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A Trial to Compare Nintedanib With Placebo for Patients With Scleroderma Related Lung Fibrosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02597933
Recruitment Status : Completed
First Posted : November 5, 2015
Results First Posted : December 13, 2019
Last Update Posted : December 13, 2019
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Tracking Information
First Submitted Date  ICMJE October 8, 2015
First Posted Date  ICMJE November 5, 2015
Results First Submitted Date  ICMJE October 28, 2019
Results First Posted Date  ICMJE December 13, 2019
Last Update Posted Date December 13, 2019
Actual Study Start Date  ICMJE November 12, 2015
Actual Primary Completion Date October 31, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 26, 2019)
Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks [ Time Frame: up to week (wk) 52 after the start of administration ]
Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test. For this endpoint reported means represent the adjusted rate.
Original Primary Outcome Measures  ICMJE
 (submitted: November 4, 2015)
Annual rate of decline in FVC in mL [ Time Frame: 52 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 26, 2019)
  • Absolute Change From Baseline in the Modified Rodnan Skin Score (mRSS) at Week 52 [ Time Frame: Baseline and up to 52 weeks after the start of administration ]
    This is the first key secondary endpoint. The modified Rodnan Skin Score (mRSS) is an evaluation of the patient's skin thickness rated by clinical palpation using a 0 to 3 scale. The scale differentiates between 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness with inability to pinch the skin into a fold. The palpation is done for each of the 17 surface anatomic areas of the body: face, anterior chest, abdomen, fingers (right and left separately), forearms, upper arms, thighs, lower legs, dorsum of hands and feet. The sum of these individual values is defined as the total skin score. The mRSS has a range from 0 (no thickening) to 51 (severe thickening in all 17 areas). A high score corresponds to worse skin thickness. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).
  • Absolute Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score at Week 52. [ Time Frame: Baseline and up to 52 weeks after the start of administration ]
    This is the second key secondary endpoint. The Saint George's Respiratory Questionnaire measures the health status in patients with chronic airflow limitation. It consists of 2 parts that cover 3 domains: symptoms, activities, and impacts. The symptom domain relates to the effect, frequency and severity of respiratory symptoms. The activity domain relates to activities that cause or are limited by breathlessness. The impact domain evaluates a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. The scores of these domains range from 0 (no impairment) to 100 (worst possible). The calculated total score summarises the impact of the disease on overall health status. A high score corresponds to worse health. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).
  • Annual Rate of Decline in FVC in Percentage (%) Predicted Over 52 Weeks [ Time Frame: up to 52 weeks after the start of administration ]
    Annual rate of decline in FVC in percentage (%) predicted over 52 weeks. For this endpoint reported means represent the adjusted rate.
  • Absolute Change From Baseline in FVC in mL at Week 52 [ Time Frame: Baseline and up to 52 weeks after the start of administration ]
    Absolute change from baseline in FVC in mL at Week 52. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).
  • Relative Change From Baseline [%] of mRSS at Week 52 [ Time Frame: Baseline and up to 52 weeks after the start of administration ]
    Relative change from baseline [%] of mRSS at Week 52. The modified Rodnan Skin Score (mRSS) is an evaluation of the patient's skin thickness rated by clinical palpation using a 0 to 3 scale. The scale differentiates between 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness with inability to pinch the skin into a fold. The palpation is done for each of the 17 surface anatomic areas of the body: face, anterior chest, abdomen, fingers (right and left separately), forearms, upper arms, thighs, lower legs, dorsum of hands and feet. The sum of these individual values is defined as the total skin score. The mRSS has a range from 0 (no thickening) to 51 (severe thickening in all 17 areas). A high score corresponds to worse skin thickness. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).
  • Time to Death [ Time Frame: From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks) ]
    Time to event analysis of patients with death. The number of observed patients with death are reported.
  • The Percentage (%) of Responder Based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52 [ Time Frame: Week 52 ]
    The percentage (%) of responder based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52. This is a composite endpoint, based on the mRSS, FVC percent predicted, HAQ-DI, patient's global impression of overall health Visual Analogue Scale (VAS) and physician's global impression of patient's overall health VAS, as well as the absence of significant worsening of interstitial lung disease, a new scleroderma renal crisis, left ventricular failure or pulmonary arterial hypertension. The CRISS index score represents a probability of improvement and ranges between 0 and 1. This is a 2 stage process to predict probability of improvement: Step 1 - absence of major organ progression (SRC etc.) - score "0" Step 2 - predicted probability of improvement - (score "0 - 1")
  • Absolute Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco) in % Predicted at Week 52 [ Time Frame: Baseline and up to 52 weeks after the start of administration ]
    Absolute change from baseline in Carbon Monoxide Diffusion Capacity (DLco) in % predicted at Week 52. Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).
  • Absolute Change From Baseline in Digital Ulcer Net Burden at Week 52 [ Time Frame: Baseline and up to 52 weeks after the start of administration ]
    Absolute change from baseline in digital ulcer net burden (defined as the number of new digital ulcers (DUs) plus the number of DUs that have been verified at any earlier assessment during the trial) at Week 52. It is calculated at a visit by counting the total number of fingertips with ulcers (i.e. number of fingers with presence of digital ulcer ticked "Yes") at the corresponding visit Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).
  • Absolute Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 [ Time Frame: Baseline and up to 52 weeks after the start of administration ]
    Absolute change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 52. The HAQ-DI score is calculated as follows: Each question is scored 0-3 (where 0= "without difficulty" & 3= "unable to do"). There are 8 categories (Dressing & Grooming, Arising, Eating, Walking, Hygiene, Reach, Grip, Activities), each including 2 or 3 questions. The score for each category corresponds to maximum question score within each category. Finally, HAQ-DI score corresponds to sum of the sub-scores of all 8 categories divided by number of categories completed. Please note that if there are fewer than 6 categories with responses, then a score cannot be calculated. The HAQ-DI score scale has 25 possible values (i.e., 0, 0.125, 0.250, 0.375 … 3). A high score corresponds to worse impairment. Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).
  • Absolute Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnoea Score at Week 52 [ Time Frame: Baseline and up to 52 weeks after the start of administration ]
    Absolute change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) dyspnoea score at Week 52. FACIT-Dyspnoea (Dyspnoea) 10 Item Short Form include a 4-point rating scale (no shortness of breath=0; mildly short of breath=1; moderately short of breath = 2; severely short of breath =3; or I did not do this in the past 7 days =4). A raw score is calculated as: Sum individual item scores * 10 / number of items answered. Raw scores are then converted to scale scores using the table included in the FACIT Dyspnoea Scale Short Form Scoring Guideline. FACIT dyspnea scale score ranges between 0 and 75.9. The FACIT-Dyspnea short forms are scored such that a high score represents high levels of dyspnea. Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).
Original Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2015)
  • Time to all-cause mortality [ Time Frame: 52 weeks ]
  • Absolute change from baseline in FACIT dyspnoea score [ Time Frame: 52 weeks ]
  • Absolute change from baseline in the mRSS [ Time Frame: 52 weeks ]
  • Absolute change from baseline in SGRQ total score [ Time Frame: 52 weeks ]
  • Annual rate of decline in FVC in percent predicted [ Time Frame: 52 weeks ]
  • Absolute change from baseline in FVC in mL [ Time Frame: 52 weeks ]
  • Relative change from baseline (%) of mRSS [ Time Frame: 52 weeks ]
  • Absolute change from baseline in DLCO in percent predicted [ Time Frame: 52 weeks ]
  • Absolute change from baseline in digital ulcer net burden (defined as the number of new digital ulcers (DUs) plus the number of DUs that have been verified at any earlier assessment during the trial) [ Time Frame: 52 weeks ]
  • Absolute change from baseline in SHAQ total score [ Time Frame: 52 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Trial to Compare Nintedanib With Placebo for Patients With Scleroderma Related Lung Fibrosis
Official Title  ICMJE A Double Blind, Randomised, Placebo-controlled Trial Evaluating Efficacy and Safety of Oral Nintedanib Treatment for at Least 52 Weeks in Patients With Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD)
Brief Summary Systemic Sclerosis (SSc) is a devastating disease of unknown etiology. Patients suffer from multiple organ fibrosis whereas lung fibrosis (interstitial lung disease, ILD) is one of the main driver for mortality. There is preclinical evidence for efficacy of nintedanib in SSc and associated ILD (SSc-ILD) and the anti-fibrotic efficacy of nintedanib was proven in idiopathic pulmonary fibrosis patients, who are presenting a similar pattern regarding lung fibrosis. Hence it is the purpose of the trial to confirm the efficacy and safety of nintedanib 150 mg bid in treating patients with SSc-ILD, compared with placebo. The trial will be conducted as a double blind, randomised, placebo-controlled trial with primary efficacy evaluation at week 52 and placebo-controlled treatment until last patient out (up to a maximum of 100 weeks). Respiratory function is globally accepted for assessment of treatment effects in patients with lung fibrosis. The chosen endpoint (Forced Vital Capacity (FVC) decline) is easy to obtain and is part of the usual examinations done in patients with SSc-ILD.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Scleroderma, Systemic
Intervention  ICMJE
  • Drug: Nintedanib
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: Nintedanib
    patient receives capsules containing nintedanib twice a day
    Intervention: Drug: Nintedanib
  • Placebo Comparator: Placebo
    patient receives capsules identical to those containing active drug
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 16, 2018)
580
Original Estimated Enrollment  ICMJE
 (submitted: November 4, 2015)
520
Actual Study Completion Date  ICMJE November 28, 2018
Actual Primary Completion Date October 31, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • Age >= 18 years
  • 2013 American College of Rheumatology (ACR) / EULAR classification criteria for SSc fulfilled
  • SSc disease onset (defined by first non-Raynaud symptom) within 7 years
  • SSc related Interstitial Lung Disease confirmed by High Resolution Computer Tomography (HRCT); Extent of fibrotic disease in the lung >= 10%
  • FVC >= 40% of predicted normal
  • Carbon Monoxide Diffusion Capacity (DLCO) 30% to 89% of predicted normal

Exclusion criteria:

  • Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) >1.5 x ULN
  • Bilirubin >1.5 x ULN
  • Creatinine clearance <30 mL/min
  • Airway obstruction (pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)/FVC <0.7)
  • Other clinically significant pulmonary abnormalities
  • Significant Pulmonary Hypertension (PH)
  • Cardiovascular diseases
  • More than 3 digital fingertip ulcers or a history of severe digital necrosis requiring hospitalization or severe other ulcers
  • Bleeding risk (such as predisposition to bleeding, fibrinolysis, full-dose anticoagulation, high dose antiplatelet therapy, history of hemorrhagic central nervous system (CNS) event within last year
  • international normalised ratio (INR) >2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by >1.5 x ULN)
  • History of thrombotic event within last year
  • Clinical signs of malabsorption or needing parenteral nutrition
  • Previous treatment with nintedanib or pirfenidone
  • Treatment with prednisone >10 mg/day, azathioprine, hydroxychloroquine, colchicine, D-penicillamine, sulfasalazine, cyclophosphamide, rituximab, tocilizumab, abatacept, leflunomide, tacrolimus, newer anti-arthritic treatments like tofacitinib and cyclosporine A, potassium para-aminobenzoate
  • Unstable background therapy with either mycophenolate mofetil or methotrexate
  • Previous or planned hematopoietic stem cell transplantation
  • Patients with underlying chronic liver disease (Child Pugh A, B, C hepatic impairment)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   Chile,   China,   Czechia,   Denmark,   Finland,   France,   Germany,   Greece,   Hungary,   India,   Ireland,   Israel,   Italy,   Japan,   Malaysia,   Mexico,   Netherlands,   Norway,   Poland,   Portugal,   Spain,   Sweden,   Switzerland,   Thailand,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02597933
Other Study ID Numbers  ICMJE 1199.214
2015-000392-28 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Boehringer Ingelheim
Study Sponsor  ICMJE Boehringer Ingelheim
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
PRS Account Boehringer Ingelheim
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP