Clinical Trial Ceftriaxone in Subjects With ALS

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00349622
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 513
• Locations: 58
• Arms: 2
• Duration (Months): 76.1
• Patients Per Site: 8.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

• Study Type: Interventional
• 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: Jul 1, 2006
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

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

Primary Outcome Measures

1. Survival [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 [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 [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 [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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Neurological Associates	Phoenix	Arizona	United States	85018
2	University of California, Davis	Davis	California	United States	95819
3	University of California, San Francisco- Fresno	Fresno	California	United States	93701
4	Loma Linda University School of Medicine (CA)	Loma Linda	California	United States	92354
5	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
6	University of California, Los Angeles	Los Angeles	California	United States	90095
7	University of California, Irvine - MDA ALS Neuromuscular Center	Orange	California	United States	92868
8	California Pacific Medical Center	San Francisco	California	United States	94115
9	University of California, San Francisco	San Francisco	California	United States	94117
10	University of Colorado Health Sciences Center	Aurora	Colorado	United States	80045
11	Hospital for Special Care	New Britain	Connecticut	United States	06053
12	George Washington University	Washington	District of Columbia	United States	20037
13	Mayo Clinic Jacksonville	Jacksonville	Florida	United States	32224
14	University of Miami School of Medicine	Miami	Florida	United States	33136
15	ALS Center at Emory University	Atlanta	Georgia	United States	30322
16	Medical College of Georgia	Augusta	Georgia	United States	30912
17	Northwestern University Medical School	Chicago	Illinois	United States	60611
18	Indiana University (Regenstrief Health Center)	Indianapolis	Indiana	United States	46202
19	University of Kansas Medical Center	Kansas City	Kansas	United States	66161
20	University of Kentucky Medical Center	Lexington	Kentucky	United States	40536
21	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
22	Lahey Clinic	Burlington	Massachusetts	United States	01805
23	Henry Ford Health System	Detroit	Michigan	United States	48202
24	Saint Mary's Healthcare	Grand Rapids	Michigan	United States	49503
25	Hennepin County Medical Center (Berman Center)	Minneapolis	Minnesota	United States	55404
26	St. Louis University	St. Louis	Missouri	United States	63104
27	Washington University	St. Louis	Missouri	United States	63110
28	Bryan LGH Medical Center (University of Nebraska)	Lincoln	Nebraska	United States	68506
29	UMDNJ- Robert Wood Johnson School of Medicine	New Brunswick	New Jersey	United States	08901
30	Albany Medical Center	Albany	New York	United States	12208
31	Beth Israel Medical Center (NY)	New York	New York	United States	10003
32	Cornell Medical Center	New York	New York	United States	10021
33	Columbia University	New York	New York	United States	10032
34	SUNY Upstate Medical University	Syracuse	New York	United States	13210
35	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
36	Wake Forest University School of Medicine	Winston-Salem	North Carolina	United States	27157
37	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
38	Ohio State University	Columbus	Ohio	United States	43210
39	Oregon Clinic (Providence Clinic)	Portland	Oregon	United States	97213
40	Pennsylvania State University, Hershey Medical Center	Hershey	Pennsylvania	United States	17033
41	Drexel University College of Medicine (Hahnemann Campus)	Philadelphia	Pennsylvania	United States	19107
42	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19107
43	Allegheny Hospital	Pittsburgh	Pennsylvania	United States	15212
44	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
45	Medical University of South Carolina	Charleston	South Carolina	United States	29403
46	Vanderbilt University	Nashville	Tennessee	United States	37232
47	Texas Neurology	Dallas	Texas	United States	75214
48	Methodist Neurological Institute	Houston	Texas	United States	77030
49	University of Utah Health Sciences Center	Salt Lake City	Utah	United States	84132
50	University of Virginia	Charlottesville	Virginia	United States	22908
51	University of Calgary	Calgary	Alberta	Canada	T2N 4Z6
52	Univeristy of Alberta ALS Clinic	Edmonton	Alberta	Canada	T6G 2B7
53	Dalhousie University	Halifax	Nova Scotia	Canada
54	London Health Sciences Center, University Campus	London	Ontario	Canada
55	University of Toronto	Toronto	Ontario	Canada
56	CHUM (Centre Hospitalier de l'Université de Montréal), Notre-Dame Hospital	Montreal	Quebec	Canada
57	Montreal Neurological Institute (McGill University)	Montreal	Quebec	Canada
58	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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Northeast ALS Consortium website

Publications

None provided.

• Responsible Party: Merit E. Cudkowicz, MD, Professor of Neurology, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00349622
• Other Study ID Numbers: U01NS049640-02; NINDS; U01NS049640-02; NINDS CRC
• First Posted: Jul 7, 2006
• Last Update Posted: Apr 21, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Merit E. Cudkowicz, MD, Professor of Neurology, Massachusetts General Hospital: amyotrophic lateral sclerosis; ALS; ceftriaxone; cephalosporin antibiotic; motor neurons
• Additional relevant MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Ceftriaxone

Study Results

Participant Flow

Recruitment Details	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 Detail	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.

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	340	173
COMPLETED	162	77
NOT COMPLETED	178	96

Baseline Characteristics

Arm/Group Title	Ceftriaxone	Placebo	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	340	173	513
Age (years) [Mean (Standard Deviation) ]
Age at Screening	55.6 (10.4)	54.8 (10.3)	55.4 (10.4)
Sex: Female, Male (Count of Participants)
Female	131 38.5%	72 41.6%	203 39.6%
Male	209 61.5%	101 58.4%	310 60.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	17 5%	6 3.5%	23 4.5%
Not Hispanic or Latino	320 94.1%	165 95.4%	485 94.5%
Unknown or Not Reported	3 0.9%	2 1.2%	5 1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.6%	0 0%	2 0.4%
Asian	6 1.8%	5 2.9%	11 2.1%
Native Hawaiian or Other Pacific Islander	1 0.3%	0 0%	1 0.2%
Black or African American	8 2.4%	3 1.7%	11 2.1%
White	320 94.1%	163 94.2%	483 94.2%
More than one race	2 0.6%	0 0%	2 0.4%
Unknown or Not Reported	1 0.3%	2 1.2%	3 0.6%
Region of Enrollment (participants) [Number]
United States	293 86.2%	151 87.3%	444 86.5%
Canada	47 13.8%	22 12.7%	69 13.5%
ALS Family History (participants) [Number]
Familial History of ALS	26 7.6%	8 4.6%	34 6.6%
No Known Familial History of ALS	307 90.3%	161 93.1%	468 91.2%
Unknown	7 2.1%	4 2.3%	11 2.1%
Site of Onset (participants) [Number]
Limb	257 75.6%	137 79.2%	394 76.8%
Bulbar	75 22.1%	35 20.2%	110 21.4%
Both	8 2.4%	1 0.6%	9 1.8%
Riluzole Use (participants) [Number]
On Riluzole	249 73.2%	128 74%	377 73.5%
Not on Riluzole	91 26.8%	45 26%	136 26.5%
Vital Capacity Percent Predicted (percent predicted based on age and heigh) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent predicted based on age and heigh]	87.9 (16.6)	91.1 (18.4)	89.0 (17.3)
Time to Screening (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 Outcome

Title	Survival
Description	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).
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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	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.	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.
Measure Participants	340	173
Median (95% Confidence Interval) [days]	664	581

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	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.	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.
Measure Participants	340	173
Mean (Standard Error) [units on a scale per 8 weeks]	-1.1311 (0.04395)	-1.2208 (0.06177)

3. Secondary Outcome

Title	Change in % Vital Capacity From Screening to One Year
Description	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.
Time Frame	Every 12 weeks for one Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	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.	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.
Measure Participants	340	173
Mean (Standard Error) [percent change in VC per 12 weeks]	-2.772 (0.1417)	-3.0826 (0.1970)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	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.	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.
Measure Participants	340	173
Mean (Standard Error) [Percent change per 12 weeks]	-5.2735 (0.2178)	-5.5526 (0.3040)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	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.	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.
Measure Participants	340	173
Mean (Standard Error) [units on a scale per 12 weeks]	-3.5084 (0.3297)	-3.4401 (0.4629)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftriaxone	Placebo
Arm/Group Description	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.	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.
Measure Participants	340	173
Mean (Standard Error) [Percent change per 12 weeks]	-4.1530 (0.2591)	-4.4807 (0.3625)

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.
Adverse Event Reporting 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.
Arm/Group Title	Ceftriaxone		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Ceftriaxone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ceftriaxone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	276/340 (81.2%)		125/173 (72.3%)
Blood and lymphatic system disorders
Blood/Bone Marrow - Other	1/340 (0.3%)	1	1/173 (0.6%)	1
Febrile neutropenia (fever of unknown origin w/out clinically/microbiologically documented infection	1/340 (0.3%)	1	0/173 (0%)	0
Cardiac disorders
Cardiac ischemia/infarction	6/340 (1.8%)	8	0/173 (0%)	0
Cardiac/Arrhythmia Other	1/340 (0.3%)	1	0/173 (0%)	0
Left ventricular diastolic dysfunction	1/340 (0.3%)	1	0/173 (0%)	0
Supraventricular and nodal arrhythmias: Sinus bradycardia	0/340 (0%)	0	1/173 (0.6%)	1
Ventricular arrhythmia: Ventricular tachycardia	1/340 (0.3%)	1	0/173 (0%)	0
Gastrointestinal disorders
Dysphagia	4/340 (1.2%)	4	2/173 (1.2%)	2
Pain: Abdomen NOS	3/340 (0.9%)	3	1/173 (0.6%)	1
Constipation	1/340 (0.3%)	1	2/173 (1.2%)	2
Diarrhea	3/340 (0.9%)	3	0/173 (0%)	0
Gastrointestinal - Other	0/340 (0%)	0	3/173 (1.7%)	3
Colitis	1/340 (0.3%)	1	0/173 (0%)	0
Gastritis (including bile reflux gastritis)	1/340 (0.3%)	1	0/173 (0%)	0
Heartburn/Dyspepsia	0/340 (0%)	0	1/173 (0.6%)	1
Hemmorhage, GI: Lower GI NOS	0/340 (0%)	0	1/173 (0.6%)	1
Hemmorhage, GI: Stomach	1/340 (0.3%)	1	0/173 (0%)	0
Obstruction, GI: Ileum	1/340 (0.3%)	2	0/173 (0%)	0
Obstruction, GI: Stomach	1/340 (0.3%)	1	0/173 (0%)	0
Pain: Stomach	1/340 (0.3%)	1	0/173 (0%)	0
Vomiting	1/340 (0.3%)	1	0/173 (0%)	0
Pancreatitis	7/340 (2.1%)	7	0/173 (0%)	0
General disorders
Death not associated with CTCAE Term: Disease Progression NOS	4/340 (1.2%)	4	4/173 (2.3%)	4
Death not associated with CTCAE term: Death NOS	3/340 (0.9%)	3	1/173 (0.6%)	1
Fever (in the absense of neutropenia, where neutropenia is defined as AGC<1.0 x 10e9/L)	2/340 (0.6%)	2	2/173 (1.2%)	2
Death not associated with CTCAE Term: Sudden Death	2/340 (0.6%)	2	0/173 (0%)	0
Line break/tear	2/340 (0.6%)	2	0/173 (0%)	0
Line Displacement	1/340 (0.3%)	1	1/173 (0.6%)	1
Line Thrombosis	1/340 (0.3%)	1	0/173 (0%)	0
Pain: Chest/thorax NOS	1/340 (0.3%)	1	0/173 (0%)	0
Hepatobiliary disorders
Cholelithiasis	28/340 (8.2%)	30	0/173 (0%)	0
Cholecystitis	5/340 (1.5%)	5	0/173 (0%)	0
Biliary Sludge	1/340 (0.3%)	1	0/173 (0%)	0
Hepatobiliary - Other	1/340 (0.3%)	1	0/173 (0%)	0
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	4/340 (1.2%)	4	0/173 (0%)	0
Infections and infestations
Infections with unknown ANC: Lung (pneumonia)	13/340 (3.8%)	17	12/173 (6.9%)	14
Line Infection	3/340 (0.9%)	4	9/173 (5.2%)	11
Infection with normal ANC or grade 1 or 2 neutrophils: Lung (pneumonia)	4/340 (1.2%)	4	2/173 (1.2%)	2
Catheter Exit Site Infection	2/340 (0.6%)	2	3/173 (1.7%)	3
Infection with normal ANC or grade 1 or 2 neutrophils: Blood	1/340 (0.3%)	1	3/173 (1.7%)	3
Infections with unknown ANC: Blood	1/340 (0.3%)	1	3/173 (1.7%)	3
Colitis infectious (Clostridium difficile)	3/340 (0.9%)	3	0/173 (0%)	0
Infection with unknown ANC: Urinary tract NOS	0/340 (0%)	0	3/173 (1.7%)	3
Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia: Lung	0/340 (0%)	0	1/173 (0.6%)	1
Infection - Other	1/340 (0.3%)	1	0/173 (0%)	0
Infection with normal ANC or grade 1 or 2 neutrophils: Bronchus	1/340 (0.3%)	1	0/173 (0%)	0
Infection with normal ANC or grade 1 or 2 neutrophils: Vagina	1/340 (0.3%)	1	0/173 (0%)	0
Infection with unknown ANC: Abdomen NOS	1/340 (0.3%)	2	0/173 (0%)	0
Infection with unknown ANC: Catheter-related	0/340 (0%)	0	1/173 (0.6%)	1
Infection with unknown ANC: Foreign body (e.g. graft, implant, prosthesis, stent)	0/340 (0%)	0	1/173 (0.6%)	1
Infection with unknown ANC: Soft tissue NOS	0/340 (0%)	0	1/173 (0.6%)	1
Injury, poisoning and procedural complications
Fracture	3/340 (0.9%)	3	3/173 (1.7%)	3
Hemmorhage, pulmonary/Upper Respiratory: Stoma	1/340 (0.3%)	1	0/173 (0%)	0
Hemorrhage/bleeding associated with surgery, intraoperative or postoperative	1/340 (0.3%)	1	0/173 (0%)	0
Leak (including anastomotic), GI: Stomach	0/340 (0%)	0	1/173 (0.6%)	1
Investigations
FEV (1)	0/340 (0%)	0	1/173 (0.6%)	1
Metabolic/Laboratory - Other	1/340 (0.3%)	1	0/173 (0%)	0
Neutrophils/granulocytes (ANC/AGC)	1/340 (0.3%)	1	0/173 (0%)	0
Potassium, serum-low (hypokalemia)	1/340 (0.3%)	1	0/173 (0%)	0
Weight loss	0/340 (0%)	0	1/173 (0.6%)	1
Metabolism and nutrition disorders
Dehydration	2/340 (0.6%)	2	0/173 (0%)	0
Musculoskeletal and connective tissue disorders
Joint-function	2/340 (0.6%)	2	1/173 (0.6%)	1
Musculoskeletal - Other	2/340 (0.6%)	2	0/173 (0%)	0
Pain: chest wall	1/340 (0.3%)	1	0/173 (0%)	0
Nervous system disorders
CNS cerebrovascular ischemia	1/340 (0.3%)	1	1/173 (0.6%)	1
Neurology - Other	1/340 (0.3%)	1	1/173 (0.6%)	1
Somnolence/depressed level of consciousness	1/340 (0.3%)	1	1/173 (0.6%)	1
Cognitive disturbance	1/340 (0.3%)	1	0/173 (0%)	0
Hemmorhage, CNS	0/340 (0%)	0	1/173 (0.6%)	1
Pain: Head/headache	1/340 (0.3%)	1	0/173 (0%)	0
Psychiatric disorders
Mood alteration: Depression	1/340 (0.3%)	1	1/173 (0.6%)	1
Confusion	1/340 (0.3%)	1	0/173 (0%)	0
Mood alteration: Agitation	1/340 (0.3%)	1	0/173 (0%)	0
Mood alteration: Anxiety	1/340 (0.3%)	1	0/173 (0%)	0
Renal and urinary disorders
Renal/Genitourinary - Other	10/340 (2.9%)	10	1/173 (0.6%)	1
Renal failure	0/340 (0%)	0	1/173 (0.6%)	1
Stricture/stenosis (including anastomotic), GU: Ureter	0/340 (0%)	0	1/173 (0.6%)	1
Urinary retention (including nerogenic bladder)	1/340 (0.3%)	1	0/173 (0%)	0
Reproductive system and breast disorders
Sexual/Reproductive Function - Other	0/340 (0%)	0	1/173 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	74/340 (21.8%)	79	34/173 (19.7%)	35
Aspiration	6/340 (1.8%)	6	2/173 (1.2%)	2
Pulmonary - Other	4/340 (1.2%)	5	0/173 (0%)	0
Hypoxia	2/340 (0.6%)	2	0/173 (0%)	0
Obstruction/stenosis of airway: Larynx	1/340 (0.3%)	1	1/173 (0.6%)	1
Pneumonitis/pulmonary infiltrates	1/340 (0.3%)	1	1/173 (0.6%)	1
Pneumothorax	2/340 (0.6%)	2	0/173 (0%)	0
Atelectasis	1/340 (0.3%)	1	0/173 (0%)	0
Cough	1/340 (0.3%)	1	0/173 (0%)	0
Obstruction/stenosis of airway: Trachea	0/340 (0%)	0	1/173 (0.6%)	1
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other	1/340 (0.3%)	1	0/173 (0%)	0
Surgical and medical procedures
PEG Placement (outpatient)	4/340 (1.2%)	4	5/173 (2.9%)	6
Vascular disorders
Thrombosis/thrombus/embolism	20/340 (5.9%)	20	4/173 (2.3%)	4
Hematoma	2/340 (0.6%)	2	0/173 (0%)	0
Hypotension	0/340 (0%)	0	1/173 (0.6%)	1
Thrombosis/embolism (vascular access-related)	0/340 (0%)	0	1/173 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Ceftriaxone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	331/340 (97.4%)		153/173 (88.4%)
Blood and lymphatic system disorders
Lymphopenia	20/340 (5.9%)	24	4/173 (2.3%)	6
Gastrointestinal disorders
Diarrhea	152/340 (44.7%)	220	41/173 (23.7%)	51
Constipation	66/340 (19.4%)	76	30/173 (17.3%)	34
Nausea	64/340 (18.8%)	115	28/173 (16.2%)	39
Dysphagia, (difficult swallowing)	35/340 (10.3%)	38	17/173 (9.8%)	17
Gastrointestinal - Other	36/340 (10.6%)	41	12/173 (6.9%)	16
Heartburn/Dyspepsia	24/340 (7.1%)	26	12/173 (6.9%)	14
Vomiting	24/340 (7.1%)	33	10/173 (5.8%)	13
General disorders
Catheter Exit Site Reaction	98/340 (28.8%)	143	45/173 (26%)	69
Pain: Abdomen NOS	75/340 (22.1%)	114	16/173 (9.2%)	17
Edema: Limb	54/340 (15.9%)	68	22/173 (12.7%)	25
Fatigue (asthenia, lethargy, malaise)	41/340 (12.1%)	44	24/173 (13.9%)	26
Pain: Neck	34/340 (10%)	37	15/173 (8.7%)	17
Fever (absence of neutropenia, where neutropenia is AGC <1.0x10e9/L)	27/340 (7.9%)	28	12/173 (6.9%)	15
Line break/tear	19/340 (5.6%)	21	11/173 (6.4%)	12
Pain - Other	18/340 (5.3%)	26	12/173 (6.9%)	13
Hepatobiliary disorders
Cholelithiasis	158/340 (46.5%)	193	5/173 (2.9%)	5
Biliary Sludge	100/340 (29.4%)	110	12/173 (6.9%)	12
Hepatobiliary - Other	20/340 (5.9%)	25	5/173 (2.9%)	6
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	19/340 (5.6%)	25	7/173 (4%)	7
Infections and infestations
Infection - Other	42/340 (12.4%)	64	15/173 (8.7%)	18
Infection with normal ANC or grade 1 or 2 neutrophils: Urinary Tract NOS	25/340 (7.4%)	29	17/173 (9.8%)	24
Infection with unknown ANC: Upper airway NOS	20/340 (5.9%)	34	9/173 (5.2%)	10
Infection with unkown ANC: Urinary tract NOS	17/340 (5%)	18	11/173 (6.4%)	15
Injury, poisoning and procedural complications
Bruising (in absence of grade 3 or 4 thrombocytopenia)	24/340 (7.1%)	44	10/173 (5.8%)	15
Fracture	24/340 (7.1%)	29	10/173 (5.8%)	11
Investigations
ALT SGPT (serum glutamic pyruvic transaminase)	32/340 (9.4%)	42	5/173 (2.9%)	6
Neutrophils/granulocytes (ANC/AGC)	30/340 (8.8%)	41	2/173 (1.2%)	2
Metabolic/Laboratory	18/340 (5.3%)	22	13/173 (7.5%)	20
AST SGOT (serum glutamic oxaloacetic transaminase)	23/340 (6.8%)	27	4/173 (2.3%)	5
Weight loss	15/340 (4.4%)	16	11/173 (6.4%)	11
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy): Extremity-lower	46/340 (13.5%)	61	26/173 (15%)	30
Pain: Back	53/340 (15.6%)	59	17/173 (9.8%)	22
Pain: Joint	47/340 (13.8%)	62	19/173 (11%)	24
Musculoskeletal - Other	45/340 (13.2%)	57	17/173 (9.8%)	24
Muscle weakness, generalized or specific area (not due to neuropathy): Extremity-upper	39/340 (11.5%)	48	19/173 (11%)	22
Pain: Extremity-limb	38/340 (11.2%)	53	10/173 (5.8%)	12
Pain: chest wall	25/340 (7.4%)	29	12/173 (6.9%)	17
Muscle weakness, generalized of specific area (not due to neuropathy): Whole body/generalized	27/340 (7.9%)	29	8/173 (4.6%)	9
Nervous system disorders
Neurology - Other	97/340 (28.5%)	183	52/173 (30.1%)	92
Pain: head/headache	53/340 (15.6%)	79	32/173 (18.5%)	37
Drooling	30/340 (8.8%)	30	16/173 (9.2%)	16
Dizziness	25/340 (7.4%)	32	15/173 (8.7%)	18
Voice changes/dysarthria (e.g., hoarseness, loss or alteration of voice, laryngitis)	25/340 (7.4%)	27	11/173 (6.4%)	11
Psychiatric disorders
Insomnia	40/340 (11.8%)	42	19/173 (11%)	19
Mood alteration: Depression	33/340 (9.7%)	33	21/173 (12.1%)	21
Mood alteration: Anxiety	34/340 (10%)	38	14/173 (8.1%)	14
Renal and urinary disorders
Renal/Genitourinary - Other	37/340 (10.9%)	57	13/173 (7.5%)	20
Urinary frquency/urgency	20/340 (5.9%)	21	11/173 (6.4%)	13
Respiratory, thoracic and mediastinal disorders
Dyspnea	32/340 (9.4%)	38	24/173 (13.9%)	26
Pulmonary - Other	46/340 (13.5%)	57	20/173 (11.6%)	25
Cough	41/340 (12.1%)	48	12/173 (6.9%)	15
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	23/340 (6.8%)	25	14/173 (8.1%)	16
Skin and subcutaneous tissue disorders
Rash/desquamation	92/340 (27.1%)	122	29/173 (16.8%)	36
Dermatology/Skin - Other	57/340 (16.8%)	78	21/173 (12.1%)	25
Pruritis/itching	33/340 (9.7%)	41	14/173 (8.1%)	14
Vascular disorders
Hypertension	16/340 (4.7%)	22	9/173 (5.2%)	9

Limitations/Caveats

[Not Specified]

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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.