Systemic Sclerosis-associated Interstitial Lung Disease Clinical Trial
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)
| Verified date | May 2019 |
| Source | EMD Serono |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Terminated |
| Enrollment | 24 |
| Est. completion date | May 30, 2018 |
| Est. primary completion date | May 30, 2018 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years to 75 Years |
| Eligibility |
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. |
| Country | Name | City | State |
|---|---|---|---|
| Argentina | Research site 1 | Ciudad Autonoma Buenos Aires | Buenos Aires |
| Argentina | Research site 2 | Ciudad Autonoma Buenos Aires | Buenos Aires |
| Argentina | Research site 3 | Ciudad Autonoma Buenos Aires | Buenos Aires |
| Argentina | Research site | San Fernando | Buenos Aires |
| Argentina | Research site | San Juan | |
| Argentina | Research site | San Miguel De Tucuman | Tucuman |
| Australia | Research site | Camperdown | New South Wales |
| Australia | Research site | Woodville South | South Australia |
| Canada | Research site | Toronto | Ontario |
| Canada | Research site | Vancouver | British Columbia |
| Israel | Research site | Haifa | |
| Israel | Research site | Jerusalem | |
| Israel | Research site | Kfar- Saba | |
| Israel | Research site | Petach Tikva | |
| Israel | Research site | Ramat Gan | |
| Israel | Research site | Tel Aviv | |
| Italy | Research site 1 | Milano | |
| Italy | Research site 2 | Milano | |
| Italy | Research site | Napoli | |
| Italy | Research site | Pisa | |
| Italy | Research site | Reggio Emilia | |
| Italy | Research site 1 | Roma | |
| Italy | Research site 2 | Roma | |
| Italy | Research site | Rozzano | Milano |
| Italy | Research site | Torrette | Ancona |
| Poland | Research site | Gdansk | |
| Poland | Research site | Lódz | |
| Poland | Research site 1 | Warszawa | |
| Poland | Research site 2 | Warszawa | |
| Spain | Research site | Madrid | |
| Spain | Research site | Valladolid | |
| United Kingdom | Research site | Birmingham | West Midlands |
| United Kingdom | Research site | Cambridge | Cambridgeshire |
| United Kingdom | Research site | Cannock | Staffordshire |
| United Kingdom | Research site | Dundee | Tayside Region |
| United Kingdom | Research site | London | Greater London |
| United Kingdom | Research site | Sheffield | West Midlands |
| United States | Research site | Ann Arbor | Michigan |
| United States | Research site 1 | Boston | Massachusetts |
| United States | Research site 2 | Boston | Massachusetts |
| United States | Research site | Chicago | Illinois |
| United States | Research site | Dallas | Texas |
| United States | Research site | Farmington | Connecticut |
| United States | Research site | Great Neck | New York |
| United States | Research site | Houston | Texas |
| United States | Research site | Los Angeles | California |
| United States | Research site 1 | Los Angeles | California |
| United States | Research site | Nashville | Tennessee |
| United States | Research site | New Brunswick | New Jersey |
| United States | Research site 1 | New York | New York |
| United States | Research site 2 | New York | New York |
| United States | Research site | Orlando | Florida |
| United States | Research site | Portland | Oregon |
| United States | Research site | Washington | District of Columbia |
| United States | Research site | Weston | Florida |
| Lead Sponsor | Collaborator |
|---|---|
| EMD Serono Research & Development Institute, Inc. | Merck KGaA, Darmstadt, Germany |
United States, Argentina, Australia, Canada, Israel, Italy, Poland, Spain, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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. | Baseline, Week 52 | |
| Secondary | 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. | Baseline, Week 52 | |
| Secondary | 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. | Baseline, Week 52 | |
| Secondary | 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. | Baseline, Week 52 | |
| Secondary | 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. | Baseline, Week 52 | |
| Secondary | 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. | Time from date of randomization until death, assessed up to 2 years | |
| Secondary | 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%. | upto Week 52 | |
| Secondary | 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. | upto Week 52 | |
| Secondary | 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. | upto Week 52 | |
| Secondary | 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. | upto Week 52 |