C80 ALS TRIAL DESIGN: CAN WE DO BETTER?
MILLER RG, KATZ JS, MOORE DH
California Pacific Medical Center, San Francisco, CA, USA
Email address for correspondence: [email protected]
Keywords: clinical trials, trial design, historical controls
The data from Phase II trials are critical to informing the decision about moving forward into Phase III. Phase II methods are particularly important in ALS, where the opportunity to test many promising agents must be balanced against relatively low funding and a paucity of patients enrolling in trials. Innovative approaches in recent trials provide important clues for improving efficiency of ALS trials.
The goals of Phase II trials are to examine a biologic effect, evaluate dose ranging and pharmacokinetics, and look for a hint of efficacy. The biologic effect is best shown through an impact on a biomarker. An example is the beneficial change in a biomarker of macrophage activation after a single dose of NP001 (Neuraltus) reported elsewhere at this meeting.
Another critical issue is dose finding. The failure of high dose minocycline provides one example of insufficient attention to dose ranging. In contrast, the current phase III trial of Dexpramipexole (Knopp) shows how phase II dose-response data may provide a basis for moving to Phase III.
New ALS trial designs show great promise. Small futility trials can benefit the field by eliminating agents not meeting a pre-set target. The recent NEALS lithium trial, using a novel “6 point drop” endpoint, reduced trial time and excluded the large benefit that had been reported in an earlier trial. The futility study of Coenzyme Q10 used a two-stage design to compare different doses, before testing the “winner” against placebo in stage two.
Historical placebo controls aim to further reduce costs and increase power, and are attractive to subjects who are more likely to receive drug. Critical to this method is excluding any disease-related drift of endpoints over time, which occurred in Parkinson's disease. Our placebo database, of 475 controls from six ALS trials, shows no change in the rate of functional decline over the past decade, provided that patients are matched for differences in inclusion criteria. This provided a basis for a WALS historically controlled lithium trial, which reached conclusions that were similar to lithium studies using contemporary controls (NEALS, Chio 2010). Increased efficiency might result from combining concurrent and historical controls, thereby reducing sample size, in terms of new enrollment, required for a predefined power. Shorter duration (6 months) trials using endpoints such as ALSFRS and FVC also reduce cost and sample size compared to trials based on survival.
Renewed focus on the goals and efficiencies of phase II trials in ALS will move the field forward. There is room for improvement also in phase III regarding inclusion criteria, endpoints and trial design.
C81 LITHIUM WITH RILUZOLE FOR THE TREATMENT OF ALS: A RANDOMISED, SEQUENTIAL, PLACEBO-CONTROLLED TRIAL ON SURVIVAL
VERSTRAETE E1, VELDINK JH1, VAN DER TWEEL I1, SCHELHAAS HJ2, DE VISSER M3, VAN DEN BERG LH1
1University Medical Center Utrecht, Utrecht, The Netherlands, 2University Nijmegen Medical Centre, Nijmegen, The Netherlands, 3Amsterdam Academic Medical Center, Amsterdam, The Netherlands
Email address for correspondence: [email protected]
Keywords: lithium, trial, survival
Background: We studied the effects on survival of lithium in combination with riluzole in patients with ALS. After the publication of a pilot study in 2008 reporting lithium could slow disease progression in ALS, a number of clinical trials were set up to examine its true effects. Thus far, several of these trials have published their results, none of these were able to reproduce the positive findings of the initial pilot study. However, the effect of lithium on survival in patients with ALS remained unknown.
Objectives: To study the effects of lithium versus placebo on survival in ALS with a randomised, sequential trial.
Methods: A randomized, sequential trial with lithium versus placebo was performed in 133 patients with ALS. Between November 2008 and June 2011, patients were randomized to receive lithium carbonate (target blood level 0.4–0.6) or placebo. Primary end point was survival. Secondary outcome measures were decline of functional status measured by the revised ALS Functional Rating Scale and vital capacity. Analysis was by intention to treat and according to a sequential trial design. Secondary outcome measures were analysed using a linear mixed-effects model. This trial was registered with the Netherlands trial registry (number NTR1448).
Results: A total of 61 patients reached a primary endpoint, 33 of 66 in the lithium group compared with 28 of 67 patients in the placebo group. Lithium did not significantly affect survival (cumulative survival probability of 0.73 in the lithium group (standard error (SE), 0.06) versus 0.75 in the placebo group (SE 0.06) at 12 months and 0.62 in the lithium group [SE 0.06] versus 0.67 in the placebo group (SE 0.06) at 16 months). In addition, the rate of functional decline did not differ between treatment groups (p = 0.97). There were no major safety concerns.
Conclusions: We found no evidence that lithium in combination with riluzole affects survival or functional decline of patients with ALS. The current study is the first report of a placebo controlled trial with lithium taking survival as primary endpoint. In addition, the trial was designed to detect small beneficial treatment effects similar to that of riluzole. However, with the cumulative evidence currently available, we unfortunately conclude lithium has not shown to benefit patients with ALS.
C82 A RANDOMIZED, DOUBLE-BLIND, DOSE-RANGING STUDY OF MEMANTINE IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS
CHAN KM, TSUYUKI R, BAKER G, SEKHON R, YANG K, HANSTOCK C, KALRA s
University of Alberta, Edmonton, Alberta, Canada
Email address for correspondence: [email protected]
Keywords: randomized controlled trial, memantine, human
Background: Toxicity caused by glutamate contributes to motoneuron (MN) destruction in ALS. While memantine inhibits the deleterious effects of glutamate, it does not affect its normal action and has been shown to prolong survival in SOD1 transgenic mice.
Objectives: 1) to test the hypotheses that memantine would slow MN degeneration and functional decline; 2) to identify the optimum dose.
Methods: Adult ALS subjects with symptom duration < 3 years and forced vital capacity (FVC) > 60% predicted were recruited. Motor unit number estimation (MUNE) was done on the median innervated hand muscles using multipoint stimulation. To gauge upper motoneuron (UMN) changes, n-acetylaspartate levels in the motor cortex were measured using magnetic resonance spectroscopic imaging (MRSI). Functional changes were evaluated using the ALSFRS-R, FVC and manual muscle testing (MMT). At the end of a 4 month run-in period, subjects were randomized to either receive low dose (5 mg bid) or high dose (10 mg bid) memantine for 5 months. MUNE and MRSI were done at baseline and repeated at the end of the run-in and treatment phases. Functional measures were checked monthly throughout the study. Double blinding was maintained by a drug safety monitoring board that worked at arms length and was responsible for randomization, data analysis and monitoring of adverse events. Medication compliance was monitored through monthly serum samples.
Results: Of 29 potentially suitable subjects screened, 24 who qualified were equally divided to each treatment arm. One patient in the high dose group died leaving 11 subjects available for final analysis while in the low dose group, 2 patients died and 1 withdrew leaving 9 subjects. Serum concentration analysis revealed good compliance. Reported adverse events were similar between the run-in and treatment phases. There was significant slowing of spinal MN loss in the high dose group from −12.4 ± 3.7 (mean ± sd)/month at run-in to −5.3 ± 2.2/month during treatment (p = 0.03). When all subjects were combined, they showed a trend of slowing in spinal MN loss that approached significance (−7.8 ± 2.4/month at run-in vs. −4.2 ± 1.3/month during treatment, p = 0.05). However, none of the functional measures or MRSI revealed a significant treatment effect: ALSFRS-R −1.5 ± 0.2 vs. −1.2 ± 0.2, p = 0.22; FVC −2.3 ± 0.7 vs. −2.4 ± 0.7%, p = 0.96; MMT −6.6 ± 1.2 vs. −7.1 ± 1.3, p = 0.69; MRSI 0.0004 ± 0.002 vs. + 0.0006 ± 0.004, p = 0.86.
Discussion and conclusions: In this pilot study, we found that memantine at 10 mg bid was effective in slowing spinal MN loss in ALS patients. However, functional measures and UMN degeneration were not significantly improved. The latter could be due to the small sample size. Based on these observations, the fact that memantine is well tolerated and that a previous human study in ALS patients also showed benefits, a multicentre full scale clinical trial aimed at recruiting patients at earlier stages of ALS may be warranted.
C83 A FIRST-TIME-IN-HUMAN STUDY IN ALS PATIENTS WITH THE ANTI-NOGO-A MONOCLONAL ANTIBODY GSK1223249: PRELIMINARY RESULTS
PRADAT P-F1, CORSE A2, SHEFNER J3, ROTHSTEIN JD4, LEIGH PN5, MORRISON KE6, MEYER T7, AL-SARRAJ S8, PETERS G9, ORRELL R10, MILLERI S11, CARESS J12, BROOKS B13, KOLB SJ14, LANGE D15, FAULKNER J16, ABILA B17, WILLIAMS N18, HUGHES S19, BERGES A18, MEININGER V1, WURTHNER J17
1AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Neurological Department, Paris, France, 2Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA, 3Department of Neurology, SUNY Upstate Medical University, Syracuse, NY, USA, 4Departments of Neurology/Neurosciences, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA, 5Brighton and Sussex Medical School, Trafford Centre for Biomedical Research, University of Sussex, Brighton, UK, 6Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, UK, 7Charité – Universitätsmedizin, Berlin Campus Virchow-Klinikum, Neurologische Klinik, Berlin, Germany, 8Department of Clinical Neuropathology, King's College Hospital, London, UK, 9CUC, Addenbrooke's Centre for Clinical Investigation, Cambridge, UK, 10UCL Institute of Neurology, Royal Free Hospital, London, UK, 11Centro Ricerche Cliniche di Verona s.r.l., Azienda Ospedaliera,Universitaria Integrata, c/o Policlinico G.B. Rossi, Verona, Italy, 12Wake Forest University Health Science Department: Neurology, Winston-Salem NC, USA, 13Carolinas Medical Center, Charlotte, NC, USA, 14Departments of Neurology and Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH, USA, 15Hospital for Special Surgery, Department of Neurology, New York, NY, USA, 16Rare Disease Unit, GlaxoSmithKline, Brentford, Middlesex, UK, 17Translational Pharmacology & Discovery Medicine. GlaxoSmithKline, Stevenage, UK, 18Quantitative Science, GlaxoSmithKline, Stevenage, UK, 19Neurosciences SERM. Global Clinical Safety &Pharmacovigilance, GlaxoSmithKline, Stockley Park, UK
Email address for correspondence: [email protected]
Keywords: Nogo-A, monoclonal antibody, therapeutic trial
Background: Nogo-A (neurite outgrowth inhibitor A) is a high molecular weight transmembrane protein initially identified as a potent myelin-associated inhibitor of axonal growth expressed mostly by oligodendrocytes. Over-expression of Nogo-A in skeletal muscle of amyotrophic lateral sclerosis (ALS) patients has been implicated in the pathophysiology of this disease.
GSK1223249 is a humanized monoclonal antibody (mAb) that potently binds to a specific epitope on Nogo-A to neutralize/antagonize this protein. It is hypothesized that GSK1223249 may promote neuro-regeneration and synaptic plasticity, thus leading to clinical improvement or slowing of disease-progression in certain degenerative neurological disorders such as ALS.
Objectives: GSK has conducted a First-Time-in-Human trial (FTIH) with this mAb between 2009 and 2011 with the primary objective to assess its safety & tolerability in ALS patients. Secondary objectives included an investigation of its pharmacokinetics (PK), immunogenicity and effects on different clinical and pharmacodynamic (PD) endpoints, such as ALSFRS-R scores, Slow Inspirational Vital Capacity (SVC), Motor Unit Number Estimation (MUNE) and biochemical biomarkers in skeletal muscle tissue.
Methods: The FTIH NOG111330 trial was a randomized, placebo-controlled, double-blind, multi-centre, sequential dose escalation, 2-part fusion protocol. Seventy-six patients with ALS were randomized 3:1 (active: placebo) and enrolled into 8 cohorts, subdivided into 2 parts. In Part 1, single escalating intravenous (i.v.) doses of GSK1223249 were evaluated in 5 sequential patient cohorts (0.01 to 15 mg/kg, n = 8/cohort), whilst in Part 2 patients in each of the 3 cohorts received 2 repeat i.v. doses approximately 4 weeks apart (0.5 to 15 mg/kg per dose, n = 12/cohort).
Results: The trial is currently ongoing, but it will have concluded by the time of the meeting, and headline data on the safety/tolerability, pharmacokinetics and potentially pharmacodynamic endpoints of GSK1223249 in ALS patients will then be available.
Discussion and conclusions: If GSK1223249 is safe and well tolerated with a favourable PK profile and demonstrates target engagement, then progression to a large proof-of-concept study is currently planned.
C84 EFFECTS OF NP001 TREATMENT ON MONOCYTE/MACROPHAGE ACTIVATION IN PATIENTS WITH ALS
MILLER RG1, KATZ J1, FORSHEW DA1, BAROHN RJ2, KASARSKIS E3, AZHIR A4, BLOCK G4, ZHANG R5, McGRATH MS4,5
1California Pacific Medical Center, San Francisco, CA, USA, 2University of Kansas Medical Center, Kansas City, KS, USA, 3University of Kentucky, Lexington, KY, USA, 4Neuraltus Pharmaceuticals, Palo Alto, CA, USA, 5University of California, San Francisco, San Francisco, CA, USA
Email address for correspondence: [email protected]
Keywords: monocyte/macrophage activation, biomarker, NP001
Background: Elevated blood levels of abnormally activated monocyte/macrophages (MO) are present in patients with ALS (1). These CD14 + cells have high levels of activation/inflammation marker HLA-DR and a subset express elevation of the activation marker CD16. NP001 is a systemic macrophage activation regulator for treatment of ALS. A recently completed phase 1 single ascending dose safety and biomarker study in 32 ALS patients established the tolerability and safety of single dose administration of NP001. This abstract details the effects of NP001 on MO HLA-DR and CD16 expression as potential biomarkers for disease activity of ALS.
Objectives: 1) To evaluate the potential of blood MO immune parameters as biomarkers in ALS; 2) To determine blood MO biomarker response to single doses of NP001 in ALS.
Methods: This was a double-blind, placebo-controlled single ascending dose, phase 1 study in 32 patients with ALS. NP001 was administered to 24 patients (6 at each of four different doses: 0.2, 0.8, 1.6, and 3.2 mg/kg) and 8 patients received placebo. Flow cytometry was performed to assess expression of blood MO activation/inflammation markers pre- and 24 hours after a single dose of NP001 or placebo in 32 ALS patients.
Results: HLA-DR and CD16 MO expression demonstrated positive responses to NP001 treatment at 24 hours post-dosing. Reduction of MO HLA-DR expression was directly related to the patient's prior disease progression rate as assessed by ALSFRS-R decline per month (DP rate). Post-dosing, significant dose-independent trends in reduction of HLA-DR expression were seen when patients were categorized into three groups: DP rate: < 0.5, ≥ 0.5 but < 1, ≥ 1 (r2 = 0.2922, p = 0.0075). NP001 dose-dependently decreased levels of MO CD16 expression (r2 = 0.2352, p = 0.0129). Additionally, there was no relationship between MO marker response and concomitant riluzole use.
Importantly, baseline levels of MO activation defined by CD14 co-expression of HLA-DR was directly related to the patient's DP rate (r = 0.4310, p = 0.0138). A positive correlation was found between levels of CD16 MO expression and DP rate (r = 0.4499, p = 0.0098). These two parameters were independent of each other and when combined showed a more powerful relationship with DP rate in ALS (Multiple R = 0.5734, p = 0.0031).
Conclusions: Two MO activation/inflammation markers, HLA-DR and CD16, were independently associated with DP rate in ALS patients, which suggests their potential as biomarkers desperately needed for ALS. Single doses of NP001 reduced levels of both HLA-DR and CD16 MO expression with the degree of reduction dependent on prior DP rate (HLA-DR) and NP001 dose (CD16). Based on the relationship between DP rate and levels of HLA-DR and CD16 expression in ALS, NP001 induced reduction of MO activation/inflammation may slow disease progression.
Reference
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