Clinical Trial Ceftriaxone in Subjects With ALS

Study Description

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Brief Summary:

The purpose of the study is to evaluate the safety and efficacy of ceftriaxone treatment in amyotrophic lateral sclerosis (ALS).

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis; ALS	Drug: ceftriaxone; Other: placebo	Phase 3

Detailed Description:

It is known that nerve cells called motor neurons die in the brains and spinal cords of people with amyotrophic lateral sclerosis (ALS). However, the cause of this 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—a semi-synthetic, third generation cephalosporin antibiotic—may 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 from injury.

Ceftriaxone is approved by the U.S. Food and Drug Administration (FDA) for treating bacterial infections but not for treating ALS. Also, ceftriaxone has not been given to people over a long period of time, such as months or years. The goals of this study are to evaluate the safety and effectiveness of ceftriaxone as a treatment for ALS, and to determine the safety and effectiveness of long-term use of the drug in people with ALS.

A total of 600 eligible people with ALS will be enrolled in this multi-center research study. Participants will be randomly assigned to receive treatment with ceftriaxone (2/3 of participants) or placebo (1/3 of participants) for at least 12 months.

The study consists of three stages. The first stage, which has completed enrollment, will look at whether ceftriaxone enters the cerebrospinal fluid (the fluid that surrounds the spinal cord, also called CSF) in amounts that are high enough to be of possible benefit. The second stage, which has also completed enrollment, will look at the safety and side effects of the study drug when taken daily for at least 20 weeks. The study is currently enrolling subjects for the third stage, which began in Spring 2009, and will determine whether the study drug prolongs survival and slows decline in function due to ALS.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	513 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	Clinical Trial Ceftriaxone in Subjects With Amyotrophic Lateral Sclerosis (ALS)
Study Start Date :	July 2006
Actual Primary Completion Date :	November 2012
Actual Study Completion Date :	November 2012

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Ceftriaxone; Two thirds of participants were assigned to 4 grams of ceftriaxone per day. This is a blinded study, so neither participants nor study staff will know which treatment a participant is receiving. Ceftriaxone is a cephalosporin antibiotic and was administered intravenously via a central venous catheter twice a day.	Drug: ceftriaxone; Participants will be randomly assigned to receive treatment with ceftriaxone or placebo for at least 12 months. Two thirds of participants will receive ceftriaxone and one third will receive placebo. This is a blinded study, so neither participants nor study staff will know which treatment a participant is receiving. Ceftriaxone is approved by the U.S. Food and Drug Administration (FDA) for treating bacterial infections but not for treating ALS. Also, ceftriaxone has not been given to people over a long period of time, such as months or years.
Placebo Comparator: Placebo; One third of participants were assigned to placebo, or an inactive substance. This is a blinded study, so neither participants nor study staff will know which treatment a participant is receiving. Pediatric multivitamin solution was used as the placebo in this study and was administered intravenously via a central venous catheter twice a day.	Other: placebo; an inactive substance

Outcome Measures

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Primary Outcome Measures :

1. Survival [ Time Frame: From date of randomization until date of death, tracheostomy, or the initiation of permanent assisted ventilation (PAV). This was assessed at time of each participant's drug discontinuation and every 2 months thereafter for the life of the study (6 yrs) ]
   Survival is presented as median day of survival for each group. Survival is defined as time to death, tracheostomy or the initiation of permanent assisted ventilation (PAV).
2. Change From Baseline in ALS Functional Rating Scale, Revised (ALSFRS-R) at One Year [ Time Frame: Every 8 weeks for one year ]

   Amyotrophic Lateral Sclerosis Functional Rating Scale, Revised (ALSFRS-R) is a quickly administered (five minute) ordinal rating scale used to determine patients' assessment of their capability and independence in 12 functional activities/questions. The 12 functional activities/questions are rated on a scale of 0 to 4 for a total scoring range of 0-48, with 48 representing optimal function. All 12 activities are relevant in ALS.

   This outcome measure calculation is based on measurements every 8 weeks from the Baseline Visit up until one year.

Secondary Outcome Measures :

1. Change in % Vital Capacity From Screening to One Year [ Time Frame: Every 12 weeks for one Year ]

   Vital Capacity is measured as the percent predicted per subject based on age, gender, and height, and is performed as a Slow Vital Capacity.

   This outcome measure calculation is based on measurements every 12 weeks from the Baseline Visit up until one year.

2. Change From Baseline in Evaluation of Multiple Upper Extremity Muscles Using Hand Held Dynamometry at One Year [ Time Frame: Every 12 weeks for one Year ]

   Hand-held Dynamometry (HHD) is used to evaluate muscle strength. Six proximal muscle groups were examined bilaterally in both upper and lower extremities (shoulder flexion, elbow flexion, elbow extension, hip flexion, knee flexion, and knee extension). In addition, wrist extension, first dorsal interosseous contraction and ankle dorsiflexion were measured bilaterally.

   HHD analysis was performed using Percent Change from Baseline. Each subject's baseline strength value for each muscle group is considered 100%. During successive visits strength for each muscle group was measured using HHD and was calculated as a percentage of the initial baseline value recorded. Upper extremity and lower extremity values were calculated as the sum of all tests for that extremity to create one megascore for upper and one megascore for lower extremity muscles.

   This outcome measure calculation is based on measurements every 12 weeks from the Baseline Visit up until one year.

3. Change From Baseline in the ALS-Specific Quality of Life Scale (ALSQOL) at One Year [ Time Frame: Every 12 weeks for one Year ]

   The ALS-Specific Quality of Life Scale (ALSQOL). was developed, tested, and validated in subjects with ALS, and is not a health-related quality of life scale. The scale consists of 59 questions that ask about severity of the symptoms of ALS, mood and affect, intimacy, and social issues. Each question for the ALSQOL is scored from 0-10. With 59 questions, total score ranges from 0-590 with scores simply added, with 590 representing highest quality of life. However since 10 is maximally weighted towards negative values on some questions and positive values on others, the following questions must have results transposed (Simply reverse the scale, for instance 10=0 and 0=10) prior to analysis: 1-10, 11, 16, 19, 24, 26, 28, 32, 35, 36, 38, and 41. Optional items are 50, 53, 56, and 59. These questions are not included on any scale or in any quantitative analyses.

   This outcome measure calculation is based on measurements every 12 weeks from the Baseline Visit up until one year.

4. Change From Baseline in Evaluation of Multiple Lower Extremity Muscles Using Hand Held Dynamometry at One Year [ Time Frame: Every 12 weeks for one Year ]

   Hand-held Dynamometry (HHD) is used to evaluate muscle strength. Six proximal muscle groups were examined bilaterally in both upper and lower extremities (shoulder flexion, elbow flexion, elbow extension, hip flexion, knee flexion, and knee extension). In addition, wrist extension, first dorsal interosseous contraction and ankle dorsiflexion were measured bilaterally.

   HHD analysis was performed using Percent Change from Baseline. Each subject's baseline strength value for each muscle group is considered 100%. During successive visits strength for each muscle group was measured using HHD and was calculated as a percentage of the initial baseline value recorded. Upper extremity and lower extremity values were calculated as the sum of all tests for that extremity to create one megascore for upper and one megascore for lower extremity muscles.

   This outcome measure calculation is based on measurements every 12 weeks from the Baseline Visit up until one year.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Participants will be people with ALS, at least 18 years of age.
• Participants must be medically able to undergo the study procedures and have a caregiver or other individual who will be available to help with daily study medication administration.
• Participants should live within a reasonable distance of the study site, due to frequent study visits.

Exclusion Criteria:

• Participants cannot be taking any other experimental medications for ALS, or have a history of sensitivity to cephalosporin antibiotics (such as Ancef, Keflex, Ceclor, Ceftin, Lorabid, Suprax, or Fortaz).

Contacts and Locations

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Locations

United States, Arizona
Phoenix Neurological Associates
Phoenix, Arizona, United States, 85018
United States, California
University of California, Davis
Davis, California, United States, 95819
University of California, San Francisco- Fresno
Fresno, California, United States, 93701
Loma Linda University School of Medicine (CA)
Loma Linda, California, United States, 92354
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
University of California, Los Angeles
Los Angeles, California, United States, 90095
University of California, Irvine - MDA ALS Neuromuscular Center
Orange, California, United States, 92868
California Pacific Medical Center
San Francisco, California, United States, 94115
University of California, San Francisco
San Francisco, California, United States, 94117
United States, Colorado
University of Colorado Health Sciences Center
Aurora, Colorado, United States, 80045
United States, Connecticut
Hospital for Special Care
New Britain, Connecticut, United States, 06053
United States, District of Columbia
George Washington University
Washington, District of Columbia, United States, 20037
United States, Florida
Mayo Clinic Jacksonville
Jacksonville, Florida, United States, 32224
University of Miami School of Medicine
Miami, Florida, United States, 33136
United States, Georgia
ALS Center at Emory University
Atlanta, Georgia, United States, 30322
Medical College of Georgia
Augusta, Georgia, United States, 30912
United States, Illinois
Northwestern University Medical School
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana University (Regenstrief Health Center)
Indianapolis, Indiana, United States, 46202
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66161
United States, Kentucky
University of Kentucky Medical Center
Lexington, Kentucky, United States, 40536
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Lahey Clinic
Burlington, Massachusetts, United States, 01805
United States, Michigan
Henry Ford Health System
Detroit, Michigan, United States, 48202
Saint Mary's Healthcare
Grand Rapids, Michigan, United States, 49503
United States, Minnesota
Hennepin County Medical Center (Berman Center)
Minneapolis, Minnesota, United States, 55404
United States, Missouri
St. Louis University
St. Louis, Missouri, United States, 63104
Washington University
St. Louis, Missouri, United States, 63110
United States, Nebraska
Bryan LGH Medical Center (University of Nebraska)
Lincoln, Nebraska, United States, 68506
United States, New Jersey
UMDNJ- Robert Wood Johnson School of Medicine
New Brunswick, New Jersey, United States, 08901
United States, New York
Albany Medical Center
Albany, New York, United States, 12208
Beth Israel Medical Center (NY)
New York, New York, United States, 10003
Cornell Medical Center
New York, New York, United States, 10021
Columbia University
New York, New York, United States, 10032
SUNY Upstate Medical University
Syracuse, New York, United States, 13210
United States, North Carolina
Carolinas Medical Center
Charlotte, North Carolina, United States, 28203
Wake Forest University School of Medicine
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
The Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
Ohio State University
Columbus, Ohio, United States, 43210
United States, Oregon
Oregon Clinic (Providence Clinic)
Portland, Oregon, United States, 97213
United States, Pennsylvania
Pennsylvania State University, Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
Drexel University College of Medicine (Hahnemann Campus)
Philadelphia, Pennsylvania, United States, 19107
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19107
Allegheny Hospital
Pittsburgh, Pennsylvania, United States, 15212
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29403
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
United States, Texas
Texas Neurology
Dallas, Texas, United States, 75214
Methodist Neurological Institute
Houston, Texas, United States, 77030
United States, Utah
University of Utah Health Sciences Center
Salt Lake City, Utah, United States, 84132
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
Canada, Alberta
University of Calgary
Calgary, Alberta, Canada, T2N 4Z6
Univeristy of Alberta ALS Clinic
Edmonton, Alberta, Canada, T6G 2B7
Canada, Nova Scotia
Dalhousie University
Halifax, Nova Scotia, Canada
Canada, Ontario
London Health Sciences Center, University Campus
London, Ontario, Canada
University of Toronto
Toronto, Ontario, Canada
Canada, Quebec
CHUM (Centre Hospitalier de l'Université de Montréal), Notre-Dame Hospital
Montreal, Quebec, Canada
Montreal Neurological Institute (McGill University)
Montreal, Quebec, Canada
Laval University
Quebec City, Quebec, Canada

Sponsors and Collaborators

Massachusetts General Hospital

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

Principal Investigator:	Merit Cudkowicz, MD, MSc.	Associate Professor of Neurology, Harvard Medical School, Massachusetts General Hospital

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Northeast ALS Consortium website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

McDonnell E, Schoenfeld D, Paganoni S, Atassi N. Causal inference methods to study gastric tube use in amyotrophic lateral sclerosis. Neurology. 2017 Oct 3;89(14):1483-1489. doi: 10.1212/WNL.0000000000004534. Epub 2017 Sep 1.

Cudkowicz ME, Titus S, Kearney M, Yu H, Sherman A, Schoenfeld D, Hayden D, Shui A, Brooks B, Conwit R, Felsenstein D, Greenblatt DJ, Keroack M, Kissel JT, Miller R, Rosenfeld J, Rothstein JD, Simpson E, Tolkoff-Rubin N, Zinman L, Shefner JM; Ceftriaxone Study Investigators. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014 Nov;13(11):1083-1091. doi: 10.1016/S1474-4422(14)70222-4. Epub 2014 Oct 5.

Berry JD, Shefner JM, Conwit R, Schoenfeld D, Keroack M, Felsenstein D, Krivickas L, David WS, Vriesendorp F, Pestronk A, Caress JB, Katz J, Simpson E, Rosenfeld J, Pascuzzi R, Glass J, Rezania K, Rothstein JD, Greenblatt DJ, Cudkowicz ME; Northeast ALS Consortium. Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis. PLoS One. 2013 Apr 17;8(4):e61177. doi: 10.1371/journal.pone.0061177. Print 2013.

Responsible Party:	Merit E. Cudkowicz, MD, Professor of Neurology, Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT00349622 History of Changes
Other Study ID Numbers:	U01NS049640-02 ( U.S. NIH Grant/Contract ); NINDS ( Other Identifier: NINDS ); NINDS CRC ( Other Identifier: NINDS Clinical Research Collaboration )
First Posted:	July 7, 2006
Results First Posted:	April 1, 2014
Last Update Posted:	April 21, 2014
Last Verified:	April 2014

Keywords provided by Merit E. Cudkowicz, MD, Massachusetts General Hospital:

amyotrophic lateral sclerosis; ALS; ceftriaxone; cephalosporin antibiotic; motor neurons

Additional relevant MeSH terms:

Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases	Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Ceftriaxone; Cephalosporins; Anti-Bacterial Agents; Anti-Infective Agents