Amyotrophic Lateral Sclerosis (ALS)Phase 1NCT07875972
Safety, Tolerability, and Pharmacodynamic Exploration of Orelabrutinib in Patients With Amyotrophic Lateral Sclerosis (ALS)
A Phase 1 study testing Orelabrutinib in people with Amyotrophic Lateral Sclerosis (ALS), run by Liu Qing.
Trial summary
This is a single-center, open-label, dose-escalation, investigator-initiated pilot study to evaluate the safety, tolerability, dose-limiting toxicity (DLT), and pharmacodynamic signals of orelabrutinib in patients with amyotrophic lateral sclerosis (ALS). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Amyotrophic Lateral Sclerosis (ALS)
- What is being tested?
- Orelabrutinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- No sites listed yet
- Study dates
- Oct 2026to Oct 2028
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18-75 years, either sex.
- Confirmed diagnosis of ALS by a neurologist according to the Gold Coast criteria or the revised El Escorial (Airlie House) criteria, with other diseases excluded.
- Duration from disease onset to enrollment no more than 36 months.
- ALSFRS-R score ≥ 35 at screening.
- FVC% predicted ≥ 70% and SVC% predicted ≥ 70%; no resting dyspnea, orthopnea, or need for long-term non-invasive ventilation/oxygen therapy.
- Participants are able to take medication orally and are independent of enteral nutrition support (e.g., PEG, gastric tube) at screening, as judged by the principal investigator.
- Stable-dose riluzole (≥ 30 days) and/or edaravone (stable use for one course) is permitted.
- Assessed as having full capacity to provide informed consent.
Who cannot join
- Tracheostomy or use of non-invasive ventilation (NIV) > 23 h/day.
- Abnormal liver function (ALT/AST ≥ 3×ULN), abnormal renal function (eGFR < 60 mL/min/1.73 m²), absolute neutrophil count (ANC) ≤ 1.5×10⁹/L, platelet count ≤ 100×10⁹/L, or hemoglobin ≤ 100 g/L; international normalized ratio (INR) ≥ 1.5×ULN, activated partial thromboplastin time (APTT) ≥ 1.5×ULN.
- Unable to swallow or tolerate oral medication at screening.
- Prior or current malignancy.
- Known active HBV, HCV, or HIV infection, or any uncontrolled active systemic infection.
- Major surgery within 6 weeks before screening, or need for major surgery during the study period.
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- Current clinically significant cardiovascular disease, including: NYHA class 3 or 4 heart disease, such as arrhythmia, congestive heart failure, or myocardial infarction, or left ventricular ejection fraction (LVEF) < 50%; primary cardiomyopathy; history of clinically significant QTc prolongation, or QTc > 470 ms (women), QTc > 450 ms (men); uncontrolled hypertension.
- Bleeding disorders or active bleeding events within 3 months, or current use of anticoagulant/antiplatelet drugs.
- Diseases significantly affecting gastrointestinal function, such as dysphagia, chronic diarrhea, intestinal obstruction, or gastrectomy.
- Any history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severe pulmonary function impairment.
- Prior exposure to BTK pathway inhibitors.
- Current use of moderate or strong CYP3A inhibitors or strong CYP3A inducers that cannot be safely discontinued or replaced before screening; moderate CYP3A4 inducers require evaluation by a pharmacist and the investigator.
- Receipt of a live vaccine within 2 weeks or planned receipt of a live vaccine during the study period (Note: inactivated vaccines may be administered according to local regulations, but the vaccination time and AEs must be recorded).
- Substance abusers or alcohol abusers.
- Breastfeeding or pregnant women, or women of childbearing age who are unwilling to use contraceptive measures during the trial and for 180 days after the last dose of study drug.
- Unable to understand the informed consent form (ICF).
- Any other relevant medically significant condition that may pose a risk to the participant, interfere with safety assessments, or increase the risk of death during the trial.
About this study
Official title: Safety, Tolerability, and Pharmacodynamic Exploration of Orelabrutinib in Patients With Amyotrophic Lateral Sclerosis (ALS): A Single-Center, Open-Label, Single-Arm, Dose-Escalation Investigator-Initiated Clinical Study
This is a single-center, open-label, dose-escalation, investigator-initiated pilot study to evaluate the safety, tolerability, dose-limiting toxicity (DLT), and pharmacodynamic signals of orelabrutinib in patients with amyotrophic lateral sclerosis (ALS). A 12-week run-in observation period will be used to establish each participant's historical ALSFRS-R decline slope. Participants will receive orelabrutinib 50 mg once daily (QD), 100 mg QD, or optional 150 mg QD using a 3+3 dose-escalation design for 24 weeks, followed by a 4-week safety follow-up.
Read the detailed description
Orelabrutinib is an oral, irreversible, highly selective Bruton's tyrosine kinase (BTK) inhibitor. Preclinical studies suggest that BTK inhibition may suppress neuroinflammation and promote motor neuron survival through a "dual decoupling" mechanism. This study will assess safety and tolerability, pharmacokinetics (PK), BTK target occupancy, inflammatory biomarkers, and exploratory efficacy signals in patients with ALS.
- Conditions
- Amyotrophic Lateral Sclerosis (ALS)
- Being tested
- Orelabrutinib
- Keywords
- Amyotrophic Lateral Sclerosis, Orelabrutinib, BTK inhibitor, Neuroinflammation, Safety, Open-label
- Medical subject headings
- Amyotrophic Lateral Sclerosis, Neuroinflammatory Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OrelabrutinibDrug
Cohort 1 planned enrollment: 3 participants; may expand to 6 if 1/3 participants experience a dose-limiting toxicity (DLT).
Cohort 2 planned enrollment: 3 participants. This cohort will be initiated only after Cohort 1 completes the 28-day DLT observation period and the DSMB approves dose escalation.
Cohort 3 (Optional) planned enrollment: 3 participants. This cohort will be initiated only if Cohorts 1 and 2 are safe and if BTK target occupancy / PD signals suggest insufficient target coverage, with written DSMB approval.
A traditional 3+3 dose-escalation design is used,. Dose-escalation rules: If 0/3 patients experience a DLT, escalate to the next dose level; if 1/3 patients experience a DLT, expand that dose level to 6 patients; if 1/6 patients experience a DLT, escalation may proceed, whereas if ≥2/6 patients experience a DLT, the dose is deemed intolerable and escalation must stop; if ≥2/3 patients experience a DLT, escalation must stop immediately.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1: Orelabrutinib 50 mg QD | Experimental | Participants receive orelabrutinib 50 mg orally once daily (QD) for 24 weeks. Receives: Drug: Orelabrutinib |
| Cohort 2: Orelabrutinib 100 mg QD | Experimental | Participants receive orelabrutinib 100 mg orally once daily (QD) for 24 weeks. Receives: Drug: Orelabrutinib |
| Cohort 3 (Optional): Orelabrutinib 150 mg QD | Experimental | Optional exploratory cohort. Participants receive orelabrutinib 150 mg orally once daily (QD) for 24 weeks. Receives: Drug: Orelabrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Serious adverse event (SAE) incidence
ICH-GCP definition
Measured: Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28
Adverse event (AE) incidence and severity
CTCAE v5.0 grading
Measured: Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28
Dose-limiting toxicity (DLT)
Measured: Week 4
Number of subjects who discontinue treatment prematurely
Measured: Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, and Week 24
Number of patients who discontinue treatment prematurely due to adverse events
Measured: Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, and Week 24
Number of patients with clinically significant abnormal laboratory and ancillary examinations (including routine laboratory tests, cardiac safety, infection markers, bleeding markers, and new-onset tumor examinations)
Measured: Week -12, Week -8, Week -4, Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, and Week 24; tumor markers and echocardiography at Week 0, Week 4, Week 12, and Week 24; CT of the chest, abdomen, and pelvis at Week 0 and Week 24
Secondary outcomes (15)
Plasma Orelabrutinib concentration
Measured: Week 0 (pre-dose, 2 h, and 8 h); trough concentrations at Week 1, Week 4, Week 12, and Week 24
Cerebrospinal fluid (CSF) Orelabrutinib concentration
Measured: Week 0 and Week 4 (optional; only if the subject consents and the procedure is considered safe)
Peripheral blood PBMC BTK target occupancy (TOR %)
Measured: Week 0, Week 1, Week 4, Week 12, and Week 24
Peripheral blood PBMC p-BTK level
Measured: Week 0, Week 4, Week 12, and Week 24
Peripheral blood B-cell count
Measured: Week 0, Week 1, Week 4, Week 12, and Week 24
ALSFRS-R score and its rate of change slope
Measured: Week -12, Week -8, Week -4, Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28
Forced vital capacity (FVC)
Measured: Week -12, Week -8, Week -4, Week 0, Week 8, Week 16, and Week 24
Medical Research Council (MRC) Muscle Strength Score
The Medical Research Council (MRC) Muscle Strength Score ranges from 0 to 5 (minimum value: 0, maximum value: 5). Higher scores indicate better muscle strength (a better outcome), while lower scores indicate worse muscle strength (a worse outcome).
Measured: Week -12, Week -8, Week -4, Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28
Composite survival rate at 6 months of treatment(Composite endpoint of overall survival (defined as time to death from any cause) or respiratory insufficiency (defined as tracheostomy or daily use of non-invasive ventilation ≥22 hours for ≥10 consecutive
Measured: Week 24
Change from baseline to the follow-up time point in ALSAQ-40 quality of life
Measured: Week -12, Week 0, Week 4, Week 12, and Week 24
Slow vital capacity (SVC)
Measured: Week -12, Week -8, Week -4, Week 0, Week 8, Week 16, and Week 24
Cerebrospinal fluid (CSF)-to-plasma concentration ratio
Measured: Week 0 and Week 4 (optional; only if the subject consents and the procedure is considered safe)
Change from baseline to the follow-up time point in EuroQol 5-Dimension (EQ-5D)
Measured: Week -12, Week 0, Week 4, Week 12, and Week 24
Change from baseline to the follow-up time point in Mini-Mental State Examination (MMSE)
Measured: Week -12, Week 0, Week 4, Week 12, and Week 24
Change from baseline to the follow-up time point in Edinburgh Cognitive and Behavioural ALS Screen (ECAS)
Measured: Week -12, Week 0, Week 4, Week 12, and Week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Oct 2026
- Study startOct 2026 (estimated)
- Primary completionSep 2028 (estimated)
- Study completionOct 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Amyotrophic Lateral Sclerosis (ALS)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Liu Qing
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Liu Qing, Peking Union Medical College Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07875972
- Sponsor's protocol ID
- I-26PJ2099
- Status last verified
- Oct 2026
- First submitted
- 28 Sep 2026
- Last updated
- 15 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No