Alopecia Areata, Atopic Dermatitis / Eczema, Down Syndrome, Hidradenitis Suppurativa, Psoriasis, Vitiligo
Conditions
Keywords
Interferon, Autoimmunity, Down syndrome, Skin disorder, JAK inhibitor, Inflammation, JAK/STAT, Dermatology
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: 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.
Interventions
DRUGTofacitinib
Treatment with oral Tofacitinib for immune mediated skin conditions in adults with Down syndrome
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All participants will receive the investigational product, Tofacitinib.
Eligibility
Sex/Gender
ALL
Age
12 Years to 50 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Serious Adverse Events (SAE) Definitely Related to Tofacitinib Treatment. | Baseline to 16 weeks | Safety as measured by the number of serious adverse events definitely related to tofacitinib treatment. |
| Change in Whole Blood Transcriptome Interferon (IFN) Score | Baseline and 16 weeks | The Interferon Score is a composite molecular measure used to quantify activation of the interferon signaling pathway. Interferon Scores are calculated by summing standardized expression (i.e. (expression value - mean) / standard deviation) of a predefined panel of 16 interferon-stimulated genes, measured by RNA-sequencing of whole blood samples. The resulting composite value provides an integrated measure of interferon pathway activity, with higher scores indicating greater pathway activation. No clinical relevance threshold has been established. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Eczema Area and Severity Index (EASI) Score in Participants With Atopic Dermatitis | Baseline and 16 weeks | The EASI is 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 | Baseline and 16 weeks | The SALT is used to assess changes in degree and extent (area) of hair loss due to alopecia areata 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 | Baseline and 16 weeks | The MSS is 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 Investigator's Global Assessment (IGA) | Baseline and 16 weeks | The IGA is used to assess overall changes in severity across five skin conditions (alopecia areata, atopic dermatitis, vitiligo, psoriasis and hidradenitis suppurativa) scored from 0 (clear) to 4 - 5 (very severe). |
| Change in Vitiligo Extent Tensity Index (VETI) in Participants With Vitiligo | Baseline and 16 weeks | The VETI is 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 Cytokine Score Generated Using the Meso Scale Discovery (MSD) Platform Used to Assess Inflammatory Changes in Plasma. | Baseline and 16 weeks | The Cytokine Score is a composite molecular measure used to quantify inflammatory changes. Cytokine Scores are calculated by summing standardized abundance (i.e. (abundance value - mean) / standard deviation) of a predefined panel of four inflammatory cytokines, measured in plasma samples using the Meso Scale Discovery platform. The resulting composite value provides an integrated measure of inflammatory activity, with higher scores indicating a more inflammatory state. No clinical relevance threshold has been established. |
| Change in Psoriasis Area and Severity Index (PASI) Score in Participants With Psoriasis | Baseline and 16 weeks | The PASI is 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 Dermatology Life Quality Index (DLQI) | Baseline and 16 weeks | The DLQI is 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| On Treatment Tofacitinib 5mg oral tablets twice daily for 16 weeks. | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | On Treatment |
|---|---|
| Age, Continuous | 22 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 40 Participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 24 Participants |
| Whole Blood Transcriptome Interferon (IFN) Score | 5.28 IFN score |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 47 |
| other Total, other adverse events | 45 / 47 |
| serious Total, serious adverse events | 1 / 47 |
Outcome results
Primary
Change in Whole Blood Transcriptome Interferon (IFN) Score
The Interferon Score is a composite molecular measure used to quantify activation of the interferon signaling pathway. Interferon Scores are calculated by summing standardized expression (i.e. (expression value - mean) / standard deviation) of a predefined panel of 16 interferon-stimulated genes, measured by RNA-sequencing of whole blood samples. The resulting composite value provides an integrated measure of interferon pathway activity, with higher scores indicating greater pathway activation. No clinical relevance threshold has been established.
Time frame: Baseline and 16 weeks
Population: All participants meeting medication compliance criteria and for whom IFN scores were available at Baseline and 16 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| On Treatment | Change in Whole Blood Transcriptome Interferon (IFN) Score | -8.41 Change in IFN score at 16 weeks |
p-value: 0.00000621t-test, 2 sided
Primary
Number of Serious Adverse Events (SAE) Definitely Related to Tofacitinib Treatment.
Safety as measured by the number of serious adverse events definitely related to tofacitinib treatment.
Time frame: Baseline to 16 weeks
Population: All participants who attended Baseline appointment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| On Treatment | Number of Serious Adverse Events (SAE) Definitely Related to Tofacitinib Treatment. | 0 Serious Adverse Events |
Secondary
A Composite Cytokine Score Generated Using the Meso Scale Discovery (MSD) Platform Used to Assess Inflammatory Changes in Plasma.
The Cytokine Score is a composite molecular measure used to quantify inflammatory changes. Cytokine Scores are calculated by summing standardized abundance (i.e. (abundance value - mean) / standard deviation) of a predefined panel of four inflammatory cytokines, measured in plasma samples using the Meso Scale Discovery platform. The resulting composite value provides an integrated measure of inflammatory activity, with higher scores indicating a more inflammatory state. No clinical relevance threshold has been established.
Time frame: Baseline and 16 weeks
Population: All participants meeting medication compliance criteria and for whom Cytokine scores were collected at Baseline and 16 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| On Treatment | A Composite Cytokine Score Generated Using the Meso Scale Discovery (MSD) Platform Used to Assess Inflammatory Changes in Plasma. | -2.15 Change in score at 16 weeks |
p-value: 9e-8t-test, 2 sided
Secondary
Change in Dermatology Life Quality Index (DLQI)
The DLQI is 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.
Time frame: Baseline and 16 weeks
Population: All participants meeting medication compliance criteria and for whom DLQI scores were collected at Baseline and 16 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| On Treatment | Change in Dermatology Life Quality Index (DLQI) | -2.88 Change in score at 16 weeks |
p-value: 4e-8t-test, 2 sided
Secondary
Change in Eczema Area and Severity Index (EASI) Score in Participants With Atopic Dermatitis
The EASI is 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.
Time frame: Baseline and 16 weeks
Population: All participants meeting medication compliance criteria and for whom qualifying EASI scores were collected at Baseline and 16 weeks. None of the completed trial participants had qualifying EASI scores for atopic dermatitis.
Secondary
Change in Investigator's Global Assessment (IGA)
The IGA is used to assess overall changes in severity across five skin conditions (alopecia areata, atopic dermatitis, vitiligo, psoriasis and hidradenitis suppurativa) scored from 0 (clear) to 4 - 5 (very severe).
Time frame: Baseline and 16 weeks
Population: All participants meeting medication compliance criteria and for whom IGA scores were collected at Baseline and 16 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On Treatment | Change in Investigator's Global Assessment (IGA) | -1.31 Change in score at 16 weeks | 95% Confidence Interval 0.5 |
p-value: 6.1e-7t-test, 2 sided
Secondary
Change in Modified Sartorius Score (MSS) Score in Participants With Hidradenitis Suppurativa
The MSS is 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.
Time frame: Baseline and 16 weeks
Population: All participants meeting medication compliance criteria and for whom qualifying MSS scores were collected at Baseline and 16 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| On Treatment | Change in Modified Sartorius Score (MSS) Score in Participants With Hidradenitis Suppurativa | -19.56 Change in score at 16 weeks |
p-value: 0.00399t-test, 2 sided
Secondary
Change in Psoriasis Area and Severity Index (PASI) Score in Participants With Psoriasis
The PASI is 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.
Time frame: Baseline and 16 weeks
Population: All participants meeting medication compliance criteria and for whom qualifying PASI scores were collected at Baseline and 16 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| On Treatment | Change in Psoriasis Area and Severity Index (PASI) Score in Participants With Psoriasis | -7.3 Change in score at 16 weeks |
p-value: 0.146t-test, 2 sided
Secondary
Change in Severity of Alopecia Tool (SALT) Score in Participants With Alopecia
The SALT is used to assess changes in degree and extent (area) of hair loss due to alopecia areata 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.
Time frame: Baseline and 16 weeks
Population: All participants meeting medication compliance criteria and for whom qualifying SALT scores were collected at Baseline and 16 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| On Treatment | Change in Severity of Alopecia Tool (SALT) Score in Participants With Alopecia | -28.10 Change in score at 16 weeks |
p-value: 0.0000393t-test, 2 sided
Secondary
Change in Vitiligo Extent Tensity Index (VETI) in Participants With Vitiligo
The VETI is 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.
Time frame: Baseline and 16 weeks
Population: All participants meeting medication compliance criteria and for whom qualifying VETI scores were collected at Baseline and 16 weeks. None of the completed trial participants had qualifying VETI scores for vitiligo.