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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01257581

Acronym

SDALS-001

Enrollment

Registered

2010-12-09

Start date

2011-03-31

Completion date

2013-02-28

Last updated

2014-12-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Amyotrophic Lateral Sclerosis

Keywords

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

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).

Interventions

DRUGcreatine

creatine monohydrate powder

DRUGtamoxifen

Tamoxifen citrate capsules

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
Dose Adjustments	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	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	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.
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.
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.
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.
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.
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.
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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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.	22
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.	21
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.	17
Total	60

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Death	2	2	4
Overall Study	Early Termination	3	1	2

Baseline characteristics

Characteristic	Creatine 30gm	Tamoxifen 40mg	Tamoxifen 80mg	Total
Age, Continuous	55.5 years STANDARD_DEVIATION 11.4	60.3 years STANDARD_DEVIATION 10.6	56.3 years STANDARD_DEVIATION 11.3	57.4 years STANDARD_DEVIATION 11.1
Baseline ALS Functional Rating Scale - Revised (ALSFRS-R) Total	35.82 Score on a scale STANDARD_DEVIATION 7.2	36.19 Score on a scale STANDARD_DEVIATION 6.04	34.76 Score on a scale STANDARD_DEVIATION 6.56	35.65 Score on a scale STANDARD_DEVIATION 6.54
Baseline VC% Predicted Max	90.64 % of predicted max value STANDARD_DEVIATION 20.29	86.90 % of predicted max value STANDARD_DEVIATION 13.92	81.71 % of predicted max value STANDARD_DEVIATION 19.93	86.80 % of predicted max value STANDARD_DEVIATION 18.31
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	22 Participants	21 Participants	17 Participants	60 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	22 Participants	20 Participants	17 Participants	59 Participants
Region of Enrollment United States	22 participants	21 participants	17 participants	60 participants
Sex: Female, Male Female	6 Participants	4 Participants	9 Participants	19 Participants
Sex: Female, Male Male	16 Participants	17 Participants	8 Participants	41 Participants
Years from Diagnosis to Screening	1.3 years STANDARD_DEVIATION 0.8	0.9 years STANDARD_DEVIATION 0.8	1.0 years STANDARD_DEVIATION 0.8	1.1 years STANDARD_DEVIATION 0.8
Years from Symptom Onset to Diagnosis	1.6 years STANDARD_DEVIATION 1.5	0.9 years STANDARD_DEVIATION 0.8	1.0 years STANDARD_DEVIATION 0.8	1.2 years STANDARD_DEVIATION 1.1
Years from Symptom Onset to Screening	2.8 years STANDARD_DEVIATION 1.7	1.9 years STANDARD_DEVIATION 1.4	2.0 years STANDARD_DEVIATION 1	2.3 years STANDARD_DEVIATION 1.5

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	21 / 22	17 / 21	15 / 17
serious Total, serious adverse events	6 / 22	3 / 21	5 / 17

Outcome results

Primary

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.