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

• Sponsor: Nazem Atassi (Other)
• Overall Status: Completed
• CT.gov ID: NCT01257581
• Collaborator: ALS Therapy Alliance (Other), State University of New York - Upstate Medical University (Other)
• Enrollment: 60
• Locations: 9
• Arms: 3
• Duration (Months): 23.1
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.3

Study Details

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
• 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: Mar 1, 2011
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Feb 1, 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 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

Outcome Measures

Primary Outcome Measures

1. Change in ALS Functional Rating Scale - Revised (ALSFRS-R) [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 [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 [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 [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 [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 [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 [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 [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 [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) [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) [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
2	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	University of Massachusetts Medical Center	Worcester	Massachusetts	United States	01655
4	Washington University at St. Louis	St. Louis	Missouri	United States	63110
5	SUNY Upstate Medical University	Syracuse	New York	United States	13210
6	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
7	Pennsylvania State University, Hershey Medical Center	Hershey	Pennsylvania	United States	17033
8	University of Washington Medical Center	Seattle	Washington	United States	98195
9	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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Northeast ALS Consortium website

Publications

None provided.

• Responsible Party: Nazem Atassi, Nazem Atassi, MD. MMSc., Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01257581
• Other Study ID Numbers: SDALS-001
• First Posted: Dec 9, 2010
• Last Update Posted: Dec 4, 2014
• Last Verified: Dec 1, 2014

• Keywords provided by Nazem Atassi, Nazem Atassi, MD. MMSc., 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; Tamoxifen

Study Results

Participant Flow

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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. creatine: creatine monohydrate powder	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. tamoxifen: Tamoxifen citrate capsules	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. tamoxifen: Tamoxifen citrate capsules
Period Title: Overall Study
STARTED	22	21	17
COMPLETED	17	18	11
NOT COMPLETED	5	3	6

Baseline Characteristics

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	22	21	17	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.5 (11.4)	60.3 (10.6)	56.3 (11.3)	57.4 (11.1)
Sex: Female, Male (Count of Participants)
Female	6 27.3%	4 19%	9 52.9%	19 31.7%
Male	16 72.7%	17 81%	8 47.1%	41 68.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	22 100%	21 100%	17 100%	60 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 4.8%	0 0%	1 1.7%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	22 100%	20 95.2%	17 100%	59 98.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	22 100%	21 100%	17 100%	60 100%
Years from Symptom Onset to Screening (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.8 (1.7)	1.9 (1.4)	2.0 (1.0)	2.3 (1.5)
Years from Diagnosis to Screening (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.3 (0.8)	0.9 (0.8)	1.0 (0.8)	1.1 (0.8)
Years from Symptom Onset to Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.6 (1.5)	0.9 (0.8)	1.0 (0.8)	1.2 (1.1)
Baseline ALS Functional Rating Scale - Revised (ALSFRS-R) Total (Score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on a scale]	35.82 (7.20)	36.19 (6.04)	34.76 (6.56)	35.65 (6.54)
Baseline VC% Predicted Max (% of predicted max value) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% of predicted max value]	90.64 (20.29)	86.90 (13.92)	81.71 (19.93)	86.80 (18.31)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Mean (95% Confidence Interval) [scores on a scale]	-0.905	-0.983	-0.743

2. Secondary Outcome

Title	Vital Capacity/Pulmonary Function Testing
Description	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.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Mean (95% Confidence Interval) [Percentage of predicted max value]	-3.386	-2.915	-3.377

3. Secondary Outcome

Title	Tracheostomy-free Survival
Description	Secondary efficacy will be assessed by analyzing rate of tracheostomy-free survival at nine months.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Number (95% Confidence Interval) [proportion of participants]	0.455 2.1%	0.286 1.4%	0.412 2.4%

4. Secondary Outcome

Title	Dose Adjustments
Description	These events were due to a double-blinded study design.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Number of Creatine Reductions due to AEs	6	3	0
Tamoxifen Redutions due to AEs	5	4	0
Suspensions due to AEs	9	1	2
Discontinuations due to AEs	10	5	4

5. Secondary Outcome

Title	Lab Abnormal Reports by Treatment Assignment
Description	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.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
ALT (SGOT)	0	1	0
Creatinine	4	0	0
Glucose	0	0	1
Hematocrit	1	0	0
Lymphocytes	1	0	0
MCH	1	0	0
Neutrophils	0	0	1
Absolute Neutrophils	0	0	1
GFR Non-African American	2	0	0
Potassium	0	0	1
Red Blood Count (RBC)	1	0	0
White Blood Count (WBC)	1	0	0

6. Secondary Outcome

Title	Hand Held Dynamometry (HHD) Lower Z-score
Description	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.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Mean (95% Confidence Interval) [Z-score]	-0.094	-0.067	-0.016

7. Secondary Outcome

Title	HHD Lower % Baseline
Description	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.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Mean (95% Confidence Interval) [percent change]	-9.258	-6.711	-2.897

8. Secondary Outcome

Title	HHD Upper Z-score
Description	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.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Mean (95% Confidence Interval) [Z-score]	-0.103	-0.089	-0.039

9. Secondary Outcome

Title	HHD Upper % Baseline
Description	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.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Mean (95% Confidence Interval) [percent change]	-8.451	-7.720	-4.515

10. Secondary Outcome

Title	Accurate Test of Limb Isometric Strength (ATLIS) Lower Percentage of Predicted Normal (PPN)
Description	The ATLIS PPN measures are percentages of predicted normal strength based on age, gender, height, and weight using normative data.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Mean (95% Confidence Interval) [percentages of predicted normal strength]	-2.098	-2.375	-0.491

11. Secondary Outcome

Title	ATLIS Upper Percentage of Predicted Normal (PPN)
Description	The ATLIS PPN measures are percentages of predicted normal strength based on age, gender, height, and weight using normative data.
Time Frame	38 weeks of treatment followed by a telephone interview at 42 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg
Arm/Group Description	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.	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.	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.
Measure Participants	22	21	17
Mean (95% Confidence Interval) [percentages of predicted normal strength]	-1.932	-1.845	0.436

Adverse Events

Arm/Group Title	Creatine 30gm		Tamoxifen 40mg		Tamoxifen 80mg
Arm/Group Description	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.		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.		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.
All Cause Mortality
	Creatine 30gm		Tamoxifen 40mg		Tamoxifen 80mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Creatine 30gm		Tamoxifen 40mg		Tamoxifen 80mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/22 (27.3%)		3/21 (14.3%)		5/17 (29.4%)
Gastrointestinal disorders
Abdominal Pain	1/22 (4.5%)	1	0/21 (0%)	0	0/17 (0%)	0
Abdominal Pain Upper	1/22 (4.5%)	1	0/21 (0%)	0	0/17 (0%)	0
Pneumoperitoneum	0/22 (0%)	0	1/21 (4.8%)	1	0/17 (0%)	0
General disorders
Death	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Hepatobiliary disorders
Cholecystitis Acute	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Infections and infestations
Pneumonia	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Metabolism and nutrition disorders
Malnutrition	1/22 (4.5%)	1	0/21 (0%)	0	0/17 (0%)	0
Nervous system disorders
Subarachnoid Haemorrhage	1/22 (4.5%)	1	0/21 (0%)	0	0/17 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	0/22 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1
Respiratory Arrest	1/22 (4.5%)	1	0/21 (0%)	0	0/17 (0%)	0
Respiratory Distress	1/22 (4.5%)	1	0/21 (0%)	0	0/17 (0%)	0
Respiratory Failure	0/22 (0%)	0	1/21 (4.8%)	1	2/17 (11.8%)	2
Vascular disorders
Deep Vein Thrombosis	1/22 (4.5%)	1	0/21 (0%)	0	0/17 (0%)	0
Other (Not Including Serious) Adverse Events
	Creatine 30gm		Tamoxifen 40mg		Tamoxifen 80mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/22 (95.5%)		17/21 (81%)		15/17 (88.2%)
Blood and lymphatic system disorders
Leukocytosis	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Ear and labyrinth disorders
Tinnitus	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Eye disorders
Dry Eye	2/22 (9.1%)	2	0/21 (0%)	0	1/17 (5.9%)	1
Eye Pain	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Gastrointestinal disorders
Abdominal Distention	1/22 (4.5%)	1	0/21 (0%)	0	1/17 (5.9%)	1
Abdominal Pain	1/22 (4.5%)	1	0/21 (0%)	0	1/17 (5.9%)	1
Abdominal Pain Upper	3/22 (13.6%)	5	0/21 (0%)	0	1/17 (5.9%)	1
Constipation	6/22 (27.3%)	7	5/21 (23.8%)	5	3/17 (17.6%)	5
Diarrhoea	6/22 (27.3%)	7	3/21 (14.3%)	8	1/17 (5.9%)	1
Dry Mouth	1/22 (4.5%)	1	0/21 (0%)	0	2/17 (11.8%)	2
Dysphagia	1/22 (4.5%)	1	0/21 (0%)	0	2/17 (11.8%)	2
Gastrooesophageal Reflux Disease	2/22 (9.1%)	2	0/21 (0%)	0	1/17 (5.9%)	1
Nausea	6/22 (27.3%)	9	4/21 (19%)	4	2/17 (11.8%)	3
Retching	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Salivary Hypersecretion	1/22 (4.5%)	1	1/21 (4.8%)	1	1/17 (5.9%)	1
Vomiting	3/22 (13.6%)	3	1/21 (4.8%)	1	0/17 (0%)	0
General disorders
Application Site Rash	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Asthenia	2/22 (9.1%)	2	0/21 (0%)	0	4/17 (23.5%)	4
Chills	0/22 (0%)	0	1/21 (4.8%)	2	1/17 (5.9%)	1
Death	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Fatigue	6/22 (27.3%)	6	4/21 (19%)	4	7/17 (41.2%)	7
Oedema Peripheral	4/22 (18.2%)	5	2/21 (9.5%)	2	1/17 (5.9%)	1
Thirst	2/22 (9.1%)	2	0/21 (0%)	0	0/17 (0%)	0
Hepatobiliary disorders
Cholecystitis Acute	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Infections and infestations
Gastroenteritis Viral	2/22 (9.1%)	2	0/21 (0%)	0	0/17 (0%)	0
Nasopharyngitis	0/22 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1
Pneumonia	0/22 (0%)	0	0/21 (0%)	0	3/17 (17.6%)	3
Sinusitis	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Staphylococcal Infection	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Upper Respiratory Tract Infection	2/22 (9.1%)	2	0/21 (0%)	0	1/17 (5.9%)	1
Urinary Tract Infection	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Injury, poisoning and procedural complications
Procedural Pain	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Ankle Fracture	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Contusion	0/22 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1
Fall	1/22 (4.5%)	2	2/21 (9.5%)	2	3/17 (17.6%)	3
Joint Injury	0/22 (0%)	0	2/21 (9.5%)	2	0/17 (0%)	0
Post Procedural Haemorrhage	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Skin Laceration	2/22 (9.1%)	2	0/21 (0%)	0	0/17 (0%)	0
Investigations
Vital Capacity Decreased	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Weight Decreased	1/22 (4.5%)	1	1/21 (4.8%)	1	1/17 (5.9%)	1
Metabolism and nutrition disorders
Decreased Appetite	4/22 (18.2%)	4	4/21 (19%)	4	1/17 (5.9%)	1
Dehydration	1/22 (4.5%)	1	0/21 (0%)	0	1/17 (5.9%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Arthritis	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Joint Stiffness	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Mobility Decreased	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Muscle Spasms	5/22 (22.7%)	5	0/21 (0%)	0	1/17 (5.9%)	1
Muscular Weakness	6/22 (27.3%)	9	3/21 (14.3%)	3	2/17 (11.8%)	2
Neck Pain	1/22 (4.5%)	1	0/21 (0%)	0	1/17 (5.9%)	1
Pain in Extremity	2/22 (9.1%)	2	2/21 (9.5%)	2	0/17 (0%)	0
Pain in Jaw	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Tendonitis	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Nervous system disorders
Burning Sensation	1/22 (4.5%)	1	0/21 (0%)	0	1/17 (5.9%)	1
Dizziness	3/22 (13.6%)	5	2/21 (9.5%)	4	0/17 (0%)	0
Dysarthria	1/22 (4.5%)	1	1/21 (4.8%)	1	1/17 (5.9%)	1
Headache	1/22 (4.5%)	2	2/21 (9.5%)	7	2/17 (11.8%)	2
Hypoaesthesia	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	2
Lethargy	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Muscle Contractions Involuntary	1/22 (4.5%)	1	0/21 (0%)	0	1/17 (5.9%)	1
Peroneal Nerve Palsy	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Psychiatric disorders
Affect Lability	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Anxiety	0/22 (0%)	0	0/21 (0%)	0	2/17 (11.8%)	2
Depression	2/22 (9.1%)	2	1/21 (4.8%)	1	2/17 (11.8%)	2
Insomnia	0/22 (0%)	0	0/21 (0%)	0	2/17 (11.8%)	2
Mood Swings	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Renal and urinary disorders
Nephrolithiasis	2/22 (9.1%)	2	0/21 (0%)	0	0/17 (0%)	0
Reproductive system and breast disorders
Vaginal Discharge	0/22 (0%)	0	0/21 (0%)	0	2/17 (11.8%)	2
Respiratory, thoracic and mediastinal disorders
Cough	0/22 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1
Dyspnoea	1/22 (4.5%)	1	6/21 (28.6%)	6	4/17 (23.5%)	4
Increased Bronchial Secretion	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Increased Upper Airway Secretion	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Nasal Congestion	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Oropharyngeal Pain	0/22 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1
Pulmonary Embolism	0/22 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1
Respiratory Arrest	1/22 (4.5%)	1	0/21 (0%)	0	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/22 (4.5%)	1	0/21 (0%)	0	1/17 (5.9%)	1
Decubitus Ulcer	0/22 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1
Hair Growth Abnormal	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Night Sweats	0/22 (0%)	0	1/21 (4.8%)	1	1/17 (5.9%)	1
Pruritis	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Surgical and medical procedures
Mole Excision	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Tooth Extraction	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1
Vascular disorders
Deep Vein Thrombosis	1/22 (4.5%)	1	2/21 (9.5%)	2	1/17 (5.9%)	1
Hot Flush	0/22 (0%)	0	0/21 (0%)	0	4/17 (23.5%)	4
Hypotension	0/22 (0%)	0	0/21 (0%)	0	1/17 (5.9%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.