Drug Trials Snapshots: IOMERVU

How were the trials designed? 

In Studies 1 through 4, adult patients underwent cerebral arteriography, visceral and peripheral arteriography and aortography, coronary arteriography and cardiac ventriculography, and CT of the head and body. In each study, patients were randomized to receive either IOMERVU or a comparator drug. The dose administered varied according to the indication and imaging procedure for each patient. Images obtained for each patient were assessed as a single set with an overall score. Three readers who were blinded to the study drug independently scored the images as having adequate or inadequate visualization using rating scales specific for the vessels and anatomical structures that were assessed.

In Studies 5 to 7, adult patients underwent cerebral arteriography, visceral and peripheral arteriography and aortography with digital subtraction angiography. In each study, patients were randomized to receive either IOMERVU or a comparator drug. Two readers who were blinded to the study drug independently scored the images for quality of visualization on a 5-point scale.
In Studies 8 and 9, adult patients being evaluated for hematuria or other urologic diseases underwent CT urography with IOMERVU. In Study 8, patients were randomized to undergo either a single bolus three-phase scan protocol or a split-bolus dual-phase protocol. Two readers assessed parenchymal image quality on a 3-point scale. In Study 9, patients underwent a split-bolus dual-phase protocol. Two readers assessed visualization quality for the urinary system overall on a 6-point scale.

In Studies 10 and 11, adult patients with suspected or known peripheral arterial disease underwent CT angiography with IOMERVU. Both studies assessed sensitivity and specificity against a digital subtraction angiography reference standard and readers were blinded to the reference standard information. In Study 10, three readers independently evaluated for ≥70% stenosis at the arterial segment level. In Study 11, two readers independently evaluated for >50% stenosis at the lesion level.
In Studies 12 and 13, adult patients with suspected coronary artery disease underwent coronary CT angiography with IOMERVU. In both studies, two readers blinded to the findings of invasive coronary angiography (reference standard) independently evaluated for ≥50% stenosis at the arterial segment level and sensitivity and specificity were reported.

Who participated in the trials?

Table 1. Demographic and Baseline Characteristics of the Safety Population

_{Source: Adapted from FDA Review
Abbreviation: SD, standard deviation}

What are the benefits of this drug (results of trials used to assess efficacy)? 

In Studies 1 through 4, adult patients were randomized to receive either IOMERVU or a comparator drug. The dose administered varied according to the indication and imaging procedure for each patient. In each study, three blinded readers independently assessed the images as having adequate or inadequate visualization using rating scales specific for the vessels and anatomical structures that were assessed.

In Study 1, adult patients underwent cerebral arteriography and the mean total iodine dose administered was 29 grams. Visualization was rated as adequate in 100% of patients. In Study 2, adult patients underwent visceral and peripheral arteriography and aortography and the mean total iodine dose administered was 48 grams. Visualization was rated as adequate in 98% of patients. In Study 3, adult patients underwent coronary arteriography and cardiac ventriculography and the mean total iodine dose administered was 45 grams. Visualization was rated as adequate in 93% to 100% of patients. In Study 4, adult patients underwent CT of the head and body and the mean total iodine dose administered was 41 grams. Visualization was rated as adequate in 98% to 100% of patients. 

In Studies 5 to 7, adult patients underwent cerebral arteriography, visceral and peripheral arteriography and aortography with digital subtraction angiography. In each study, patients were randomized to receive either IOMERVU or a comparator drug. Two readers who were blinded to the study drug independently scored the images for quality of visualization on a 5-point scale. The findings from these studies were comparable to cerebral arteriography, visceral and peripheral arteriography and aortography studies 1 to 3. 
In Studies 8 and 9, adult patients being evaluated for hematuria or other urologic diseases underwent CT urography with IOMERVU. In Study 8, two readers assessed parenchymal image quality on a 3-point scale (inadequate, diagnostic, or very good or excellent) as very good or excellent in 64% to 98% of the patients depending on scan protocol. In Study 9, two blinded readers assessed visualization quality for the urinary system overall (calyces, renal pelvis, ureter, and bladder), on a scale of 0 (absence of visualization) to 5 (excellent visualization), with the mean score (standard deviation) for reader 1 being 4.2 (1.4) and for reader 2 being 4.1 (1.5).

In Studies 10 and 11, adult patients with suspected or known peripheral arterial disease underwent CT angiography with IOMERVU. Both studies assessed the diagnostic performance for detection of significant stenosis at the arterial segment level using digital subtraction angiography as the reference standard. In Study 10, 212 patients (7,392 segments, 42% positive by reference standard) were independently evaluated by three blinded readers. The reported   segment-level sensitivity and specificity for the detection of ≥70% stenosis were 99% (95% confidence interval: 98%, 99%) and 97% (95% confidence interval: 96%, 97%), respectively. In Study 11, 50 patients (929 to 933 lesions, 34% positive by reference standard) were evaluated by two blinded readers. The reported lesion-level sensitivity and specificity (95% confidence interval) for the detection of >50% stenosis were 93% (91%, 96%) and 97% (95%, 98%), respectively, for reader 1 and 90% (87%, 93%) and 96% (94%, 97%), respectively, for reader 2.

In Studies 12 and 13, adult patients with suspected coronary artery disease underwent coronary CT angiography with IOMERVU. Both studies assessed the diagnostic performance for detection of ≥50% stenosis at the coronary artery segment level using invasive coronary angiography as the reference standard. In Study 12, 210 patients (2,532 segments, 22% positive by reference standard) were independently evaluated by two blinded readers with discrepancies resolved by consensus. The segment-level sensitivity and specificity (95% confidence interval) were 84% (81%, 87%) and 94% (92%, 95%), respectively. In Study 13, 91 patients (1,456 segments, 18% positive by reference standard) were independently evaluated by two blinded readers with discrepancies resolved by a third reader. The segment-level sensitivity and specificity (95% confidence interval) were 97% (95%, 99%) and 91% (89%, 92%), respectively.

Were  there any differences in how well the drug worked in clinical trials among sex, race, and age groups? 

Table 2. Efficacy Results by Sex, Age, and Race – Percentage of Adequate Quality, Studies 1 to 4 (Efficacy Populations)

<sub>Source: Adapted from Clinical Study Reports and FDA Review
* Race: The number of patients other than White was small; therefore, differences in how IOMERVU worked among races could not be determined. 
Note: The readers were different among these (sub)studies. Two-sided 95% confidence intervals were calculated based on Wilson score method.  
Abbreviations: CA, cerebral arteriography; CACV, coronary arteriography and cardiac ventriculography; CT, computed tomography; CTHB, CT of the head and body; CI, confidence interval; N, number of patients dosed with IOMERVU; NA, not applicable; VPA, visceral and peripheral arteriography</sub>

Note: There were no data to perform subgroup analyses for studies 5 to 13. 

What are the possible side effects (results of trials used to assess safety)? 

The safety of IOMERVU was evaluated in 4,804 patients who received a total iodine dose of IOMERVU less than 86 grams intra-arterially or intravenously. The adverse reactions reported in ≥0.5% of adult patients are shown in Table 3.

Table 3. Adverse Reactions Reported in ≥0.5% of 4,621 Adult Patients Who Received IOMERVU at the Recommended Dose

_{Source: IOMERVU Prescribing Information}

The following adverse reactions were observed in <0.5% of the adult patients receiving IOMERVU:

• Blood and lymphatic system disorders: activated partial thromboplastin time prolonged, prothrombin time prolonged
• Cardiovascular disorders: ventricular fibrillation, hypertensive crisis, coronary arteriospasm, congestive cardiac failure, cardiac flutter, atrioventricular block, right bundle branch block, hypotension, arrhythmia, bradycardia, supraventricular extrasystoles, ventricular extrasystoles, increased blood pressure, flushing
• Ear and labyrinth disorders: vertigo, ear discomfort
• Eye disorder: vision blurred, periorbital edema, photopsia
• Gastrointestinal: esophageal varices hemorrhage, abdominal pain, abdominal distension, alanine aminotransferase (ALT) increased, constipation, diarrhea, dry mouth, salivary hypersecretion, oral paresthesia
• General disorders: pain, injection site reactions (pain, discomfort, or warmth), peripheral edema, chills, asthenia, malaise
• Musculoskeletal and connective tissue disorders: arthralgia, pain in jaw
• Nervous system disorders: cerebrovascular disorder, dysarthria, visual field defect, burning sensation, presyncope, dizziness, dysgeusia, paresthesia
• Psychiatric disorders: delirium, anxiety, insomnia
• Renal and urinary disorders: acute kidney injury, increased blood creatinine, urinary urgency
• Respiratory, thoracic, and mediastinal disorders: respiratory arrest, pulmonary edema, bronchospasm, dyspnea, cough, rhinitis, throat irritation or tightness, sneezing
• Skin and subcutaneous tissue disorders: urticaria, blister, purpura, ecchymosis, rash, pruritus, erythema

Were there any differences in side effects of the clinical trials among sex, race and age groups? 

The proportion of females with at least one adverse event and the proportion of adverse events reported by females was greater than the fraction of females in the analysis for safety, indicating that females were more likely to experience adverse events. However, the clinical significance of the observed differences is doubtful due to the relatively modest effect size and similar types of adverse events experienced overall by both sexes.

Table 4. Adverse Events by Patient Sex Among Patients Who Received IOMERVU at the Recommended Dose

_{Source: Adapted from FDA Review
Abbreviations: AE, adverse event; NA, not applicable} 

The proportion of patients with at least one adverse event and the proportion of adverse events reported in each patient race were similar to the proportion of patients of that race enrolled in the clinical studies.

Table 5. Adverse Events by Patient Race Among Patients Who Received IOMERVU at the Recommended Dose

_{Source: Adapted from FDA Review
Abbreviations: AE, adverse event}

The proportion of patients with at least one adverse event and the proportion of adverse events in each age range were similar to the proportion of patients of that age.

Table 6. Adverse Events by Patient Age Among Patients Who Received IOMERVU at the Recommended Dose

_{Source: Adapted from FDA Review
Abbreviations: AE, adverse event; NA, not applicable}