Abituzumab in SSc-ILD

Merck KGaA (EMD Serono)

Status and phase: Terminated; Phase 2

Conditions: Systemic Sclerosis-associated Interstitial Lung Disease

Treatments: Drug: Abituzumab 500 mg; Drug: Abituzumab 1500 mg; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT02745145

2015-005023-11 (EudraCT Number)

EMR 200017-014

Details and patient eligibility

About

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.

Enrollment: 24 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

---

24 participants in 3 patient groups, including a placebo group

Abituzumab 1500 milligram (mg)

Experimental group

Treatment:

Drug: Abituzumab 1500 mg

Abituzumab 500 mg

Experimental group

Treatment:

Drug: Abituzumab 500 mg

Placebo

Placebo Comparator group

Treatment:

Drug: Placebo