Neurodegenerative Alzheimer's Disease and Amyotrophic Lateral Sclerosis (NADALS) Basket Proof of Concept Trial Including Asymptomatic Individuals Using Baricitinib
This is an open-label, biomarker-driven basket trial of baricitinib in people with subjective cognitive disorder, mild cognitive impairment, Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), or asymptomatic carriers of an ALS-related gene, such as a hexanucleotide expansion in the C9ORF72 gene, with evidence of abnormal inflammatory signaling in cerebrospinal fluid (CSF) at baseline. Each participant will be treated with baricitinib for 24 weeks; no placebo will be given. Participants will receive baricitinib 2 mg per day by mouth for the first 8 weeks and baricitinib 4 mg per day by mouth for the remaining 16 weeks. This proof of concept trial will ascertain whether baricitinib at 2 mg per day, 4 mg per day, or both reaches therapeutic levels in the CSF and suppresses inflammatory biomarkers associated with type I interferon signaling among the study participants.
∙ Study participants meeting all of the following criteria will be allowed to enroll in the study:
• Must be 55-90 years old, inclusive and have one of the following:
‣ Subjective cognitive decline(SCD)
⁃ Minor neurocognitive disorder(mild cognitive impairment(MCI))
⁃ Major neurocognitive disorder(possible or probable AD) OR
• Must be 18-80 years old, inclusive and have one of the following:
⁃ Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by the revised El Escorial criteria
⁃ Asymptomatic carrier of an ALS-causative mutation per CLIA-certified genetic testing results (MGH site only)
• Screening CSF level of CCL2 level ≥ 250 pg/mL
• Up-to-date immunization records per CDC guidelines
‣ Routine vaccinations should be administered at a minimum of 14 days prior to any study visit with an LP
• Must have received the Recombinant Zoster Vaccine (RZV, also known as Shingrix) within 4 years prior to enrollment. Note: Only one dose of RZV is needed prior to the Baseline Visit.
• Must be fully vaccinated for COVID-19 per CDC guidelines
‣ If a participant is planning to receive a COVID-19 booster shot, should be administered a minimum of 14 days prior to the Screening LP.
• For participants with ALS:
‣ Must either not be taking or be on a stable dose of any FDA approved treatment for ALS for at least 30 days or at least 1 cycle prior to screening
⁃ ALSFRS-R score ≥ 27
⁃ Must be ambulatory, defined as able to walk at least within the home every day. Use of gait assistive devices is allowed. Some use of a wheelchair is also allowed.
⁃ Greater than 12-month life expectancy in the opinion of the investigator
• For participants with AD:
⁃ MoCA score ≥ 8
⁃ The participant must have a study partner that can accompany them to every visit and co-sign any informed consent document.
⁃ Must either not be taking or be on a stable dose of any FDA approved treatment for AD for at least 30 days prior to screening. Participants cannot be taking Aducanumab(see exclusion criterion #15).
• Ability to medically undergo LP in the opinion of the investigator (e.g., no bleeding disorder, allergy to local anesthetics, prior lumbar surgery which might make LP difficult, a skin infection at or near the LP site, evidence of high intracranial pressure, or anticipated difficulty getting into position for LP).
• Capable of providing informed consent and following study procedures.
‣ In the case that a participant lacks the ability to provide informed consent, informed consent will be obtained from the participant's surrogate representative and assent obtained from the participant.