Table 3.
Summary of Adverse Events and ARIA.*
| Variable | GRADUATE I | GRADUATE II | Pooled | |||
|---|---|---|---|---|---|---|
| Gantenerumab (N = 503) | Placebo (N = 481) | Gantenerumab (N = 501) | Placebo (N = 474) | Gantenerumab (N = 1004) | Placebo (N = 955) | |
| Adverse events | ||||||
| Any adverse event — no. (%) | 454 (90.3) | 423 (87.9) | 451 (90.0) | 409 (86.3) | 905 (90.1) | 832 (87.1) |
| Serious adverse event — no. (%)† | 76 (15.1) | 95 (19.8) | 61 (12.2) | 63 (13.3) | 137 (13.6) | 158 (16.5) |
| Adverse event that led to discontinuation of gantenerumab or placebo — no. (%)‡ | 47 (9.3) | 10 (2.1) | 44 (8.8) | 7 (1.5) | 91 (9.1) | 17 (1.8) |
| Death — no. (%)§ | 3 (0.6) | 10 (2.1) | 7 (1.4) | 4 (0.8) | 10 (1.0) | 14 (1.5) |
| ARIA ¶ | ||||||
| ARIA-E — no./total no. (%) | ||||||
| Any ARIA-E | 119/497 (23.9) | 8/476 (1.7) | 128/496 (25.8) | 18/470 (3.8) | 247/993 (24.9) | 26/946 (2.7) |
| ARIA-E according to APOE ε4 genotype | ||||||
| No ε4 allele | 20/172 (11.6) | 2/155 (1.3) | 24/163 (14.7) | 7/155 (4.5) | 44/335 (13.1) | 9/310 (2.9) |
| One ε4 allele | 57/236 (24.2) | 4/237 (1.7) | 60/242 (24.8) | 6/249 (2.4) | 117/478 (24.5) | 10/486 (2.1) |
| Two ε4 alleles | 42/89 (47.2) | 2/84 (2.4) | 44/91 (48.4) | 5/66 (7.6) | 86/180 (47.8) | 7/150 (4.7) |
| Symptomatic ARIA-E‖ | 26/497 (5.2) | 0/476 | 24/496 (4.8) | 2/470 (0.4) | 50/993 (5.0) | 2/946 (0.2) |
| Symptomatic ARIA-E according to APOE ε4 genotype‖ | ||||||
| No ε4 allele | 7/172 (4.1) | 0/155 | 6/163 (3.7) | 1/155 (0.6) | 13/335 (3.9) | 1/310 (0.3) |
| One ε4 allele | 10/236 (4.2) | 0/237 | 8/242 (3.3) | 1/249 (0.4) | 18/478 (3.8) | 1/486 (0.2) |
| Two ε4 alleles | 9/89 (10.1) | 0/84 | 10/91 (11.0) | 0/66 | 19/180 (10.6) | 0/150 |
| Serious symptomatic ARIA-E** | 7/497 (1.4) | 0/476 | 4/496 (0.8) | 0/470 | 11/993 (1.1) | 0/946 |
| Recurrent ARIA-E | 48/497 (9.7) | 0/476 | 47/496 (9.5) | 3/470 (0.6) | 95/993 (9.6) | 3/946 (0.3) |
| Radiologic severity of ARIA†† | ||||||
| BGTS score | 9.4±7.6 | 2.8±2.5 | 8.5±7.6 | 4.0±3.2 | 9±7.6 | 3.7±3.0 |
| BGTS score ≥4 — no./total no. (%) | 155/191 (81.2) | 2/8 (25.0) | 138/189 (73.0) | 9/21 (42.9) | 293/380 (77.1) | 11/29 (37.9) |
| Concurrent ARIA-E and ARIA-H — no./total no. (%) | 69/497 (13.9) | 3/476 (0.6) | 65/496 (13.1) | 4/470 (0.9) | 134/993 (13.5) | 7/946 (0.7) |
| ARIA-H — no./total no. (%) | ||||||
| Any new ARIA-H | 118/497 (23.7) | 59/476 (12.4) | 109/496 (22.0) | 57/470 (12.1) | 227/993 (22.9) | 116/946 (12.3) |
| New isolated ARIA-H | 46/497 (9.3) | 55/476 (11.6) | 39/496 (7.9) | 53/470 (11.3) | 85/993 (8.6) | 108/946 (11.4) |
Plus−minus values are means ±SD. Percentages may not total 100 because of rounding. The safety analysis included participants who had received at least one dose of gantenerumab or placebo; those who had received at least one dose of gantenerumab were included in the gantenerumab group, regardless of the trial-group assignment. Data for additional adverse events are provided in Table S6. ARIA denotes amyloid-related imaging abnormalities, ARIA-E ARIA with edema, and ARIA-H ARIA with hemosiderosis.
In accordance with Medical Dictionary for Regulatory Activities preferred terms, the most frequently reported serious adverse events (occurring in ≥1% of the participants in either trial group across both trials) were coronavirus disease 2019, fall, pneumonia, pulmonary embolism, and ARIA-E.
The most frequently reported adverse events that led to discontinuation of gantenerumab or placebo were ARIA-H, cerebral hemorrhage, ARIA-E, asthenia, cerebral infarction, confusional state, delirium, and subdural hematoma. Such events were predominantly driven by protocol-specified discontinuation criteria for ARIA-H (the accumulation of >15 ARIA-H or >3 focal areas of leptomeningeal hemosiderosis, including baseline findings, during the trials).
All deaths that occurred in the gantenerumab group were considered by the primary investigator and sponsor to be unrelated to the trial drug, including deaths that occurred in the double-blind treatment period and safety follow-up period.
Data for ARIA findings are shown for participants who underwent magnetic resonance imaging after baseline; those who discontinued the trial before assessment are not included.
Symptomatic ARIA-E was defined as ARIA-E temporally associated with central nervous system (CNS) symptoms.
Serious symptomatic ARIA-E was defined as a case of symptomatic ARIA-E in which ARIA-E or the associated CNS symptom was reported as a serious adverse event. Of the 11 participants in the gantenerumab group who had serious symptomatic ARIA-E, 9 fully recovered and 2 recovered with sequelae during the reporting period (with 1 of these 2 participants fully recovering after the reporting period).
Confirmation of the safety of dose escalation was performed with the use of an algorithm for the management of ARIA, shown in Table S1. The radiologic severity of ARIA was assessed with the score on the Barkhof Grand Total Scale (BGTS; range, 0 to 60, with higher scores indicating a greater extent of ARIA-E). If the BGTS score was 4 or higher, dose escalation was suspended; if the BGTS score was less than 4 and the participant was asymptomatic, dose escalation was continued.