045

Sponsors and Collaborators

University of Colorado, Denver

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

• Principal Investigator: Joaquin Espinosa, PhD; Linda Crnic Institute, University of Colorado Anschutz Medical Campus
• Principal Investigator: David Norris, MD; Department of Dermatology, University of Colorado Anschutz Medical Campus

More Information

Additional Information:

The Crnic Institute Human Trisome Project 

Publications:

Rachubinski AL, Estrada BE, Norris D, Dunnick CA, Boldrick JC, Espinosa JM. Janus kinase inhibition in Down syndrome: 2 cases of therapeutic benefit for alopecia areata. JAAD Case Rep. 2019 Apr 5;5(4):365-367. doi: 10.1016/j.jdcr.2019.02.007. eCollection 2019 Apr. No abstract available.

Pham AT, Rachubinski AL, Enriquez-Estrada B, Worek K, Griffith M, Espinosa JM. JAK inhibition for treatment of psoriatic arthritis in Down syndrome. Rheumatology (Oxford). 2021 Sep 1;60(9):e309-e311. doi: 10.1093/rheumatology/keab203. No abstract available.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT04246372
• Other Study ID Numbers: 19-1362; R33AR077495 ( U.S. NIH Grant/Contract )
• First Posted: January 29, 2020
• Last Update Posted: January 19, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data will be made available for all primary outcome measures.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR); Analytic Code
• Time Frame: Data will be made available upon publication in a peer-reviewed journal.
• Access Criteria: Data access requests will be reviewed by the sponsor-investigator and collaborators.

• 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 University of Colorado, Denver:

Interferon; Autoimmunity; Down syndrome; Skin disorder; JAK inhibitor; Inflammation; JAK/STAT; Dermatology

Additional relevant MeSH terms:

Hidradenitis Suppurativa; Down Syndrome; Dermatitis; Alopecia; Vitiligo; Hidradenitis; Alopecia Areata; Skin Diseases; Syndrome; Disease; Pathologic Processes; Genetic Diseases, Inborn; Hypotrichosis; Hair Diseases; Pathological Conditions, Anatomical; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Chromosome Disorders; Hypopigmentation; Pigmentation Disorders; Sweat Gland Diseases; Skin Diseases, Bacterial; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Skin Diseases, Infectious