Neurodegenerative Alzheimer's Disease and Amyotrophic Lateral Sclerosis (NADALS) Basket Trial

NCT05189106 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: NADALS
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Amyotrophic Lateral Sclerosis; Alzheimer Disease; Mild Cognitive Impairment

Keywords

Amyotrophic Lateral Sclerosis; Alzheimer Disease; Mild Cognitive Impairment; Baricitinib; Dementia; C9ORF72

Outcome Measures

Primary Outcomes (2)

• CSF Concentration of baricitinib

  Total levels of baricitinib in the CSF of participants 2 hours after 2 mg and 4 mg oral dosing of baricitinib.

  Measured at baseline, 8 weeks and 16 weeks, results reported at the completion of the study

• CSF CCL2 Concentration

  The inflammatory biomarker CCL2 quantified in the CSF of participants after 2 mg of 4 mg oral dose relative to baseline.

  Measured at baseline, 8 weeks and 16 weeks, results reported at the completion of the study

Secondary Outcomes (11)

• CSF protein-kinase R (PKR) Concentration

  Measured at baseline, 8 weeks and 16 weeks, results reported at the completion of the study

• CSF phospho-PKR (pPKR) Concentration

  Measured at baseline, 8 weeks and 16 weeks, results reported at the completion of the study

• CSF pPKR/PKR ratio Concentration

  Measured at baseline, 8 weeks and 16 weeks, results reported at the completion of the study

• CSF C-X-C motif chemokine ligand 10 (CXCL10) Concentration

  Measured at baseline, 8 weeks and 16 weeks, results reported at the completion of the study

• CSF interferon gamma (IFNG) Concentration

  Measured at baseline, 8 weeks and 16 weeks, results reported at the completion of the study

Study Arms (1)

Baricitinib

EXPERIMENTAL

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

Drug: Baricitinib

Interventions

Baricitinib DRUG

Each participant will be treated with open-label baricitinib for 24 weeks. Participants will receive 2 mg baricitinib by mouth daily for the first 8 weeks and 4 mg baricitinib by mouth daily for the remaining 16 weeks.

Also known as: Olumiant, INCB28050, LY3009104

Baricitinib

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• Study participants meeting any of the following criteria during screening evaluations will be excluded from entry into the study:
• Women who are pregnant, breastfeeding, or planning to become pregnant during the trial
• Any unstable clinically significant medical condition other than ALS or AD (e.g., within six months of baseline, including but not limited to myocardial infarction, angina pectoris, congestive heart failure, or neoplasm undergoing active treatment).
• Active cancer or history of cancer, except for the following: basal cell carcinoma, cervical carcinoma in situ, prostatic carcinoma in situ, or other malignancies curatively treated and with no evidence of disease recurrence for at least 5 years. Active cancer includes cancers with current disease manifestations or therapy that could adversely affect participant safety and longevity, create the potential for drug-drug interactions, or compromise the interpretation of study results.
• History of diverticulitis or bowel perforation.
• Active ulcerative colitis, Crohn's disease, and history of peptic ulcer disease within the past 5 years or after the age of 65.
• Active, serious infection, including localized infection in the opinion of the investigator.
• Positive for latent or active tuberculosis (TB). Note: Patients with a history of latent or active TB must have had an adequate course of treatment documented prior to study participation.
• Evidence of active hepatitis B or C infection.
• History of severe hepatic or renal impairment.
• eGFR \< 60 mL/min/1.73 m2
• Have any of the following specific abnormalities on screening laboratory tests:
• ALT or AST \>2.5x upper limits of normal (ULN)
• Alkaline phosphatase (ALP) ≥2x ULN
• Total bilirubin ≥1.5x ULN, Note: patients with elevated bilirubin secondary to Gilbert's disease are eligible to participate in the study.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Congressionally Directed Medical Research Programs: collaborator

Study Sites (2)

Massachusetts General Hospital - ALS Site

Boston, Massachusetts, 02129, United States

Location

Massachusetts General Hospital - AD Site

Charlestown, Massachusetts, 02129, United States

Location

Related Publications (2)

• Rodriguez S, Sahin A, Schrank BR, Al-Lawati H, Costantino I, Benz E, Fard D, Albers AD, Cao L, Gomez AC, Evans K, Ratti E, Cudkowicz M, Frosch MP, Talkowski M, Sorger PK, Hyman BT, Albers MW. Genome-encoded cytoplasmic double-stranded RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss. Sci Transl Med. 2021 Jul 7;13(601):eaaz4699. doi: 10.1126/scitranslmed.aaz4699.

  PMID: 34233951 BACKGROUND

• Rodriguez S, Hug C, Todorov P, Moret N, Boswell SA, Evans K, Zhou G, Johnson NT, Hyman BT, Sorger PK, Albers MW, Sokolov A. Machine learning identifies candidates for drug repurposing in Alzheimer's disease. Nat Commun. 2021 Feb 15;12(1):1033. doi: 10.1038/s41467-021-21330-0.

  PMID: 33589615 BACKGROUND

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis; Alzheimer Disease; Cognitive Dysfunction; Dementia; Frontotemporal Dementia With Motor Neuron Disease

Interventions

baricitinib

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Brain Diseases; Tauopathies; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Study Officials

• Mark W Albers, MD, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 30, 2021
• First Posted: January 12, 2022
• Study Start: December 5, 2022
• Primary Completion: April 24, 2025
• Study Completion: June 20, 2025
• Last Updated: January 2, 2026

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: De-identified data set will be made available to researchers after completion and full publication of the trial.
• Access Criteria: All requests for sharing will be reviewed by the NADALS Steering Committee.

Locations

US (2)