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

Tracking Information

• First Submitted Date: December 8, 2010
• First Posted Date: December 9, 2010
• Results First Submitted Date: March 10, 2014
• Results First Posted Date: December 4, 2014
• Last Update Posted Date: December 4, 2014
• Study Start Date: March 2011
• Actual Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 3, 2014)

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.

Original Primary Outcome Measures (submitted: December 8, 2010)

Decline in 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.

Current Secondary Outcome Measures (submitted: December 3, 2014)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: December 8, 2010)

• 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.
• 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.
• Incidence of Falls [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
  Secondary efficacy will be assessed by analyzing the estimated mean rate of falls over nine months.
• Analysis of Safety and Tolerability Measures [ Time Frame: 38 weeks of treatment followed by a telephone interview at 42 weeks. ]
  The safety data will be summarized according to treatment arm. Total number of AEs, AEs that cause study drug withdrawal and abnormal laboratory tests will be compared among treatment arms.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy Study of Creatine and Tamoxifen in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
• Official Title: Phase 2 Selection Trial of High Dosage Creatine and Two Dosages of Tamoxifen in Amyotrophic Lateral Sclerosis (ALS)
• 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).

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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Amyotrophic Lateral Sclerosis

Intervention

• Drug: creatine
  creatine monohydrate powder
• Drug: tamoxifen
  Tamoxifen citrate capsules
  Other Name: Nolvadex, Istubal, Valodex

Study Arms

• 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.

  Intervention: Drug: creatine
• 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.

  Intervention: Drug: tamoxifen
• 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.

  Intervention: Drug: tamoxifen

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 8, 2010): 60
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: February 2013
• Actual Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01257581
• Other Study ID Numbers: SDALS-001
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Nazem Atassi, Massachusetts General Hospital
• Original Responsible Party: Nazem Atassi, MD MMSc, Massachusetts General Hospital - Neurology Clinical Trials Unit
• Current Study Sponsor: Nazem Atassi
• Original Study Sponsor: Massachusetts General Hospital

Collaborators

• ALS Therapy Alliance
• State University of New York - Upstate Medical University

Investigators

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

• PRS Account: Massachusetts General Hospital
• Verification Date: December 2014