Clinical Trials

Inclusion Criteria: 

• Male or female ≥ 18 years of age at the time of signed informed consent;
• SSc classification as defined by the 2013 American College of Rheumatology/European League Against Rheumatism criteria. An enrollment cap will apply to the limited/sine cutaneous SSc subtype. The enrollment cap will allow for ≤ 30% of limited/sine cutaneous SSc subtype study participants for each Regimen-specific Subprotocol (IP);
• Onset of SSc (defined by first non-Raynaud’s symptom) ≤ 5 years prior to the Screening Visit;
• Modified Rodnan skin score (mRSS) of 10 to 35, inclusive, in participants with diffuse cutaneous SSc;
• Presence of ILD with evidence of any fibrosis on HRCT (within ≤ 3 months of randomization) and at least 1 of the following:
  • > 10% total lung involvement on HRCT (assessed by QILD-WL); or
  • Elevation of acute phase reactants (APRs) (see Note (i) below) at the Screening Visit; or
  • Progression of ILD (see Note (ii) below) in the previous 24 months; or
  • FVC < 80% predicted in participants with SSc onset (defined by first non-Raynaud’s symptom) ≤ 3 years prior to the Screening Visit;
  • Note (i): Elevation of APRs is defined as having at least 1 of the following:
    • C-reactive protein ≥ 6 mg/L;
    • Erythrocyte sedimentation rate ≥ 28 mm/hr; or
    • Platelet count > 330 × 10^9 /L (330,000/µL):
      • Note (ii): ILD progression (determined based on data collected as part of clinical care) is defined as 1 of the following:
        • Relative decline in FVC of ≥ 10%; or
        • Relative decline in FVC of ≥ 5% to < 10% with worsening respiratory symptoms or any increased extent of fibrosis on HRCT; or
        • Worsening of respiratory symptoms and any increased extent of fibrosis on HRCT.
    • Note (iii): Enrollment of participants who fulfill only the criterion of 10% total lung involvement on HRCT (assessed by QILD-WL) will be capped at 20%. This enrollment cap allows for 20% of study participants who fulfill only this criterion for each Regimen-specific Subprotocol (IP).
• Presence of an FVC ≥ 45% predicted normal.
• Presence of a diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 30% predicted normal, corrected for hemoglobin
• Meeting drug stabilization requirements, as applicable:
  • Background mycophenolate, methotrexate, or azathioprine (no more than 1 therapy) for ≥ 6 months without dose adjustments in the last 3 months prior to randomization (temporary withholding for no more than 7 days is allowed for treatment of infections and other adverse events [AEs]); and
  • Note: Use of immunosuppressive therapy is not a requirement to enter the study;
  • Oral corticosteroids equivalent to ≤ 10 mg/day prednisone if started at least ≤ 2 weeks prior to randomization. Inhaled and topical corticosteroids are permitted. Refer to Appendix C for a corticosteroid dose conversion table.
• Women of childbearing potential (WOCBP) and male study participants with female partners of childbearing potential must be willing and able to use highly effective methods of birth control (please refer to Section 5.6.3); and Note: Additional contraception requirements may be described in the Regimen-specific Subprotocols inclusion criteria, as appropriate.
• Willing and able to comply with the study requirements and give informed consent for participation in the study. Where permitted by local regulations, a legally authorized representative will be allowed to sign the consent form as a proxy for study participants who are unable to physically sign but are able to give a verbal informed consent.

Exclusion Criteria:

• Presence of clinically significant pulmonary abnormalities inconsistent with ILD on HRCT (e.g., scarring due to previous active tuberculosis [TB], sarcoidosis, lung mass, or other findings unrelated to SSc-ILD, as determined by a local radiologist/Investigator).
• History of stem cell transplantation, bone marrow transplantation, chimeric antigen receptor T-cell therapy, or solid organ transplantation.
• Women who are pregnant, nursing, or who plan to become pregnant while in the clinical study.
• History of Child-Pugh Class B or Class C liver disease.
• Presence of any of the following laboratory findings at the Screening Visit:
  • Estimated glomerular filtration rate < 45 mL/min/1.73 m^2 , calculated using the Chronic Kidney Disease Epidemiology Collaboration equation;
  • Alanine aminotransferase or aspartate aminotransferase level >   1.5 × upper limit of normal (ULN);
  • Platelets < 100 × 10^9 /L (100,000/µL);
  • White blood cell count  < 2500/µL;
  • Neutrophil blood count  < 1500/µL;
  • Prolongation of prothrombin time and partial thromboplastin time > 1.5 × ULN, or international normalized ratio > 2; or
  • Any other laboratory test result, that in the opinion of the Investigator, might place the study participant at risk for participation in the study.
• History of major trauma or hemorrhage within 30 days of the Screening Visit.
• History of any clinically significant chronic intermittent bleeding, such as active gastric antral vascular ectasia or active peptic ulcer disease, within 60 days of the Screening Visit.
• Presence of other clinically significant risk of bleeding events, including coagulation or platelet disorders, at the Screening Visit as determined by the Investigator.
• History of any cerebrovascular events (e.g., transient ischemic attack or stroke) within 6 months of the Screening Visit.
• History of myocardial infarction or unstable angina within 6 months of the Screening Visit, or plans to undergo a coronary procedure during participation in the study.
• Presence of acute or chronic congestive heart failure (New York Heart Association Class III [moderate] or Class IV [severe]) at the Screening Visit.
• History of restrictive or congestive cardiomyopathy (other than mild), uncontrolled by medication or implanted device.
• History of life-threatening cardiac arrhythmias.
• History of hemodynamically significant aortic or mitral valve disease.
• Documented significant pulmonary hypertension with a mean pulmonary artery pressure > 30 mm Hg by right heart catheterization.
• History of pulmonary veno-occlusive disease.
• Forced expiratory volume in 1 second/FVC < 0.65 (pre-bronchodilator) at the Screening Visit.
• History of scleroderma renal crisis within 6 months prior to the Screening Visit.
• Presence of a concomitant life-threatening disease with life expectancy < 12 months based on the Investigator’s assessment.
• Treatment with tocilizumab, nintedanib, pirfenidone, abatacept, leflunomide, tacrolimus, tofacitinib, or any FDA-approved biologic or immunomodulator for rheumatic diseases within 3 months of the Screening Visit.
• History of treatment with rituximab within the 6 months prior to the Screening Visit; Note: Participants who have received the rituximab treatment between 6 and 12 months prior to the Screening Visit may be included if B cells are within normal ranges.
• History of treatment with cell-depleting therapies other than rituximab, including, but not limited to, CAMPATH®; anti-cluster of differentiation (CD)3, anti-CD4, anti-CD5, anti-CD19, and anti-CD20 agents; and investigational agents.
• Treatment with cyclophosphamide within 6 months prior to the Screening Visit. 
• Smoking of tobacco cigarettes, e-cigarettes, or vaping products, or inhaling cannabis within 6 months prior to the Screening Visit.
• Presence of a clinically significant disorder that, in the opinion of the Investigator, could contraindicate the administration of study product, affect compliance, interfere with study evaluations, or confound the interpretation of study results.
• Any documented active or suspected malignancy or history of malignancy within 5 years prior to the Screening Visit, except appropriately treated basal cell carcinoma of the skin, in situ squamous cell carcinoma of the skin, or in situ carcinoma of uterine cervix. Malignancy in remission is not allowed.
• Female participants who have had a breast cancer screening that is suspicious for malignancy, and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory, or other diagnostic evaluations.
• Evidence of active TB or being at high risk for TB based on:
  • History of active TB or untreated/incompletely treated latent TB. Participants with a history of active TB who have documentation of completion of treatment according to local guidelines may be enrolled;
  • Participants with latent TB will not be eligible for the study unless active TB infection has been ruled out, an appropriate course of intervention for latent TB has been initiated at least 2 weeks prior to randomization, and there is no evidence of active TB on chest X-ray during Screening;
  • History of recent (≤ 12 weeks before Screening) close contact with someone with active TB (close contact is defined as ≥ 4 hours/week, living in the same household, or in a house where a person with active TB is a frequent visitor);
  • Signs or symptoms that could represent active TB by medical history or physical examination;  
  • Positive, indeterminate, or invalid interferon-gamma release assay test result at Screening, unless previously treated for TB. Participants with an indeterminate test result can repeat the test once, but if the repeat test is also indeterminate, a purified protein derivative skin test should be performed; or
  • Chest radiograph, chest computed tomography, or magnetic resonance imaging scan that suggests a possible diagnosis of TB or suggests that a work-up for TB should be considered; all participants must have had lung imaging with an acceptable reading within 3 months prior to consent, or during Screening.
• History of any serious infection within 3 months prior to the Screening Visit, or presence of any chronic bacterial infection (such as chronic pyelonephritis, osteomyelitis, or bronchiectasis).
• Presence of severe uncontrolled hypertension (systolic blood pressure160 mmHg and/or diastolic blood pressure > 100 mmHg) at the Screening Visit.
• Presence of > 3 digital ulcers or gangrene at the Screening Visit.
• Presence of any active infections (excluding fungal or bacterial infections that require only topical antimicrobials) including, but not limited to, those that require intravenous antimicrobial treatment within 4 weeks or oral antimicrobial treatment within 2 weeks prior to randomization:
  • Note: Participants with evidence of hepatitis B infection detected during Screening are excluded. Participants with hepatitis C infection detected during Screening are excluded unless the infection is successfully treated with no recurrence for 1 year. Study participants with active documented or suspected COVID-19 infection within 4 weeks prior to randomization, or with positive asymptomatic severe acute respiratory syndrome coronavirus polymerase chain reaction test within 2 weeks prior to randomization, are excluded. Such participants may be rescreened once asymptomatic and polymerase chain reaction test is negative for more than 4 weeks.
• Receipt of any live vaccines within 3 months of the anticipated first dose of study IP or anticipated need of a live vaccine at any time during the study. or
• History of use of any investigational medication or device for any indication within 30 days or 5 half-lives (whichever is longer) prior to the Screening Visit.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 11/14/23. Questions regarding updates should be directed to the study team contact.