Abituzumab in SSc-ILD
Condition: Systemic Sclerosis-associated Interstitial Lung Disease
MeSH terms: Lung Diseases; Lung Diseases, Interstitial; Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Intervention: Abituzumab 1500 mg; Abituzumab 500 mg; Placebo
Intervention description: Participants received Abituzumab 1500 mg administered as an intravenous infusion for 1 hour every 4 weeks up to Week 64.; Participants received Abituzumab 500 mg administered as an intravenous infusion for 1 hour every 4 weeks up to Week 64.; Participants received Placebo matched to Abituzumab administered as an intravenous infusion for 1 hour every 4 weeks up to Week 64.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Double-Blind Method; Interstitial Lung Diseases; Systemic Scleroderma; Abituzumab; Mycophenolate; Efficacy, Safety

Summary:

      The purpose of this trial was to compare two doses of abituzumab with placebo and determine
      whether abituzumab was more effective, safer, would be better tolerated and could provoke
      better immune response than placebo in the treatment of participants with SSc-ILD who already
      receive constant doses of mycophenolate.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants were eligible for this trial if they fulfill all of the following
             inclusion criteria:

          -  Female or male participants aged between 18 and 75 years of age who provide informed
             written consent.

          -  Participants 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.

          -  Participants who had 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 were met, then High-resolution computed
             tomography (HRCT) of lungs will be performed, and must show at least 5% fibrosis for
             participants to be eligible.

          -  Female participants 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 were defined as "All female participants after puberty
             unless they were post-menopausal for at least 2 years or weresurgically 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 were 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 were allowed.

          -  Suspected/confirmed significant aspiration within the previous 6 months, for example.

               -  viral/bacterial/fungal infection

               -  infection requiring hospitalization

               -  Treatment with parenteral anti-infectives within 4 weeks prior/during Screening
                  Period

               -  Completion of oral anti-infectives within 2 weeks of Screening

               -  Use of oral anti-infectives during Screening Period

               -  Vaginal candidiasis

               -  onychomycosis

               -  chronically suppressed oral herpes simplex virus

               -  Prophylaxis for Pneumocystis jiroveci pneumonia

          -  History 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 were
             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 were
             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. Participants 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. Participants 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.