Clinical trial NCT02745145: Abituzumab in SSc-ILD
Official title: A Phase II, Randomized, Double-blind, Placebo Controlled, Parallel-group, Multicenter Trial to Evaluate the Efficacy and Safety of Abituzumab in Subjects With Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Systemic Sclerosis-associated Interstitial Lung Disease
Keywords: Double-Blind Method
Interstitial Lung Diseases
Systemic Scleroderma
Abituzumab
Mycophenolate
Efficacy, Safety
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2016-04-20
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Change From Baseline in Absolute Forced Vital Capacity (FVC) at Week 52
timeFrame: Baseline, Week 52
Secondary outcomes:
measure: Change From Baseline in Dyspnea as Measured by the Mahler's Transition Dyspnea Index (TDI) at Week 52
timeFrame: Baseline, Week 52
measure: Absolute Change From Baseline in St. George Respiratory Questionnaire (SGRQ) Total Score at Week 52
timeFrame: Baseline, Week 52
measure: Absolute Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 52 in Participants With Diffuse Cutaneous Skin Involvement at Baseline
timeFrame: Baseline, Week 52
measure: Absolute Change From Baseline in Quantitative Lung Fibrosis (QLF) in the Region of Highest Baseline Severity at Week 52
timeFrame: Baseline, Week 52
measure: Overall Survival (OS)
timeFrame: Time from date of randomization until death, assessed up to 2 years
measure: Number of Participants With Clinically Meaningful Progression of Systemic Sclerosis (SSc) by Meeting Criterion 1 (Interstitial Lung Disease [ILD])
timeFrame: upto Week 52
measure: Number of Participants With Clinically Meaningful Progression of Systemic Sclerosis (SSc) by Meeting Criterion 2 (SSc Progression Other Than ILD)
timeFrame: upto Week 52
measure: Number of Participants With Clinically Meaningful Progression
timeFrame: upto Week 52
measure: Number of Participants With Absolute Decrease From Baseline of FVC Percentage (%) Predicted Greater Than or Equal to (>=) 10% on 2 or More Consecutive Occasions at Least 4 Weeks Apart
timeFrame: upto Week 52
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research site 1
state: California
city: Los Angeles
country: United States
facility: Research site
state: California
city: Farmington
country: United States
facility: Research site
state: Connecticut
city: Washington
country: United States
facility: Research site
state: District of Columbia
city: Orlando
country: United States
facility: Research site
state: Florida
city: Weston
country: United States
facility: Research site
state: Florida
city: Chicago
country: United States
facility: Research site
state: Illinois
city: Boston
country: United States
facility: Research site 1
state: Massachusetts
city: Boston
country: United States
facility: Research site 2
state: Massachusetts
city: Ann Arbor
country: United States
facility: Research site
state: Michigan
city: New Brunswick
country: United States
facility: Research site
state: New Jersey
city: Great Neck
country: United States
facility: Research site
state: New York
city: New York
country: United States
facility: Research site 1
state: New York
city: New York
country: United States
facility: Research site 2
state: New York
city: Portland
country: United States
facility: Research site
state: Oregon
city: Nashville
country: United States
facility: Research site
state: Tennessee
city: Dallas
country: United States
facility: Research site
state: Texas
city: Houston
country: United States
facility: Research site
state: Texas
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Research site 1
state: Buenos Aires
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Research site 2
state: Buenos Aires
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Research site 3
state: Buenos Aires
city: San Fernando
country: Argentina
facility: Research site
state: Buenos Aires
city: San Miguel De Tucuman
country: Argentina
facility: Research site
state: Tucuman
city: San Juan
country: Argentina
facility: Research site
city: Camperdown
country: Australia
facility: Research site
state: New South Wales
city: Woodville South
country: Australia
facility: Research site
state: South Australia
city: Vancouver
country: Canada
facility: Research site
state: British Columbia
city: Toronto
country: Canada
facility: Research site
state: Ontario
city: Haifa
country: Israel
facility: Research site
city: Jerusalem
country: Israel
facility: Research site
city: Kfar- Saba
country: Israel
facility: Research site
city: Petach Tikva
country: Israel
facility: Research site
city: Ramat Gan
country: Israel
facility: Research site
city: Tel Aviv
country: Israel
facility: Research site
city: Torrette
country: Italy
facility: Research site
state: Ancona
city: Rozzano
country: Italy
facility: Research site
state: Milano
city: Milano
country: Italy
facility: Research site 1
city: Milano
country: Italy
facility: Research site 2
city: Napoli
country: Italy
facility: Research site
city: Pisa
country: Italy
facility: Research site
city: Reggio Emilia
country: Italy
facility: Research site
city: Roma
country: Italy
facility: Research site 1
city: Roma
country: Italy
facility: Research site 2
city: Gdansk
country: Poland
facility: Research site
city: Warszawa
country: Poland
facility: Research site 1
city: Warszawa
country: Poland
facility: Research site 2
city: Łódź
country: Poland
facility: Research site
city: Madrid
country: Spain
facility: Research site
city: Valladolid
country: Spain
facility: Research site
city: Cambridge
country: United Kingdom
facility: Research site
state: Cambridgeshire
city: London
country: United Kingdom
facility: Research site
state: Greater London
city: Cannock
country: United Kingdom
facility: Research site
state: Staffordshire
city: Dundee
country: United Kingdom
facility: Research site
state: Tayside Region
city: Birmingham
country: United Kingdom
facility: Research site
state: West Midlands
city: Sheffield
country: United Kingdom
facility: Research site
state: West Midlands
Study officials:
affiliation: EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Khanna D, Tashkin DP, Wells AU, Seibold JR, Wax S, Vazquez-Mateo C, Fleuranceau-Morel P, Damian D, Denton CP. STRATUS: A Phase II Study of Abituzumab in Patients With Systemic Sclerosis-associated Interstitial Lung Disease. J Rheumatol. 2021 Aug;48(8):1295-1298. doi: 10.3899/jrheum.191365. Epub 2020 Oct 1.