Trial Outcomes & Findings for Trial of Image-Guided Adaptive Conformal Photon vs Proton Therapy, With Concurrent Chemotherapy, for Locally Advanced Non-Small Cell Lung Carcinoma: Treatment Related Pneumonitis and Locoregional Recurrence (NCT NCT00915005)

Last Updated: 2020-05-26

Results Overview

The Primary Objective is assess and compare the incidence and time to development of CTCAE v3.0 grade \> 3 TRP, among IMRT-Group 1 or PSPT-Group 2 using Bayesian randomization. TRP will be diagnosed clinically by the treating investigator. Any questions regarding the diagnosis or grade of TRP will be resolved by the Protocol PI or by his/her designee(s). The outcomes review committee will meet to discuss each and every patient reported to have developed symptomatic TRP. The final grading of TRP will be decided by the outcomes review committee. Diagnosis of TRP included receipt of radiation that included a certain volume of normal lung, radiographic changes that suggested inflammation consistent with the radiation dose distribution within 12 months after starting chemoradiation, and symptoms attributable to TRP. Final TRP outcomes also were reviewed and approved by independent external experts.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

275 participants

Primary outcome timeframe

From date of protocol registration until the date of first documented development of CTCAE v3.0 grade > 3 TRP or local failure, whichever occurs first, in both treatment groups, assessed up to 6 years.

Results posted on

2020-05-26

Participant Flow

A total of 149 lung non-small cell lung cancer (NSCLC) patients with stage II to IV or recurrent tumor were consented, randomized, and treated under 2008-0133 protocol from June 2009 to March 2014. Intensity-modulated (photon) radiotherapy (IMRT) in 92; passive scattering proton therapy (PSPT) in 57.

A total of 275 NSCLC patients were consented. 2 patients were consented twice and 1 person denied by Massachusetts General Hospital.47 patients were excluded before the planning process began. 44 patients did not allow random assignment. 32 patients were not treated according to protocol allocation.

Participant milestones

Participant milestones
Measure	Intensity-modulated (Photon) Radiotherapy (IMRT) All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).	Passive Scattering Proton Therapy (PSPT) All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).
Overall Study STARTED	105	76
Overall Study COMPLETED	92	57
Overall Study NOT COMPLETED	13	19

Reasons for withdrawal

Reasons for withdrawal
Measure	Intensity-modulated (Photon) Radiotherapy (IMRT) All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).	Passive Scattering Proton Therapy (PSPT) All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).
Overall Study Withdrawal by Subject	4	4
Overall Study Patient preferred protons therapy	6	0
Overall Study Insurance denial	3	15

Baseline Characteristics

Trial of Image-Guided Adaptive Conformal Photon vs Proton Therapy, With Concurrent Chemotherapy, for Locally Advanced Non-Small Cell Lung Carcinoma: Treatment Related Pneumonitis and Locoregional Recurrence

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Intensity-modulated (Photon) Radiotherapy (IMRT) n=92 Participants All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).	Passive Scattering Proton Therapy (PSPT) n=57 Participants All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).	Total n=149 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=113 Participants	0 Participants n=163 Participants	0 Participants n=160 Participants
Age, Categorical Between 18 and 65 years	39 Participants n=113 Participants	22 Participants n=163 Participants	61 Participants n=160 Participants
Age, Categorical >=65 years	53 Participants n=113 Participants	35 Participants n=163 Participants	88 Participants n=160 Participants
Age, Continuous	66 years n=113 Participants	67 years n=163 Participants	66.5 years n=160 Participants
Sex: Female, Male Female	45 Participants n=113 Participants	24 Participants n=163 Participants	69 Participants n=160 Participants
Sex: Female, Male Male	47 Participants n=113 Participants	33 Participants n=163 Participants	80 Participants n=160 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=113 Participants	3 Participants n=163 Participants	7 Participants n=160 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	88 Participants n=113 Participants	54 Participants n=163 Participants	142 Participants n=160 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=113 Participants	0 Participants n=163 Participants	0 Participants n=160 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=113 Participants	0 Participants n=163 Participants	0 Participants n=160 Participants
Race (NIH/OMB) Asian	1 Participants n=113 Participants	1 Participants n=163 Participants	2 Participants n=160 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=113 Participants	0 Participants n=163 Participants	0 Participants n=160 Participants
Race (NIH/OMB) Black or African American	7 Participants n=113 Participants	3 Participants n=163 Participants	10 Participants n=160 Participants
Race (NIH/OMB) White	83 Participants n=113 Participants	52 Participants n=163 Participants	135 Participants n=160 Participants
Race (NIH/OMB) More than one race	0 Participants n=113 Participants	0 Participants n=163 Participants	0 Participants n=160 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=113 Participants	1 Participants n=163 Participants	2 Participants n=160 Participants
Region of Enrollment United States	92 participants n=113 Participants	57 participants n=163 Participants	149 participants n=160 Participants
Karnofsky performance score (KPS) KPS≤ 80	61 participants n=113 Participants	37 participants n=163 Participants	98 participants n=160 Participants
Karnofsky performance score (KPS) KPS≥ 90	31 participants n=113 Participants	20 participants n=163 Participants	51 participants n=160 Participants
Smoking history Never	9 participants n=113 Participants	3 participants n=163 Participants	12 participants n=160 Participants
Smoking history Ever	83 participants n=113 Participants	54 participants n=163 Participants	137 participants n=160 Participants
Induction chemotherapy Yes	61 participants n=113 Participants	42 participants n=163 Participants	103 participants n=160 Participants
Induction chemotherapy No	31 participants n=113 Participants	15 participants n=163 Participants	46 participants n=160 Participants
Tumor histology Adenocarcinoma	49 participants n=113 Participants	30 participants n=163 Participants	79 participants n=160 Participants
Tumor histology Squamous cell carcinoma	31 participants n=113 Participants	17 participants n=163 Participants	48 participants n=160 Participants
Tumor histology NSCLC unspecified	7 participants n=113 Participants	9 participants n=163 Participants	16 participants n=160 Participants
Tumor histology Large cell	2 participants n=113 Participants	1 participants n=163 Participants	3 participants n=160 Participants
Tumor histology Other	3 participants n=113 Participants	0 participants n=163 Participants	3 participants n=160 Participants
Clinical disease stage (American Joint Committee on Cancer [AJCC] 7th Ed) AJCC IIA/B	6 participants n=113 Participants	8 participants n=163 Participants	14 participants n=160 Participants
Clinical disease stage (American Joint Committee on Cancer [AJCC] 7th Ed) AJCC IIIA	44 participants n=113 Participants	21 participants n=163 Participants	65 participants n=160 Participants
Clinical disease stage (American Joint Committee on Cancer [AJCC] 7th Ed) AJCC IIIB	28 participants n=113 Participants	24 participants n=163 Participants	52 participants n=160 Participants
Clinical disease stage (American Joint Committee on Cancer [AJCC] 7th Ed) AJCC IV	5 participants n=113 Participants	3 participants n=163 Participants	8 participants n=160 Participants
Clinical disease stage (American Joint Committee on Cancer [AJCC] 7th Ed) ACC Recurrence	9 participants n=113 Participants	1 participants n=163 Participants	10 participants n=160 Participants

PRIMARY outcome

Timeframe: From date of protocol registration until the date of first documented development of CTCAE v3.0 grade > 3 TRP or local failure, whichever occurs first, in both treatment groups, assessed up to 6 years.

Outcome measures

Outcome measures
Measure	Intensity-modulated (Photon) Radiotherapy (IMRT) n=92 Participants All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).	Passive Scattering Proton Therapy (PSPT) n=57 Participants All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).
The Incidence and Time to Development of Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) Grade > 3 Treatment-related Pneumonitis (TRP) Grade 3	6 participants	6 participants
The Incidence and Time to Development of Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) Grade > 3 Treatment-related Pneumonitis (TRP) Grade 5	2 participants	0 participants
The Incidence and Time to Development of Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) Grade > 3 Treatment-related Pneumonitis (TRP) Grade 4	0 participants	0 participants

PRIMARY outcome

The Primary Objective is assess and compare the incidence and time to development of local failure, among IMRT-Group 1 or PSPT-Group 2 using Bayesian randomization. Local failure was defined as treatment failure within the planning target volume plus a # 1-cm margin. Images used to report Local failure were registered with radiation dose distribution to accurately assess the location of the failure. Biopsy to confirm Local failure was strongly recommended (Data Supplement). An internal outcomes review committee reviewed each event to ensure objectivity and consistency in reporting Local failure. Final RP outcomes also were reviewed and approved by independent external experts. 1. Tumor recurrence after achieving complete response, 2. Residual tumor enlargement of 20% or more on CT according to RECIST criteria, 3. Recurrence of PET FDG Avidity after achieving complete metabolic response, 4. Increase in FDG avidity in residual tumor, 5. Pathologically proven recurrence

Outcome measures

Outcome measures
Measure	Intensity-modulated (Photon) Radiotherapy (IMRT) n=92 Participants All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).	Passive Scattering Proton Therapy (PSPT) n=57 Participants All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).
The Incidence and Time to Development of Local Failure (LF) Local Failure	18 participants	14 participants
The Incidence and Time to Development of Local Failure (LF) Local Failure at 12 months	10 participants	6 participants

Adverse Events

Intensity-modulated (Photon) Radiotherapy (IMRT)

Serious events: 28 serious events

Other events: 82 other events

Deaths: 2 deaths

Passive Scattering Proton Therapy (PSPT)

Serious events: 22 serious events

Other events: 52 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Zhongxing Liao, MD/Professor, Radiation Oncology Department

UT MD Anderson Cancer Center

Phone: (713) 563-2300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Intensity-modulated (Photon) Radiotherapy (IMRT) n=92 participants at risk All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).	Passive Scattering Proton Therapy (PSPT) n=57 participants at risk All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).
Respiratory, thoracic and mediastinal disorders Cough	4.3% 4/92 • Number of events 4 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	7.0% 4/57 • Number of events 4 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Dyspnea	5.4% 5/92 • Number of events 5 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	10.5% 6/57 • Number of events 7 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Esophatitis	10.9% 10/92 • Number of events 10 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	17.5% 10/57 • Number of events 10 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Hypoxia	1.1% 1/92 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	1.8% 1/57 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Pneumonia	2.2% 2/92 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	14.0% 8/57 • Number of events 8 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Pneumonitis	8.7% 8/92 • Number of events 10 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	10.5% 6/57 • Number of events 6 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Skin and subcutaneous tissue disorders Radiation Induced Dermatitis	5.4% 5/92 • Number of events 5 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	10.5% 6/57 • Number of events 6 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Dysphagia	2.2% 2/92 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	3.5% 2/57 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Gastro Stricutre	2.2% 2/92 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	0.00% 0/57 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Odynophagia	2.2% 2/92 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	3.5% 2/57 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Cardiac disorders Cardiac Ischemia / Infarction	1.1% 1/92 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	0.00% 0/57 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Cardiac disorders Hypotension	0.00% 0/92 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	1.8% 1/57 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Cardiac disorders Pericardial effusion	0.00% 0/92 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	1.8% 1/57 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/92 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	1.8% 1/57 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Hemorrhage, pulmonary/ upper respiratory	0.00% 0/92 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	1.8% 1/57 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Anorexia	1.1% 1/92 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	3.5% 2/57 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Dehydration	1.1% 1/92 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	3.5% 2/57 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Congenital, familial and genetic disorders Fatigue	3.3% 3/92 • Number of events 3 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	14.0% 8/57 • Number of events 8 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Congenital, familial and genetic disorders Fever	0.00% 0/92 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	1.8% 1/57 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.

Measure	Intensity-modulated (Photon) Radiotherapy (IMRT) n=92 participants at risk All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).	Passive Scattering Proton Therapy (PSPT) n=57 participants at risk All patients on this trial will receive concurrent weekly carboplatin and paclitaxel chemotherapy with radiation therapy 74 or 66 Gy(RBE).
Respiratory, thoracic and mediastinal disorders Cough	48.9% 45/92 • Number of events 56 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	49.1% 28/57 • Number of events 32 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Dyspnea	44.6% 41/92 • Number of events 51 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	38.6% 22/57 • Number of events 25 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Esophatitis	52.2% 48/92 • Number of events 64 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	64.9% 37/57 • Number of events 45 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Pneumonia	7.6% 7/92 • Number of events 7 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	3.5% 2/57 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Pneumonitis	23.9% 22/92 • Number of events 24 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	31.6% 18/57 • Number of events 19 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	5.4% 5/92 • Number of events 5 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	1.8% 1/57 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Skin and subcutaneous tissue disorders Radiation Induced Dermatitis	70.7% 65/92 • Number of events 81 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	78.9% 45/57 • Number of events 57 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Dysphagia	38.0% 35/92 • Number of events 38 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	50.9% 29/57 • Number of events 38 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Gastro Stricutre	2.2% 2/92 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	8.8% 5/57 • Number of events 5 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Odynophagia	32.6% 30/92 • Number of events 35 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	31.6% 18/57 • Number of events 23 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Respiratory, thoracic and mediastinal disorders Pleural effusion	12.0% 11/92 • Number of events 11 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	12.3% 7/57 • Number of events 9 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Anorexia	30.4% 28/92 • Number of events 31 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	22.8% 13/57 • Number of events 13 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Gastrointestinal disorders Dehydration	7.6% 7/92 • Number of events 7 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	7.0% 4/57 • Number of events 4 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Congenital, familial and genetic disorders Fatigue	72.8% 67/92 • Number of events 91 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	86.0% 49/57 • Number of events 65 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Congenital, familial and genetic disorders Fever	4.3% 4/92 • Number of events 4 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	8.8% 5/57 • Number of events 6 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.
Cardiac disorders Pericardial effusion	2.2% 2/92 • Number of events 2 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.	1.8% 1/57 • Number of events 1 • From date of protocol registration until the date of documented development of adverse events (AEs) in both treatment groups, assessed up to 6 years.