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Tofacitinib for Immune Skin Conditions in Down Syndrome

Primary Purpose

Down Syndrome, Alopecia Areata, Atopic Dermatitis / Eczema

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Tofacitinib

About this trial

This is an interventional treatment trial for Down Syndrome focused on measuring Interferon, Autoimmunity, Down syndrome, Skin disorder, JAK inhibitor, Inflammation, JAK/STAT, Dermatology

Eligibility Criteria

12 Years - 50 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Linda Crnic Institute for Down SyndromeRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

On Treatment

Arm Description

Tofacitinib 5mg oral tablets twice daily for 16 weeks

Outcomes

Primary Outcome Measures

Safety as Assessed by Number of Serious Adverse Events (SAE)

Number of SAEs that are definitely related to Tofacitinib treatment

Change in Interferon (IFN) Scores in the Transcriptome of White Blood Cells

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

Change in Investigator's Global Assessment (IGA)

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).

Change in Dermatology Life Quality Index (DLQI)

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.

Change in Eczema Area and Severity Index (EASI) Score in Participants with Atopic Dermatitis

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.

Change in Severity of Alopecia Tool (SALT) Score in Participants with Alopecia

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.

Change in Modified Sartorius Score (MSS) Score in Participants with Hidradenitis Suppurativa

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.

Change in Psoriasis Area and Severity Index (PASI) Score in Participants with Psoriasis

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.

Change in Vitiligo Extent Tensity Index (VETI) in Participants with Vitiligo

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.

A composite score generated using the Meso Scale Discovery (MSD) platform used to assess inflammatory changes in plasma.

Possible total scores increase from zero, with higher scores indicating a higher inflammatory state.

Full Information

NCT ID

NCT04246372

First Posted

January 27, 2020

Last Updated

January 17, 2023

Sponsor

University of Colorado, Denver

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT04246372

Brief Title

Tofacitinib for Immune Skin Conditions in Down Syndrome

Official Title

Safety and Efficacy of Tofacitinib for Immune Skin Conditions in Down Syndrome

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Recruiting

Study Start Date

October 21, 2020 (Actual)

Primary Completion Date

August 2024 (Anticipated)

Study Completion Date

December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Colorado, Denver

Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Down Syndrome, Alopecia Areata, Atopic Dermatitis / Eczema, Hidradenitis Suppurativa, Vitiligo, Psoriasis

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Model Description

All participants will receive the investigational product, Tofacitinib.

Masking

None (Open Label)

Allocation

N/A

Enrollment

47 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

On Treatment

Arm Type

Experimental

Arm Description

Tofacitinib 5mg oral tablets twice daily for 16 weeks

Intervention Type

Drug

Intervention Name(s)

Tofacitinib

Other Intervention Name(s)

Xeljanz

Intervention Description

Treatment with oral Tofacitinib for immune mediated skin conditions in adults with Down syndrome

Primary Outcome Measure Information:

Title

Safety as Assessed by Number of Serious Adverse Events (SAE)

Description

Number of SAEs that are definitely related to Tofacitinib treatment

Time Frame

Up to Week 18

Title

Change in Interferon (IFN) Scores in the Transcriptome of White Blood Cells

Description

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.

Time Frame

Baseline and 16 weeks

Secondary Outcome Measure Information:

Title

Change in Investigator's Global Assessment (IGA)

Description

Time Frame

Baseline and 16 weeks

Title

Change in Dermatology Life Quality Index (DLQI)

Description

Time Frame

Baseline and 16 weeks

Title

Change in Eczema Area and Severity Index (EASI) Score in Participants with Atopic Dermatitis

Description

Time Frame

Baseline and 16 weeks

Title

Change in Severity of Alopecia Tool (SALT) Score in Participants with Alopecia

Description

Time Frame

Baseline and 16 weeks

Title

Change in Modified Sartorius Score (MSS) Score in Participants with Hidradenitis Suppurativa

Description

Time Frame

Baseline and 16 weeks

Title

Change in Psoriasis Area and Severity Index (PASI) Score in Participants with Psoriasis

Description

Time Frame

Baseline and 16 weeks

Title

Change in Vitiligo Extent Tensity Index (VETI) in Participants with Vitiligo

Description

Time Frame

Baseline and 16 weeks

Title

A composite score generated using the Meso Scale Discovery (MSD) platform used to assess inflammatory changes in plasma.

Description

Possible total scores increase from zero, with higher scores indicating a higher inflammatory state.

Time Frame

Baseline and 16 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

12 Years

Maximum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility 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: Moderate-to-severe atopic dermatitis Alopecia areata affecting at least 25% of the scalp Moderate-to-severe hidradenitis suppurativa Moderate-to-severe psoriasis 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Angela Rachubinski, PhD

Phone

303-724-7366

DSresearch@cuanschutz.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Belinda Enriquez Estrada, MS

Phone

303-724-0491

DSresearch@cuanschutz.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joaquin Espinosa, PhD

Organizational Affiliation

Linda Crnic Institute, University of Colorado Anschutz Medical Campus

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

David Norris, MD

Organizational Affiliation

Department of Dermatology, University of Colorado Anschutz Medical Campus

Official's Role

Principal Investigator

Facility Information:

Facility Name

Linda Crnic Institute for Down Syndrome

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Individual Site Status

Recruiting

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

De-identified individual participant data will be made available for all primary outcome measures.

IPD Sharing Time Frame

Data will be made available upon publication in a peer-reviewed journal.

IPD Sharing Access Criteria

Data access requests will be reviewed by the sponsor-investigator and collaborators.

Citations:

PubMed Identifier

31008170

Citation

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.

Results Reference

background

PubMed Identifier

33630031

Citation

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.

Results Reference

background

Links:

URL

http://www.trisome.org

Description

The Crnic Institute Human Trisome Project

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Tofacitinib for Immune Skin Conditions in Down Syndrome

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