Chronic Obstructive Pulmonary Disease: Safety and Tolerability of Hyperpolarized 129Xe MR Imaging in Healthy Volunteers and Patients

© RSNA, 2011




 

Appendix E1

Clinical Laboratory Parameters Assessed at Screening and 24-hour Follow-up

 

Appendix E1

 

Appendix E2

Detailed Description of Moderate Adverse Events in the Age-matched Control Subject

The two adverse events classified as moderate are described in more detail here. Both events were experienced by a single age-matched control subject: a 51-year-old white woman with a history of multiple sclerosis, hypertension, hyperlipidemia, B12 deficiency, and Graves disease. Concurrent medications included atenolol, levothyroxine, captopril, fish oil, and B12 supplements. She experienced drowsiness, sleepiness, and numbness after dose 2 but responded appropriately and was neurologically intact. These events resolved in about 7 minutes. All vital signs, ECG, and pulse oximetry were stable without change after dose 2. During the approximately 30-minute wait for dose 3 to be prepared, the subject napped on the imager bed. She was then awakened to receive dose 3 and completed the breath hold and MR acquisition. After the examination, the subject was difficult to arouse (adverse event of depressed level of consciousness) for approximately 3 minutes and was drowsy (adverse event of somnolence) for approximately 10 minutes. Eye examination result was normal (pupils equal, round, reactive to light and accommodation and extraocular movements intact). No seizure activity or decrease in pulse oximetry readings was noted, and no change in ECG pattern was observed. The subject reported being able to hear commands but being unable to respond.

After 3 minutes, full function began to return, and the subject could open her eyes, grip appropriately, and reported no other changes. The subject rested, and, at the 10-minute postdose assessment, had no further feeling of inability to respond, and her neurologic examination results had returned to baseline. She reported feeling drowsy, as if she had undergone anesthesia, and she complained of mouth dryness. Vital signs and monitoring parameters remained stable, although there was an elevated systolic blood pressure recording of 157 mm Hg at 5 minutes after dose and a slightly elevated heart rate of 85 beats per minute at 10 minutes after dose. At the 30-minute postdose assessment, the subject reported less drowsiness, and all vital signs were stable. At 60 minutes after dose, vital signs, ECG, and pulse oximetry remained at baseline levels. The subject returned the following day for the 24-hour follow-up visit and reported no further symptoms during the night. However, she noted that she did not remember the period between dose 2 and dose 3 (adverse event of amnesia). It is interesting to note that Latchaw et al (21) discuss that xenon appears to augment emotional liability in patients with multiple sclerosis. Given that the subject in our study who experienced the strongest response to xenon also had multiple sclerosis, it may be prudent to pay particular attention to this condition when considering hyperpolarized xenon administration.

 

Appendix E3

24-hour Follow-up Safety Assessment Details

No subjects exhibited a change in serum biochemistry values at 24-hour follow-up relative to baseline that was deemed to be clinically important. No subjects exhibited a change in any parameter exceeding 80% of the span of normal limits. In a few subjects, some parameters changed by more than 40% of the span of normal limits. These included glucose level increasing in five (11%) subjects and decreasing in three (7%), creatine kinase level increasing in three (7%) subjects and decreasing in three (7%), blood urea nitrogen level increasing in three (7%) subjects, and phosphate increasing in three (7%) subjects. Any other parameters that changed by more than 40% of the span of normal limits were reported in fewer than three (7%) subjects overall.

No subjects exhibited a change in hematology at 24-hour follow-up relative to their baseline that was deemed to be clinically important. No subjects exhibited a change in any hematology parameter exceeding 80% of the span of normal limits. A change of more than 40% of span was seen in the ratio of eosinophils to leukocytes in six (14%) subjects. All other changes exceeding 40% of the span of normal limits were reported in fewer than three (7%) subjects.

No subjects exhibited clinically noteworthy changes relative to screening at 12-lead ECG at either 1 hour after the last dose or at 24-hour follow-up. There were abnormal ECG findings both at screening and at postdose time points for all subject groups. Abnormal ECG results at 1 hour after the final dose included a low heart rate in 11 (25%) subjects, abnormal R-R interval in 10 (23%) subjects, abnormal QRS interval in three (7%) subjects, and abnormal PR interval in one (2%) subject. Findings at 24-hour follow-up were similar, and there were no abnormal QT findings for any subject. Postadministration ECG changes from baseline that qualified as outlying results were QRS changes in two (5%) subjects and corrected QT interval (Fridericia) changes in two (5%) subjects.

Physical examination results at 24-hour follow-up noted no clinically important differences. One healthy volunteer did have a change in assessment of the lungs during physical examination (decrease in breath sounds) from normal to abnormal. However, this subject had also exhibited substantial ventilation defects at 129Xe MR imaging, which likely influenced the clinical personnel to more carefully check for such findings at follow-up. No subject had an abnormal neurologic examination finding at any of the examination times.