Relapse Rate and MRI Activity in Young Adult Patients With Multiple Sclerosis: A Post Hoc Analysis of Phase 3 Fingolimod Trials.

BACKGROUND: Disease activity differs in young patients with multiple sclerosis (MS) compared with the overall adult MS population. OBJECTIVE: The objective of this paper is to evaluate the effect of fingolimod 0.5 mg on disease activity in young adults with MS from three randomized, double-blind Phase 3 trials. METHODS: Annualized relapse rate (ARR), number of new/newly enlarging T2 lesions (neT2), and no evidence of disease activity (NEDA-3) were estimated in the intent-to-treat population at age 20 (youngest) and 30 (young) and compared to the overall population. Models used included a negative binomial regression (ARR/neT2) and a logistic regression (NEDA), with age at baseline as a continuous covariate. RESULTS: ARRs were higher in younger patients (all p < 0.05), and significantly reduced with fingolimod versus placebo or interferon beta-1a (IFN ß-1a), with the percentage reduction inversely proportional to age. Fingolimod was significantly associated with a lower number of neT2 lesions versus placebo/IFN in all age groups except versus IFN in the youngest patients. Regardless of age, fingolimod-treated patients were more likely to achieve NEDA-3 versus placebo/IFN ß-1a, with strongest benefits in the youngest patients (all p < 0.05). CONCLUSIONS: Young adults show higher levels of MS disease activity, and may particularly benefit from fingolimod treatment compared with the overall study population.

Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study.

BACKGROUND: Fingolimod 0·5 mg once daily is approved for treatment of relapsing multiple sclerosis (MS). In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. We aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics. METHODS: We did subgroup analyses of ARRs (primary outcome) and confirmed disability progression (a secondary outcome) over 24 months in the FREEDOMS study, a randomised, double-blind study that included 1272 patients with relapsing-remitting MS who were assigned 1:1:1 to fingolimod (0·5 mg or 1·25 mg) or placebo once daily for 24 months. Subgroups were predefined, predefined and slightly modified, or defined post hoc, by demographic factors (including sex and age), disease characteristics (including baseline disability scores, relapse rates, and lesion parameters), and response to previous therapy (including analyses in patients eligible for fingolimod treatment according to the European label). Data were analysed by intention to treat. The FREEDOMS study is registered with ClinicalTrials.gov, number NCT00289978. FINDINGS: Treatment with fingolimod 0·5 mg was associated with significantly lower ARRs versus placebo across all subgroups except for patients aged over 40 years. ARR ratios ranged from 0·76 (95% CI 0·54-1·09; p=0·13) in patients aged over 40 years to 0·29 (0·16-0·52; p<0·0001) in patients who had relapse activity despite receiving interferon beta during the year before study enrolment. Hazard ratios for confirmed disability progression over 24 months with fingolimod 0·5 mg versus placebo ranged from 0·85 (95% CI 0·53-1·36; p=0·50) in patients with a T2 lesion volume of 3300 mm(3) or less to 0·32 (0·14-0·73; p=0·0066) in patients with an EDSS over 3·5. In patients who relapsed and had lesion activity despite treatment with interferon beta in the previous year, the ARR ratio for fingolimod 0·5 mg versus placebo was 0·38 (95% CI 0·21-0·68, p=0·0011), and for treatment-naive patients with rapidly evolving severe disease it was 0·33 (0·18-0·62, p=0·0006). Hazard ratios for confirmed disability progression over 24 months were 0·68 (0·29-1·62; p=0·39) and 0·73 (0·25-2·07; p=0·55), respectively, in these groups. INTERPRETATION: Patients with relapsing-remitting MS with a wide spectrum of clinical and MRI features including subgroups specified by the European label can potentially benefit from treatment with 0·5 mg fingolimod. FUNDING: Novartis.

Individual administration of three tanniferous forage plants to lambs artificially infected with Haemonchus contortus and Cooperia curticei.

We investigated direct anthelmintic effects associated with the feeding of fresh tanniferous forages against established populations of Haemonchus contortus and Cooperia curticei in lambs. Twenty-four parasite naive lambs were inoculated with a single dose of infective larvae of these two parasites 27 days prior to the start of the feeding experiment. Lambs were individually fed with either chicory (Cichorium intybus), birdsfoot trefoil (Lotus corniculatus), sainfoin (Onobrychis viciifolia) or a ryegrass/lucerne mixture (control) for 17 days. Animals where then united to one flock and subjected to control feeding for another 11 days to test the sustainability of potentially lowered egg excretion generated by tanniferous forage feeding. When compared to the control, administration of all tanniferous forages was associated with significant reductions of total daily faecal egg output specific to H. contortus (chicory: 89%; birdsfoot trefoil: 63%; sainfoin: 63%; all tests P<0.05) and a tendency of reduced H. contortus worm burden (chicory: 15%; birdsfoot trefoil: 49% and sainfoin: 35% reduction). Irrespective of the condensed tannin (CT) containing fodder, no anthelmintic effects were found against C. curticei. Cessation of CT-feeding followed by non-CT control feeding did not result in a re-emergence of faecal egg counts based on faecal dry matter (FECDM) in any group, suggesting that egg output reductions are sustainable. The moderate to high concentrations of CTs in birdsfoot trefoil (15.2 g CTs kg(-1) dry matter (DM)) and sainfoin (26.1 g CTs kg(-1) DM) were compatible with the hypothesis that the antiparasitic effect of these forages is caused by their content of CTs. For chicory (3 g CTs kg(-1) DM), however, other secondary metabolites need to be considered. Overall, birdsfoot trefoil and in particular sainfoin seem promising candidates in contributing to an integrated control strategy against H. contortus not only by mitigating parasite related health disturbances of the host but also by a sustained reduction of pasture contamination.

Effect of sainfoin (Onobrychis viciifolia) silage and hay on established populations of Haemonchus contortus and Cooperia curticei in lambs.

The objective of the study was to examine the effect of dried and ensiled sainfoin (Onobrychis viciifolia) on established populations of Haemonchus contortus (abomasum) and Cooperia curticei (small intestine) in lambs under controlled conditions. Twenty-four parasite naïve lambs were inoculated with a single dose of infective larvae of these parasites 28 days prior to the start of the feeding experiment. Twenty-four days post-infection, 4 days prior to the start of the feeding experiment, animals were allocated to four groups according to egg excretion, live weight and sex. Groups A and B received sainfoin hay and control hay, respectively, for 16 days. Groups C and D were fed on sainfoin silage or control silage for the same period. Feeds were offered ad libitum and on the basis of daily refusals were supplemented with concentrate in order to make them isoproteic and isoenergetic. Individual faecal egg counts on a dry matter basis (FECDM) were performed every 3-4 days and faecal cultures and packed cell volume (PCV) measurements were done weekly. After 16 days of experimental feeding, all animals were slaughtered and adult worm populations were determined. The consumption of conserved sainfoin was associated with a reduction of adult H. contortus (47% in the case of hay, P<0.05; 49% in the case of silage, P=0.075) but had little effect on adult C. curticei. Compared to the controls, H. contortus specific FECDM was reduced by 58% (P<0.01) in the sainfoin hay group and by 48% (P=0.075) in the sainfoin silage group. For both sainfoin feeds FECDM specific to C. curticei were significantly decreased when compared to the control feeds (hay 81% and silage 74%, both tests P<0.001). Our data suggest that different mechanisms were responsible for the reduction in FECDM in response to feeding tanniferous fodder. For H. contortus, the decrease seemed to be due to a nematocidal effect towards adult H. contortus. In contrast for C. curticei, the reduction in FECDM appeared to be a result of a reduced per capita fecundity. For both, hay and silage, an antiparasitic effect could be shown, offering promising perspectives for the use of conserved tanniferous fodder as a complementary control approach against GIN.