Baricitinib for Alzheimer's & ALS

(NADALS Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether baricitinib, a medication, can help manage Alzheimer's and ALS by reducing brain inflammation. Participants will receive baricitinib over 24 weeks, starting with a lower dose for the first 8 weeks, then increasing the dose for the remaining 16 weeks. The trial is open to individuals with Alzheimer's, ALS, or those carrying certain genetic markers related to these conditions, particularly if they show signs of brain inflammation. People with mild to moderate memory issues or those diagnosed with ALS who can walk at least within their home might be suitable candidates. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that baricitinib is likely to be safe for humans?

Research has shown that baricitinib is generally safe for humans. It has treated conditions like rheumatoid arthritis, providing some reassurance about its safety in this trial. Studies involving over 3,770 patients have demonstrated a consistent safety record, with no unexpected safety issues found.

However, specific safety information for baricitinib in treating Alzheimer's disease and ALS (a disease affecting nerve cells in the brain and spinal cord) is not yet available. As the trial is in its early stages, researchers are focusing on understanding its safety and possible side effects. While baricitinib has been well-tolerated in the past, researchers are still confirming its safety specifically for Alzheimer’s and ALS. ^{1 2 3 4 5}

Why are researchers excited about this possible treatment for Alzheimer's and ALS?

Baricitinib is unique because it targets the Janus kinase (JAK) pathway, which plays a role in inflammation and immune responses. Most treatments for Alzheimer's and ALS focus on managing symptoms rather than addressing underlying inflammatory processes. By inhibiting specific JAK enzymes, Baricitinib could potentially reduce inflammation in the brain and nervous system, offering a novel approach to treating these conditions. Researchers are excited about its potential to modify the disease process itself, which could lead to more effective long-term outcomes for patients.

What evidence suggests that baricitinib could be an effective treatment for Alzheimer's and ALS?

Research has shown that baricitinib may help with brain inflammation, which is linked to diseases like Alzheimer's and ALS. In some studies, 73% of ALS patients responded well to baricitinib, compared to 45% who did not receive it. This suggests it might help reduce symptoms or slow these diseases. Baricitinib targets inflammation, potentially easing brain-related symptoms. However, its effectiveness for Alzheimer's remains debated because it may not reach the brain well at normal doses. Participants in this trial will receive baricitinib to further investigate its potential benefits for these conditions. ^{1 2 3 6 7}

Who Is on the Research Team?

Mark W Albers, MD, PhD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05189106

NCT05189106 | Neurodegenerative Alzheimer's Disease ... This is an open-label, biomarker-driven basket trial of baricitinib in individuals with mild cognitive impairment (MCI), subjective cognitive decline (SCD), AD, ...

2. alzdiscovery.org alzdiscovery.org/uploads/cognitive_vitality_media/Baricitinib.pdf

Baricitinib At 12 weeks of treatment, efficacy outcomes including disease activity (as measured by SDAI) and reduction in progression of joint damage (as ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10962475/

Baricitinib and tofacitinib off‐target profile, with a focus on ... The results suggest a low likelihood of successful repurposing in AD due to low brain permeability, even at the maximum recommended daily dose. While additional ...

4. withpower.com withpower.com/trial/phase-2-amyotrophic-lateral-sclerosis-1-2022-f2405

Baricitinib for Alzheimer's & ALS (NADALS Trial) What data supports the effectiveness of the drug Baricitinib for ALS? ... outcomes, with 73% of patients showing positive responses compared to 45% in the ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0024320524004284

A potential role of JAK2/STAT3-PI3K/AKT/mTOR signaling ... BAR could be an effective therapy against neuroinflammation, astrogliosis and cognitive impairment induced by OVX/ D-gal where inhibiting JAK2/STAT3- AKT/PI3K/ ...

6. pharmacytimes.com pharmacytimes.com/view/baricitinib-demonstrates-consistent-safety-profile-in-patients-with-rheumatoid-arthritis

Baricitinib Demonstrates Consistent Safety Profile in ... The investigators analyzed the safety of baricitinib across 9 randomized studies and 1 long-term extension study in a total of 3770 patients.

7. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.12445

Baricitinib and tofacitinib off‐target profile, with a focus on ... The results suggest a low likelihood of successful repurposing in AD due to low brain permeability, even at the maximum recommended daily dose.