ALS, Amyotrophic Lateral Sclerosis
Conditions
Keywords
amyotrophic lateral sclerosis, ALS, ceftriaxone, cephalosporin antibiotic, motor neurons
Brief summary
The purpose of the study is to evaluate the safety and efficacy of ceftriaxone treatment in amyotrophic lateral sclerosis (ALS).
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.
Interventions
DRUGceftriaxone
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.
OTHERplacebo
an inactive substance
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Canada, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 340 |
| 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. | 173 |
| Total | 513 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 168 | 86 |
| Overall Study | Lost to Follow-up | 5 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 9 |
Baseline characteristics
| Characteristic | Total | Placebo | Ceftriaxone |
|---|---|---|---|
| Age, Continuous Age at Screening | 55.4 years STANDARD_DEVIATION 10.4 | 54.8 years STANDARD_DEVIATION 10.3 | 55.6 years STANDARD_DEVIATION 10.4 |
| ALS Family History Familial History of ALS | 34 participants | 8 participants | 26 participants |
| ALS Family History No Known Familial History of ALS | 468 participants | 161 participants | 307 participants |
| ALS Family History Unknown | 11 participants | 4 participants | 7 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 6 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 485 Participants | 165 Participants | 320 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 483 Participants | 163 Participants | 320 Participants |
| Region of Enrollment Canada | 69 participants | 22 participants | 47 participants |
| Region of Enrollment United States | 444 participants | 151 participants | 293 participants |
| Riluzole Use Not on Riluzole | 136 participants | 45 participants | 91 participants |
| Riluzole Use On Riluzole | 377 participants | 128 participants | 249 participants |
| Sex: Female, Male Female | 203 Participants | 72 Participants | 131 Participants |
| Sex: Female, Male Male | 310 Participants | 101 Participants | 209 Participants |
| Site of Onset Both | 9 participants | 1 participants | 8 participants |
| Site of Onset Bulbar | 110 participants | 35 participants | 75 participants |
| Site of Onset Limb | 394 participants | 137 participants | 257 participants |
| Time to Screening Years from Diagnosis to Screening | 0.57 years STANDARD_DEVIATION 0.49 | 0.58 years STANDARD_DEVIATION 0.49 | 0.56 years STANDARD_DEVIATION 0.49 |
| Time to Screening Years from Symptom Onset to Diagnosis | 0.92 years STANDARD_DEVIATION 0.56 | 0.92 years STANDARD_DEVIATION 0.58 | 0.93 years STANDARD_DEVIATION 0.55 |
| Time to Screening Years from Symptom Onset to Screening | 1.49 years STANDARD_DEVIATION 0.68 | 1.50 years STANDARD_DEVIATION 0.67 | 1.49 years STANDARD_DEVIATION 0.68 |
| Vital Capacity Percent Predicted | 89.0 percent predicted based on age and heigh STANDARD_DEVIATION 17.3 | 91.1 percent predicted based on age and heigh STANDARD_DEVIATION 18.4 | 87.9 percent predicted based on age and heigh STANDARD_DEVIATION 16.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 331 / 340 | 153 / 173 |
| serious Total, serious adverse events | 276 / 340 | 125 / 173 |
Outcome results
Primary
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.
Time frame: Every 8 weeks for one year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ceftriaxone | Change From Baseline in ALS Functional Rating Scale, Revised (ALSFRS-R) at One Year | -1.1311 units on a scale per 8 weeks | Standard Error 0.04395 |
| Placebo | Change From Baseline in ALS Functional Rating Scale, Revised (ALSFRS-R) at One Year | -1.2208 units on a scale per 8 weeks | Standard Error 0.06177 |
Primary
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).
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceftriaxone | Survival | 664 days |
| Placebo | Survival | 581 days |
Secondary
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.
Time frame: Every 12 weeks for one Year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ceftriaxone | Change From Baseline in Evaluation of Multiple Lower Extremity Muscles Using Hand Held Dynamometry at One Year | -4.1530 Percent change per 12 weeks | Standard Error 0.2591 |
| Placebo | Change From Baseline in Evaluation of Multiple Lower Extremity Muscles Using Hand Held Dynamometry at One Year | -4.4807 Percent change per 12 weeks | Standard Error 0.3625 |
Secondary
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.
Time frame: Every 12 weeks for one Year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ceftriaxone | Change From Baseline in Evaluation of Multiple Upper Extremity Muscles Using Hand Held Dynamometry at One Year | -5.2735 Percent change per 12 weeks | Standard Error 0.2178 |
| Placebo | Change From Baseline in Evaluation of Multiple Upper Extremity Muscles Using Hand Held Dynamometry at One Year | -5.5526 Percent change per 12 weeks | Standard Error 0.304 |
Secondary
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.
Time frame: Every 12 weeks for one Year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ceftriaxone | Change From Baseline in the ALS-Specific Quality of Life Scale (ALSQOL) at One Year | -3.5084 units on a scale per 12 weeks | Standard Error 0.3297 |
| Placebo | Change From Baseline in the ALS-Specific Quality of Life Scale (ALSQOL) at One Year | -3.4401 units on a scale per 12 weeks | Standard Error 0.4629 |
Secondary
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.
Time frame: Every 12 weeks for one Year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ceftriaxone | Change in % Vital Capacity From Screening to One Year | -2.772 percent change in VC per 12 weeks | Standard Error 0.1417 |
| Placebo | Change in % Vital Capacity From Screening to One Year | -3.0826 percent change in VC per 12 weeks | Standard Error 0.197 |