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A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.

ABSTRACT: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS).We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p?=?0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated.Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole.Clinicaltrials.gov NCT00690118.

SUBMITTER: Dupuis L

PROVIDER: S-EPMC3371007 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.

Dupuis Luc L Dengler Reinhard R Heneka Michael T MT Meyer Thomas T Zierz Stephan S Kassubek Jan J Fischer Wilhelm W Steiner Franziska F Lindauer Eva E Otto Markus M Dreyhaupt Jens J Grehl Torsten T Hermann Andreas A Winkler Andrea S AS Bogdahn Ulrich U Benecke Reiner R Schrank Bertold B Wessig Carsten C Grosskreutz Julian J Ludolph Albert C AC

PloS one 20120608 6

<h4>Background</h4>Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS).<h4>Methods/principal findings</h4>We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoi ...[more]

PMID: 22715372

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Project description:In a pilot study, lithium treatment slowed progression of amyotrophic lateral sclerosis (ALS). We aimed to confirm or disprove these findings by assessing the safety and efficacy of lithium in combination with riluzole in patients with ALS.We did a double-blind, placebo-controlled trial with a time-to-event design. Between January and June, 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned (1:1) by a centralised computer to receive either lithium or placebo. Patients, caregivers, investigators, and all site study staff with the exception of site pharmacists were masked to treatment assignment. The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death. Interim analyses were planned for when 84 patients had been allocated treatment, 6 months later or after 55 events, and after 100 events. Analysis was by intention to treat. The stopping boundary for futility at the first interim analysis was a p value of at least 0.68. We used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. This trial is registered with ClinicalTrials.gov, NCT00818389.At the first interim analysis, 22 of 40 patients in the lithium group had an event compared with 20 of 44 patients in the placebo group (log rank p=0.51). The hazard ratio of reaching the primary endpoint was 1.13 (95% CI 0.61-2.07). The study was stopped at the first interim analysis because criterion for futility was met (p=0.78). The difference in mean decline in the ALS functional rating scale score between the lithium group and the placebo group was 0.15 (95% CI -0.43 to 0.73, p=0.61). There were no major safety concerns. Falls (p=0.04) and back pain (p=0.05) were more common in the lithium group than in the placebo group.We found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone. The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly. This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS.National Institute of Neurological Disorders and Stroke, ALS Association, and ALS Society of Canada.

Project description:BackgroundGlutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, and ceftriaxone increases EAAT2 activity. We aimed to assess the safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 2, and 3 clinical trial.MethodsThis three-stage randomised, double-blind, placebo-controlled study was done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital capacity of more than 60% of that predicted for age and height, and symptom duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or placebo. Participants, family members, and site staff were masked to treatment assignment. Randomisation was done by a computerised randomisation sequence with permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice daily through a central venous catheter administered at home by a trained caregiver. To minimise biliary side-effects, participants assigned to ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those assigned to placebo received matched placebo capsules. The coprimary efficacy outcomes were survival and functional decline, measured as the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00349622.FindingsStage 3 included 66 participants from stages 1 and 2 and 448 new participants. In total, 340 participants were randomly allocated to ceftriaxone and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in participants who received 4 g ceftriaxone than in those on placebo (difference 0·51 units per month, 95% CI 0·02 to 1·00; p=0·0416), but in stage 3 functional decline between the treatment groups did not differ (0·09, -0·06 to 0·24; p=0·2370). No significant differences in survival between the groups were recorded in stage 3 (HR 0·90, 95% CI 0·71 to 1·15; p=0·4146). Gastrointestinal adverse events and hepatobiliary adverse events were more common in the ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] ceftriaxone vs 97 of 173 [56%] placebo, p=0·0004; hepatobiliary, 211 [62%] vs 19 [11%], p<0·0001). Significantly more participants who received ceftriaxone had serious hepatobiliary serious adverse events (41 participants [12%]) than did those who received placebo (0 participants).InterpretationDespite promising stage 2 data, stage 3 of this trial of ceftriaxone in amyotrophic lateral sclerosis did not show clinical efficacy. The adaptive design allowed for seamless transition from one phase to another, and central venous catheter use in the home setting was shown to be feasible.FundingNational Institute of Neurological Disorders and Stroke.

Project description:BackgroundLithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS.MethodsThe lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31.FindingsBetween May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ(2) on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40-1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event.InterpretationWe found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments.FundingThe Motor Neurone Disease Association of Great Britain and Northern Ireland.

Project description:BackgroundEnhanced glutamatergic transmission leading to motor neuron death is considered the major pathophysiological mechanism of amyotrophic lateral sclerosis (ALS). Motor cortex excitability can be suppressed by transcranial static magnetic stimulation (tSMS), thus tSMS can be evaluated as a potential treatment for ALS. The aim of present study was to investigate the efficacy and safety of tSMS in ALS.MethodsIn this phase 2 trial, we randomly assigned ALS patients to receive daily tSMS or placebo stimulation over a period of 6 months. For each participant we calculated mean disease monthly progression rate (MPR) as the variation of the total ALS Functional Rating Scale-Revised (ALSRFS-R) score, before the beginning of the treatment (over a period of at least three months) and over the six-month treatment period. The primary efficacy outcome was the difference in MPR before and after the beginning of treatment. Secondary outcomes included safety and tolerability, compliance, and changes in corticospinal output. A long-term follow-up of 18 months was performed in all patients who completed the six-month treatment considering a composite endpoint event (tracheostomy or death). Trial registered at ClinicalTrials.gov, ID: NCT04393467, status: closed.FindingsForty participants were randomly assigned to real (n = 21) or placebo stimulation (n = 19). Thirty-two participants (18 real and 14 placebo) completed the 6-month treatment. The MPR did not show statistically significant differences between the two arms during the pre-treatment (mean ± Standard deviation; Real: 1.02 ± 0.62, Sham: 1.02 ± 0.57, p-value = 1.00) and treatment period (Real: 0.90 ± 0.55, Sham: 0.94 ± 0.55, p-value = 0.83). Results for secondary clinical endpoints showed that the treatment is feasible and safe, being compliance with tSMS high. The change in corticospinal output did not differ significantly between the two groups. At the end of the long-term follow-up of 18 months, patients of real group had a statistically significant higher tracheostomy-free survival compared with patients of placebo group (Hazard Ratio = 0.27 95% Confidence interval 0.09-0.80, p-value = 0.019).InterpretationtSMS did not modify disease progression during the 6 months of treatment. However, long-term follow-up revealed a substantial increase in tracheostomy free survival in patients treated with real stimulation supporting the evaluation of tSMS in larger and more prolonged studies.FundingThe "Fondazione 'Nicola Irti' per le opere di carità e di cultura", Rome, Italy, supported present study.

Dataset Information

A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.

Publications

A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.

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