Phase III trials in neurology – 2018 in review


A dozen phase III trials in neurology were published in 2018, many of which led to FDA approvals. The following is a summary of the study results.


Galcanezumab is a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) ligand for migraine prophylaxis. Efficacy was evaluated versus placebo in three phase III studies in episodic migraine (EVOLVE-1 and -2, n=1773) and in chronic migraine (REGAIN, n=1113) (Forderreuther et al. J Headache Pain 2018;19:121; free full text at

Two regimens were examined: 240 mg loading dose s.c. followed by 120 mg/month; and 240 mg/month s.c. In episodic migraine, ≥50% response was maintained for >3 months in 41.5% (120 mg) and 41.1% (240 mg) of patients in the galcanezumab groups versus 21.4% with placebo. Response was maintained for >6 months in 19.0% and 20.5% of patients in the galcanezumab groups versus 8.0% with placebo. The proportion of patients with >75% response for all 6 months was 6% with active therapy versus 2.0% with placebo. A separate safety analysis of galcanezumab-exposed subjects reported that the most common adverse effects were injection site pain, upper respiratory tract infection, injection site reaction, back pain and sinusitis (Camporeale et al. BMC Neurol 2018;18:188). There were no clinically significant changes in laboratory values. Serious adverse events occurred in 3.7%; and 4.8% discontinued treatment due to adverse events. Galcanezumab received FDA approval in September 2018.

Multiple sclerosis

The EXPAND trial investigated siponimod, a selective sphingosine 1-phosphate (S1P) receptor modulator, in 1645 patients with secondary-progressive MS (Kappos et al. Lancet 2018;391:1263-1273). Mean duration of MS at entry was 16.8 years; mean time to conversion to SPMS was 3.8 years; 64% had not experienced a relapse in the prior 2 years; and 56% required walking assistance. The rate of 3-month confirmed disability progression was 26% with siponimod versus 32% with placebo (hazard ratio 0.79). Adverse events included lymphopenia, elevated liver enzymes, bradycardia at first dose, macular edema and zoster reactivation. Siponimod is dose-titrated at treatment start which mitigated first-dose effects.

The PARADIGMS study compared fingolimod 0.5 mg/day to interferon-beta-1a in children and adolescents aged 10-17 years (mean age 15.3 years) (Chitnis et al. N Engl J Med 2018;379:1017-1027). Annualized relapse rate was 0.12 with fingolimod compared to 0.67 with IFN-beta. The annualized rate of new/enlarged T2 lesions was 4.39 with fingolimod vs. 9.27 with IFN-beta. Serious adverse events were reported in 16.8% of fingolimod-treated patients (including seizures in 4 patients) versus 6.5% with IFN-beta. Fingolimod (Gilenya) received approval for pediatric use (ages 10-17) by the FDA and Health Canada in 2018.


The PATH study examined the use of subcutaneous immunoglobulin in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who had previously responded to IVIg (van Schaik et al. Lancet Neurol 2018;17:35-46). Patients (n=172) received SCIg 0.2 or 0.4 g/kg or placebo weekly. The proportion of patients with a relapse or who withdrew from the study was 39% with low-dose SCIg, 33% with high-dose SCIg versus 63% with placebo. Treatment was well-tolerated, suggested that SCIg may be used as a maintenance treatment in CIDP.


The TICH-2 trial investigated tranexamic acid, a synthetic lysine analogue used as an antifibrinolytic agent, in patients with intracerebral hemorrhage (Sprigg et al. Lancet 2018;391:2107-2115). Patients (n=2325) received placebo or tranexamic acid administered as a 1-g bolus following by 1 g infusion over 8 hours. There was no significant difference in functional status at day 90, although there were fewer deaths by day 7 in the tranexamic acid group (9% vs. 11%) and fewer serious adverse by day 2 (33% vs. 36%). There was no difference in mortality at 90 days.

TARDIS was an open-label phase III study that examined antiplatelet therapy regimens (ASA/clopidogrel/dipyridamole vs. clopidogrel vs. ASA/dipyridamole) in 3096 patients with acute cerebral ischemia or TIA within 48 hours of onset (Bath et al. Lancet 2018;391:850-859). Dosing for the intensive antiplatelet regimen was ASA 75 mg, clopidogrel 75 mg and dipyridamole 200 mg BID. The primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic) or TIA within 90 days. The trial was stopped early. No difference was seen with intensive antiplatelet therapy compared to the other regimens, but the intensive regimen was associated with more bleeding and severe bleeding events. The conclusion was that triple-therapy antiplatelet regimens should not be used.


A number of studies, such as EXPEDITION-I and -II, failed to show improvement in cognition or function with solanezumab, a monoclonal antibody targeting beta-amyloid peptides (Doody et al. N Engl J Med 2014;370:311-321). The most recent study also showed that solanezumab did not slow cognitive decline in patients with mild dementia due to Alzheimer’s disease (Honig et al. N Engl J Med 2018;378:321-330).


Cannabidiol 20 mg/kg add-on therapy was evaluated in the GWPCARE4 study of 171 patients with Lennox-Gastaut syndrome who had not responded to at least two prior antiepileptic drugs (Thiele et al. Lancet 2018;391:1085-1096). The median reduction from baseline in monthly drop seizure frequency was 43.9% with cannibidiol group and 21.8% with placebo during the 14-week treatment period. The most common adverse effects with cannabidiol were diarrhea, somnolence, pyrexia, decreased appetite and vomiting; 14% of patients in the add-on group withdrew due to adverse events. Cannabidiol was approved for use by the FDA in Lennox-Gastaut syndrome in 2018.

Spinal cord atrophy

CHERISH was the second phase III trial of nusinersen, a survival motor neuron-2 (SMN2) antisense oligonucleotide that promotes production of full-length SMA protein. In the first trial, ENDEAR, was terminated early when 41% of infants with spinal muscular atrophy had a motor milestone response compared to 0% in the sham control group; 51% had a response in the final analysis (Finkel et al. N Engl J Med 2017;377:1723-1732). The likelihood of survival was higher with active treatment versus control (hazard ratio 0.37). For CHERISH, nusinersen was compared to sham control in 126 older-onset SMA patients (symptom onset after age 6 months) (Finkel et al. N Engl J Med 2018;378:625-635). Subjects received intrathecal nusinersen 12 mg on days 1, 29, 85 and 274. Least-squares mean increase from baseline to month 15 in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score was 4 points compared to -1.9 points in controls. This study was also terminated early. In the final analysis, 57% in the active treatment group had >3-point increase in HFMSE score compared to 26% of controls. Treatment was well-tolerated. Nusinersen (Spinraza) received FDA approval as the first treatment for SMA in pediatric and adult patients in December 2016.

Hereditary transthyretin amyloidosis

Two trials led to FDA approvals for two agents to treat hereditary transthyretin amyloidosis (hATTR). The antisense oligonucleotide inotersen (Tegsedi) was examined in adults with stage 1 or 2 hATTR with polyneuropathy (Benson et al. N Engl J Med 2018;379:22-31). A total of 172 subjects received weekly subcutaneous injections of placebo or inotersen 300 mg for 15 months. The primary endpoint was change in the modified Neuropathy Impairment Score+7. Least-squares mean change from baseline to week 66 was a -19.7-point difference with active treatment versus control (higher scores indicate poor function); the minimal clinically meaningful change is considered to be 2 points. The most frequent serious adverse events were glomerulonephritis (3%) and thrombocytopenia (3%). Patisiran is a small interfering RNA (siRNA) agent that inhibits transthyredtin synthesis in the liver. In the trial, 225 subjects with hATTR with polyneuropathy were randomized to placebo or IV patisiran 0.3 mg/kg every three weeks (Adams et al. N Engl J Med 2018;379:11-21). The primary endpoint was the change in the modified Neuropathy Impairment Score+7 at 18 months. Least-squares mean change from baseline to week 66 was a -34.0-point difference with active treatment versus control (-6.0 vs. +28.0) at 18 months. The most common adverse effect was infusion reactions (20% vs. 10% with placebo). Both Tegsedi and Onpattro received FDA approval in 2018.

Recommend to a Colleague

Related Posts

Go back to home page