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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Scleroderma, Systemic

Intervention / Treatment
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* Drug: Nintedanib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nintedanib<br>patient receives capsules containing nintedanib twice a day | Drug: Nintedanib<br> <br> |
| Placebo Comparator: Placebo<br>patient receives capsules identical to those containing active drug | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks | 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. | up to week (wk) 52 after the start of administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in the Modified Rodnan Skin Score (mRSS) at Week 52 | 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). | Baseline and up to 52 weeks after the start of administration | 
| Absolute Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score at Week 52. | 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). | Baseline and up to 52 weeks after the start of administration | 
| Annual Rate of Decline in FVC in Percentage (%) Predicted Over 52 Weeks | Annual rate of decline in FVC in percentage (%) predicted over 52 weeks. For this endpoint reported means represent the adjusted rate. | up to 52 weeks after the start of administration | 
| Absolute Change From Baseline in FVC in mL at Week 52 | 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). | Baseline and up to 52 weeks after the start of administration | 
| Relative Change From Baseline [%] of mRSS at Week 52 | 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). | Baseline and up to 52 weeks after the start of administration | 
| Time to Death | Time to event analysis of patients with death. The number of observed patients with death are reported. | From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks) | 
| The Percentage (%) of Responder Based on Combined Response Index in Systemic Sclerosis (CRISS) at 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) | Week 52 | 
| Absolute Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco) in % Predicted at Week 52 | 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). | Baseline and up to 52 weeks after the start of administration | 
| Absolute Change From Baseline in Digital Ulcer Net Burden at Week 52 | 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). | 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 | 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). | 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 | 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). | Baseline and up to 52 weeks after the start of administration |