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

• ClinicalTrials.gov Identifier: NCT01257581
• Recruitment Status: Completed
• First Posted: December 9, 2010
• Results First Posted: December 4, 2014
• Last Update Posted: December 4, 2014
• Sponsor: Nazem Atassi
• Collaborators: ALS Therapy Alliance; State University of New York - Upstate Medical University
• Information provided by (Responsible Party): Nazem Atassi, Massachusetts General Hospital

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: creatine; Drug: tamoxifen	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 2 Selection Trial of High Dosage Creatine and Two Dosages of Tamoxifen in Amyotrophic Lateral Sclerosis (ALS)
• Study Start Date: March 2011
• Actual Primary Completion Date: December 2012
• Actual Study Completion Date: February 2013

Arms and Interventions

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 Name: 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 Name: Nolvadex, Istubal, Valodex

Outcome Measures

Primary Outcome Measures :

1. Change in ALS Functional Rating Scale - Revised (ALSFRS-R) [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   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.

Secondary Outcome Measures :

1. Vital Capacity/Pulmonary Function Testing [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   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.
2. Tracheostomy-free Survival [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   Secondary efficacy will be assessed by analyzing rate of tracheostomy-free survival at nine months.
3. Dose Adjustments [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   These events were due to a double-blinded study design.
4. Lab Abnormal Reports by Treatment Assignment [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   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.
5. Hand Held Dynamometry (HHD) Lower Z-score [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   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.
6. HHD Lower % Baseline [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   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.
7. HHD Upper Z-score [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   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.
8. HHD Upper % Baseline [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   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.
9. Accurate Test of Limb Isometric Strength (ATLIS) Lower Percentage of Predicted Normal (PPN) [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
   The ATLIS PPN measures are percentages of predicted normal strength based on age, gender, height, and weight using normative data.
10. ATLIS Upper Percentage of Predicted Normal (PPN) [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
    The ATLIS PPN measures are percentages of predicted normal strength based on age, gender, height, and weight using normative data.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

University of Massachusetts Medical Center

Worcester, Massachusetts, United States, 01655

United States, Missouri

Washington University at St. Louis

St. Louis, Missouri, United States, 63110

United States, New York

SUNY Upstate Medical University

Syracuse, New York, United States, 13210

United States, North Carolina

Carolinas Medical Center

Charlotte, North Carolina, United States, 28203

United States, Pennsylvania

Pennsylvania State University, Hershey Medical Center

Hershey, Pennsylvania, United States, 17033

United States, Washington

University of Washington Medical Center

Seattle, Washington, United States, 98195

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Nazem Atassi

ALS Therapy Alliance

State University of New York - Upstate Medical University

Investigators

• Principal Investigator: Nazem Atassi, MD, MMSc; Masaschusetts General Hospital, Boston, MA

More Information

Additional Information:

Northeast ALS Consortium website 

• Responsible Party: Nazem Atassi, Nazem Atassi, MD. MMSc., Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01257581
• Other Study ID Numbers: SDALS-001
• First Posted: December 9, 2010
• Results First Posted: December 4, 2014
• Last Update Posted: December 4, 2014
• Last Verified: December 2014

Keywords provided by Nazem Atassi, Massachusetts General Hospital:

ALS; Lou Gehrig's Disease; Amyotrophic Lateral Sclerosis; Creatine; Tamoxifen; Selection Design

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Tamoxifen; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Bone Density Conservation Agents