BackgroundGantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer’s disease (AD).MethodsIn this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose.ResultsOf the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints.ConclusionsThe study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy.Trial registrationClinicalTrials.gov, NCT01224106. Registered on October 14, 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0318-y) contains supplementary material, which is available to authorized users.

Background: Gantenerumab is a fully human anti-A␤ monoclonal antibody in clinical development for the treatment of Alzheimer disease (AD). Objectives: To investigate whether treatment with gantenerumab leads to a measurable reduction in the level of A␤ amyloid in the brain and to elucidate the mechanism of amyloid reduction. Design: A multicenter, randomized, double-blind, placebo-controlled, ascending-dose positron emission tomographic study. Additionally, ex vivo studies of human brain slices from an independent sample of patients who had AD were performed.

This double-blind, placebo-controlled, multicenter, parallel-group study assessed whether subcutaneous sumatriptan administered during the migraine aura would prolong or modify the aura and prevent or delay development of the headache. One hundred seventy-one patients (88 receiving 6 mg sumatriptan, 83 receiving placebo) treated a single attack of migraine with typical aura at home, by self-injection. The median duration of aura following the first injection was 25 minutes for the sumatriptan group and 30 minutes for the placebo group (NS). The aura symptom profile was similar for the two treatment groups. The proportion of patients who developed a moderate or severe headache within 6 hours after dose administration was similar in the two groups--68% among those receiving sumatriptan and 75% among those receiving placebo (NS). Sumatriptan given during the aura did not prolong or alter the nature of the migraine aura and did not prevent or significantly delay headache development.

Oral sumatriptan in a dose of 100 mg aborts about 60% of migraine attacks within 2 h, but the headache may recur within 24 h. We investigated: (i) the incidence of headache recurrence after oral sumatriptan (ii) whether a second tablet of sumatriptan at 2 h increases initial efficacy and/or (iii) prevents headache recurrence and (iv) whether a further tablet of sumatriptan treats headache recurrence. In a randomized parallel-group clinical trial, 1246 patients treated one to three migraine attacks (with or without aura), with 100 mg oral sumatriptan. Two hours later they all took a double-blind randomized second table of sumatriptan (group I) or placebo (group II). Patients who initially improved, but then experienced headache recurrence took a further double-blind randomized tablet of sumatriptan or placebo. Proportions of patients who improved from moderate/severe headache to mild/none were similar in groups I and III at 2 h (55 vs 56%) and 4 h (80 vs 77%). Incidences of headache recurrence (moderate/severe-any grade of headache) and median times to headache recurrence were also similar: 22-32% at 16 h in group I and 25-33% at 16.5 h in group II. Sumatriptan was superior to placebo in treating headache recurrence: 74 vs 49% (p = 0.017) in group I and 70 vs 30% (p = 0.0001) in group II. Thus, one-fourth of patients experience headache recurrence at about 16 h after successful treatment of a migraine attack with 100 mg oral sumatriptan. A second tablet of sumatriptan at 2 h does not increase initial efficacy and neither prevents nor delays headache recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

We compared the efficacy and safety of subcutaneous (SC) sumatriptan (6 mg) with that of dihydroergotamine (DHE) nasal spray (1 mg plus optional 1 mg) in the acute treatment of migraine. Two hundred sixty-six adult migraineurs (International Headache Society criteria) completed a multicenter, double-blind, double-dummy, cross-over study. Patients took SC sumatriptan for one attack and DHE nasal spray for the other in random order. Data from both treatment periods show that at all time points from 15 minutes, SC sumatriptan was significantly better than DHE nasal spray at providing both headache relief (moderate/severe headache improving to mild/none) and resolution of headache. Similarly, SC sumatriptan was superior to DHE nasal spray for the other efficacy end points assessed in the study. Patients reported that both treatments were well tolerated. Adverse events were reported by 43% of patients taking SC sumatriptan and 22% of patients taking DHE nasal spray. These were usually mild and transient. We conclude that subcutaneous sumatriptan has a faster onset of action than DHE nasal spray and provides greater relief of acute migraine symptoms.