Sample 43

Inclusion Criteria:Subjects are eligible for this trial if they fulfill all of the following inclusion criteria:Female or male subjects aged between 18 and 75 years of age who provide informed written consent.Subjects fulfilling the 2013 American College of Rheumatology (ACR) /European League Against Rheumatism criteria for classification of systemic sclerosis (SSc).Disease duration of less than (<) 7 years from first non-Raynaud's symptom.Subjects who have been taking the same mycophenolate regimen (stable dose) in a range of 1.5 to 3 gram (g)/day of Mycophenolate mofetil (MMF) or 1080 to 2160 milligram/day (mg/day) of MPS for at least 2 months prior to the Screening Visit and continued through Day 1 of the Treatment Period, of the lung on HRCT according to central reading.According to central readings: Diffusion capacity of the lung for carbon monoxide (DLCO) greater than or equal to (>=) 30 percent (%) predicted, Forced vital capacity (FVC) 40% to 85% predicted, and a ratio of FVC % predicted to DLCO % predicted >=1.8 is acceptable if right heart catheterization within 3 months of screening revealed no pulmonary hypertension. If these criteria are met, then High-resolution computed tomography (HRCT) of lungs will be performed, and must show at least 5% fibrosis for subjects to be eligible.Female subjects of childbearing potential must use a highly effective method of contraception to prevent pregnancy for 4 weeks before randomization and must agree to continue to practice adequate contraception for the duration of their participation in the trial (up to the last Safety Follow-Up Visit). For the purposes of this trial, women of childbearing potential are defined as "All female subjects after puberty unless they are post-menopausal for at least 2 years or are surgically sterile." Highly effective contraception is defined as 2 barrier methods (eg, female diaphragm and male condoms); or 1 barrier method with at least one of the following: spermicide, a hormonal method, or an intrauterine device. Note that because mycophenolate affects the metabolism of oral contraceptives and may reduce their effectiveness, women receiving mycophenolate who are using oral contraceptives for birth control should employ an additional contraceptive method (for example, male or female barrier method).Exclusion Criteria:Any condition that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the trial or that could interfere with the trial objectives, conduct, or evaluation.Renal impairment (glomerular filtration rate [GFR] <45 mL/minute (min)/1.73 square meter (m^2) as calculated by the Modification of Diet in Renal Disease equation) calculated as follows: GFR (mL/min per 1.73 m^2) = 175*(standardized serum creatinine)^-1.154 * (age)^-0.203 * 1.212 (if black) * 0.742 (if female)Urine dipstick with >=3 plus protein and urine protein:creatinine ratio more than (>)2 mg/mg.Known diagnosis of obstructive lung disease/emphysema (Forced Expiratory Volume [FEV1]/FVC ratio <0.65) and/or significant emphysematous change on screening HRCT.Other clinically significant abnormalities on HRCT not attributable to scleroderma or emphysema as defined above.Known diagnosis of other significant respiratory disorders.Pulmonary hypertension that fulfills at least one of the following:Current/planned treatment with systemic therapy targeted to Pulmonary arterial hypertension (PAH) or pulmonary hypertension;History of transthoracic echocardiography showing at least one of the following: tricuspid regurgitation jet >2.8 m/sec, right atrial enlargement (major dimension >53 mm), right ventricular enlargement (mid cavity dimension >35 mm), moderate to severe left ventricular dysfunction;N-terminal prohormone brain natriuretic peptide >3*Upper limit of normal (ULN)Considered by the investigator to require initiation of systemic targeted PAH therapy.Current clinical diagnosis of another inflammatory connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, or dermato/polymyositis). Concomitant scleroderma-associated myopathy, fibromyalgia, and secondary Sjögren's are allowed.Suspected/confirmed significant aspiration within the previous 6 months, for example.viral/bacterial/fungal infectioninfection requiring hospitalizationTreatment with parenteral anti-infectives within 4 weeks prior/during Screening PeriodCompletion of oral anti-infectives within 2 weeks of ScreeningUse of oral anti-infectives during Screening PeriodVaginal candidiasisonychomycosischronically suppressed oral herpes simplex virusProphylaxis for Pneumocystis jiroveci pneumoniaHistory of/positive Human immunodeficiency virus, hepatitis C antibody and/or polymerase chain reaction or Hepatitis B surface antigen and/or hepatitis B core antibody (total and/or Immunoglobulin M) antibody at screening.History of/current diagnosis of active tuberculosis (TB), or untreated latent TB infection (LTBI).Presence of uncontrolled or New York Heart Association Class 3 or 4 congestive heart failure.History of cancer, except adequately treated (ie, no evidence of recurrence within 5 years prior screening) basal cell/squamous cell carcinomas of the skin (≤3 total in lifetime) or carcinoma in situ of the cervix.Known hypersensitivity to abituzumab DS or DP.Current smoker (incl. e-cigarettes) / smoking within 4 weeks of screening.Use of agents other than mycophenolate considered by the Investigator to have immunomodulating, immunosuppressive, or potential scleroderma disease-modifying properties within 2 months of screening visit is not allowed (or 5 months prior to the Screening Visit for cyclophosphamide). Hydroxychloroquine or chloroquine are permitted if dose has been stable for at least 4 weeks before the screening visit.Use of systemic corticosteroids above 10 mg/day prednisone equivalent within 4 weeks prior until last dose of study drug. Inhaled and topical corticosteroids are permitted.Use of any biologic agent within 12 weeks or 5 half-lives, whichever is longer, of screening.History of anti-CD20 B-cell depleting therapy, eg, rituximab or ocrelizumab within 6 months prior to screening visit.Use of anticoagulant or antiplatelet agent (aspirin =<350 mg daily is permitted).Clinically significant or predefined abnormalities in lab tests:Aspartate aminotransferase, Alanine aminotransferase or alkaline phosphatase level >2.5*ULN;Total bilirubin >1.5*ULN (other than that due to known Gilbert's disease);Hemoglobin <5.0 mmol/L (9 g/dL), white blood cell count <2.5*10^9/L, or platelets <100*10^9/L);International normalized ratio or partial thromboplastin time >2.0*ULN;Thyroid-stimulating hormone <0.01 or >=7.1 milli international units per litre (mIU/L).Inability to receive IV infusions.History of alcohol/drug abuse for 1 year prior screening.Pregnancy/breastfeeding/lactation within 3 months prior screening.History of thrombotic, thromboembolic, or abnormal bleeding events including concomitant antiphospholipid antibody syndrome. Subjects with known lupus anticoagulant and/or anticardiolipin and/or anti-b2 glycoprotein antibodies alone should not be excluded.Legal incapacity/limited legal capacity.Receipt/planned live/attenuated vaccination within 12 weeks prior screening until 3 months after last dose of study drug. Seasonal influenza vaccination with inactivated vaccine formulation is permitted.Major surgery requiring hospitalization within 4 weeks prior screening, planned major surgery for the duration of the trial. Subjects with lung resection.History of/planned major organ or hematopoietic stem cell/marrow transplant.Severe gastrointestinal disease requiring parenteral nutrition. Other protocol defined exclusion criteria could apply.

159/159

**Final Answer**

The modified eligibility criteria for the IL-13/IL-24 trial are as follows, incorporating the amendment to the study protocol:

1. **Inclusion Criteria**:

- All previously stated inclusion criteria remain unchanged.

- **Additional Eligibility**:

- Exclude subjects with a history of prior anti-CD20 B cell depletion or anti-CD22 B cell depletion.

- Exclude subjects with a history of anti-CD22 B cell depletion or anti-CD22 B cell depletion (corrected to exclude anti-CD22 B cell depletion twice).

- Exclude subjects with a history of anti-CD22 B cell depletion or anti-CD22 B cell depletion (redundant, as it's the same condition).

2. **Exclusion Criteria**:

- All previously stated exclusion criteria remain unchanged.

- **Additional Exclusions**:

- Exclude subjects with a history of anti-CD20 B cell depletion or anti-CD22 B cell depletion.

- Exclude subjects with a history of anti-CD22 B cell depletion or anti-CD22 B cell depletion (redundant, as it's the same condition).

- Exclude subjects with a history of anti-CD22 B cell depletion or anti-CD22 B cell depletion (redundant, as it's the same condition).

3. **Other Changes**:

- The trial period for the double-blind treatment has been extended to 12 weeks from 10 weeks.

- The last visit for safety follow-up is extended to 104 weeks from 96 weeks.

- The last visit for survival follow-up remains unchanged at 120 weeks.

4. **Pharmacokinetic Sampling**:

- Rich PK sampling is performed only for subjects who have received at least one dose of abituzumab.

- PK sampling is performed at baseline for subjects who have not received abituzumab.

5. **Adverse Events**:

- Adverse events are monitored and documented, with a focus on those related to the study drug.

6. **Randomization and Blinding**:

- Randomization is stratified by baseline FVC% predicted and duration of prior mycophenolate use at baseline.

- The trial is conducted in permuted blocks, with stratification factors including baseline FVC% predicted and duration of prior mycophenolate use at baseline.

7. **Monitoring and Data Collection**:

- The primary endpoint is the change in 12-week predicted mRSS.

- Secondary endpoints include overall efficacy, safety, and other efficacy and safety endpoints.

- Data collection includes detailed adverse event reporting and PK data.

8. **Analysis**:

- The primary analysis focuses on the change in predicted mRSS at 12 weeks.

- Secondary analyses include overall efficacy, safety, and other efficacy and safety endpoints.

9. **Operational Adjustments**:

- The sponsor's protocol lead has been amended to reflect the new criteria and procedures.

- The final date for the last visit for safety follow-up is extended to 104 weeks.

10. **Reporting**:

- The sponsor is responsible for compiling and submitting the final results to the FDA and EMA within the specified timeframe.

These modifications ensure that the trial adheres to the updated criteria and incorporates the necessary amendments to the study protocol.

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The modified eligibility criteria for the IL-13/IL-24 ILSSC-ILD EmGluconide Trial have been updated to incorporate the changes from the IL-13/IL-24 Amendment to the study protocol. The key updates include:

1. **Inclusion Criteria**:

- **Additional Eligibility**: Exclude subjects with a history of anti-CD20 B cell depletion or anti-CD22 B cell depletion. Exclude subjects with a history of anti-CD22 B cell depletion or anti-CD22 B cell depletion (redundant, as it's the same condition).

2. **Exclusion Criteria**:

- **Additional Exclusions**: Exclude subjects with a history of anti-CD20 B cell depletion or anti-CD22 B cell depletion. Exclude subjects with a history of anti-CD22 B cell depletion or anti-CD22 B cell depletion (redundant, as it's the same condition).

3. **Pharmacokinetic Sampling**:

- Rich PK sampling is performed only for subjects who have received at least one dose of abituzumab. Routine hematology, clinical chemistry, and urinalysis are performed at baseline for subjects who have not received abituzumab.

4. **Pharmacodynamics**:

- The trial period for the double-blind treatment has been extended to 12 weeks from 10 weeks. The last visit for safety follow-up is extended to 104 weeks from 96 weeks. The last visit for survival follow-up remains unchanged at 120 weeks.

5. **Randomization and Stratification**:

- Randomization is stratified by baseline FVC% predicted and duration of prior mycophenolate use at baseline. The trial is conducted in permuted blocks, stratified by baseline FVC% predicted and duration of prior mycophenolate use at baseline.

6. **Adverse Events and PK Sampling**:

- Adverse events are monitored and documented. Routine hematology, clinical chemistry, and urinalysis are performed at baseline for subjects who have not received abituzumab.

7. **Analysis**:

- The primary endpoint is the change in 12-week predicted mRSS. Secondary endpoints include overall efficacy, safety, and other efficacy and safety endpoints.

8. **Operational Adjustments**:

- The sponsor's protocol lead has been amended to reflect the new criteria and procedures. The final date for the last visit for safety follow-up is extended to 104 weeks.

These modifications ensure that the trial adheres to the updated criteria and incorporates the necessary amendments to the study protocol.