SUR TROIS SPÉCIMENSDE STENELLA EUPHROSYNE (Gray, 1846)(CETACEA, DELPHINIDAE) DE MÉDITERRANÉE(RÉGION DE BANYULS-SUR-MER, FRANCE)

International audienc

SUR TROIS SPÉCIMENSDE STENELLA EUPHROSYNE (Gray, 1846)(CETACEA, DELPHINIDAE) DE MÉDITERRANÉE(RÉGION DE BANYULS-SUR-MER, FRANCE)

International audienc

Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial

BACKGROUND: Glutamate excitotoxicity may contribute to the pathophysiology of amyotrophic lateral sclerosis (ALS). Studies in ALS animal models show decreased excitatory amino acid transporter 2 (EAAT2) overexpression delays onset and prolongs survival, and that ceftriaxone increases EAAT2 activity in rodent brains. Phase 1, 2, and 3 clinical studies of ceftriaxone for ALS were combined into a three-stage, nonstop study. METHODS: 514 participants were randomised to ceftriaxone (n=341) or placebo (n=173); 66 participants were enrolled in stages 1 (pharmacokinetics) and 2 (safety) to determine cerebrospinal fluid and blood pharmacokinetics and safety of two dosages: 2 grams and 4 grams/day of ceftriaxone. All participants continued into stage 3 (efficacy) in blinded fashion with participants who began treatment on the discontinued dose analysed in the same group as those on the dose that that was continued. In stage 3, 44 participants previously assigned to 2 or 4 g ceftriaxone in stage 2 received 4 g ceftriaxone; 21 participants assigned to placebo in stage 2 continued on placebo. 448 new participants were randomized in stage 3 to 4 g ceftriaxone or placebo (2:1). Participants, family members and all site staff were blinded to treatment assignment. Computerized randomisation sequence using permuted blocks of 3 was stratified by riluzole use and blocked by site. Participants received 2g ceftriaxone or placebo BID via a central venous catheter (CVC) administered in the home setting by a trained caregiver. To minimize biliary side effects, participants assigned to ceftriaxone also received 300 mg ursodiol BID in a blinded manner; those assigned to placebo received matched placebo capsules BID. The co-primary efficacy outcomes were survival and functional decline, using the slope of scores on the ALS Functional Rating Scale-Revised (ALSFRS-R). The first participant entered the trial on September 4, 2006 (stage 1); the first stage-3 participant entered on June 4, 2009. The trial was stopped in July 2012. FINDINGS: During stages 1 and 2, ALSFRS-R functional decline was 0.5076±0.2440 units per month slower in participants taking 4 g ceftriaxone versus those taking placebo (95% CI 0.0196, 0.9956, p=0.0416), yet in stage 3, functional decline differed only by 0.08975±0.07581 units per month (95% CI −0.05919, 0.2387; p=0.2370). No significant differences were seen in stage 3 survival (hazard ratio, 0.904 [95% CI 0.710, 1.152]; p=0.4146). Adverse events rates were higher in the ceftriaxone versus placebo group for gastrointestinal (72% [245/340] vs 56% [97/173]; p=0.0004) and hepatobiliary events (62% [211/340] vs 11% [19/173]; p<0.0001). Add-on ursodiol reduced these events in participants taking ceftriaxone. A significantly larger percentage of ceftriaxone versus placebo participants experienced hepatobiliary serious adverse events (12% [41/340] vs 0% [0/173]). INTERPRETATION: Despite promising stage-2 efficacy data, the stage-3 ceftriaxone in ALS study failed to show clinical efficacy. The adaptive design approach allowed for seamless movement from one phase to another obviating the need for multiple grant submissions. CVC use in the home setting was shown to be not only possible, but also safe