Baricitinib for Alzheimer's & ALS

(NADALS Trial)

Recruiting at 3 trial locations

Overseen By Katharine A Nicholson, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Massachusetts General Hospital

Must not be taking: Aducanumab, OAT3 inhibitors

Disqualifiers: Pregnancy, Active cancer, Severe infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 24 weeks

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests baricitinib, a pill taken daily, in people with early signs of Alzheimer's or ALS, or those at risk. The goal is to see if it can reduce harmful inflammation in the brain. Participants will take the medication for several months to check if it reaches the brain and lowers inflammation. Baricitinib is used for the treatment of rheumatoid arthritis and has shown promising preliminary data for moderate-to-severe atopic dermatitis.

Do I need to stop taking my current medications to join the trial?

The trial requires that participants either not be taking or be on a stable dose of any FDA-approved treatment for ALS or AD for at least 30 days prior to screening. Additionally, certain medications like strong OAT3 inhibitors and Aducanumab must be stopped within 30 days of screening.

What data supports the effectiveness of the drug Baricitinib for ALS?

Research suggests that Baricitinib, a Janus kinase inhibitor, could be effective for ALS because it can penetrate the central nervous system and positively affect the immune system, potentially reducing disease progression. ^{1 2 3 4 5}

Is Baricitinib safe for use in humans?

Baricitinib, also known as Olumiant or LY3009104, has been studied for various conditions, and its safety profile is generally considered acceptable based on previous research. It has been used in humans for other conditions, which suggests it is generally safe, but specific safety data for Alzheimer's and ALS is not provided in the available research. ^{1 2 3 6 7}

How is the drug Baricitinib different from other treatments for Alzheimer's and ALS?

Baricitinib is unique because it is primarily used as a treatment for rheumatoid arthritis and works by inhibiting Janus kinases (JAKs), which are enzymes involved in inflammation. This mechanism is different from current Alzheimer's treatments, which often focus on neurotransmitter systems or amyloid plaques. ^{8 9 10 11 12}

Research Team

Mark W Albers, MD, PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Adults aged 55-90 with cognitive issues like Alzheimer's or mild impairment, and those aged 18-80 with ALS or carrying an ALS-related gene. Participants must have up-to-date vaccinations including Shingrix and COVID-19, be able to consent, and for those with AD, a MoCA score ≥8 plus a study partner is required. For ALS patients: stable on FDA treatments if any, able to walk at home daily, and life expectancy over 12 months.

Inclusion Criteria

I am between 18-80 years old and have been diagnosed with ALS or carry an ALS-causing gene.

I am between 55 and 90 years old and have been experiencing memory problems or have been diagnosed with a cognitive disorder.

Up-to-date immunization records per CDC guidelines

Exclusion Criteria

I have been treated with baricitinib before.

I have not had major surgery in the last 8 weeks and do not need any during the study.

You have an active hepatitis B or C infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive baricitinib 2 mg per day for the first 8 weeks and 4 mg per day for the remaining 16 weeks

24 weeks

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Baricitinib

Trial Overview The trial tests baricitinib in participants with various neurodegenerative conditions over 24 weeks without using a placebo. It starts at a lower dose for the first eight weeks before doubling. The goal is to see if it can reach therapeutic levels in the brain/spinal fluid and reduce inflammation markers linked to these diseases.

Participant Groups

Group I: Baricitinib Experimental Treatment 1 Intervention

Baricitinib 2mg administered by mouth once daily for the first 8 weeks, followed by baricitinib 4mg administered by mouth once daily for 16 weeks.

Baricitinib is already approved in United States, European Union for the following indications:

Approved in United States as Olumiant for:

• Rheumatoid arthritis
• Severe alopecia areata
• COVID-19

Approved in European Union as Olumiant for:

• Rheumatoid arthritis
• Severe alopecia areata
• COVID-19

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Findings from Research

Riluzole is currently the only approved treatment for ALS, but its efficacy is mild, and despite extensive research, most clinical trials for new ALS treatments have not shown significant benefits.

Recent studies on oral masitinib and intravenous edaravone suggest they may be promising new therapies for ALS, with masitinib including a broader patient population in its trials compared to edaravone, which could impact their future use in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment? Petrov, D., Mansfield, C., Moussy, A., et al.[2022]

A signal was detected indicating a potential link between statin use and amyotrophic lateral sclerosis (ALS) based on reports in the FDA's adverse event reporting system, with 91 cases identified.

However, a comprehensive analysis of 41 long-term clinical trials involving around 200,000 patient-years of exposure showed no increased incidence of ALS in patients treated with statins compared to those on placebo, suggesting that the initial signal may not indicate a true causal relationship.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA's spontaneous adverse event reporting system. Colman, E., Szarfman, A., Wyeth, J., et al.[2019]

In a study involving 400 ALS patients treated with riluzole, pentoxifylline did not improve survival rates compared to placebo, with a significant adjusted risk indicating a potential negative effect on survival (p = 0.02).

While pentoxifylline was associated with some adverse reactions like nausea and flushing, these were reversible upon discontinuation, but the drug is not recommended for ALS patients due to its lack of benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pentoxifylline in ALS: a double-blind, randomized, multicenter, placebo-controlled trial. Meininger, V., Asselain, B., Guillet, P., et al.[2013]

Donanemab, administered at a dose of 10 mg/kg, was generally well tolerated in patients with mild cognitive impairment or mild to moderate Alzheimer's disease, showing a significant reduction of amyloid deposits by 40% to 50%.

Despite a shorter than expected half-life of approximately 10 days at the highest dose, about 90% of subjects developed anti-drug antibodies within 3 months, indicating a robust immune response to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donanemab (LY3002813) dose-escalation study in Alzheimer's disease. Lowe, SL., Willis, BA., Hawdon, A., et al.[2022]

In a study of 166 patients with moderately severe to severe dementia, memantine treatment resulted in a significant improvement in clinical outcomes, with 73% of patients showing positive responses compared to 45% in the placebo group.

Memantine also led to a notable reduction in care dependence, with an average improvement of 3.1 points on the Behavioral Rating Scale compared to 1.1 points for placebo, indicating its efficacy in enhancing daily functioning without significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Winblad, B., Poritis, N.[2019]

In a double-blind, randomized, placebo-controlled trial involving subjects with multiple sclerosis and cognitive impairment, memantine did not show any significant improvement in cognitive performance compared to placebo, as measured by the PASAT and CVLT-II tests.

While memantine was generally safe with no serious adverse events reported, it was associated with increased fatigue and neurological side effects, and family members reported less cognitive improvement and more neuropsychiatric symptoms in those taking memantine compared to those on placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Lovera, JF., Frohman, E., Brown, TR., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment? [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Long-term survival analysis of masitinib in amyotrophic lateral sclerosis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Emerging Drugs for the Treatment of Amyotrophic Lateral Sclerosis: A Focus on Recent Phase 2 Trials. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis. [2023]

6. England pubmed.ncbi.nlm.nih.gov

An evaluation of a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA's spontaneous adverse event reporting system. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Pentoxifylline in ALS: a double-blind, randomized, multicenter, placebo-controlled trial. [2013]

8. United States pubmed.ncbi.nlm.nih.gov

Donanemab (LY3002813) dose-escalation study in Alzheimer's disease. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Alzheimer's disease and the glutamate NMDA receptor. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. [2021]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic strategies for Alzheimer's disease in clinical trials. [2020]