A Phase I Study to Assess the Effect of Speed of Injection on Pain, Tolerability, and Pharmacokinetics After High-volume Subcutaneous Administration of Gantenerumab in Healthy Volunteers.

PURPOSE: Gantenerumab, a fully human anti-amyloid-ß IgG1 monoclonal antibody that binds to aggregated forms of amyloid-ß, is being investigated as a potential disease-modifying treatment for early (prodromal to mild) Alzheimer disease (AD). Our study compared the pain associated with 5- and 15-s subcutaneous injections of gantenerumab and evaluated the tolerability and pharmacokinetic properties of subcutaneous gantenerumab. METHODS: This randomized, open-label, single-active-dose, placebo-controlled crossover study was conducted in 50 healthy volunteers aged 40-80 years with no history of clinically significant disorders, drug or alcohol abuse, familial history of early-onset AD, or prior gantenerumab exposure. Eligible participants were randomized to a sequence of one 300-mg SC gantenerumab injection into the abdomen and 2 SC placebo injections (1 into the abdomen and 1 into the thigh) during 5 or 15 s. All injections were administered at least 90 min apart. Participants were assessed for local pain by visual analog scale (VAS) and verbal rating scale; safety profiles were assessed by recording adverse events (AEs), and plasma pharmacokinetic properties were also evaluated. FINDINGS: Immediately after the subcutaneous gantenerumab injection, the pain VAS score was numerically higher without reaching statistical significance in the 5-s versus 15-s injection group (VAS least-squares mean difference, 7.492 mm; 95% CI, -4.439-19.423 mm). In both injection speed groups, the mean pain VAS score was comparable after subcutaneous gantenerumab and placebo injections into the abdomen. Pain was reported after needle insertion and immediately after dosing, subsiding within 5 min after the dose. The pain VAS score was numerically higher after SC placebo injection into the thigh versus abdomen (5-s injection group: mean [SD] VAS score, 26.68 [27.83] vs 19.20 [25.60] mm; 15-s injection group: mean [SD] VAS score, 14.16 [20.62] vs 9.48 [12.04] mm). No serious AEs were reported; no participants withdrew because of an AE. All AEs were of mild intensity, were transient, and had resolved without sequelae at follow-up. The most common AEs were injection site reactions; redness was the most frequently observed skin reactivity event after subcutaneous gantenerumab administration (5-s injection group: 36%; 15-s injection group: 32%). After subcutaneous administration, gantenerumab reached a peak plasma concentration at a median time of 119 h (approximately 5 days); plasma concentrations declined in a monoexponential manner. Comparable pharmacokinetic profiles were observed between the injection speed groups. IMPLICATIONS: Subcutaneous gantenerumab injections at speeds of 5 and 15 s were well tolerated in healthy volunteers and could enable at-home administration by patients with AD or their caregivers. ClinicalTrials.gov identifier: NCT02882009.

Long-term outcome following traumatic brain injury: a comparison of subjective reports by those injured and their relatives.

Many long-term outcome studies have documented changes following injury using subjective reports from TBI patients and close others. It is known that factors such as self-awareness and emotional adjustment can influence subjective reports, but there has been limited research comparing reports by those injured with those of their close others at longer periods post-injury. The aims of the present study were to compare TBI participants' and close others' subjective reports of cognitive and behavioural problems 10 years following TBI and to investigate the relationship between subjective reports of cognitive impairments and TBI participants' performances on cognitive tests. Fifty-four participants who had sustained mild to very severe TBI were followed up a mean of 10 years post-injury and 54 close others also participated. Measures included the Neurobehavioural Functioning Inventory (NFI), the Hospital Anxiety and Depression Scale (HADS), and cognitive measures of attention, memory and executive function. TBI participants and close others showed strong agreement in their reporting of problems on the NFI. However, there was no strong relationship between subjective reports of cognitive problems and test performances. Much stronger relationships were found between subjective reports of cognitive change and emotional state. This study highlights the importance of assessing emotional state when utilising subjective report data, as well as the need to use objective measures of cognitive impairment.

Cognitive functioning ten years following traumatic brain injury and rehabilitation.

Many previous studies investigating long-term cognitive impairments following traumatic brain injury (TBI) have focused on extremely severely injured patients, relied on subjective reports of change and failed to use demographically relevant control data. The aim of this study was to investigate cognitive impairments 10 years following TBI and their association with injury severity. Sixty TBI and 43 control participants were assessed on tests of attention, processing speed, memory, and executive function. The TBI group demonstrated significant cognitive impairment on measures of processing speed (Symbol Digit Modalities Test [SDMT], Smith, 1973; Digit Symbol Coding, Wechsler, 1997), memory (Rey Auditory Verbal Learning Test [RAVLT]; Rey, 1958; Lezak, 1976), Doors and People tests; Baddeley, Emslie & Nimmo-Smith, 1994) and executive function (Hayling C [Burgess & Shallice, 1997] and SART errors, Robertson, Manly, Andrade, Baddeley & Yiend, 1997). Logistic Regression analyses indicated that the SDMT, Rey AVLT and Hayling C and SART errors most strongly differentiated the groups in the domains of attention/processing speed, memory and executive function, respectively. Greater injury severity was significantly correlated with poorer test performances across all domains. This study shows that cognitive impairments are present many years following TBI and are associated with injury severity.

Functional outcome 10 years after traumatic brain injury: its relationship with demographic, injury severity, and cognitive and emotional status.

Previous investigations of long-term outcome following traumatic brain injury (TBI) have yielded mixed results regarding the predictive power of injury severity and demographic factors. Furthermore, there has been limited investigation of the association between long-term outcome and current cognitive functioning and psychiatric state. The aim of this study was to investigate the association of injury severity, demographic factors, and concurrent cognitive and psychiatric functioning with functional outcome 10 years following mild to severe TBI. Outcome was rated using the Extended Glasgow Outcome Scale (GOSE) for 60 participants, who also completed neuropsychological measures of attention, speed of processing, memory and executive function and the Hospital Anxiety and Depression Scale (HADS). Outcome on the GOSE ranged from upper good recovery (32%) to lower severe disability (2%). Participants showing poorer outcome on the GOSE had significantly longer posttraumatic amnesia duration; less education; performed more poorly on cognitive measures of information processing speed, attention, memory, and executive function; and showed higher levels of anxiety on the HADS.

Psychosocial and emotional outcomes 10 years following traumatic brain injury.

OBJECTIVES: To investigate the association of psychosocial outcome 10 years following traumatic brain injury (TBI) with demographic variables, injury severity, current cognitive functioning, emotional state, aggression, alcohol use, and fatigue. SETTING: Community-based follow-up. PARTICIPANTS: Fifty-three participants with mild to very severe TBI sustained 10 years previously and significant others. MEASURES: Sydney Psychosocial Reintegration Scale, Extended Glasgow Outcome Scale, Hospital Anxiety and Depression Scale, NFI Aggression scale, Fatigue Severity Scale, Alcohol Use Disorders Identification Test, neuropsychological tests of attention/processing speed, memory, and executive function. RESULTS: Psychosocial functioning was lowest in the occupational activity domain and highest in the living skills domains. Variables including education, posttraumatic amnesia duration, numerous cognitive measures, concurrent fatigue, aggression, anxiety, and depression were all significantly associated with psychosocial outcome, although the strength of correlations varied between ratings of participants with TBI and relatives. Posttraumatic amnesia duration was most strongly associated with psychosocial outcome measured by relatives; anxiety, aggression, and depression were the strongest predictors when ratings were assigned by participants with TBI. Self-reported fatigue, depression, and alcohol use were the strongest predictors of aggression. CONCLUSIONS: It is important to address problems with anxiety, depression, fatigue, and alcohol use as a possible means of improving long-term psychosocial outcome following TBI.