Clinical Trial Ceftriaxone in Subjects With ALS

Clinical Trial Ceftriaxone in Subjects With Amyotrophic Lateral Sclerosis (ALS)

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

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis; ALS
• Intervention / Treatment: Other: placebo; Drug: ceftriaxone

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 Type: Interventional
• Enrollment (Actual): 513
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	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).	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)
Change From Baseline in ALS Functional Rating Scale, Revised (ALSFRS-R) at 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.	Every 8 weeks for one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in % Vital Capacity From Screening to 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.	Every 12 weeks for one Year
Change From Baseline in Evaluation of Multiple Upper Extremity Muscles Using Hand Held Dynamometry at 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.	Every 12 weeks for one Year
Change From Baseline in the ALS-Specific Quality of Life Scale (ALSQOL) at 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.	Every 12 weeks for one Year
Change From Baseline in Evaluation of Multiple Lower Extremity Muscles Using Hand Held Dynamometry at 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.	Every 12 weeks for one Year

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: 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

Publications and helpful links

General Publications

• 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.

Helpful Links

• Northeast ALS Consortium Website

Study record dates

Study Major Dates

• Study Start: July 1, 2006
• Primary Completion (ACTUAL): November 1, 2012
• Study Completion (ACTUAL): November 1, 2012

Study Registration Dates

• First Submitted: July 5, 2006
• First Submitted That Met QC Criteria: July 5, 2006
• First Posted (ESTIMATE): July 7, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): April 21, 2014
• Last Update Submitted That Met QC Criteria: April 1, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: ALS; amyotrophic lateral sclerosis; ceftriaxone; motor neurons; cephalosporin antibiotic
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Anti-Infective Agents; Anti-Bacterial Agents; Ceftriaxone
• Other Study ID Numbers: U01NS049640-02 (NIH); NINDS (OTHER: NINDS); NINDS CRC (OTHER: NINDS Clinical Research Collaboration)