Amyotrophic Lateral Sclerosis
Conditions
Keywords
amyotrophic lateral sclerosis, ALS, progressive weakness, insulin-like growth factor-1, IGF-I, Myotrophin
Brief summary
The purpose of this multicenter study is to determine if insulin-like growth factor-1 (IGF-I) slows the progressive weakness in amyotrophic lateral sclerosis (ALS) patients. Study participants will be followed for 2 years once enrolled. They will receive either placebo or the active IGF-I. Examinations will take place at approximately 6-month intervals.
Detailed description
The objective of this trial was to determine whether IGF-1 (MyotrophinTM) slows progression of weakness in amyotrophic lateral sclerosis (ALS). Three hundred thirty patients with ALS from 20 medical centers participated in this double blind, placebo-controlled two-year study. Half the patients received IGF-1 and the other half received placebo. The drug will be administered twice a day. ALS is a neurodegenerative disorder that causes progressive muscle weakness and loss of motor neurons. IGF-1 is a neurotrophic factor essential for normal development of the nervous system and shows protection of motor neurons in animal models and cell culture systems. It is thought to block cell death pathways and promote muscle re-innervation and axonal growth and regeneration.
Interventions
DRUGInsulin like growth factor, type 1
0.05 mg per kg body weight given subcutaneously twice daily
DRUGPlacebo
The placebo represented the inert suspension vehicle for the IGF-1. It was given as equal volume as the active drug based upon body weight, subcutaneously twice daily.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
ALS Association
Cephalon
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Patients entering this study: * Are between the ages of 18-80 years old. * Legal residents of the United States or Canada. * Have a history of a chronic onset of a progressive motor weakness of less than 24 months duration. * Fulfill El Escorial criteria of probable or definite ALS. * If female, are surgically sterile, two years postmenopausal, or if of child-bearing potential, must be using a medically acceptable method of birth control and agree to continue use of this method for the duration of the study. Acceptable methods include a barrier method with spermicide, oral contraceptives (normal doses are acceptable; low dose oral contraceptives or contraceptive implants must be used with a barrier method), intrauterine device (IUD), or abstinence. Have a negative pregnancy test. * Are able to comply with protocol requirements. * Can provide written informed consent. * Have a manual muscle testing score of less than 8. * Have a forced vital capacity by pulmonary function testing \*60% predicted.
Exclusion criteria
Patients entering this study will not: * Have any of the following conditions:renal disease (Creatine \> 2.0) or other active systemic disease * Have any clinically significant abnormalities on the prestudy laboratory evaluation, physical examination, ECG, chest x-ray or ophthalmologic exam. * Have any clinically significant medical condition (e.g., within six months of baseline, had myocardial infarction, angina pectoris, and/or congestive heart failure) that, in the opinion of the investigator, would compromise the safety of patient. * Have Type I or Type II diabetes. * Have a history of cancer including melanoma with the exception of localized skin cancers (with no evidence of metastasis, significant invasion, or re-occurrence within three years of baseline) and carcinoma in-situ of the cervix (women only). * Have used an investigational drug within 30 days of baseline visit. * Have had a tracheostomy. * Have a Beck's Depression Inventory score \* 12. * Have legal residency outside of the United States or Canada. * Be pregnant or breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change in Composite Manual Muscle Testing (MMT) Score | Baseline and 24 months | The primary outcome measure was the rate of change in the MMT score. MMT involved the examination of 34 muscle groups with standard positioning. The final MMT score represented an average of the 34 muscles examined, and ranged from 10 to 0(10 normal strength, 0 paralyzed). The individual muscle score was based on the medical research council (MRC) grading scale (1-5) modified to a 10 point system corresponding to the MRC modifications of plus and minus (5, 5-,4+,4,4-,3+,3, 3-,2,1,0; with 5 being normal strength and 0 paralyzed). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Alive and Tracheostomy-free at 24 Months | baseline to 24 months | Patients who elected to proceed to tracheostomy were assessed the month of their procedure. Subjects who continuously utilized non-invasive positive pressure ventilation for greater than 10 days were assessed as being ventilator-dependent on the first day they began continuous Non Invasive Positive Pressure Ventilation (NIPPV). All subjects were followed for the 24 month time period. |
| Rate of Change in ALS Functional Rating Scale. | Baseline and 24 months | The final secondary outcome measure was the rate of change in the ALS Functional Rating Scale (ALSFRS-r) score. The ALSFRS-r was completed at each visit (randomization and then at 3, 6, 12, 18 and 24 months post-randomization). This is a scale from 0 to 48 assessing functional impairment in 12 clinically relevant areas in ALS. Forty-eight is normal with full function and zero is total loss of function in all clinical functions. As with the MMT scores a score of 0 was imputed on the day of death. Analysis of the ALSFRS-r scores as a secondary outcome was performed in similar manner as MMT score. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Subjects recruited from 20 medical centers from June 2003 to August 2005.
Pre-assignment details
Patients were randomized and initiated on treatment at the time of enrollment.
Participants by arm
| Arm | Count |
|---|---|
| IGF-1 The IGF-1 arm was the active treatment group. They received 0.05 mg/kg body weight administered subcutaneously twice daily. | 167 |
| Placebo Placebo group received the equal volume (based on kg of body weight) of the inert suspension vehicle in which the IGF-1 was suspended. | 163 |
| Total | 330 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 17 | 11 |
Baseline characteristics
| Characteristic | Placebo | IGF-1 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 34 Participants | 32 Participants | 66 Participants |
| Age, Categorical Between 18 and 65 years | 129 Participants | 135 Participants | 264 Participants |
| Age Continuous | 54.8 years STANDARD_DEVIATION 11.2 | 53.9 years STANDARD_DEVIATION 12.2 | 54.4 years STANDARD_DEVIATION 11.7 |
| Region of Enrollment United States | 163 participants | 167 participants | 330 participants |
| Sex: Female, Male Female | 63 Participants | 57 Participants | 120 Participants |
| Sex: Female, Male Male | 100 Participants | 110 Participants | 210 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 103 / 167 | 92 / 163 |
| serious Total, serious adverse events | 18 / 167 | 12 / 163 |
Outcome results
Primary
Rate of Change in Composite Manual Muscle Testing (MMT) Score
The primary outcome measure was the rate of change in the MMT score. MMT involved the examination of 34 muscle groups with standard positioning. The final MMT score represented an average of the 34 muscles examined, and ranged from 10 to 0(10 normal strength, 0 paralyzed). The individual muscle score was based on the medical research council (MRC) grading scale (1-5) modified to a 10 point system corresponding to the MRC modifications of plus and minus (5, 5-,4+,4,4-,3+,3, 3-,2,1,0; with 5 being normal strength and 0 paralyzed).
Time frame: Baseline and 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IGF-1 | Rate of Change in Composite Manual Muscle Testing (MMT) Score | 0.44 MMT units per month | Standard Deviation 0.57 |
| Placebo | Rate of Change in Composite Manual Muscle Testing (MMT) Score | 0.39 MMT units per month | Standard Deviation 0.39 |
Comparison: Analysis of MMT was calculated as a ratio of change from baseline to last follow-up to time to duration until last follow-up. For the patients that died during the study period, the last follow-up time was considered as the time of death with a zero score for MMT measurement. Analysis was performed using intention to treat approach. Comparison of rate of change in MMT scores between the placebo and IGF-1 group was made using two sample t-test or Wilcoxon rank sum test as appropriate.p-value: 0.529Wilcoxon (Mann-Whitney)
Secondary
Number of Participants Alive and Tracheostomy-free at 24 Months
Patients who elected to proceed to tracheostomy were assessed the month of their procedure. Subjects who continuously utilized non-invasive positive pressure ventilation for greater than 10 days were assessed as being ventilator-dependent on the first day they began continuous Non Invasive Positive Pressure Ventilation (NIPPV). All subjects were followed for the 24 month time period.
Time frame: baseline to 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGF-1 | Number of Participants Alive and Tracheostomy-free at 24 Months | 93 participants |
| Placebo | Number of Participants Alive and Tracheostomy-free at 24 Months | 90 participants |
Comparison: Patients who elected to proceed to tracheostomy were assessed on the day of their procedure. Subjects who continuously utilized NIPPV for greater than 10 days were assessed as being ventilator-dependent on the first day they began continuous NIPPV. Survival between groups was compared using the Cox-proportional Hazards model.p-value: 0.41595% CI: [0.77, 1.4]Regression, Cox
Secondary
Rate of Change in ALS Functional Rating Scale.
The final secondary outcome measure was the rate of change in the ALS Functional Rating Scale (ALSFRS-r) score. The ALSFRS-r was completed at each visit (randomization and then at 3, 6, 12, 18 and 24 months post-randomization). This is a scale from 0 to 48 assessing functional impairment in 12 clinically relevant areas in ALS. Forty-eight is normal with full function and zero is total loss of function in all clinical functions. As with the MMT scores a score of 0 was imputed on the day of death. Analysis of the ALSFRS-r scores as a secondary outcome was performed in similar manner as MMT score.
Time frame: Baseline and 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IGF-1 | Rate of Change in ALS Functional Rating Scale. | 2.5 Units on a scale per month | Standard Deviation 3.2 |
| Placebo | Rate of Change in ALS Functional Rating Scale. | 2.2 Units on a scale per month | Standard Deviation 2.1 |
Comparison: The final secondary outcome measure was the rate of change in the ALSFRS-r score. The ALSFRS-r was completed at each visit (randomization and then at 3, 6, 12, 18 and 24 months post-randomization). As with the MMT scores a score of 0 was imputed on the day of death. Analysis of the ALSFRS-r scores as a secondary outcome was performed in similar manner as MMT score.p-value: 0.321Wilcoxon (Mann-Whitney)