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The purpose of this study is to assess the safety and tolerability of clenbuterol (taken by mouth) in subjects with ALS (amyotrophic lateral sclerosis) and to assess the effectiveness of clenbuterol with regard to motor function in subjects with ALS. Subjects will be in this study approximately 24 weeks. The study drug, clenbuterol, is taken twice a day. As part of this study subjects will have the following tests and procedures: medical history, vital signs, physical examination, blood tests, heart and lung function tests, muscle function test, ALSFRS-R (ALS Functional Rating Scale Revised), thyroid function and for women who can become pregnant, pregnancy tests.
This is an open label pilot trial in which 25 people with ALS will take clenbuterol orally at 40-80 micrograms twice daily for 24 weeks. In person visits will occur at weeks 0, 4, 12 and 24. Telephone visits will occur at weeks 1, 6, 16 and 20. During these visits several safety and efficacy outcome measures will be performed for research purposes including safety labs, thyroid functions, pregnancy testing, ALSFRS-R, FVC (forced vital capacity), and muscle strength testing (myometry). The critical test of treatment efficacy will be the comparison of the ALSFRS-R slope during treatment to the estimated pre-treatment slope. All participants will continue to have standard follow up care for their ALS at Duke (for patients followed here) or their local ALS clinic
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Open label Arm | Experimental | This is an open label pilot trial in which 25 people with ALS will take clenbuterol orally at 40-80 micrograms twice daily for 24 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clenbuterol | Drug | The intervention is treatment with oral clenbuterol at 40-80 micrograms twice daily for 24 weeks. Dosage will initially be 40 mcg daily for one week, then 40 mcg BID per oral daily for the next 5 weeks. If the 40 mcg BID per oral is well tolerated in the opinion of Dr. Bedlack, the dose will be increased to 80 mcg each morning/40 mcg each evening for one week, followed by 80 mcg BID per oral for the remainder of the study. The selected target dose (80 mcg BID) is based upon the experience with the long-term administration of clenbuterol, specifically the beneficial muscle effects in a Phase I/II clinical trial that enrolled patients with late-onset Pompe disease who were previously treated with enzyme replacement therapy (Koeberl et al. 2018). |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Serious Adverse Events as Measured by Patient Reporting | The primary endpoint is safety of clenbuterol at 80 mcg BID. Adverse events and serious adverse events will be systematically gathered as the dose is increased. | Up to 24 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Motor Function Measured by ALSFRS-R | The ALS Functional Rating Scale (ALSFRS-R) - 12 questions rated on a five-point scale, where 0= can't do, to 5= normal ability. It is utilized for monitoring the progression of disability in patients with ALS. The critical test for efficacy was comparison of the mean slope of the ALSFRS-R during treatment compared to pre-treatment. Pre-treatment slope for each participant was estimated as follows: (48-enrollment ALSFRS-R)/months since symptom onset. A statistically significant treatment effect was determined by a two-tailed, t-test, with a critical p value < .05. Other analyses included a repeated measures ANOVA design (between and within subjects) of ALSFRS-R slopes before and during treatment. |
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Inclusion Criteria:
Exclusion Criteria:
diuretics (furosemide, Lasix), digoxin (digitalis, Lanoxin);blockers such as atenolol (Tenormin), metoprolol (Lopressor), and propranolol (Inderal); tricyclic antidepressants such as amitriptyline (Elavil, Etrafon), doxepin (Sinequan), imipramine (Janimine, Tofranil), and nortriptyline (Pamelor); monoamine oxidase inhibitors such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate); or other bronchodilators such as albuterol (Ventolin), levalbuterol (Xopenex), bitolterol (Tornalate), pirbuterol (Maxair), terbutaline (Brethine, Bricanyl), salmeterol (Serevent), isoetherine (Bronkometer), metaproterenol (Alupent, Metaprel), or isoproterenol (Isuprel Mistometer).
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Duke University Medical center | Durham | North Carolina | 27705 | United States |
there is no plan to share individual participant data (IPD) with other researchers.
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| ID | Title | Description |
|---|---|---|
| FG000 | Open Label Arm | This is an open label pilot trial in which 25 people with ALS will take clenbuterol orally at 40-80 micrograms twice daily for 24 weeks. Clenbuterol: The intervention is treatment with oral clenbuterol at 40-80 micrograms twice daily for 24 weeks. Dosage will initially be 40 mcg daily for one week, then 40 mcg BID per oral daily for the next 5 weeks. If the 40 mcg BID per oral is well tolerated in the opinion of Dr. Bedlack, the dose will be increased to 80 mcg each morning/40 mcg each evening for one week, followed by 80 mcg BID per oral for the remainder of the study. The selected target dose (80 mcg BID) is based upon the experience with the long-term administration of clenbuterol, specifically the beneficial muscle effects in a Phase I/II clinical trial that enrolled patients with late-onset Pompe disease who were previously treated with enzyme replacement therapy (Koeberl et al. 2018). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The baseline analysis population was determined as follows: Intention to treat analyses were performed for 20 participants (of 25 enrolled) who had at least one ALSFRS-R measurement post-treatment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Open Label Arm | This is an open label pilot trial in which 25 people with ALS will take clenbuterol orally at 40-80 micrograms twice daily for 24 weeks. Clenbuterol: The intervention is treatment with oral clenbuterol at 40-80 micrograms twice daily for 24 weeks. Dosage will initially be 40 mcg daily for one week, then 40 mcg BID per oral daily for the next 5 weeks. If the 40 mcg BID per oral is well tolerated in the opinion of Dr. Bedlack, the dose will be increased to 80 mcg each morning/40 mcg each evening for one week, followed by 80 mcg BID per oral for the remainder of the study. The selected target dose (80 mcg BID) is based upon the experience with the long-term administration of clenbuterol, specifically the beneficial muscle effects in a Phase I/II clinical trial that enrolled patients with late-onset Pompe disease who were previously treated with ERT (Koeberl et al. 2018). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Serious Adverse Events as Measured by Patient Reporting | The primary endpoint is safety of clenbuterol at 80 mcg BID. Adverse events and serious adverse events will be systematically gathered as the dose is increased. | Intention to treat analyses were performed for 20 participants who had at least one ALSFRS-R measurement post-treatment. | Posted | Count of Participants | Participants | Up to 24 weeks |
|
24 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Open Label Arm | This is an open label pilot trial in which 25 people with ALS will take clenbuterol orally at 40-80 micrograms twice daily for 24 weeks. Clenbuterol: The intervention is treatment with oral clenbuterol at 40-80 micrograms twice daily for 24 weeks. Dosage will initially be 40 mcg daily for one week, then 40 mcg BID per oral daily for the next 5 weeks. If the 40 mcg BID per oral is well tolerated in the opinion of Dr. Bedlack, the dose will be increased to 80 mcg each morning/40 mcg each evening for one week, followed by 80 mcg BID per oral for the remainder of the study. The selected target dose (80 mcg BID) is based upon the experience with the long-term administration of clenbuterol, specifically the beneficial muscle effects in a Phase I/II clinical trial that enrolled patients with late-onset Pompe disease who were previously treated with ERT (Koeberl et al. 2018). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Near-drowning accident | Injury, poisoning and procedural complications | Non-systematic Assessment | The participant was swimming and became submerged for some time before being rescued and recovering. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Jitters/tremors | Nervous system disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dwight Koeberl, MD,PhD | Duke University | 919-681-9919 | dwight.koeberl@duke.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 10, 2020 | Feb 14, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000690 | Amyotrophic Lateral Sclerosis |
| ID | Term |
|---|---|
| D013118 | Spinal Cord Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D016472 | Motor Neuron Disease |
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| ID | Term |
|---|---|
| D002976 | Clenbuterol |
| ID | Term |
|---|---|
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
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|
| Baseline, week 4, week 12, week 16, week 20, and week 24 |
| FVC Decline, Per-protocol Comparison | Comparison of the mean slope of percent predicted FVC during treatment versus pre-treatment. Pre-treatment slope for each participant was estimated as follows: (100%-enrollment percent predicted FVC)/months since symptom onset. | Baseline, week 4, week 12, and week 24 |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Secondary | Change in Motor Function Measured by ALSFRS-R | The ALS Functional Rating Scale (ALSFRS-R) - 12 questions rated on a five-point scale, where 0= can't do, to 5= normal ability. It is utilized for monitoring the progression of disability in patients with ALS. The critical test for efficacy was comparison of the mean slope of the ALSFRS-R during treatment compared to pre-treatment. Pre-treatment slope for each participant was estimated as follows: (48-enrollment ALSFRS-R)/months since symptom onset. A statistically significant treatment effect was determined by a two-tailed, t-test, with a critical p value < .05. Other analyses included a repeated measures ANOVA design (between and within subjects) of ALSFRS-R slopes before and during treatment. | Intention to treat analyses were performed for 20 participants who had at least one ALSFRS-R measurement post-treatment. These calculations for ALSFRS-R were based on the 11 patients who completed all 6 months on some dose of the drug, e.g. the per-protocol group. | Posted | Mean | Standard Deviation | slope | Baseline, week 4, week 12, week 16, week 20, and week 24 |
|
|
|
| Secondary | FVC Decline, Per-protocol Comparison | Comparison of the mean slope of percent predicted FVC during treatment versus pre-treatment. Pre-treatment slope for each participant was estimated as follows: (100%-enrollment percent predicted FVC)/months since symptom onset. | For the 11 patients who completed all 6 months on some dose of the drug, there were 10 who had at least two FVC measurements. Seven patients had a baseline FVC measurement which was used to calculate the pre-treatment slope estimate, for the 3 patients without a baseline measurement, imputation of the baseline FVC was performed using all data available for each patient. | Posted | Mean | Standard Deviation | slope | Baseline, week 4, week 12, and week 24 |
|
|
|
| 0 |
| 25 |
| 2 |
| 25 |
| 25 |
| 25 |
|
| Pulmonary emboli | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Patient developed pulmonary emboli during the study. |
|
| Insomnia | General disorders | Non-systematic Assessment |
|
| Cramps/spasms | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Stiffness/spasticity | Nervous system disorders | Non-systematic Assessment |
|
| Elevated liver transaminases | Hepatobiliary disorders | Non-systematic Assessment |
|
| Increased work of breathing | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Decreased appetite/weight loss | General disorders | Non-systematic Assessment |
|
| GI upset/nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Palpitations | Cardiac disorders | Non-systematic Assessment |
|
| Elevated creatine kinase (CK) | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Elevated PSA | Renal and urinary disorders | Non-systematic Assessment |
|
| Tooth removal | General disorders | Non-systematic Assessment |
|
| Pruritis | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Foot pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Restless legs | Nervous system disorders | Non-systematic Assessment |
|
| Tendinitis | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Hot flashes | General disorders | Non-systematic Assessment |
|
| Dizziness/instability | Nervous system disorders | Non-systematic Assessment |
|
| Increased fasciculations | Nervous system disorders | Non-systematic Assessment |
|
| Anxiety | Psychiatric disorders | Non-systematic Assessment |
|
| ECG changes | Cardiac disorders | Non-systematic Assessment |
|
| Elevated thyroxine (T4) | Endocrine disorders | Non-systematic Assessment |
|
| Tachycardia | Cardiac disorders | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
|
| Urinary tract infection | Renal and urinary disorders | Non-systematic Assessment |
|
| Accelerated disease progression | Nervous system disorders | Non-systematic Assessment |
|
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| D019636 | Neurodegenerative Diseases |
| D057177 | TDP-43 Proteinopathies |
| D009468 | Neuromuscular Diseases |
| D057165 | Proteostasis Deficiencies |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D000588 |
| Amines |