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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02745145




Registration number
NCT02745145
Ethics application status
Date submitted
15/04/2016
Date registered
20/04/2016
Date last updated
18/06/2019

Titles & IDs
Public title
Abituzumab in SSc-ILD
Scientific 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)
Secondary ID [1] 0 0
2015-005023-11
Secondary ID [2] 0 0
EMR 200017-014
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Systemic Sclerosis-associated Interstitial Lung Disease 0 0
Condition category
Condition code
Inflammatory and Immune System 0 0 0 0
Autoimmune diseases
Skin 0 0 0 0
Dermatological conditions
Skin 0 0 0 0
Other skin conditions
Respiratory 0 0 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Abituzumab 1500 mg
Treatment: Drugs - Abituzumab 500 mg
Treatment: Drugs - Placebo

Experimental: Abituzumab 1500 milligram (mg) -

Experimental: Abituzumab 500 mg -

Placebo Comparator: Placebo -


Treatment: Drugs: Abituzumab 1500 mg
Participants received Abituzumab 1500 mg administered as an intravenous infusion for 1 hour every 4 weeks up to Week 64.

Treatment: Drugs: Abituzumab 500 mg
Participants received Abituzumab 500 mg administered as an intravenous infusion for 1 hour every 4 weeks up to Week 64.

Treatment: Drugs: Placebo
Participants received Placebo matched to Abituzumab administered as an intravenous infusion for 1 hour every 4 weeks up to Week 64.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change From Baseline in Absolute Forced Vital Capacity (FVC) at Week 52 - FVC was the maximum amount of air exhaled from the lungs after taking the deepest breath possible. The FVC assessments were done using spirometry. Change from baseline in fvc at week 52 was reported.
Timepoint [1] 0 0
Baseline, Week 52
Secondary outcome [1] 0 0
Change From Baseline in Dyspnea as Measured by the Mahler's Transition Dyspnea Index (TDI) at Week 52 - Mahler's TDI was an interview-administered instrument that allows participants to assess their level of dyspnea which was assessed by functional impairment, magnitude of task and magnitude of effort. Scores for each subscale range from -3 to +3 so that the TDI focal score ranges from -9 (major deterioration) to +9 (major improvement). For all subscale scores and the TDI focal score a higher value indicates a better outcome.
Timepoint [1] 0 0
Baseline, Week 52
Secondary outcome [2] 0 0
Absolute Change From Baseline in St. George Respiratory Questionnaire (SGRQ) Total Score at Week 52 - The SGRQ assesses health-related quality of life in participants with chronic pulmonary disease by evaluating 3 health domains: symptoms (distress caused by respiratory symptoms); activity (effects of disturbances on mobility and physical activity); and impacts (the effect of disease on factors such as employment, personal control of one's health, and need for medication). A composite total score is derived as the weighted sum of domain scores for symptoms, activity, and impact (0=the best possible score and 100=the worst possible score). A reduction in score of 4 units is generally recognized as a clinically meaningful improvement in quality of life.
Timepoint [2] 0 0
Baseline, Week 52
Secondary outcome [3] 0 0
Absolute Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 52 in Participants With Diffuse Cutaneous Skin Involvement at Baseline - The Modified Rodnan Skin Score (mRSS) measures dermal skin thickness through the examination of 17 body areas: fingers, hands, forearms, arms, feet, legs, and thighs (in pairs), and face, chest, and abdomen. The skin score is evaluated by manual palpation in each of these areas. The skin score is 0 for uninvolved skin, 1 for mild thickening, 2 for moderate thickening, and 3 for severe thickening (hidebound skin). The total skin score is the sum of the skin scores of the individual areas where the minimum score is 0 and the maximum score is 51. A higher score indicates greater severity of disease.
Timepoint [3] 0 0
Baseline, Week 52
Secondary outcome [4] 0 0
Absolute Change From Baseline in Quantitative Lung Fibrosis (QLF) in the Region of Highest Baseline Severity at Week 52 - Absolute change from baseline in QLF score at week 52 was calculated as the difference of the QLF score at week 52 minus the QLF score at baseline divided in the region of highest baseline severity at Week 52 .The QLF score itself ranges from 0 to 100, where greater values represent a greater amount of lung fibrosis and are considered a worse health status.
Timepoint [4] 0 0
Baseline, Week 52
Secondary outcome [5] 0 0
Overall Survival (OS) - Overall survival (OS) was defined as the time (in months) from randomization to death. Data has been presented in terms of number participants who died and number of censored participants.
Timepoint [5] 0 0
Time from date of randomization until death, assessed up to 2 years
Secondary outcome [6] 0 0
Number of Participants With Clinically Meaningful Progression of Systemic Sclerosis (SSc) by Meeting Criterion 1 (Interstitial Lung Disease [ILD]) - Clinically Meaningful Progression SSc-ILD was defined as one of the following (in the absence of causative intercurrent illness) on at least 2 occasions within approximately 4 weeks (per Outcome Measures in Rheumatology criteria): Relative decrease from baseline in forced vital capacity (FVC) % predicted greater than or equal to (>=)10%; Relative decrease from baseline in FVC % predicted of >=5% to less than (<) 10% and relative decrease from baseline in Diffusion capacity of the lung for carbon monoxide % predicted >=15%.
Timepoint [6] 0 0
upto Week 52
Secondary outcome [7] 0 0
Number of Participants With Clinically Meaningful Progression of Systemic Sclerosis (SSc) by Meeting Criterion 2 (SSc Progression Other Than ILD) - Clinically Meaningful Progression SSc other than ILD was defined as new onset of one or more of the following: Scleroderma renal crisis; Left ventricular failure (defined as ejection fraction <=45%); Pulmonary arterial hypertension requiring treatment.
Timepoint [7] 0 0
upto Week 52
Secondary outcome [8] 0 0
Number of Participants With Clinically Meaningful Progression - Participants meeting one or both of the below criteria was considered as having clinically meaningful disease progression. Clinically Meaningful SSc-ILD defined as one of the following (in the absence of causative intercurrent illness) on at least 2 occasions within approximately 4 weeks (per Outcome Measures in Rheumatology criteria): Relative decrease from baseline in forced vital capacity (FVC) % predicted greater than or equal to (>=)10%; Relative decrease from baseline in FVC % predicted of >=5% to less than (<) 10% and relative decrease from baseline in Diffusion capacity of the lung for carbon monoxide % predicted >=15%. Clinically Meaningful SSc progression other than ILD defined as new onset of one or more of the following: Scleroderma renal crisis; Left ventricular failure (defined as ejection fraction <=45%); Pulmonary arterial hypertension requiring treatment.
Timepoint [8] 0 0
upto Week 52
Secondary outcome [9] 0 0
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 - FVC is the maximum amount of air exhaled from the lungs after taking the deepest breath possible. The FVC assessments were done using spirometry.
Timepoint [9] 0 0
upto Week 52

Eligibility
Key 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).
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA
Recruitment hospital [1] 0 0
Research site - Camperdown
Recruitment hospital [2] 0 0
Research site - Woodville South
Recruitment postcode(s) [1] 0 0
- Camperdown
Recruitment postcode(s) [2] 0 0
- Woodville South
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Massachusetts
Country [7] 0 0
United States of America
State/province [7] 0 0
Michigan
Country [8] 0 0
United States of America
State/province [8] 0 0
New Jersey
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
Oregon
Country [11] 0 0
United States of America
State/province [11] 0 0
Tennessee
Country [12] 0 0
United States of America
State/province [12] 0 0
Texas
Country [13] 0 0
Argentina
State/province [13] 0 0
Buenos Aires
Country [14] 0 0
Argentina
State/province [14] 0 0
Tucuman
Country [15] 0 0
Argentina
State/province [15] 0 0
San Juan
Country [16] 0 0
Canada
State/province [16] 0 0
British Columbia
Country [17] 0 0
Canada
State/province [17] 0 0
Ontario
Country [18] 0 0
Israel
State/province [18] 0 0
Haifa
Country [19] 0 0
Israel
State/province [19] 0 0
Jerusalem
Country [20] 0 0
Israel
State/province [20] 0 0
Kfar- Saba
Country [21] 0 0
Israel
State/province [21] 0 0
Petach Tikva
Country [22] 0 0
Israel
State/province [22] 0 0
Ramat Gan
Country [23] 0 0
Israel
State/province [23] 0 0
Tel Aviv
Country [24] 0 0
Italy
State/province [24] 0 0
Ancona
Country [25] 0 0
Italy
State/province [25] 0 0
Milano
Country [26] 0 0
Italy
State/province [26] 0 0
Napoli
Country [27] 0 0
Italy
State/province [27] 0 0
Pisa
Country [28] 0 0
Italy
State/province [28] 0 0
Reggio Emilia
Country [29] 0 0
Italy
State/province [29] 0 0
Roma
Country [30] 0 0
Poland
State/province [30] 0 0
Gdansk
Country [31] 0 0
Poland
State/province [31] 0 0
Warszawa
Country [32] 0 0
Poland
State/province [32] 0 0
Lódz
Country [33] 0 0
Spain
State/province [33] 0 0
Madrid
Country [34] 0 0
Spain
State/province [34] 0 0
Valladolid
Country [35] 0 0
United Kingdom
State/province [35] 0 0
Cambridgeshire
Country [36] 0 0
United Kingdom
State/province [36] 0 0
Greater London
Country [37] 0 0
United Kingdom
State/province [37] 0 0
Staffordshire
Country [38] 0 0
United Kingdom
State/province [38] 0 0
Tayside Region
Country [39] 0 0
United Kingdom
State/province [39] 0 0
West Midlands

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
EMD Serono Research & Development Institute, Inc.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Merck KGaA, Darmstadt, Germany
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02745145
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Responsible
Address 0 0
EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02745145