Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial

Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS)

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.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Insulin like growth factor, type 1; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 330
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • University of Puerto Rico
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Scottsdale
  • California
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic in Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Hennepin County Medical Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi
  • New York
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • University of Pennsylvania, Pennsylvania Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Methodist Hospital
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and Medical College Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: IGF-1; Insulin like growth factor, type 1 will be given 0.05 mg per kg body weight subcutaneously twice daily	Drug: Insulin like growth factor, type 1; 0.05 mg per kg body weight given subcutaneously twice daily; Other Names: Mycotrophin
PLACEBO_COMPARATOR: Placebo; Placebo arm	Drug: Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Baseline and 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	baseline to 24 months
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.	Baseline and 24 months

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); ALS Association; Cephalon
• Investigators: Principal Investigator: Eric Sorenson, M.D., Department of Neurology, Mayo Clinic

Publications and helpful links

General Publications

• Howe CL, Bergstrom RA, Horazdovsky BF. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology. 2009 Oct 13;73(15):1247; author reply 1247-8. doi: 10.1212/WNL.0b013e3181b26ae6. No abstract available.
• Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, Barkhaus PE, Bosch P, Boylan K, David WS, Feldman E, Glass J, Gutmann L, Katz J, King W, Luciano CA, McCluskey LF, Nash S, Newman DS, Pascuzzi RM, Pioro E, Sams LJ, Scelsa S, Simpson EP, Subramony SH, Tiryaki E, Thornton CA. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology. 2008 Nov 25;71(22):1770-5. doi: 10.1212/01.wnl.0000335970.78664.36.

Helpful Links

• The ALS Association website.

Study record dates

Study Major Dates

• Study Start: June 1, 2003
• Primary Completion (ACTUAL): August 1, 2007
• Study Completion (ACTUAL): December 1, 2007

Study Registration Dates

• First Submitted: May 6, 2002
• First Submitted That Met QC Criteria: May 6, 2002
• First Posted (ESTIMATE): May 7, 2002

Study Record Updates

• Last Update Posted (ESTIMATE): February 15, 2013
• Last Update Submitted That Met QC Criteria: February 13, 2013
• Last Verified: February 1, 2013

More Information

Terms related to this study

• Keywords: ALS; amyotrophic lateral sclerosis; IGF-I; insulin-like growth factor-1; progressive weakness; Myotrophin
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Molecular Mechanisms of Pharmacological Action; Mitosis Modulators; Mitogens
• Other Study ID Numbers: 1461-01; R01NS042759 (NIH)