The monoclonal antibody against CGRP receptor, erenumab, administered subcutaneously once a month, significantly reduced migraine frequency by approximately 2 days per month and reduced the effects ...of migraine on daily functioning.
Background
Calcitonin gene-related peptide plays an important role in migraine pathophysiology. Erenumab, a human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor, is ...being evaluated for migraine prevention.
Methods
In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly migraine days. Secondary endpoints were ≥50% reduction in monthly migraine days, change in acute migraine-specific medication treatment days, and ≥5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the Migraine Physical Function Impact Diary. All endpoints assessed change from baseline at month 3.
Results
Patients receiving erenumab experienced −2.9 days change in monthly migraine days, compared with −1.8 days for placebo, least-squares mean (95% CI) treatment difference of −1.0 (−1.6, −0.5) (p < 0.001). A ≥ 50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of patients (OR:1.59 (95% CI: 1.12, 2.27) (p = 0.010). Migraine-specific medication treatment days were reduced by −1.2 (erenumab) and −0.6 (placebo) days, a treatment difference of −0.6 (−1.0, −0.2) (p = 0.002). The ≥5-point reduction rates in Migraine Physical Function Impact Diary – Physical Impairment were 33.0% and 27.1% (OR:1.33 (0.92, 1.90) (p = 0.13) and in Migraine Physical Function Impact Diary – Everyday Activities were 40.4% and 35.8% (OR:1.22 (0.87, 1.71) (p = 0.26). Safety and adverse event profiles of erenumab were similar to placebo. Most frequent adverse events were upper respiratory tract infection, injection site pain, and nasopharyngitis.
Conclusions
As a preventive treatment of episodic migraine, erenumab at a dosage of 70 mg monthly significantly reduced migraine frequency and acute migraine-specific medication use. (Funded by Amgen).
Trial registration
ClinicalTrials.gov, NCT02483585.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Subcutaneous erenumab reduced monthly migraine days and increased the likelihood of achieving a ≥ 50% reduction at all monthly assessment points tested in 2 pivotal trials in episodic ...migraine (EM) and chronic migraine (CM). Early efficacy of migraine preventive medications is an important treatment characteristic to patients. Delays in achievement of efficacy can result in failed adherence. The objective of these post-hoc analyses were to evaluate efficacy in the first 4 weeks after initial subcutaneous administration of erenumab 70 mg, erenumab 140 mg, or placebo.
Methods
There is no generally accepted methodology to measure onset of action for migraine preventive medications. We used a comprehensive approach with data from both studies to evaluate change from baseline in weekly migraine days (WMD), achievement of ≥ 50% reduction in WMD, and proportion of patients experiencing migraine measured on a daily basis. The 7-day moving averages were overlaid with observed data.
Results
In both studies (EM:
N
= 955; CM:
N
= 667), there was evidence of onset of efficacy of erenumab vs. placebo during the first week of treatment, which in some cases reached nominal significance. For EM the changes in WMD were (least squares mean LSM 95% CI): placebo, − 0.1 (− 0.3, 0.0); erenumab 70 mg, − 0.3 (− 0.5, − 0.2)
p
= 0.130; erenumab 140 mg, − 0.6 (− 0.7, − 0.4)
p
< 0.001. For CM the changes were: placebo, − 0.5 (− 0.8, − 0.3); erenumab 70 mg, − 0.9 (− 1.2, − 0.7)
p
= 0.047; erenumab 140 mg, − 0.8 (− 1.1, − 0.5)
p
= 0.18. Achievement of ≥ 50% reduction in WMD was observed as early as Week 1 (adjusted OR 95% CI erenumab vs placebo) in EM: erenumab 70 mg, 1.3 (1.0, 1.9)
p
= 0.097; erenumab 140 mg, 2.0 (1.4, 2.7)
p
< 0.001. A similar outcome was observed for CM: erenumab 70 mg, 1.8 (1.1, 2.8)
p
= 0.011; erenumab 140 mg, 1.9 (1.2, 2.9)
p
= 0.009. Seven-day moving averages of observed data showed each treatment arm differed from placebo by Week 1 (OR 95% CI): in EM Day 3 for erenumab 140 mg, 0.7 (0.5, 1.0)
p
= 0.031 and at Day 7 for 70 mg, 0.6 (0.4, 0.8)
p
= 0.002; in CM: Day 6 for erenumab 70 mg, 0.6 (0.4, 0.9)
p
= 0.022 and at Day 7 for 140 mg, 0.7 (0.4, 1.0);
p
= 0.038.
Conclusion
Erenumab showed early onset of efficacy with separation from placebo within the first week of treatment in both chronic and episodic migraine patients.
The role of the cerebellum in schizophrenia has been highlighted by Andreasen's hypothesis of "cognitive dysmetria," which suggests a general dyscoordination of sensorimotor and mental processes. ...Studies in schizophrenic patients have brought observations supporting a cerebellar impairment: high prevalence of neurological soft signs, dyscoordination, abnormal posture and propioception, impaired eyeblink conditioning, impaired adaptation of the vestibular-ocular reflex or procedural learning tests, and lastly functional neuroimaging studies correlating poor cognitive performances with abnormal cerebellar activations. Despite those compelling evidences, there has been, to our knowledge, no recent review on the clinical, cognitive, and functional literature supporting the role of the cerebellum in schizophrenia. We conducted a Medline research focusing on cerebellar dysfunctions in schizophrenia. Emphasis was given to recent literature (after 1998). The picture arising from this review is heterogeneous. While in some domains, the role of the cerebellum seems clearly defined (ie, neurological soft signs, posture, or equilibrium), in other domains, the cerebellar contribution to schizophrenia seems limited or indirect (ie, cognition) if present at all (ie, affectivity). Functional models of the cerebellum are proposed as a background for interpreting these results.
Background
We performed a post hoc, subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled study of erenumab for prevention of episodic migraine (STRIVE) to determine the ...efficacy and safety of erenumab in women with self-reported menstrual migraine.
Methods
Patients received placebo, erenumab 70 mg, or erenumab 140 mg subcutaneously once monthly during the 6-month double-blind treatment phase of STRIVE. Women who reported history of menstrual migraine and who were ≤ 50 years old were included in the analysis. Endpoints were change from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication days (MSMD; among patients who took acute migraine-specific medications at baseline), proportion of patients achieving ≥ 50% reduction from baseline in MMD, and incidence of adverse events.
Results
Among 814 women enrolled in STRIVE, 232 (28.5%) reported a history of menstrual migraine and were ≤ 50 years old. Of the 232 patients, 214 (92%) had a baseline MMD > 5, suggesting a high proportion of women with attacks outside of the 5-day perimenstrual window (2 days before and 3 days after the start of menstruation). Information on “migraine days” includes (and does not discriminate between) perimenstrual and intermenstrual migraine attacks. Between-group differences from placebo over months 4–6 for erenumab 70 mg and 140 mg were − 1.8 (
P
= 0.001) and − 2.1 (
P
< 0.001) days for MMD and − 1.6 (
P
= 0.002) and − 2.4 (
P
< 0.001) days for acute MSMD, respectively. The odds of having a ≥ 50% reduction from baseline in MMD over months 4–6 were 2.2 (
P
= 0.024) and 2.8 (
P
= 0.002) times greater for erenumab 70 mg and 140 mg, respectively, than for placebo. Erenumab had an overall safety profile comparable to placebo.
Conclusion
Data from this subgroup analysis of women with menstrual migraine are consistent with data from the overall STRIVE episodic migraine population, supporting the efficacy and safety of erenumab in women who experience menstrual migraine.
Trial registration: ClinicalTrials.gov, NCT02456740. Registered 28 May 2015.
Background
In patients with migraine, overuse of acute medication, including migraine-specific medication (MSM) such as triptans and ergots, can lead to adverse health outcomes, including development ...of medication overuse headache. Here, we examined the effect of erenumab on reducing acute medication use, in particular MSM, in patients with episodic migraine (EM) and chronic migraine (CM).
Methods
The current post-hoc analyses were based on data from the double-blind treatment phase (DBTP) of two erenumab studies, a pivotal EM (
N
= 955) and a pivotal CM (
N
= 667) trial, and their respective extensions. Patients were administered subcutaneous placebo or erenumab (70 or 140 mg) once monthly. Daily acute headache medication use (including MSM and non-MSM) was recorded using an electronic diary during a 4-week pretreatment baseline period until the end of the treatment period. Outcome measures included change in monthly acute headache medication days (HMD) in acute headache medication users at baseline, and changes in monthly MSM days (MSMD) in MSM users at baseline and non-MSMD in non-MSM users at baseline.
Results
In total, 60 and 78 % of patients (all acute headache medication users) with EM and CM used MSM at baseline, respectively. For acute headache medication users, the change in mean monthly acute HMD over Months 4, 5 and 6 compared with the pre-DBTP was 1.5, 2.5, and 3.0 for placebo, erenumab 70 mg and 140 mg, respectively for the EM study. The respective change in monthly MSMD in MSM users was 0.5, 2.1 and 2.8, and in monthly non-MSMD in non-MSM users was 2.3, 2.6, and 2.7. In the acute headache medication users at baseline, the change in monthly acute HMD at Month 3 compared with pre-DBTP was 3.4, 5.5, and 6.5 for placebo, erenumab 70 mg and 140 mg, respectively for the CM study. The respective change in monthly MSMD in MSM users was 2.1, 4.5, and 5.4, and in monthly non-MSMD in non-MSM users was 5.9, 6.4, and 6.6. Reductions in MSMD versus placebo were sustained in the extension periods of both studies. Erenumab was also associated with a higher proportion of MSM users achieving ≥ 50 %, ≥ 75 and 100 % reduction from baseline in monthly MSMD versus placebo in both EM and CM.
Conclusions
In both EM and CM, treatment with erenumab is associated with a significant and sustained reduction in the use of acute headache medication, in particular MSM.
Trial registrations
NCT02456740; NCT02066415; NCT02174861.
Neurological Soft Signs (NSS) and impairments in oculomotor saccadic paradigms are both frequent in patients with schizophrenia but their correlation has never been explored.
78 patients with DSM-IV ...schizophrenia (including 43 non-treated) and 41 matched healthy controls were tested for NSS, and on three saccadic tasks: prosaccades, predictive saccades and memory-guided saccades) using infrared oculometry. We analyzed correlations between NSS scores and latencies in all three tasks, rate of errors in memory-guided saccades, and rate of anticipated predictive saccades.
No correlations were found in healthy controls. In the patient group, the NSS total and motor coordination scores were positively correlated with three saccadic variables: the latency of prosaccades (
r
=
0.36,
p
<
0.01 and
r
=
0.36,
p
<
0.01 respectively), of memory-guided saccades (
r
=
0.35,
p
<
0.01 and
r
=
0.32,
p
<
0.05 respectively) and, negative correlations were found, with the rate of anticipated predictive saccades (
r
=
−
0.33,
p
<
0.01;
r
=
−
0.35,
p
<
0.01 respectively). NSS total, motor coordination and sensory integration scores were correlated to the latency of non-anticipated predictive saccades (
r
=
0.34,
p
<
0.01;
r
=
0.24,
p
<
0.05 and
r
=
0.40,
p
<
0.001 respectively). The NSS total, motor integration and sensory integration scores were correlated with the rate of errors in memory-guided saccades (
r
=
0.38,
p
<
0.01;
r
=
0.37,
p
<
0.01 and
r
=
0.34,
p
<
0.01 respectively).
These results support a common pathological mechanism with partial overlapping neural substrates between NSS and saccades in schizophrenia.
Abstract Many motor and cognitive alterations in schizophrenia suggest the involvement of the cerebellum. Neurological soft signs (NSS) are frequent in patients with schizophrenia and reductions in ...cerebellar volume have been associated with high NSS scores. In this study, we tested saccadic adaptation, a well-characterised oculomotor paradigm involving the cerebellum, in schizophrenic patients with high NSS scores. We used a backward reactive saccade adaptation task, in which the target moves intrasaccadically toward initial fixation, causing the saccade to complete with an endpoint error. A group of 12 schizophrenic patients (SZ; DSM IV) with high NSS scores was compared to a group of 13 matched healthy controls (HC). SZ patients showed lower saccade adaptation than HC. Nevertheless, the time course of adaptation was similar for both groups. This study indicates cerebellar dysfunction in patients with schizophrenia and high NSS scores. Part of the deficit seen in schizophrenia may have a cerebellar origin.
Abstract Numerous reports have emphasized the value of neurological soft signs (NSS) as endophenotypic markers in schizophrenia. NSS also appear as useful prognostic predictors for functional ...outcome, response and tolerance to antipsychotics. Although several standardized scales have been proposed and offer fair inter-rater reliability, they still rely on the experience and accuracy of the investigators. This study was designed to assess NSS objectively. We evaluated 27 patients who met the Diagnostic and Statistical Manual, fourth edition (DSM-IV) criteria for schizophrenia and 15 healthy controls using a standardized examination encompassing a 23-item NSS scale as well as an assessment of parkinsonism and dyskinesia. Movements were then recorded using inertia sensors while the patients were performing a selection of motor items from the aforementioned scale (balance tasks, rapid alternative movements, rigidity). To our knowledge, this study is the first to provide an objective assessment of specific NSS in schizophrenia using inertial sensors. The results objectively demonstrate impairments in patients with schizophrenia when balance relies on proprioceptive information, with specific differences in groups of patients based on their NSS scores. Inertia sensors are promising, inexpensive and ‘easy-to-use’ tools that could improve the assessment of motor and sensory impairments in patients with schizophrenia in daily clinical practice, especially when the dysfunction is subtle.
Objective
To assess the safety and efficacy of AMG 301, an inhibitor of the pituitary adenylate cyclase-activating polypeptide (PACAP)-1 (PAC1) receptor, for prevention of migraine.
Methods
In a ...double-blind trial, patients were randomized 4:3:3 to placebo, AMG 301 210 mg every 4 weeks, or AMG 301 420 mg every 2 weeks for 12 weeks. Effect on monthly migraine days and other secondary measures were assessed over weeks 9–12. Safety and tolerability were assessed.
Results
Of 343 randomized patients (mean age, 41.8–42.5 years), the majority were women (85.4–90.4%), white (94.1–96.2%), and had episodic migraine (62.5–67.9%). A total of 305 patients completed treatment (placebo, n = 124; AMG 301 210 mg, n = 94; AMG 301 420 mg, n = 87). Least squares mean reduction at week 12 in monthly migraine days from baseline was −2.5 (0.4) days for placebo and −2.2 (0.5) days for both AMG 301 treatment groups. No difference between AMG 301 and placebo on any measure of efficacy was observed; mean (95% confidence interval) treatment difference versus placebo for monthly migraine days for AMG 301 210 mg, 0.3 (−0.9 to 1.4); AMG 301 420 mg, 0.3 (−0.9 to 1.4). The incidence of adverse events was similar across groups.
Conclusion
AMG 301 offered no benefit over placebo for migraine prevention; further studies may be necessary to fully understand the role of PACAP isoforms and its receptors in migraine pathophysiology.
Study Registration
ClinicalTrials.gov: NCT03238781
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
