Active Trials

Clinical Trial of Ceftriaxone in Subjects with ALS

Study Rationale

It is known that nerve cells called motor neurons die in the brains and spinal cords of people with ALS. However, the cause of the cell death is unknown. Researchers think that increased levels of a chemical called glutamate may be related to the cell death. For this reason researchers want to study drugs that decrease glutamate levels near nerves.

Ceftriaxone is an antibiotic (in a class known as "cephalosporins") that is approved to treat certain types of infections. The investigators involved in this study are interested in studying ceftriaxone because the drug may also increase the level of a protein that decreases glutamate levels near nerves. Studies of ceftriaxone in the laboratory suggest that it may protect motor neurons form injury.

Study Goal

The purpose of the study is to evaluate the safety and effect of intravenous ceftriaxone treatment in people with ALS.

Study Design

The study is a placebo-controlled clinical trial and will treat up to 600 research participants with ALS enrolled at up to 60 centers in the US and Canada using a three-step sequential drug development design. Enrollment began in August 2006.

Outcome Measures

The primary outcome measure is survival. The secondary outcome measures include ALSFRS-R, vital capacity, evaluation of multiple upper extremity muscles using hand held dynamometry, quality of life, and long-term safety and tolerability of ceftriaxone.

Members of the Ceftriaxone Study Team

This study is a joint project between the NEALS Consortium and the National Institute of Health. The Principal Investigator for the study is Dr. Merit Cudkowicz. Co-Principal Investigators are Drs. Jeremy Shefner and Allitia DiBernardo.

Stage 1 Study Sites

Participating NEALS Sites:

• Massachusetts General Hospital, Boston, MA
• Methodist Neurological Institute, Houston, TX
• Carolinas Neuromuscular/ALS Center, Charlotte, NC
• SUNY Upstate Medical University, Syracuse, NY
• Wake Forest University, Winston-Salem, NC
• Washington University, St. Louis, MO
• Indiana University, Indianapolis, IN
• University of Chicago, Chicago, IL
• Emory University, Atlanta, GA

Participating Non-NEALS Stage 1 Site:

• California Pacific Medical Center, San Francisco,CA

Dose-escalation, pharmacokinetic study of high dose-creatine in subjects with ALS

Study Rationale

While creatine has ample preclinical evidence for efficacy in models of neurodegeneration, optimal dosage in humans has not been clearly established. Creatine is actively transported from the gut and across the BBB by different transporters with unknown kinetics.

Study Goal

To determine the serum pharmacokinetics and brain concentrations of three dose levels of creatine monohydrate.

Outcome Measures

Serum SS creatine levels Brain creatine levels by MRS

Members of the Study Team

Dr. Allitia DiBernardo and Joanna Eckenrode

Study Sites

• Massachusetts General Hospital

Participating NEALS Sites

• Massachusetts General Hospital

Completed Trials

Trial of Sodium Phenylbutrate

Study Rationale

Sodium phenylbutyrate (NaPB) is a histone deacetylase (HDAC) inhibitor. HDAC inhibitors affect histones as well as transcription factors that are regulated by acetylation. Histone deacetylase inhibitors promote transcriptional activation by relaxing the conformation of folded DNA. The most widely studied compounds are sodium butyrate, sodium phenylbutyrate, trichostatin A and suberoylanilide hydroxamic acid (SAHA). The butyrates, however, have been the best clinically-studied compounds and are known to readily reach the brain.

Recent studies indicate that transcriptional dysregulation and apoptosis may play a role in the motor neuron cell death. A pre-clinical trial of NaPB in a transgenic mouse model of ALS demonstrated prolongation of survival by 22%, which is more dramatic than most therapies tested in this model. Strategies that correct for this transcriptional imbalance may either delay or halt clinical progression in ALS.

Study Goal

The study objective is to determine the safety and tolerability of sodium phenylbutyrate treatment in subjects with ALS.

Study Design

All research participants will receive sodium phenylbutyrate. The dose of medication will be escalated every 2 to 4 weeks until a maximum tolerable dose is achieved (study maximum is 21 g/day). Subjects will remain at this dose for a period of eight weeks.

Outcome Measures

The primary outcome measure is the ability to complete the dosage escalation and maintenance phase at 21 grams per day. Secondary outcome measures are the number of adverse events at each dosage, including abnormalities in vital signs, physical examination, laboratory tests and EKGs, change in vital capacity and ALS functional rating scale, and the relationship between blood levels and sodium phenylbutyrate dosage.

Members of the Sodium Phenylbutyrate Study Team

This study was a joint project between the NEALS Consortium and the Veterans Administration. The principal investigators for the study are Drs. Merit Cudkowicz, Robert Ferrante, and Robert Brown.

Study Sites

VA Participating Sites

• Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA
• Durham VA Medical Center, Durham, NC
• Michael E. DeBakey VA Medical Center, Houston, TX
• Iowa VAMC, Iowa City, IA
• VA Medical Center, Lexington, KY
• VA Medical Center, Syracuse, NY
• VA Pittsburgh HCS
• Cincinnati VA

Participating NEALS Sites

• Johns Hopkins University, Baltimore, MD
• Massachusetts General Hospital, Boston, MA

Trial of Arimoclomol (Phase IIa)

Enrollment in this trial is complete.

Arimoclomol was found to be safe and tolerable at all doses tested. There were no adverse events more common with arimoclomol than placebo. There were no clinically relevant laboratory or ECG abnormalities with arimoclomol treatment. Arimoclomol crossed the blood brain barrier and displayed a dose-dependent increase in CSF levels. The study results were presented at the ANA Meeting in Chicago, IL in October 2006 and the 17th International ALS/MND Association Symposium in Japan in December 2006.

Study Rationale

Arimoclomol, an analog of bimoclomol, is a hydroxylamine derivative that acts as a co-inducer of "heat shock" or "molecular chaperone" gene expression. Heat shock proteins are critical in the cellular response to stress and protein misfolding. Recent data suggest that the superoxide dismutase 1 (SOD1) mutation responsible for ALS in some patients with familial disease reduces the availability of a variety of HSPs, and thus weakens their ability to respond to cellular stress. When given both pre-symptomatically and at disease onset in a mutant superoxide dismutase transgenic mouse model of ALS, arimoclomol extends survival by five weeks. Arimoclomol delays the death of motor neurons in treated mice and delays the associated loss of motor unit potentials. Therapeutic agents such as arimoclomol that improve cellular chaperone response to protein misfolding may be helpful in ALS.

Study Goal

The study objective was to determine the safety and tolerability of arimoclomol treatment in volunteers with ALS.

Study Design

This study was a multicenter, double-blind, placebo-controlled safety and tolerability study in 84 research volunteers with ALS from 10 clinical sites across the US. Volunteers were randomized to receive 75 mg, 100 mg, or 150 mg of arimoclomol or placebo over a period of 12 weeks, with a 4-week post treatment wash out period. Visits and safety testing occurred every 2 weeks. To determine the degree to which arimoclomol entered the CSF, samples were taken at the week 4 visit in 44 subjects. All volunteers who completed 12 weeks of treatment and completed the week 16 follow-up visits were eligible to enroll in an open label extension study.

Outcome Measures

The safety of arimoclomol was evaluated using vital signs and weight, clinical laboratory determinations, electrocardiograms, physical examination, reporting of adverse events, and the proportion of subjects completing the study on assigned treatment dosages (tolerability).

The serum pharmacokinetic properties and CSF penetration of arimoclomol in the ALS patient population was determined in a subset of volunteers.

Measures of disease progression were evaluated using the ALSFRS-R and vital capacity.

Study Sites

• Duke University, Durham, NC
• Pennsylvania State University, Hershey, PA
• University of California Irvine, Irvine, CA
• Drexel University, Philadelphia, PA
• Massachusetts General Hospital, Boston, MA
• SUNY Upstate Medical University, Syracuse, NY
• University of Kansas, Kansas City, KA
• University of Miami, Miami, FL
• Hennepin Faculty Associates/Berman Center, Minneapolis, MN
• University of Texas Health Science Center at San Antonio, TX

Contacts

Please contact Elizabeth Simpson at (617) 726-3430 or esimpson1@partners.org for more information regarding this trial.

 

Trial of Celebrex in ALS

This trial is completed. The results of this study will be reported in Annals of Neurology.

At 800 mg per day, Celebrex was safe and well tolerated. Celebrex did not have any demonstrated beneficial effects on ALS disease course. Studies are underway to assess whether Celebrex as used in this study had the predicted pharmacologic effects in the treated participants. The study results were presented at the International ALS/MND Association Symposium on December 3rd, 2004.

Study Rationale

Celebrex (celecoxib) is a cyclooxygenase-2 (COX-2) inhibitor that is approved by the FDA for the relief of symptoms of osteoarthritis and rheumatoid arthritis in adults. Pre-clinical studies support the hypothesis that drugs that inhibit COX-2 activity may have neuroprotective effects in subjects with ALS. The activity of the enzyme cyclooxygenase-2 is believed to play a key role in the death of motor neurons in ALS. Glutamate-mediated excitotoxicity and oxidative toxicity are possible factors in the pathogenesis of ALS. Cyclooxygenase-2 may contribute to these processes by producing prostaglandins that trigger astrocytic glutamate release and induce free radical formation. The brain and spinal tissue of patients with ALS contain increased levels of cyclooxygenase-2. Cyclooxygenase-2 inhibition using celecoxib in an organotypic spinal cord culture model of ALS provided significant protection against loss of spinal motor neurons. COX-2 inhibition prolongs survival in the G93A mutant superoxide dismutase transgenic mouse model of ALS.

Study Goal

The study objective was to determine if treatment with Celebrex slows the progression of ALS.

Study Design

The study was a 12-month double-blind, placebo-controlled efficacy study in 300 research participants with ALS. Two hundred participants received Celebrex and one hundred received matching placebo. Research participants who completed the 12 months of the double-blind phase had the option to receive Celebrex for up to one year in an open label study. A total of 300 research participants enrolled in the trial of Celebrex at 27 sites through the United States.

Outcome Measures

The primary outcome measure used in this study was the change in the Quantitative Muscle Test (QMT) scores of eight arm muscles. The secondary outcome measures were safety and tolerability, vital capacity test (FVC), the Motor Unit Number Estimate (MUNE), and the ALS Functional Rating Scale (ALSFRS).

The trial of Celebrex in ALS was sponsored by Pharmacia/Pfizer and the Muscular Dystrophy Association.

 

Trial of Creatine in ALS

This trial is completed. The results were presented at the International ALS/MND Symposium in Milan, Italy in November, 2003.

At a dose of 5 grams per day, creatine was well tolerated, but had no positive impact on progression of ALS as measured by ALSFRS, quantitative muscle strength in the upper extremities, MUNE, or grip strength. In the trial, 102 were studied, and the study was powered to detect only a change in any measure of 50% or greater. However, confidence interval analysis of the data after collection showed that it was very unlikely that there was any effect on any measure of greater than 30%.

Study Rationale

Pre-clinical evidence suggests that impaired mitochondrial energy metabolism may lead to excitotoxic cell death in ALS. Creatine, an agent that improves mitchondrial function, has shown neuroprotective properties in animal models of ALS.

Study Goal

The study objective was to determine if treatment with creatine slows the disease progression of ALS.

Study Design

The trial of creatine in ALS was a double-blind, placebo-controlled study. One hundred four research participants with a clinical diagnosis of ALS, from 14 sites in the United States, underwent treatment for six months. One half of the subjects received creatine at five grams per day, and one half received placebo.

Outcome Measures

The outcome measure in this trial was change in the Quantitative Muscle Testing (QMT) scores. Secondary outcome measures included safety and tolerability, and the change in Motor Unit Number Estimate (MUNE).

The trial of creatine was sponsored by the Muscular Dystrophy Association and Avicena.

Results of this study have been reported in the journals Neurology (Nov 2004; 63: 1656 – 1661) and Muscle and Nerve (30: 463-469, 2004.)

 

Trial of Topiramate in ALS

This trial is completed. The results have been published in Neurology. 2003 Aug 26;61(4):456-464.

At a maximum dose of 800 milligrams per day, treatment with topiramate is not beneficial to patients with ALS. Topiramate was associated with several adverse events, including kidney stone formation, abnormal blood clotting, and nausea. The subjects treated with high doses of topiramate showed a faster rate of decline in MVIC arm strength compared to placebo. Treatment with topiramate had no effect on the rate of decline of the FVC or ALSFRS scores, or on survival.

The clinical trial of topiramate was the first drug trial in ALS to be sponsored by the National Institute of Neurdegenerative Disorders and Stroke (NINDS).

Study Rationale

Topiramate is approved by the FDA for treatment of epilepsy. It is a derivative of a naturally-occurring monosaccharide. Genetic and biochemical studies implicate glutamate excitotoxicity in the pathogenesis of familial and sporadic ALS. Topiramate affects glutamate neurotransmission by blocking one of the major ionotropic glutamate receptors, kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA). In an in vitro model of chronic glutamate toxicity, topiramate protected motor neurons in a dose-dependent fashion.

Study Goal

The study objective was to determine if chronic treatment with topiramate slows the deterioration of motor and pulmonary function in ALS by 35%.

Study Design

The trial of topiramate in ALS was a 12-month, double-blind, placebo-controlled trial in 296 research participants with ALS. 198 research participants received study medication, and 98 participants received a matching placebo. The maximum dose administered was 800 milligrams per day. Subjects who completed the double-blind phase had the option of enrolling in the open-label extension protocol.

Outcome Measures

The primary outcome measure used was the change in the Quantitative Muscle Test (QMT) scores of eight arm muscles. Secondary outcome measures included safety and tolerability, the rate of decline of Forced Vital Capacity (FVC) score, and the ALS functional rating scale (ALSFRS), safety (report of Adverse Events), and survival.

The trial of topiramate was sponsored by the National Institute of Neurdegenerative Disorders and Stroke, the Muscular Dystrophy Association, and Ortho-McNeill Pharmaceuticals.