Objectives
To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of ...migraine attacks for up to 1 year.
Methods
In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit.
Results
As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time.
Conclusions
The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period.
Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186
Background
We assessed the safety profile of lasmiditan, a selective 5-HT1F receptor agonist without vasoconstrictive activity being developed as an acute therapy for migraine.
Methods
SAMURAI and ...SPARTAN were Phase 3 double-blind studies of patients with migraine, randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo to be taken within 4 hours of onset of migraine pain. Safety data from the studies were integrated. Treatment-emergent adverse events (occurring within 48 hours of first dose) were considered in the analyses.
Results
The safety population comprised 1262 patients assigned placebo, and 654, 1265, and 1258 assigned lasmiditan 50 mg, 100 mg, and 200 mg, respectively. There were no deaths; serious adverse events were reported for seven patients (placebo, n = 2 0.2%; lasmiditan 50 mg, n = 1 0.2%; lasmiditan 100 mg, n = 1 0.2%; lasmiditan 200 mg, n = 3 0.2%). Patients reporting ≥ 1 treatment-emergent adverse events were: Placebo, n = 174 (13.5%); lasmiditan 50 mg, n = 166 (25.4%); lasmiditan 100 mg, n = 458 (36.2%); and lasmiditan 200 mg, n = 510 (40.6%). Treatment-emergent adverse events were generally mild or moderate in severity. The most common treatment-emergent adverse events with lasmiditan were dizziness, paresthesia, somnolence, fatigue, nausea, muscular weakness and hypoesthesia. There were no ischemic events.
Conclusions
As a centrally-penetrant drug, lasmiditan use was associated with neurologic treatment-emergent adverse events; most were mild or moderate in severity and self-limiting.
Trial registration at clinicaltrials.gov
SAMURAI (NCT02439320) and SPARTAN (NCT02605174).
Abstract Teriparatide is a skeletal anabolic treatment for patients with osteoporosis at high risk for fracture. Because adequate clinical trials have not yet been conducted to assess the efficacy of ...teriparatide for reducing the risk of hip fracture, we review here the literature regarding how treatment with teriparatide affects the hip in patients with osteoporosis. Teriparatide increases cancellous bone volume, improves bone architecture, and – uniquely among osteoporosis treatments – increases cortical thickness and cortical porosity. By bone scan and positron emission tomography, teriparatide increases bone formation throughout the skeleton, including the hip. Consistent with these findings, studies using dual-energy X-ray absorptiometry and quantitative computed tomography for longitudinal assessment of changes at the hip have consistently shown increases in areal and volumetric bone mineral density, cortical thickness, and finite element-estimated hip strength in patients treated with teriparatide. Finally, in clinical fracture-outcome trials, treatment with teriparatide has been shown to reduce the risk of nonvertebral fracture, a composite endpoint that includes hip fracture. Taken together, this body of evidence suggests that teriparatide positively affects the hip in patients with osteoporosis.
In randomized clinical trials (RCTs) with teriparatide, the number of patients with incident hip fractures was small and insufficiently powered to show statistically significant differences between ...groups. We, therefore, conducted a systematic review and meta-analysis of the efficacy of teriparatide in the reduction of hip and upper limb fractures in women and men with osteoporosis. A comprehensive search of databases until 22 November 2017 was conducted for RCTs of at least 6-month duration that reported non-spine fractures (hip, humerus, forearm, wrist), either as an efficacy or safety endpoint. Only RCTs that included patients with the approved treatment indications and dose for use of teriparatide were included; trials with off-label use of teriparatide were excluded. Two independent reviewers performed study selection and data extraction. Statistical procedures included Peto's method and Mantel-Haenszel with empirical correction, as most of the RCTs reported zero events in at least one of the treatment arms. Study results are expressed as odds ratios (OR) with 95% confidence intervals (CI). Publication bias and heterogeneity were evaluated with standard statistical tests. Twenty-three RCTs were included, 19 with an active-controlled arm (representing 64.9% of the patients included in the control group) and 11 double-blind, representing data on 8644 subjects, 3893 of them treated with teriparatide. Mean age (SD) was 67.0 (4.5) years, median treatment duration 18 months (range: 6 to 24 months). A total of 34 incident hip, 31 humerus, 31 forearm, and 62 wrist fractures were included. Meta-analysis results showed an OR (95% CI) for hip fractures of 0.44 (0.22–0.87; p = 0.019) in patients treated with teriparatide compared with controls. The effects on the risk of humerus 1.02 (0.50–2.08), forearm 0.53 (0.26–1.08) and wrist fractures 1.21 (0.72–2.04) were not statistically significant (p > 0.05). This meta-analysis provides evidence of efficacy of teriparatide in reducing hip fractures by 56% in patients with osteoporosis.
•Hip fractures are the most devastating complications of osteoporosis.•Evidence of hip fracture reduction with teriparatide is limited.•We conducted a meta-analysis of randomized clinical trials of teriparatide.•Teriparatide showed a 56% reduction of hip fractures versus controls.•Significant effects on fractures of upper limb bones were not observed.
Teriparatide significantly reduces fracture rates in clinical trials; however, those study populations were relatively restricted and included too few patients to analyze fracture outcomes within ...clinically important patient subgroups. We assessed fracture outcomes in subgroups of osteoporosis patients from 4 real-world teriparatide observational studies.
Patients received teriparatide 20 μg/day for up to 24 months. Fracture rates were compared between 0 to 6 months versus >6 months using a piecewise exponential model for first fracture. Analyses included incident clinical vertebral fractures (CVF) and nonvertebral fractures (NVF), and clinical fractures (CVF and NVF) by subgroups of gender, age <75 or ≥75 years, diabetes, prior bisphosphonates use, rheumatoid arthritis (RA), glucocorticoid use, prior hip, and prior vertebral fracture.
The population included 8828 patients (8117 women, 92%) with mean (SD) age 71 (10.6) years and teriparatide treatment duration 17.4 (8.6) months. Overall, CVF, NVF, clinical fracture, and hip fracture rates decreased by 62%, 43%, 50%, and 56%, respectively (all p < .005) for >6 months versus 0 to 6 months. Subgroup analyses all showed significantly decreased rates after >6 months except for NVF reduction in males (n = 710, fracture rate low during months 0 to 6) and in patients using glucocorticoids, and CVF in patients with prior hip fracture. The effects of teriparatide on CVF, NVF, and clinical fractures over time were statistically consistent in all subgroups except age for CVF (p = .074, patients <75 years of age responded better), and diabetes for clinical fractures (p = .046, patients with diabetes responded better), although all of these subgroups experienced significant reductions over time. Glucocorticoids, prior bisphosphonate, and prior vertebral fracture were associated with increased CVF, NVF, and clinical fracture rates; RA, prior hip fracture and female gender were associated with higher NVF and clinical fracture rates; increased age was associated with higher CVF and clinical fracture rates.
Data from 4 real-world observational studies showed statistically significant reductions during teriparatide treatment in rates of CVF, NVF, and clinical fractures in clinically relevant patient subgroups. These results should be interpreted in the context of the non-controlled design of the source studies.
•Limited information is available regarding the fracture efficacy of teriparatide in clinically important subgroups.•We merged the primary data from 8828 patients treated with teriparatide in four prospective observational studies.•Clinical vertebral, non-vertebral, clinical, and hip fracture rates decreased versus the first six months of treatment.•The fracture results with teriparatide were generally consistent across clinically relevant subgroups of patients.•The results should be interpreted in the context of the non-controlled design of the source studies.
We compared combination treatment with teriparatide plus raloxifene with teriparatide alone in women with postmenopausal osteoporosis in a 6‐month double‐blind, placebo‐controlled trial that measured ...biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline.
Introduction: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing teriparatide rhPTH(1–34) monotherapy with combination teriparatide and raloxifene therapy.
Materials and Methods: A 6‐month randomized, double‐blind trial comparing teriparatide plus raloxifene (n = 69) versus teriparatide plus placebo (n = 68) was conducted in postmenopausal women with osteoporosis.
Results: Bone formation (N‐terminal propeptide of type 1 collagen PINP) increased similarly in both treatment groups. However, the increase in bone resorption (serum C‐terminal telopeptide of type I collagen CTx) in the combination group was significantly smaller than in the teriparatide‐alone group (p = 0.015). Lumbar spine BMD significantly increased 5.19 ± 0.67% from baseline in the teriparatide‐alone group. In the combination group, lumbar spine (6.19 ± 0.65%), femoral neck (2.23 ± 0.64%), and total hip (2.31 ± 0.56%) BMD significantly increased from baseline to study endpoint, and the increase in total hip BMD was significantly greater than in the teriparatide‐alone group (p = 0.04). In the teriparatide‐alone group, mean serum calcium levels increased from baseline to endpoint (0.30 ± 0.06 mg/dl, p < 0.001), whereas mean serum phosphate remained unchanged. In the combination group, mean serum calcium was unchanged, and mean serum phosphate decreased (−0.20 ± 0.06 mg/dl, p < 0.001) from baseline to endpoint. Changes in serum calcium (p < 0.001) and phosphate (p < 0.004) were significantly different between treatment groups. The safety profile of combination therapy was similar to teriparatide alone.
Conclusions: Combination therapy increased bone formation to a similar degree as teriparatide alone. However, the increase in bone resorption was significantly less and total hip BMD significantly increased for combination therapy compared with teriparatide alone. Combination treatment with raloxifene may thus enhance the bone forming effects of teriparatide. Further studies over longer treatment duration that include fracture endpoints are necessary to fully ascertain the clinical significance of combination raloxifene plus teriparatide therapy in postmenopausal osteoporosis.
Background
Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and ...SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve.
Methods
Subgroups of patients reporting an overall response of “good” or “poor/none” to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient).
Results
Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients.
Conclusions
Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine.
Trial Registration
SAMURAI (NCT02439320); SPARTAN (NCT02605174).
Background
We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute ...treatment of migraine across four attacks.
Methods
Patients were randomized 1:1:1 to one of three treatment groups – lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity.
Results
Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg (p < 0.001). All gated secondary endpoints were met. The incidence of treatment-emergent adverse events (TEAEs) was highest during the first attack. The most common TEAEs with lasmiditan were dizziness, paresthesia, fatigue, and nausea; these were generally mild or moderate in severity.
Conclusions
These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks.
Trial Registration Number: NCT03670810
Abstract Despite evidence for higher fracture risk, clinical effects of osteoporosis treatments in type 2 diabetes (T2D) are largely unknown. Post hoc analyses of the DANCE observational study ...compared T2D patients and patients without diabetes to assess the effect of teriparatide, an osteoanabolic therapy on skeletal outcomes and safety. Patients included ambulatory men and women with osteoporosis receiving teriparatide 20 μg/day SQ up to 24 months followed by observation up to 24 months. Main outcome measures included nonvertebral fracture incidence comparing 0–6 months with 6 + months of teriparatide, change from baseline in BMD and back pain severity, and serious adverse events. Analyses included 4042 patients; 291 with T2D, 3751 without diabetes. Treatment exposure did not differ by group. For T2D patients, fracture incidence was 3.5 per 100 patient-years during 0–6 months treatment, and 1.6 during 6 months to treatment end (47% of baseline, 95% CI 12–187%); during similar periods, for patients without diabetes, fracture incidence was 3.2 and 1.8 (57% of baseline, 95% CI 39–83%). As determinants of fracture outcome during teriparatide treatment, diabetes was not a significant factor ( P = 0.858), treatment duration was significant ( P = 0.003), and the effect of duration was not significantly different between the groups (interaction P = 0.792). Increases in spine and total hip BMD did not differ between groups; increase in femoral neck BMD was greater in T2D patients than in patients without diabetes (+ 0.34 and + 0.004 g/cm2 , respectively; P = 0.014). Back pain severity decreased in both groups. Teriparatide was well tolerated without new safety findings. In conclusion, during teriparatide treatment, reduction in nonvertebral fracture incidence, increase in BMD, and decrease in back pain were similar in T2D and non-diabetic patients.
PDF
