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Clinical Trial Ceftriaxone in Subjects With ALS

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ClinicalTrials.gov Identifier: NCT00349622
Recruitment Status : Completed
First Posted : July 7, 2006
Results First Posted : April 1, 2014
Last Update Posted : April 21, 2014
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Merit E. Cudkowicz, MD, Massachusetts General Hospital

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions: Amyotrophic Lateral Sclerosis
ALS
Interventions: Drug: ceftriaxone
Other: placebo

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Ceftriaxone is approved by the U.S. Food and Drug Administration (FDA) for treating bacterial infections but not for treating ALS. Subjects with ALS were enrolled in 58 institutions across in the US and Canada.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants were randomly assigned to receive treatment with ceftriaxone or placebo for at least 12 months. Two thirds of participants received ceftriaxone and one third received placebo. This is a blinded study, so neither participants nor study staff knew which treatment a participant is receiving.

Reporting Groups
  Description
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.

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.


Participant Flow:   Overall Study
    Ceftriaxone   Placebo
STARTED   340   173 
COMPLETED   162   77 
NOT COMPLETED   178   96 
Death                168                86 
Lost to Follow-up                5                1 
Withdrawal by Subject                5                9 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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.

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.

Total Total of all reporting groups

Baseline Measures
   Ceftriaxone   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 340   173   513 
Age 
[Units: Years]
Mean (Standard Deviation)
     
Age at Screening   55.6  (10.4)   54.8  (10.3)   55.4  (10.4) 
Gender 
[Units: Participants]
     
Female   131   72   203 
Male   209   101   310 
Ethnicity (NIH/OMB) 
[Units: Participants]
     
Hispanic or Latino   17   6   23 
Not Hispanic or Latino   320   165   485 
Unknown or Not Reported   3   2   5 
Race (NIH/OMB) 
[Units: Participants]
     
American Indian or Alaska Native   2   0   2 
Asian   6   5   11 
Native Hawaiian or Other Pacific Islander   1   0   1 
Black or African American   8   3   11 
White   320   163   483 
More than one race   2   0   2 
Unknown or Not Reported   1   2   3 
Region of Enrollment 
[Units: Participants]
     
United States   293   151   444 
Canada   47   22   69 
ALS Family History [1] 
[Units: Participants]
     
Familial History of ALS   26   8   34 
No Known Familial History of ALS   307   161   468 
Unknown   7   4   11 
[1] Subjects were asked at screening whether or not they have a familial history of ALS.
Site of Onset [1] 
[Units: Participants]
     
Limb   257   137   394 
Bulbar   75   35   110 
Both   8   1   9 
[1] Indicates region of first symptoms
Riluzole Use [1] 
[Units: Participants]
     
On Riluzole   249   128   377 
Not on Riluzole   91   45   136 
[1] At the screening visit, subjects were asked whether or not they were taking a continuous dose of riluzole.
Vital Capacity Percent Predicted [1] 
[Units: Percent predicted based on age and heigh]
Mean (Standard Deviation)
 87.9  (16.6)   91.1  (18.4)   89.0  (17.3) 
[1] The vital capacity (lung capacity) for each subject was measured at screening.
Time to Screening 
[Units: Years]
Mean (Standard Deviation)
     
Years from Symptom Onset to Screening   1.49  (0.68)   1.50  (0.67)   1.49  (0.68) 
Years from Diagnosis to Screening   0.56  (0.49)   0.58  (0.49)   0.57  (0.49) 
Years from Symptom Onset to Diagnosis   0.93  (0.55)   0.92  (0.58)   0.92  (0.56) 


  Outcome Measures

1.  Primary:   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) ]

2.  Primary:   Change From Baseline in ALS Functional Rating Scale, Revised (ALSFRS-R) at One Year   [ Time Frame: Every 8 weeks for one year ]

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

4.  Secondary:   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 ]

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

6.  Secondary:   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 ]


  Serious Adverse Events


  Other Adverse Events

Time Frame Adverse Events were systematically assessed by study investigators at each study visit from the screening visit until 30 days after permanent study drug discontinuation. The total amount of time per subject varies by length of subject participation.
Additional Description Adverse Events were systematically assessed by study investigators at each study visit from the screening visit until 30 days after permanent study drug discontinuation.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
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.

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 Adverse Events
    Ceftriaxone   Placebo
Total, Other (not including serious) Adverse Events     
# participants affected / at risk   331/340 (97.35%)   153/173 (88.44%) 
Blood and lymphatic system disorders     
Lymphopenia † 1     
# participants affected / at risk   20/340 (5.88%)   4/173 (2.31%) 
# events   24   6 
Gastrointestinal disorders     
Diarrhea † 1     
# participants affected / at risk   152/340 (44.71%)   41/173 (23.70%) 
# events   220   51 
Constipation † 1     
# participants affected / at risk   66/340 (19.41%)   30/173 (17.34%) 
# events   76   34 
Nausea † 1     
# participants affected / at risk   64/340 (18.82%)   28/173 (16.18%) 
# events   115   39 
Dysphagia, (difficult swallowing) † 1     
# participants affected / at risk   35/340 (10.29%)   17/173 (9.83%) 
# events   38   17 
Gastrointestinal - Other † 1     
# participants affected / at risk   36/340 (10.59%)   12/173 (6.94%) 
# events   41   16 
Heartburn/Dyspepsia † 1     
# participants affected / at risk   24/340 (7.06%)   12/173 (6.94%) 
# events   26   14 
Vomiting † 1     
# participants affected / at risk   24/340 (7.06%)   10/173 (5.78%) 
# events   33   13 
General disorders     
Catheter Exit Site Reaction † 2 [1]     
# participants affected / at risk   98/340 (28.82%)   45/173 (26.01%) 
# events   143   69 
Pain: Abdomen NOS † 1     
# participants affected / at risk   75/340 (22.06%)   16/173 (9.25%) 
# events   114   17 
Edema: Limb † 1     
# participants affected / at risk   54/340 (15.88%)   22/173 (12.72%) 
# events   68   25 
Fatigue (asthenia, lethargy, malaise) † 1     
# participants affected / at risk   41/340 (12.06%)   24/173 (13.87%) 
# events   44   26 
Pain: Neck † 1     
# participants affected / at risk   34/340 (10.00%)   15/173 (8.67%) 
# events   37   17 
Fever (absence of neutropenia, where neutropenia is AGC <1.0x10e9/L) † 1     
# participants affected / at risk   27/340 (7.94%)   12/173 (6.94%) 
# events   28   15 
Line break/tear † 1 [2]     
# participants affected / at risk   19/340 (5.59%)   11/173 (6.36%) 
# events   21   12 
Pain - Other † 1     
# participants affected / at risk   18/340 (5.29%)   12/173 (6.94%) 
# events   26   13 
Hepatobiliary disorders     
Cholelithiasis † 1     
# participants affected / at risk   158/340 (46.47%)   5/173 (2.89%) 
# events   193   5 
Biliary Sludge † 1     
# participants affected / at risk   100/340 (29.41%)   12/173 (6.94%) 
# events   110   12 
Hepatobiliary - Other † 1     
# participants affected / at risk   20/340 (5.88%)   5/173 (2.89%) 
# events   25   6 
Immune system disorders     
Allergic reaction/hypersensitivity (including drug fever) † 1     
# participants affected / at risk   19/340 (5.59%)   7/173 (4.05%) 
# events   25   7 
Infections and infestations     
Infection - Other † 1     
# participants affected / at risk   42/340 (12.35%)   15/173 (8.67%) 
# events   64   18 
Infection with normal ANC or grade 1 or 2 neutrophils: Urinary Tract NOS † 1     
# participants affected / at risk   25/340 (7.35%)   17/173 (9.83%) 
# events   29   24 
Infection with unknown ANC: Upper airway NOS † 1     
# participants affected / at risk   20/340 (5.88%)   9/173 (5.20%) 
# events   34   10 
Infection with unkown ANC: Urinary tract NOS † 1     
# participants affected / at risk   17/340 (5.00%)   11/173 (6.36%) 
# events   18   15 
Injury, poisoning and procedural complications     
Bruising (in absence of grade 3 or 4 thrombocytopenia) † 1     
# participants affected / at risk   24/340 (7.06%)   10/173 (5.78%) 
# events   44   15 
Fracture † 1     
# participants affected / at risk   24/340 (7.06%)   10/173 (5.78%) 
# events   29   11 
Investigations     
ALT SGPT (serum glutamic pyruvic transaminase) † 1     
# participants affected / at risk   32/340 (9.41%)   5/173 (2.89%) 
# events   42   6 
Neutrophils/granulocytes (ANC/AGC) † 1     
# participants affected / at risk   30/340 (8.82%)   2/173 (1.16%) 
# events   41   2 
Metabolic/Laboratory † 1     
# participants affected / at risk   18/340 (5.29%)   13/173 (7.51%) 
# events   22   20 
AST SGOT (serum glutamic oxaloacetic transaminase) † 1     
# participants affected / at risk   23/340 (6.76%)   4/173 (2.31%) 
# events   27   5 
Weight loss † 1     
# participants affected / at risk   15/340 (4.41%)   11/173 (6.36%) 
# events   16   11 
Musculoskeletal and connective tissue disorders     
Muscle weakness, generalized or specific area (not due to neuropathy): Extremity-lower † 1     
# participants affected / at risk   46/340 (13.53%)   26/173 (15.03%) 
# events   61   30 
Pain: Back † 1     
# participants affected / at risk   53/340 (15.59%)   17/173 (9.83%) 
# events   59   22 
Pain: Joint † 1     
# participants affected / at risk   47/340 (13.82%)   19/173 (10.98%) 
# events   62   24 
Musculoskeletal - Other † 1     
# participants affected / at risk   45/340 (13.24%)   17/173 (9.83%) 
# events   57   24 
Muscle weakness, generalized or specific area (not due to neuropathy): Extremity-upper † 1     
# participants affected / at risk   39/340 (11.47%)   19/173 (10.98%) 
# events   48   22 
Pain: Extremity-limb † 1     
# participants affected / at risk   38/340 (11.18%)   10/173 (5.78%) 
# events   53   12 
Pain: chest wall † 1     
# participants affected / at risk   25/340 (7.35%)   12/173 (6.94%) 
# events   29   17 
Muscle weakness, generalized of specific area (not due to neuropathy): Whole body/generalized † 1     
# participants affected / at risk   27/340 (7.94%)   8/173 (4.62%) 
# events   29   9 
Nervous system disorders     
Neurology - Other † 1     
# participants affected / at risk   97/340 (28.53%)   52/173 (30.06%) 
# events   183   92 
Pain: head/headache † 1     
# participants affected / at risk   53/340 (15.59%)   32/173 (18.50%) 
# events   79   37 
Drooling † 1     
# participants affected / at risk   30/340 (8.82%)   16/173 (9.25%) 
# events   30   16 
Dizziness † 1     
# participants affected / at risk   25/340 (7.35%)   15/173 (8.67%) 
# events   32   18 
Voice changes/dysarthria (e.g., hoarseness, loss or alteration of voice, laryngitis) † 1     
# participants affected / at risk   25/340 (7.35%)   11/173 (6.36%) 
# events   27   11 
Psychiatric disorders     
Insomnia † 1     
# participants affected / at risk   40/340 (11.76%)   19/173 (10.98%) 
# events   42   19 
Mood alteration: Depression † 1     
# participants affected / at risk   33/340 (9.71%)   21/173 (12.14%) 
# events   33   21 
Mood alteration: Anxiety † 1     
# participants affected / at risk   34/340 (10.00%)   14/173 (8.09%) 
# events   38   14 
Renal and urinary disorders     
Renal/Genitourinary - Other † 1     
# participants affected / at risk   37/340 (10.88%)   13/173 (7.51%) 
# events   57   20 
Urinary frquency/urgency † 1     
# participants affected / at risk   20/340 (5.88%)   11/173 (6.36%) 
# events   21   13 
Respiratory, thoracic and mediastinal disorders     
Dyspnea † 1     
# participants affected / at risk   32/340 (9.41%)   24/173 (13.87%) 
# events   38   26 
Pulmonary - Other † 1     
# participants affected / at risk   46/340 (13.53%)   20/173 (11.56%) 
# events   57   25 
Cough † 1     
# participants affected / at risk   41/340 (12.06%)   12/173 (6.94%) 
# events   48   15 
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip) † 1     
# participants affected / at risk   23/340 (6.76%)   14/173 (8.09%) 
# events   25   16 
Skin and subcutaneous tissue disorders     
Rash/desquamation † 1     
# participants affected / at risk   92/340 (27.06%)   29/173 (16.76%) 
# events   122   36 
Dermatology/Skin - Other † 1     
# participants affected / at risk   57/340 (16.76%)   21/173 (12.14%) 
# events   78   25 
Pruritis/itching † 1     
# participants affected / at risk   33/340 (9.71%)   14/173 (8.09%) 
# events   41   14 
Vascular disorders     
Hypertension † 1     
# participants affected / at risk   16/340 (4.71%)   9/173 (5.20%) 
# events   22   9 
Events were collected by systematic assessment
1 Term from vocabulary, CTCAE (3.0)
2 Term from vocabulary, CTCAE (3.0) suppl.
[1] "Catheter Exit Site Reaction" was added to the trial database as an adverse event potentially related to the central venous catheter that all subjects received as part of the study.
[2] "Line break/tear" was added to the trial database as an adverse event potentially related to the central venous catheter that all subjects received as part of the study.



  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Merit Cudkowicz
Organization: MGH
phone: 617-724-1873
e-mail: mcudkowicz@partners.org


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

Responsible Party: Merit E. Cudkowicz, MD, 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 )
U01NS049640-02 ( U.S. NIH Grant/Contract )
NINDS CRC ( Other Identifier: NINDS Clinical Research Collaboration )
First Submitted: July 5, 2006
First Posted: July 7, 2006
Results First Submitted: October 23, 2013
Results First Posted: April 1, 2014
Last Update Posted: April 21, 2014