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Systemic SclerosisPhase 1/2TOFA-SScNCT03274076

Evaluation of Tofacitinib in Early Diffuse Cutaneous Systemic Sclerosis (dcSSc)

A Phase 1/2 study testing Tofacitinib in people with Systemic Sclerosis and Scleroderma, run by University of Michigan at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This Phase I/II placebo controlled trial will evaluate tofacitinib in subjects with diffuse cutaneous systemic scleroderma (dcSSc). This trial is intended to provide safety, and tolerability data in participants with dcSSc when dosed to target exposures similar to that used in adult participants with rheumatoid… Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Systemic Sclerosis, Scleroderma
What is being tested?
Tofacitinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
15 participants
Where
2 sitesUnited States
Study dates
25 Sep 2017to 15 Nov 2019
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Diagnosis of systemic sclerosis (SSc), as classified using the 2013 American College of Rheumatology/ European Union League Against Rheumatism classification of SSc.
  • Diffuse Cutaneous Systemic Sclerosis (dcSSc) as defined by 2001 LeRoy and Medsger
  • Disease duration ≤ 60 months (defined as time from the first non-Raynaud phenomenon manifestation)
  • Modified Rodnan Skin Score (mRSS) units ≥ 10 and ≤ 45 at screening.
  • Agreement to receive varicella-zoster vaccination (Zostavax®) or have received vaccination prior to screening.
  • Oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) are permitted if the patient is on a stable dose regimen for ≥ 2 weeks prior to and including the baseline visit.
  • Ability to provide informed consent.

Who cannot join

  • Rheumatic disease other than dcSSc; it is acceptable to include patients with fibromyalgia, Sjogren syndrome, and scleroderma-associated myopathy
  • Limited cutaneous SSc or sine scleroderma
  • Major surgery (including joint surgery) within 8 weeks prior to baseline.
  • Any infected ulcer at screening
  • Subjects with any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection (e.g., chronic pyelonephritis, osteomyelitis, or bronchiectasis)
  • Oral corticosteroids >10 mg/day of prednisone or equivalent.
Show all 46Show fewer
  • Hydroxychloroquine >400 mg/day, methotrexate >25 mg/week, D-Penicillamine >1000mg/day or mycophenolate mofetil > 2 grams/day prior to baseline. **Subjects can be on combination therapy of hydroxychloroquine and methotrexate or hydroxychloroquine and mycophenolate mofetil and must have been on a stable dose for at least 1 month prior to baseline visit.
  • Prior history of treatment in the 3 months prior to baseline with biological disease modifying anti-rheumatic drugs (DMARDs)potent immunosuppressants such as cyclosporine and azathioprine
  • Treatment with etanercept within ≤ 2 weeks of baseline: infliximab, certolizumab, golimumab, abatacept, tocilizumab, or adalimumab within ≤ 8 weeks of baseline; and anakinra within ≤ 1 week prior to the baseline visit.
  • Intravenous corticosteroids within 2 weeks prior to baseline visit.
  • Treatment with any investigational agent ≤ 4 weeks prior to baseline (or 5 half-lives of the investigational drug, whichever is longer)
  • Other investigational or marketed biologics with immunomodulatory properties within 3 months prior to baseline.
  • Treatment with anti-CD20 6 months prior to baseline and B cell counts <LLN
  • Any prior treatment with cell-depleting therapies other than anti-CD20 such as CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19
  • Any prior treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation
  • Vaccinated or exposed to a live/attenuated vaccine (other than Zostavax®) ≤ 6 weeks prior to baseline; or is expected to be vaccinated or to have household exposure to these vaccines during treatment or during the 6 weeks following discontinuation of study medication. (**See additional inclusion for obtaining Zostavax® prior to entering the study)
  • Pulmonary disease with Forced Vital Capacity (FVC) ≤ 50% of predicted, or Diffusing capacity of the lungs for carbon monoxide (DLCO),(uncorrected for hemoglobin) ≤ 40% of predicted
  • History of pulmonary arterial hypertension (PAH) with mean PAP> 30 mmHg on right heart catheterization requiring subcutaneous or intravenous prostacyclin or dual use of oral PAH therapies
  • Subjects at risk for tuberculosis (TB):
  • Specifically excluded from this study will be participants with a history of active TB within the last 3 years, even if it was treated; a history of active TB greater than 3 years ago, unless there is documentation that the prior anti-TB treatment was appropriate in duration and type; current clinical, radiographic, or laboratory evidence of active TB; (TB results within 30 days of screening will be accepted and will not to be repeated. B. Latent TB at or within 30 days of screening, history of or current positive purified protein derivative tuberculin skin test (PPD) ( >5mm induration, regardless of Bacille Calmette Guerin [BCG] vaccine and/or QuantiFERON Gold, a negative chest x-ray, and no symptoms or risk factors), unless one month of prophylaxis has been completed prior to inclusion
  • An indeterminate QuantiFERON® unless followed by a subsequent negative PPD or negative QuantiFERON® or a consultation with and clearance by local infectious disease (ID) department is required.
  • Positive for hepatitis B surface antigen at or within 30 days of screening
  • Positive for hepatitis C antigen at or within 30 days of screening
  • Current or recent history of uncontrolled clinically significant renal, hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic disease.
  • History of human immunodeficiency virus (HIV), (as determined by medical records or patient reported).
  • History of diverticulitis or chronic, ulcerative lower gastrointestinal (GI) disease such as Crohns disease, ulcerative colitis, or other symptomatic, lower GI conditions that might predispose a patient to perforations.
  • Pregnant or breastfeeding female subjects; and female subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in the protocol for the duration of the study and for at least 28 days after discontinuation of study drug.
  • Severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase risk associated with study participation and in the judgment of the investigator would make the subject inappropriate for entry into this study.
  • History of systemic sclerosis (SSc) Renal Crisis within the 6 months prior to baseline.
  • Any of the following lab results at screening:
  • Hemoglobin <9 g/dL or Hematocrit <30%
  • White Blood Cell count <3.0 x 109/L;
  • Absolute Neutrophil count <1.2 x 109/L;
  • White Blood Cell count <3.0 x 109/L;
  • Absolute Neutrophil count <1.2 x 109/L;
  • Platelet count <100 x 109/L;
  • Absolute Lymphocyte count <0.75 x 109/L.
  • ALT or AST > 1.5 × the upper limit of normal (ULN) of normal at screening or any uncontrolled clinically significant laboratory abnormality that would affect interpretation of study data or the patient's participation in the study
  • Total bilirubin > upper limit of normal (ULN) at Screening.
  • Estimated glomerular filtration rate [GFR] <40mL/min/1.73 m2
  • Prior rituximab use without documentation of normalized b cell counts.
  • History of recurrent (more than one episode) herpes zoster or disseminated (at least one episode) herpes zoster, or disseminated (at least one episode) herpes simplex
  • History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease.
  • History of any malignancy in the last 5 years with the exception of adequately treated or excised basal cell or squamous cell or cervical cancer in situ.
  • Significant trauma or surgery procedure within 1 month prior to first dose of study drug.
  • History of alcohol or substance abuse, unless in full remission for greater than 6 months prior to first dose of study drug.

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • University of Michigan

    Ann Arbor, Michigan, 48104

  • University of Pittsburgh

    Pittsburgh, Pennsylvania, 15261

Other trials in United States

About this study

Official title: Evaluation of Tofacitinib in Early Diffuse Cutaneous Systemic Sclerosis (dcSSc): A Phase I/II Two Center Safety and Tolerability Study

This Phase I/II placebo controlled trial will evaluate tofacitinib in subjects with diffuse cutaneous systemic scleroderma (dcSSc). This trial is intended to provide safety, and tolerability data in participants with dcSSc when dosed to target exposures similar to that used in adult participants with rheumatoid arthritis.

Read the detailed description

The purpose of this clinical research study is to evaluate the safety, tolerability and efficacy of treatment with tofacitinib (study drug) versus placebo (a substance with no active ingredients and therefore may have no treatment benefit) in people with diffuse cutaneous systemic scleroderma. Subjects will be randomized to tofacitinib vs. placebo in a 2:1 ratio at 5 mg twice a day for 24 weeks. Subjects will then be offered to participate in an open label phase during which they will receive tofacitinib 5 mg twice a day for 24 weeks.

Being tested
Tofacitinib, Placebo Oral Tablet
Keywords
diffuse, scleroderma, systemic sclerosis
Medical subject headings
Scleroderma, Systemic, Scleroderma, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TofacitinibDrug

    Also called Xeljanz

    Oral medication tofacitinib 5 mg twice a day for 24 weeks.

  • Placebo Oral TabletDrug

    Oral Placebo 5 mg twice a day for 24 weeks

Study groups in NCT03274076
Study groupRoleWhat they receive
TofacitinibActive comparator5mg Tofacitinib twice a day
Receives: Drug: Tofacitinib
PlaceboPlacebo comparator5mg Placebo twice a day
Receives: Drug: Placebo Oral Tablet

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants Who Experience Grade 3 or Higher Adverse Events That Occur at or Before Week 24

    Primary outcome is met if any participants experience a grade 3 or higher event prior to Week 24. A grade 3 AE would constitute as "severe". Grading was following using CTCAE v 4.03.

    Note that the planned statistical analysis (Fisher's exact test) could not be performed because there were no events.

    Measured: 24 weeks

Secondary outcomes (5)

  1. Number of Grade 3 (Severe) or Higher Adverse Events That Occur Throughout the Study

    Grade 3 or higher adverse events (AEs) assessed throughout the study ( 48 weeks). A grade 3 AE would constitute as "severe". Grading was following using CTCAE v 4.03.

    Note that the planned statistical analysis (calculation of rate ratio and 90% CI) could not be performed at Weeks 12 and 24 due to no events, and could not be performed at Week 36 because there were no events in the placebo group (denominator).

    Measured: Week 12, 24, 36, and 48

  2. Number of Grade 2 (Moderate) or Higher Adverse Events That Occur Throughout the Study

    Grade 2 or higher assessed 12 weeks apart. Grade 2 AEs are determined as " moderate". Grading was performed following CTCAE v 4.03 guidance.

    Measured: Week: 12, 24, 36, and 48

  3. Number of Adverse Events of Special Interest (AESI) Throughout the Study

    AESI are pre-defined adverse events as indicated in the protocol. They include: infections, stomach perforations, malignancy, herpes zoster and lab abnormalities.

    Note that the planned statistical analysis (calculation of rate ratio and 90% CI) could not be performed at Weeks 12 and 24 because there were no events in placebo group (denominator).

    Measured: Weeks 12, 24, 36 and 48

  4. Change in Modified Rodnan Skin Score (mRSS)

    The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness. Skin thickness in 17 anatomic areas was rated on a 0-3 scale and scores are summed to obtain the mRSS (range from 0 - 51), with higher mRSS scores indicating worse disease activity

    Measured: Change from Baseline at weeks: 12, 24, 36, and 48

  5. Provisional American College of Rheumatology Combined Response Index (CRISS) Systemic Sclerosis

    CRISS components included the following domains: modified Rodnan skin score, forced vital capacity percent predicted, Physician Global Assessment, Patient Global Assessment, and Health Assessment Questionnaire Disability-Index. An algorithm determines the predicted probability of improvement from baseline by incorporating change in the mRSS, FVC percent predicted, Physician and Patient Global Assessments, and HAQ-DI. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A cut-off at 0.6 in the predicted probability of being improved has yielded the smallest misclassification error. Subjects are not considered improved if, between Visit 1 and 6, they develop new: 1) renal crisis; 2) decline in FVC% predicted by 15% (relative) from baseline and confirmed after 1 month; or 3) left ventricular failure (systolic ejection fraction < 45%) or pulmonary artery hypertension. Higher CRISS scores indicates improvement.

    Measured: Week:12, 24, and 48

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Sep 2017
  2. Study start25 Sep 2017
  3. Primary completion8 Apr 2019
  4. Study completion15 Nov 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Eligible subjects will be randomized to tofacitinib or placebo in a 2:1 manner.
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03274076
Sponsor's protocol ID
HUM00131837
Acronym
TOFA-SSc
Status last verified
Apr 2020
First submitted
28 Aug 2017
Last updated
8 May 2020
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Khanna D, Padilla C, Tsoi LC, Nagaraja V, Khanna PP, Tabib T, Kahlenberg JM, Young A, Huang S, Gudjonsson JE, Fox DA, Lafyatis R. Tofacitinib blocks IFN-regulated biomarker genes in skin fibroblasts and keratinocytes in a systemic sclerosis trial. JCI Insight. 2022 Sep 8;7(17):e159566. doi: 10.1172/jci.insight.159566.

    PubMed 35943798

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Tofacitinib in people with Systemic Sclerosis and Scleroderma, run by University of Michigan at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 46 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 8 May 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 May 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants Who Experience Grade 3 or Higher Adverse Events That Occur at or Before Week 24 (time frame: 24 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03274076, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2020.

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