Evaluate the Impact of Afatinib on Quality of Life and Symptom Burden of Greek Subjects With Advanced NSCLC in Routine Patient Care Settings

Study Overview
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Brief Summary
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This non-interventional study will include a representative sample of patients with locally advanced or metastatic NSCLC harboring Epidermal Growth Factor Receptor (EGFR)-mutations in Greece. Eligible NSCLC patients, for whom the physician has decided to initiate treatment with the study medication (afatinib, GIOTRIF®) will be treated according to the local prescribing information and standard medical practice in terms of visit frequency and types of assessments performed. The study will investigate the impact of GIOTRIF (Afatinib) on patients' disease-related symptom burden and Health-Related Quality of Life (HRQoL) in a real world clinical setting in Greece.The Average Symptom Burden Index (ASBI) score of the Lung Cancer Symptom Scale (LCSS) in eligible patients, after 6 months of therapy, will be analyzed. The overall study duration period is expected to be 60 months, including a 48-month enrollment period and a minimum 12-month follow-up period.

Detailed Description
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Study Design:

Official Title
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A Multicentre, Cohort Study to Assess the Impact on SYMptom Burden and Patient Health-related Quality of Life of Afatinib Treatment in Advanced Non-small Cell Lung Cancer in a Real World Setting in Greece.

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: afatinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Adult outpatients (18 years and older) of either gender; Histologically or cytologically confirmed locally advanced or metastatic (IIIB/IV) NSCLC of any histological type with activating EGFR mutation(s) according to local laboratory EGFR testing; EGFR- tyrosine kinase inhibitor (TKI) naive patients; Patients for whom the decision to prescribe therapy with afatinib (GIOTRIF®) according to the locally approved product's summary of product characteristics (SmPC) has already been taken prior to their enrolment in the study; the assignment of the patient to this therapeutic strategy is not decided in advance by the study protocol but falls within current practice and the prescription of afatinib is clearly separated from the physicians decision to include the patient in the current study; Patients must be able and willing to provide written informed consent and to comply with the requirements of this study protocol; Exclusion criteria: Patients who have initiated treatment with Afatinib more than 7 days prior to their enrolment into the study; Patients that meet any of the contraindications to the administration of the study drug according to the approved SmPC; Receipt of any investigational agent within 30 days or 5 half-lives of the investigational agent (whichever is longer) before the commencement of therapy with afatinib

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with non-small cell lung cancer (NSCLC) treated with afatinib<br>Patients with advanced/metastatic non-small cell lung cancer (NSCLC) in Greece treated with afatinib. Patients were treated as per the routine medical practice in terms of visit frequency, types of assessments performed and with adherence to the local prescribing requirements for afatinib. Patients were observed in the context of the study until the end of study participation, defined as a maximum of 48 months after afatinib treatment initiation or until disease progression, death, withdrawal of consent, unacceptable toxicity, study completion or physician's decision whichever occurred earlier. | Drug: afatinib<br>* Patients were treated as per the routine medical practice in terms of visit frequency, types of assessments performed and with adherence to the local prescribing requirements for afatinib.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experienced a Minimum Clinically Important Improvement in Symptoms Over 6 Months of Treatment | Number of patients who experience a minimum clinically important improvement in symptoms is reported. A patient was categorized as having an improvement if the mean score of any two consecutive post-baseline Average Symptom Burden Index (ASBI) score of Lung Cancer Symptom Scale (LCSS) assessments for that patient was at least 10 points below the patient's ASBI score of LCSS at enrolment, over 6 months of treatment. The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Each item is scored on a 100-millimeter (mm) Visual Analogue Scale (VAS), with score reported from 0 to 100, with 0 representing the best score. ASBI score was calculated by the mean of the 6 major lung cancer symptoms (loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis). For a given assessment, if any of the six symptom-specific questions was not completed, the ASBI score was not calculated. | Baseline and 6 months following start of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-rated Average Symptom Burden Index (ASBI) Score of Lung Cancer Symptom Scale (LCSS) | Patient-rated ASBI score of LCSS at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study) is reported. The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Each item was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. ASBI score was calculated by the mean of the 6 major lung cancer symptoms (loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis). For a given assessment, if any of the six symptom-specific questions had not been completed, the ASBI score was not calculated. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Total Lung Cancer Symptom Scale (LCSS) Score | Patient-rated total LCSS score -defined as the average of the aggregate score of all 9 items that comprise the LCSS- at enrolment and at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Each item was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. ASBI score was calculated by the mean of the 6 major lung cancer symptoms (loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis). For a given assessment, if any of the six symptom-specific questions had not been completed, the ASBI score was not calculated. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Lung Cancer Symptom Scale (LCSS) Individual Item Scores: Loss of Appetite | Patient-rated LCSS individual item scores: Loss of appetite at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Loss of appetite was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Lung Cancer Symptom Scale (LCSS) Individual Item Scores: Fatigue | Patient-rated LCSS individual item scores: Fatigue at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Fatigue was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Lung Cancer Symptom Scale (LCSS) Individual Item Scores: Cough | Patient-rated LCSS individual item scores: Cough at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Cough was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Lung Cancer Symptom Scale (LCSS) Individual Item Scores: Dyspnoea | Patient-rated LCSS individual item scores: Dyspnoea at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Dyspnoea was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Lung Cancer Symptom Scale (LCSS) Individual Item Scores: Haemoptysis | Patient-rated LCSS individual item scores: Haemoptysis at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Haemoptysis was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Lung Cancer Symptom Scale (LCSS) Individual Item Scores: Pain | Patient-rated LCSS individual item scores: Pain at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Pain was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Lung Cancer Symptom Scale (LCSS) Individual Item Scores: Overall Symptomatic Distress | Patient-rated LCSS individual item scores: Overall symptomatic distress at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Overall symptomatic distress was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. ASBI score was calculated by the mean of the 6 major lung cancer symptoms (loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis). For a given assessment, if any of the six symptom-specific questions had not been completed, the ASBI score was not calculated. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Lung Cancer Symptom Scale (LCSS) Individual Item Scores: Interference With Normal Activity | Patient-rated LCSS individual item scores: Interference with normal activity at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Interference with normal activity was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. ASBI score was calculated by the mean of the 6 major lung cancer symptoms (loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis). For a given assessment, if any of the six symptom-specific questions had not been completed, the ASBI score was not calculated. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Patient-rated Lung Cancer Symptom Scale (LCSS) Individual Item Scores: Global Quality of Life (QoL) | Patient-rated LCSS individual item scores: Global Quality of Life (QoL) at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The patient-rated scale consists of six symptom-specific questions that address loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis. Global Quality of Life (QoL) was scored on a 100-mm Visual Analogue Scale (VAS), with scores reported from 0 to 100 with 0 representing the best score. ASBI score was calculated by the mean of the 6 major lung cancer symptoms (loss of appetite, fatigue, cough, dyspnoea, pain and haemoptysis). For a given assessment, if any of the six symptom-specific questions had not been completed, the ASBI score was not calculated. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Patients With Reported Problems for the European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Utility Index Score Dimension: Mobility | Percentage of patients with reported problems for the EQ-5D-3L utility index score dimension: Mobility. The EQ-5D-3L descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 1=no problems; 2=some problems; 3= extreme problems. Reported are the percentage of patients with problem, consisting of both level 2 (some problems) and level 3 (extreme problems) with the remaining subjects having reported level 1 (no problems). | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Patients With Reported Problems for the European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Utility Index Score Dimension: Self-care | Percentage of patients with reported problems for the EQ-5D-3L utility index score dimension: Self-care. The EQ-5D-3L descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 1=no problems; 2=some problems; 3= extreme problems. Reported are the percentage of patients with problem, consisting of both level 2 (some problems) and level 3 (extreme problems) with the remaining subjects having reported level 1 (no problems). | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Patients With Reported Problems for theEuropean Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Utility Index Score Dimension: Usual Activities | Percentage of patients with reported problems for the EQ-5D-3L utility index score dimension: Usual activities. The EQ-5D-3L descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 1=no problems; 2=some problems; 3= extreme problems. Reported are the percentage of patients with problem, consisting of both level 2 (some problems) and level 3 (extreme problems) with the remaining subjects having reported level 1 (no problems). | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Patients With Reported Problems for the European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Utility Index Score Dimension: Pain/Discomfort | Percentage of patients with reported problems for the EQ-5D-3L utility index score dimension: Pain/discomfort. The EQ-5D-3L descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 1=no problems; 2=some problems; 3= extreme problems. Reported are the percentage of patients with problem, consisting of both level 2 (some problems) and level 3 (extreme problems) with the remaining subjects having reported level 1 (no problems). | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Patients With Reported Problems for the European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) Utility Index Score Dimension: Anxiety/Depression | Percentage of patients with reported problems for the EQ-5D-3L utility index score dimension: Anxiety/depression. The EQ-5D-3L descriptive system consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 1=no problems; 2=some problems; 3= extreme problems. Reported are the percentage of patients with problem, consisting of both level 2 (some problems) and level 3 (extreme problems) with the remaining subjects having reported level 1 (no problems). | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| EQ-VAS Score | EQ-VAS score at enrolment and at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). The EQ-VAS is a visual analogue scale (VAS) that takes values between 100 (best imaginable health) and 0 (worst imaginable health), on which patients provide a global assessment of their health. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score 0 | Percentage of participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 0 at baseline and at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). ECOG has 6 grades (0-5, where 0 is the best possible score and 5 the worst): 0 = Fully active, able to carry on all pre-disease performance without restriction. = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. = Dead. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score 1 | Percentage of participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 1 at baseline and at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). ECOG has 6 grades (0-5, where 0 is the best possible score and 5 the worst): 0 = Fully active, able to carry on all pre-disease performance without restriction. = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. = Dead. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score 2 | Percentage of participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 2 at baseline and at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). ECOG has 6 grades (0-5, where 0 is the best possible score and 5 the worst): 0 = Fully active, able to carry on all pre-disease performance without restriction. = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. = Dead. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score 3 | Percentage of participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 3 at baseline and at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). ECOG has 6 grades (0-5, where 0 is the best possible score and 5 the worst): 0 = Fully active, able to carry on all pre-disease performance without restriction. = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. = Dead. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Percentage of Participants With Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score 4 | Percentage of participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 4 at baseline and at the post-baseline predefined timepoints (i.e., every 2 months (± 3 weeks) during the first 12 months of therapy and every 6 months (±3 weeks) thereafter until the end of patient's participation in the study). ECOG has 6 grades (0-5, where 0 is the best possible score and 5 the worst): 0 = Fully active, able to carry on all pre-disease performance without restriction. = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. = Dead. | Baseline (Day 0) and at month 2, 4, 6, 8, 10, 12, 18, 24, 30, 36 and 42 post baseline. | 
| Ratio of Afatinib Tablets Actually Taken to Doses Prescribed Over the Study Participation Period | Ratio of afatinib tablets actually taken to doses prescribed over the study participation period. Ratio = doses taken / doses prescribed. | Up to 42 months. | 
| Number of Patients With a Reason for Missing Afatinib Tablets | Number of patients with a reason for missing afatinib tablets. One participant can have multiple missing doses for multiple reasons. | Up to 42 months. | 
| Number of Patients With a Reason for Discontinuation of Afatinib | Number of patients with a reason for discontinuation of Afatinib throughout the study observation period. | Up to 42 months. | 
| Number of Patients With a Reason for Treatment Interruptions | Number of patients with a reason for treatment interruptions throughout the study observation period. One participant can have multiple interruptions for multiple reasons. | Up to 42 months. | 
| Number of Participants With Afatinib Interruptions or Dose Modifications | Number of participants with Afatinib interruptions or dose modifications (i.e., a dose increase or decrease). | Up to 42 months. | 
| Number of Patients With a Reason for Dose Reduction | Number of patients with a reason for dose reduction throughout the study observation period. | Up to 42 months. | 
| Number of Patients With a Reason for Dose Increase | Number of patients with a reason for dose increase throughout the study observation period. | Up to 42 months. |