According to the standard ICH/EU definition, serious adverse events are events which result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability or incapacity, or represent a congenital anomaly or birth defect. Table 12 provides an overview of the SAEs.

During the twelve months experimental study phase, a total of 18 SAEs occurred among 174 patients. From these, seven SAEs (involving seven patients; 7.1%) occurred among the 98 patients in the methadone alone treatment group (A), and 11 SAEs (involving nine patients; 11.8%) among the 76 patients in the co-prescribed heroin group (B). The percentage of patients with at least one SAE was not significantly different between the treatment groups A and B (Fisher's Exact Test; p=0.30).

In the methadone alone treatment group (A), one fatal event occurred. The patient died in a traffic accident. Since the patient participated in the methadone alone control treatment, this fatal event was considered to be not related to the experimental medication. For the same reason, all other SAEs in this group were registered as not related to the heroin medication.

Table 12. Overview of SAEs during the experimental treatment phase of the trial

The 11 SAEs in the co-prescribed heroin treatment group (B) occurred among nine patients (right-hand column in Table 12). One patient in this treatment group had three SAEs. The first of these SAEs concerned a hospital admission for a seizure, due to the combination of (non-prescribed) heroin and cocaine use. This seizure was considered to be possibly related to the experimental medication (heroin). The second event of this individual concerned a life-threatening grand mal epileptic seizure, which occurred approximately one hour after the self-administration of the co-prescribed heroin. Also this event was considered possibly related to the heroin medication. The third event was again a hospitalization for an epileptic seizure. The patient was treated with the opioid antagonist naloxone, and was subsequently discharged. Several hours later the patient died. Section was conducted, which revealed no specific cause of death. The cause of death was therefore designated as natural. This fatal SAE was considered to be not related to the heroin medication.

Table 13 provides an overview of the relationship between each of the 18 SAEs and the heroin medication. Four SAEs were judged to be possibly related to the intake of co-prescribed heroin. Besides the two SAEs of the (one) patient discussed above, these included one drug overdose and one case of pneumonia. The overdose case, classified as a life-threatening SAE, is described in paragraph 8A.3. The pneumonia case involved a patient who felt severely ill for three days, had a high body temperature, and was subsequently hospitalized. Notably, none of the SAEs in the injectable heroin trial were considered to be probably or definitely related to the heroin medication.

Context of the observed SAEs
The observed total number of 11 SAEs in the co-prescribed heroin group, and four possibly related SAEs occurred among the 76 patients in group B of the intention-to-treat population. From these, 69 patients started the treatment in group B (see chapter 5A). Hence, the 11 SAEs in group B correspond with an average of 0.16 SAE per patient per treatment-year, compared to an average of 0.07 SAE per patient per year in the methadone alone treatment group. In addition, the observed SAEs in group B occurred in a context in which approximately 45,000 heroin prescriptions were dispensed.

Table 13. Relationship of SAEs with heroin medication during the experimental treatment phase of the trial