Safety and Efficacy Study of Creatine and Tamoxifen in Volunteers With Amyotrophic Lateral Sclerosis (ALS) (SDALS-001)

Phase 2 Selection Trial of High Dosage Creatine and Two Dosages of Tamoxifen in Amyotrophic Lateral Sclerosis (ALS)

The purpose of the study is to evaluate the safety and efficacy of high dose creatine and two dosages of tamoxifen treatment in amyotrophic lateral sclerosis (ALS).

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: creatine; Drug: tamoxifen

Detailed Description

Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative disorder that results in progressive wasting and paralysis of voluntary muscles. 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.

In this double blind, randomized, selection design trial, researchers will evaluate the safety and effectiveness of creatine and tamoxifen in volunteers with ALS. There are a large number of potential drugs that may improve the survival or slow down the disease progression in people with ALS. The current strategy is to test one drug at a time against placebo. "Selection Design" is a different type of study design. A Selection Design study uses multiple drugs to screen against each other and picks the winner to take to a larger study. This design can speed the search for effective drugs to treat ALS. In this Selection Design study, each volunteer will take one active study drug (creatine 30gm, tamoxifen 40mg, or tamoxifen 80mg) and one placebo.

Approximately 60 eligible volunteers with ALS will be recruited from multiple centers in the US that belong to the Northeast ALS Consortium (NEALS). Volunteers will be randomly assigned equally to the three treatment arms: creatine 30gm/day, tamoxifen 40mg/day and tamoxifen 80mg/day. Volunteers will take study treatment for 38 weeks. After screening and randomization, volunteers will be followed at weeks 4, 10, 18, 28 and week 38. A final telephone interview will occur at week 42 (off study drug).

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical Center
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University at St. Louis
  • New York
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Pennsylvania State University, Hershey Medical Center
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Familial or sporadic ALS.
• Disease duration from diagnosis no greater than 36 months at Screening Visit.
• Aged 18 years or older.
• Capable of providing informed consent and complying with trial procedures.
• Vital capacity (VC) equal to or more than 50% predicted normal value for gender, height and age at the Screening Visit.
• Not taking, or on a stable dose of riluzole (50mg bid) for at least 30 days prior to the Screening Visit.
• Women must not be able to become pregnant for the duration of the study (e.g., post menopausal for at least one year, surgically sterile, or practicing adequate birth control methods) for the duration of the study. Women of childbearing potential must have a negative serum pregnancy test at the Screening Visit and be non-lactating.

Exclusion Criteria:

• History of known sensitivity or intolerability to creatine monohydrate or tamoxifen citrate or to any other related compound.
• Prior exposure to creatine or tamoxifen within 30 days of the Screening Visit.
• Exposure to any investigational agent within 30 days of the Screening Visit.
• Use of coumarin anticoagulants (warfarin sodium), rifampin, aminoglutethimide, medroxyprogesterone, letrozole, or bromocriptine.
• Presence of any of the following clinical conditions: Clinical evidence of unstable medical or psychiatric illness at the Screening Visit; Screening aspartate aminotransferase (AST) > 3 times the upper limit of normal or serum creatinine > 1.5 mg/dl (133 umol/L); Permanent assisted ventilation or mechanical ventilation; or Lactating or have a positive serum pregnancy test at the Screening Visit.
• History of any of the following: blood clots including deep vein thrombosis, pulmonary embolism, and stroke, cataracts, renal problems, endometrial cancer, uterine sarcoma, or diabetes mellitus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Creatine 30gm; Creatine will be taken as a powder mixed into food or liquid twice a day. Volunteers in this arm will take a total of 30gm of creatine per day for 38 weeks. Volunteers will also take placebo capsules twice a day for 38 weeks. This is a blinded study, so neither participants nor study staff will know which treatment a volunteer is receiving. Creatine is a nutritional supplement and is not approved by the U.S. Food and Drug Administration (FDA) for treating ALS.	Drug: creatine; creatine monohydrate powder
Experimental: Tamoxifen 40mg; Tamoxifen will be taken as capsules twice a day. Volunteers in this arm will take a total of 40mg of tamoxifen per day for 38 weeks. Volunteers will also take placebo powder twice a day for 38 weeks. This is a blinded study, so neither participants nor study staff will know which treatment a volunteer is receiving. Tamoxifen is approved by the U.S. Food and Drug Administration (FDA) for breast cancer treatment but is not approved for treating ALS.	Drug: tamoxifen; Tamoxifen citrate capsules; Other Names: Nolvadex, Istubal, Valodex
Experimental: Tamoxifen 80mg; Tamoxifen will be taken as capsules twice a day. Volunteers in this arm will take a total of 80mg of tamoxifen per day for 38 weeks. Volunteers will also take placebo powder twice a day for 38 weeks. This is a blinded study, so neither participants nor study staff will know which treatment a volunteer is receiving. Tamoxifen is approved by the U.S. Food and Drug Administration (FDA) for breast cancer treatment but is not approved for treating ALS.	Drug: tamoxifen; Tamoxifen citrate capsules; Other Names: Nolvadex, Istubal, Valodex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in ALS Functional Rating Scale - Revised (ALSFRS-R)	Primary efficacy will be assessed by analyzing the mean rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score over nine months. The ALSFRS-R is a quickly administered (5 min) ordinal rating scale used to determine a subject's assessment of their capability and independence in 12 functional activities. There are 12 questions, graded by the subject 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing.	38 weeks of treatment followed by a telephone interview at 42 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vital Capacity/Pulmonary Function Testing	Secondary efficacy will be assessed by analyzing the change in the Slow Vital Capacity score over nine months. Vital Capacity is the maximum amount of air a person can expel from the lungs after a maximum inhalation. A subject's VC depends on their age, sex and height. The value is recorded as a percentage of predicted normal.	38 weeks of treatment followed by a telephone interview at 42 weeks.
Tracheostomy-free Survival	Secondary efficacy will be assessed by analyzing rate of tracheostomy-free survival at nine months.	38 weeks of treatment followed by a telephone interview at 42 weeks.
Dose Adjustments	These events were due to a double-blinded study design.	38 weeks of treatment followed by a telephone interview at 42 weeks.
Lab Abnormal Reports by Treatment Assignment	The safety data is summarized according to treatment arm. Total number of Adverse Events (AEs), AEs that cause study drug withdrawal and abnormal laboratory tests are compared among treatment arms. A lab abnormality was a result that was out of range and considered clinically significant by the site investigator.	38 weeks of treatment followed by a telephone interview at 42 weeks.
Hand Held Dynamometry (HHD) Lower Z-score	The HHD lower z-scores are means of z-scores for right and left knee extension, knee flexion, hip flexion, and ankle dorsiflexion with z-scores calculated relative to the baseline mean and standard deviation strength of each muscle group across all participants.	38 weeks of treatment followed by a telephone interview at 42 weeks.
HHD Lower % Baseline	HHD % baseline measures are mean percent change for right and left knee extension, knee flexion, hip flexion, and ankle dorsiflexion from each participant's baseline.	38 weeks of treatment followed by a telephone interview at 42 weeks.
HHD Upper Z-score	The HHD upper z-scores are means of z-scores for right and left shoulder flexion, elbow extension, elbow flexion, write extension and first dorsal interosseous muscles with z-scores calculated relative to the baseline mean and standard deviation strength of each muscle group across all participants.	38 weeks of treatment followed by a telephone interview at 42 weeks.
HHD Upper % Baseline	The HHD % baseline measures are mean percent change for shoulder flexion, elbow extension, elbow flexion, wrist extension, and first dorsal interosseous muscles from each participant's baseline.	38 weeks of treatment followed by a telephone interview at 42 weeks.
Accurate Test of Limb Isometric Strength (ATLIS) Lower Percentage of Predicted Normal (PPN)	The ATLIS PPN measures are percentages of predicted normal strength based on age, gender, height, and weight using normative data.	38 weeks of treatment followed by a telephone interview at 42 weeks.
ATLIS Upper Percentage of Predicted Normal (PPN)	The ATLIS PPN measures are percentages of predicted normal strength based on age, gender, height, and weight using normative data.	38 weeks of treatment followed by a telephone interview at 42 weeks.

Collaborators and Investigators

• Sponsor: Nazem Atassi
• Collaborators: State University of New York - Upstate Medical University; ALS Therapy Alliance
• Investigators: Principal Investigator: Nazem Atassi, MD, MMSc, Masaschusetts General Hospital, Boston, MA

Publications and helpful links

Helpful Links

• Northeast ALS Consortium Website

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: December 8, 2010
• First Submitted That Met QC Criteria: December 8, 2010
• First Posted (Estimate): December 9, 2010

Study Record Updates

• Last Update Posted (Estimate): December 4, 2014
• Last Update Submitted That Met QC Criteria: December 3, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; ALS; Tamoxifen; Creatine; Lou Gehrig's Disease; Selection Design
• 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; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen
• Other Study ID Numbers: SDALS-001