Pilot Trial Utilizing β-hydroxy-β-methylbutyrate to Lower IGFBP7 Levels in People With ALS

This will be a widely inclusive, three-center, open-label pilot trial enrolling 100 people living with ALS. Duke (25 participants) and Temple (25 participants) will be traditional sites that consent, screen and follow participants in person, Everything ALS (50 participants) will be a decentralized site providing virtual consenting, screening and follow up. The total time commitment will be 9 months. All participants who pass screening will provide demographics, disease characteristics, co-morbidities, and concomitant medications. They will have a baseline ALSFRS-R score obtained, a baseline slope of Listener Effort Prediction Model (LEPM)-predicted Listener Effort (LE) progression, and Motor Movement Exam (MME) score. For those who enroll at Duke or Temple, blood will be drawn for neurofilament light chain (NfL) and IGFBP7 levels. For patients at Duke or Temple who consent to lumbar puncture, CSF will be drawn for NfL and IGFBP7 levels as well. Each month after baseline, participants will be contacted by phone by each site's study coordinator to review adverse events, new co-morbidities, and concomitant medications, and to generate a new clinician-administered ALSFRS-R score. For Duke and Temple participants, at month 1, 3 and 6 they will be asked to return for in person blood draws for NfL and IGFBP7 levels. Those who sign the additional consent for lumbar punctures will have CSF drawn as well and this will be checked for NfL and IGFBP7 levels at month 3, too. LSFRS-R is routinely measured as part of clinical care. All of the described blood tests and investigational treatments are being performed exclusively for research purposes. HMB will be given at a dose of 3g daily.

• β-hydroxy-β-methylbutyrate (HMB) (Drug): Our source of HMB will be Life Extension's "Wellness Code Muscle Strength \& Restore Formula. The dose will be 3g daily, which has previously been shown to be safe and well-tolerated, and to reduce IGFBP7 blood levels in humans.

Primary outcomes

• ALS Functional Rating Scale, Revised (ALSFRS-R) [Baseline, month 3, month 9]: A quickly administered (five minute) ordinal rating scale (ratings 0-4) used to determine patients' assessments of their capability and independence in 12 functional activities. All 12 activities are relevant to people living with ALS.The ALSFRS-R declines linearly with time over a wide range during the course of ALS and it has been validated for telephone use. The ALSFRS-R Range is 0-48. The more points, the better the person is functioning.
• Speech (Listener Effort) [Baseline, month 3, month 9]: Listener effort (LE) is a perceptual rating of the amount of work necessary for a listener to understand speech, rated by an expert speech-language pathologist on a visual analog scale from 0 (easily understood) - 100 (unintelligible even with full effort) and it has proven to be one of the most robust overall measures of dysarthria.

Secondary outcomes

• Neurofilament Light Chain levels (blood) [Baseline, month 3, and month 6]: Neurofilaments are neuron-specific components of the cytoskeleton. They exist in heavy, medium, and light chain forms. Neurofilament light chain levels are elevated in the spinal fluid and the blood of patients with ALS and other neurodegenerative diseases, and higher levels predict more severe disease progression.
• Neurofilament Light Chain levels (Cerebrospinal fluid (CSF)) [Baseline, month 3]: Neurofilaments are neuron-specific components of the cytoskeleton. They exist in heavy, medium, and light chain forms. Neurofilament light chain levels are elevated in the spinal fluid and the blood of patients with ALS and other neurodegenerative diseases, and higher levels predict more severe disease progression.
• Insulin-like growth-factor binding protein 7 (IGFBP7) levels (blood) [Baseline, month 3 and month 6]: Non-competitive inhibitor of the IGF-1 receptor
• Insulin-like growth-factor binding protein 7 (IGFBP7) levels (Cerebrospinal fluid (CSF)) [Baseline, month 3]: Non-competitive inhibitor of the IGF-1 receptor
• Frequency of ALS reversals [6 months]: Frequency of ALS reversals will be calculated as the number of participants who have an ALSFRS-R score that improves by 4 points or more over 6 months of treatment.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Male or female aged at least 18 years.
2. Sporadic or familial ALS diagnosed as per Gold Coast Criteria (37).
3. Patient is able to understand and express informed consent (in the opinion of the site investigator).
4. Patient is able to read and write English.
5. Patient is expected to survive for the duration of the trial.
6. Women must not be pregnant (will have evidence of a negative pregnancy test obtained by study team at baseline, or by local physician within past 7 days or be post-menopausal)
7. Women must not be able to become pregnant (e.g., post-menopausal, surgically sterile, or using adequate birth control methods) for the duration of the study and three months after study completion. Adequate contraception includes abstinence, hormonal contraception (oral contraception, implanted contraception, injected contraception, or other hormonal contraception, for example patch or contraceptive ring), intrauterine device (IUD) in place for ≥ 3 months, barrier method in conjunction with spermicide, or another adequate method.

Exclusion Criteria:

1. Actively or recently (within past 30 days) participating in another intervention trial.
2. Currently or recently (within 30 days) taking HMB
3. Prior side effects from HMB deemed to be significant by the investigator
4. Patient has a medical or psychiatric illness that could in the investigator's opinion interfere with the patient's ability to participate in this study.
5. Pregnant women or women currently breastfeeding.
6. Elevated serum calcium or vitamin D levels.
7. Life expectancy shorter than the duration of the trial.

• Richard Bedlack, MD, PhD, Principal investigator, Duke University