ALT001 in Patients With Ischemic Stroke in the Sequelae Stage
A Randomised, Double-blind, Placebo-controlled, Multicentre, Phase II Clinical Study to Evaluate the Efficacy and Safety of ALT001 in Patients With Ischemic Stroke in the Sequelae Stage
This is a phase II, randomized, double-blind, placebo-controlled, multicentre clinical study to evaluate the efficacy and safety of ALT001 in patients with ischemic stroke in the sequelae stage (≥180 days and ≤5 years after the most recent event). A total of 200 participants will be randomized 1:1:1:1 to receive ALT001 at 65 μg/day, 130 μg/day, or 260 μg/day, or matching placebo, by intravenous infusion once daily (over ~60 minutes) using a 14-day-on / 14-day-off cycle for 3 cycles (12 weeks) in the double-blind (DB) period, followed by an optional open-label extension (OLE) period of 3 additional cycles. The primary endpoint is the change from baseline in the Fugl-Meyer Assessment (FMA) motor score at Week 12.
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Descrição detalhada
Ischemic stroke (IS) is the most common type of stroke, yet for patients with persistent neurological deficits beyond 6 months (sequelae stage) there is no widely accepted effective therapy. ALT001 is an allogeneic unrelated human umbilical cord mesenchymal stem cell-derived protein complex intended to promote neurological repair. This phase II study enrolls adults (18-80 years) with unilateral limb weakness (FMA motor score ≤90) and modified Ashworth spasticity ≤2, at least 180 days but no more than 5 years after the most recent ischemic stroke. Participants are randomized to one of three ALT001 dose groups (65, 130, or 260 μg/day) or matching placebo. Study drug is reconstituted in 100 mL normal saline and given by IV infusion once daily over ~60 minutes, 14 days on / 14 days off per cycle, for 3 cycles in the DB period. Eligible participants may then enter a 3-cycle OLE period (placebo group re-randomized to an active dose). Efficacy is assessed by FMA (primary, Week 12), mRS, NIHSS, Barthel Index, and modified Ashworth scale; safety by AE/SAE monitoring; exploratory outcomes include new vascular events and immunologic/cytokine changes.
Tipo de estudo
Inscrição (Estimado)
Estágio
- Fase 2
Contactos e Locais
Contato de estudo
- Nome: Ning Wu, Director of Clinical Operations
- Número de telefone: +86-18228071008
- E-mail: wuning@darwincell.net
Locais de estudo
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Beijing Municipality
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Beijing, Beijing Municipality, China, 100070
- Capital Medical University Affiliated Beijing Tiantan Hospital
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Contato:
- Yilong Wang, MD, Principal Investigator
- Número de telefone: +86 139 1166 6571
- E-mail: yilong528@gmail.com
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
Inclusion Criteria:
Participants must meet all of the following criteria to be eligible for enrollment in this study:
- Male or female participants aged 18 to 80 years, inclusive (determined at the time of signing the informed consent form);
- A history of acute ischemic stroke confirmed by CT or MRI, with the most recent stroke occurring ≥180 days and no more than 5 years prior to enrollment;
- Unilateral limb weakness, with a total Fugl-Meyer Motor score ≤90;
- Modified Ashworth Scale score ≤2;
- Premorbid mRS ≤1 (i.e., independence in daily living prior to the most recent stroke);
- On a stable-dose standard treatment for secondary prevention of ischemic stroke (antiplatelet agents, statins, etc.) for at least 1 month prior to enrollment;
- Participants must be willing and able to participate in the study, sign the informed consent form, and commit to completing all study-related procedures and visits in accordance with the protocol.
Exclusion Criteria:
Participants who meet any of the following criteria will be excluded from this study:
- The culprit lesion of the most recent stroke is a posterior circulation infarct on imaging;
- Baseline head CT or MRI showing malformations, tumors, abscesses, or other major non-vascular brain diseases (e.g., multiple sclerosis, dementia, Parkinson's disease, and other neurodegenerative diseases);
- A cerebrovascular or cardiovascular event within the past 3 months, such as transient ischemic attack (TIA) or acute coronary syndrome (ACS);
- History of recurrent seizures or epilepsy;
- Allergic constitution (allergies to multiple drugs and foods), history of severe allergic/hypersensitivity reactions, or, in the investigator's judgment, potential allergy to the investigational drug or any of its components (e.g., history of allergy to protein-based drugs);
- At screening: positive for hepatitis B surface antigen (HBsAg) with HBV-DNA above the upper limit of normal (ULN) (if HBsAg is negative, HBV-DNA testing is not required); positive for hepatitis C antibody (anti-HCV) with HCV-RNA above the ULN (if anti-HCV is negative, HCV-RNA testing is not required); positive for human immunodeficiency virus (HIV) antibody; or positive for Treponema pallidum antibody;
- Severe hepatic impairment (defined as ALT ≥3 × ULN or AST ≥3 × ULN); severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²); severe heart failure (New York Heart Association [NYHA] class III-IV); or coagulation disorders or a history of systemic bleeding;
- Poorly controlled blood glucose or blood pressure despite systematic treatment (HbA1c ≥8.5%; systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg);
- At screening, severe autoimmune diseases, myeloproliferative disorders, leukemia or lymphoma, malignant tumors, fractures, or severe scoliosis that, in the investigator's judgment, would affect the study evaluation;
- Significant cognitive impairment (per MMSE: ≤19 for the illiterate group, ≤22 for the primary school group, ≤26 for the junior high school and above group [>8 years of education]), or other unstable psychiatric conditions that, in the investigator's judgment, render the participant unsuitable for the study (including suicidal ideation, untreated major depression, etc.), or aphasia (aphasia severity grade 0) such that the participant cannot understand and/or comply with the study procedures;
- Women who are pregnant or breastfeeding, or participants planning to conceive during the treatment period or within 3 months after treatment discontinuation;
- Alcohol dependence or a history of drug abuse within 6 months prior to screening that, in the investigator's judgment, renders the participant unsuitable for this study;
- Use of neuroprotective agents within 14 days prior to randomization, such as butylphthalide, edaravone, edaravone dexborneol, urinary kallidinogenase, citicoline, cerebroprotein hydrolysate, etc., or use of traditional Chinese medicine preparations with an indication of stroke;
- Participation in another clinical trial with use of any other investigational drug or device within 3 months prior to screening; or prior receipt of stem cell therapy or gene therapy;
- Patients who, in the investigator's judgment, are unsuitable for participation in this study (e.g., clinically significant abnormalities on physical examination or laboratory tests).
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Quadruplicar
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
|---|---|
|
Experimental: ALT001 65 μg/day
A total of 50 participants in the active treatment arm. ALT001 65 μg/day (~1.0 μg/kg), reconstituted in 100 mL normal saline, IV infusion once daily over ~60 minutes; 14 days on / 14 days off per cycle; 3 cycles in DB period. |
A total of 150 participants in the active treatment arm were randomized in a 1:1:1 ratio to the 65 μg/day ALT001 treatment group, the 130 μg/day ALT001 treatment group, or the 260 μg/day ALT001 treatment group, with 50 participants in each group. For each treatment group, according to the assigned dose, ALT001 was dissolved in 100 mL of normal saline injection and administered by intravenous infusion once daily, completed within approximately 60 minutes. Dosing schedule: Fourteen days of continuous dosing followed by 14 days off constituted one cycle. The DB period consisted of 3 consecutive cycles, Participants who complete the DB period will enter the OLE treatment period, using the same administration method as in the DB period. The active treatment groups will continue to receive the dose level of their assigned dose group, and the OLE period consisted of 3 consecutive cycles. |
|
Experimental: ALT001 130 μg/day
A total of 50 participants in the active treatment arm. ALT001 130 μg/day (~2.0 μg/kg), same administration schedule as Arm 1. |
A total of 150 participants in the active treatment arm were randomized in a 1:1:1 ratio to the 65 μg/day ALT001 treatment group, the 130 μg/day ALT001 treatment group, or the 260 μg/day ALT001 treatment group, with 50 participants in each group. For each treatment group, according to the assigned dose, ALT001 was dissolved in 100 mL of normal saline injection and administered by intravenous infusion once daily, completed within approximately 60 minutes. Dosing schedule: Fourteen days of continuous dosing followed by 14 days off constituted one cycle. The DB period consisted of 3 consecutive cycles, Participants who complete the DB period will enter the OLE treatment period, using the same administration method as in the DB period. The active treatment groups will continue to receive the dose level of their assigned dose group, and the OLE period consisted of 3 consecutive cycles. |
|
Experimental: ALT001 260 μg/day
A total of 50 participants in the active treatment arm. ALT001 260 μg/day (~4.0 μg/kg), same administration schedule as Arm 1. |
A total of 150 participants in the active treatment arm were randomized in a 1:1:1 ratio to the 65 μg/day ALT001 treatment group, the 130 μg/day ALT001 treatment group, or the 260 μg/day ALT001 treatment group, with 50 participants in each group. For each treatment group, according to the assigned dose, ALT001 was dissolved in 100 mL of normal saline injection and administered by intravenous infusion once daily, completed within approximately 60 minutes. Dosing schedule: Fourteen days of continuous dosing followed by 14 days off constituted one cycle. The DB period consisted of 3 consecutive cycles, Participants who complete the DB period will enter the OLE treatment period, using the same administration method as in the DB period. The active treatment groups will continue to receive the dose level of their assigned dose group, and the OLE period consisted of 3 consecutive cycles. |
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Comparador de Placebo: Placebo
ALT001 matching placebo (simulator) without active ingredient, same administration schedule; in the OLE period, placebo-group participants are re-randomized to one of the three active dose groups for 3 cycles (12 weeks). |
The placebo group consisted of 50 participants. The placebo was dissolved in 100 mL of normal saline injection and administered by intravenous infusion once daily, completed within approximately 60 minutes. Dosing schedule: Fourteen days of continuous dosing followed by 14 days off constituted one cycle. The DB period consisted of 3 consecutive cycles, and the OLE period consisted of 3 consecutive cycles. Participants who complete the DB period will enter the OLE treatment period. The placebo group will be randomly assigned to the 3 dose groups and receive treatment for 3 consecutive cycles (12 weeks). |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Change from baseline in Fugl-Meyer Assessment (FMA) motor score
Prazo: Week 12 (double-blind period)
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The Fugl-Meyer Assessment (FMA) is used to evaluate the motor function of patients with ischemic stroke. It comprises an upper-extremity motor function subscore (66 points) and a lower-extremity motor function subscore (34 points), for a total of 100 points. Total-score grading: 0-49 = severe motor impairment; 50-84 = marked motor impairment; 85-95 = moderate motor impairment; 96-99 = mild motor impairment. |
Week 12 (double-blind period)
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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Change from baseline in the Fugl-Meyer Assessment (FMA) Motor score
Prazo: After 4 and 8 weeks of treatment during the double-blind treatment period
|
The Fugl-Meyer Assessment (FMA) is used to evaluate the motor function of patients with ischemic stroke. It comprises an upper-extremity motor function subscore (66 points) and a lower-extremity motor function subscore (34 points), for a total of 100 points. Total-score grading: 0-49 = severe motor impairment; 50-84 = marked motor impairment; 85-95 = moderate motor impairment; 96-99 = mild motor impairment. |
After 4 and 8 weeks of treatment during the double-blind treatment period
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Change from baseline in modified Rankin Scale (mRS) distribution / proportion of patients by mRS grade
Prazo: Weeks 4, 8, and 12
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The modified Rankin Scale (mRS) is a global outcome measure of disability and functional independence after stroke, graded on an ordinal scale from 0 to 6: 0 = no symptoms, 1 = no clinically significant disability, 2 = slight disability, 3 = moderate disability (requires some help), 4 = moderately severe disability (unable to walk unassisted), 5 = severe disability (bedridden, requiring constant care), and 6 = death. The mRS score range is 0 to 6; higher scores indicate worse outcome (greater disability). The proportion of patients in each mRS grade and the shift in mRS distribution from baseline will be summarized at Weeks 4, 8, and 12. |
Weeks 4, 8, and 12
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Change from baseline in National Institutes of Health Stroke Scale (NIHSS) score
Prazo: Weeks 4, 8, and 12
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Difference in NIHSS score from baseline to Weeks 4, 8, and 12 of the double-blind treatment period. The National Institutes of Health Stroke Scale (NIHSS) is an ordinal scale used to quantify neurological impairment in stroke patients, assessing 11 domains including level of consciousness, gaze, visual fields, facial palsy, motor function of the arms and legs, limb ataxia, sensory loss, language (aphasia), dysarthria, and inattention (extinction/inattention). The NIHSS score range is 0 to 42, with lower scores indicating less severe neurological impairment. Higher scores indicate worse outcome (more severe neurological deficit). |
Weeks 4, 8, and 12
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Change from baseline in Barthel Index (BI) score
Prazo: Weeks 4, 8, and 12
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Difference in Barthel Index (BI) score from baseline to Weeks 4, 8, and 12 of the double-blind treatment period. The Barthel Index (BI) is an ordinal scale that measures functional independence in activities of daily living (ADL), assessing 10 items: feeding, bathing, grooming, dressing, bowel control, bladder control, toilet use, transfers, mobility, and stairs. Each activity is scored on a 5-level scale, with level 1 being the lowest and level 5 the highest. A higher level indicates a greater degree of independence. The BI score range is 0 to 100, with higher scores indicating better outcome (greater independence in daily living). |
Weeks 4, 8, and 12
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Change from baseline in the Modified Ashworth Scale (MAS) score
Prazo: Weeks 4, 8, and 12
|
The Modified Ashworth Scale (MAS) is used to assess muscle tone and degree of spasticity during passive movement of skeletal muscles; the investigator performs passive stretching of the target muscle group and grades the increase in tone and resistance to passive movement. Scoring ranges from grade 0 to grade 4, with grade 1+ indicating a slight increase in tone with resistance intermediate between grade 1 and grade 2 (numeric range 0 to 4). Higher scores indicate worse outcome (more severe spasticity). In this study, six movements are assessed separately: upper limb - elbow flexion, wrist flexion, forearm pronation; lower limb - knee extension, knee flexion, ankle plantar flexion. Assessed once per cycle during the 3-cycle OLE period. |
Weeks 4, 8, and 12
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Incidence of adverse events (AEs) and serious adverse events (SAEs)
Prazo: Through study completion, up to approximately 28 weeks (up to 24 weeks of treatment, comprising the 12-week double-blind period and the 12-week open-label extension period, plus a 28-day safety follow-up after the last dose).
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Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), summarized by system organ class and preferred term (MedDRA coded), and graded according to CTCAE v5.0. Events are collected from the first dose of study drug through the 28-day post-treatment safety follow-up and reported for the double-blind period, the open-label extension period, and the overall treatment period. |
Through study completion, up to approximately 28 weeks (up to 24 weeks of treatment, comprising the 12-week double-blind period and the 12-week open-label extension period, plus a 28-day safety follow-up after the last dose).
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Outras medidas de resultado
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Incidence of new-onset vascular events (new-onset stroke, myocardial infarction, and vascular death)
Prazo: From first dose through study completion, up to approximately 28 weeks (up to 24 weeks of treatment, comprising the 12-week double-blind period and the 12-week open-label extension period, plus a 28-day post-treatment safety follow-up).
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New-onset stroke, myocardial infarction, and vascular death occurring from first dose through the 28-day post-treatment follow-up will be adjudicated/confirmed by [the investigator and/or an independent endpoint adjudication committee] and reported as number and percentage of participants with each event type in each dose group. |
From first dose through study completion, up to approximately 28 weeks (up to 24 weeks of treatment, comprising the 12-week double-blind period and the 12-week open-label extension period, plus a 28-day post-treatment safety follow-up).
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Concentration of cytokines in serum (IFN-γ, IL-10, IL-13, IL-1β, IL-2, IL-4, IL-5, IL-6, GRO-α, TNF-α, IL-2)
Prazo: Baseline and Week 12 (double-blind period); Week 12 and Week 24 (open-label extension period)
|
Serum concentrations of the following cytokines, measured by central laboratory assay: IFN-γ, IL-10, IL-13, IL-1β, IL-2, IL-4, IL-5, IL-6, GRO-α, TNF-α and IL-2. Concentrations are reported in pg/mL for each cytokine. This outcome measure reports laboratory analyte concentrations, not a score on a scale; therefore an unabbreviated scale title, minimum/maximum score, and score direction do not apply. |
Baseline and Week 12 (double-blind period); Week 12 and Week 24 (open-label extension period)
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Concentration of immunoglobulins in serum (IgG, IgM, IgA)
Prazo: Baseline and Week 12 (double-blind period); Week 12 and Week 24 (open-label extension period)
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Serum concentrations of immunoglobulins IgG, IgM, and IgA measured by central laboratory assay, reported in mg/dL for each immunoglobulin. This outcome measure reports laboratory analyte concentrations, not a score on a scale. |
Baseline and Week 12 (double-blind period); Week 12 and Week 24 (open-label extension period)
|
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Number and percentage of T-cell subsets in blood (CD3+CD4+, CD3+CD8+, CD28+, CD16+)
Prazo: Baseline and Week 12 (double-blind period); Week 12 and Week 24 (open-label extension period)
|
Enumeration of T-cell subsets (CD3+CD4+, CD3+CD8+, CD28+, CD16+) by flow cytometry, reported as cell counts and percentages of lymphocytes, including the CD3+CD4+/CD3+CD8+ ratio. This outcome measure reports cell counts/percentages, not a score on a scale. |
Baseline and Week 12 (double-blind period); Week 12 and Week 24 (open-label extension period)
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Incidence of treatment-emergent anti-drug antibodies (ADA)
Prazo: Baseline and Week 12 (double-blind period); Week 12 and Week 24 (open-label extension period)
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Number and percentage of participants with treatment-emergent anti-drug antibody (ADA) responses to ALT001, measured by central laboratory assay; ADA titre is reported where applicable. This outcome measure reports incidence and titre, not a score on a scale. |
Baseline and Week 12 (double-blind period); Week 12 and Week 24 (open-label extension period)
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Change in modified Rankin Scale (mRS) score from Week 13 to the end of the open-label extension (OLE) period
Prazo: Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
|
The modified Rankin Scale (mRS) is a global outcome measure of disability and functional independence after stroke, graded on an ordinal scale from 0 to 6: 0 = no symptoms, 1 = no clinically significant disability, 2 = slight disability, 3 = moderate disability (requires some help), 4 = moderately severe disability (unable to walk unassisted), 5 = severe disability (bedridden, requiring constant care), and 6 = death. The mRS score range is 0 to 6; higher scores indicate worse outcome (greater disability). |
Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
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Change in National Institutes of Health Stroke Scale (NIHSS) score from Week 13 to the end of the open-label extension (OLE) period
Prazo: Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
|
The National Institutes of Health Stroke Scale (NIHSS) is an ordinal scale used to quantify neurological impairment in stroke patients, assessing 11 domains including level of consciousness, gaze, visual fields, facial palsy, motor function of the arms and legs, limb ataxia, sensory loss, language (aphasia), dysarthria, and inattention (extinction/inattention). The NIHSS score range is 0 to 42, with lower scores indicating less severe neurological impairment. Higher scores indicate worse outcome (more severe neurological deficit). |
Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
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Change in Barthel Index (BI) score from Week 13 to the end of the open-label extension (OLE) period
Prazo: Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
|
The Barthel Index (BI) is an ordinal scale that measures functional independence in activities of daily living (ADL), assessing 10 items: feeding, bathing, grooming, dressing, bowel control, bladder control, toilet use, transfers, mobility, and stairs. Each activity is scored on a 5-level scale, with level 1 being the lowest and level 5 the highest. A higher level indicates a greater degree of independence. The BI score range is 0 to 100, with higher scores indicating better outcome (greater independence in daily living). |
Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
|
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Change in Modified Ashworth Scale (MAS) score from Week 13 to the end of the open-label extension (OLE) period
Prazo: Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
|
The Modified Ashworth Scale (MAS) is used to assess muscle tone and degree of spasticity during passive movement of skeletal muscles; the investigator performs passive stretching of the target muscle group and grades the increase in tone and resistance to passive movement. Scoring ranges from grade 0 to grade 4, with grade 1+ indicating a slight increase in tone with resistance intermediate between grade 1 and grade 2 (numeric range 0 to 4). Higher scores indicate worse outcome (more severe spasticity). In this study, six movements are assessed separately: upper limb - elbow flexion, wrist flexion, forearm pronation; lower limb - knee extension, knee flexion, ankle plantar flexion. Assessed once per cycle during the 3-cycle OLE period. |
Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
|
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Change in Fugl-Meyer Assessment (FMA) motor score from Week 13 to the end of the open-label extension (OLE) period
Prazo: Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
|
The Fugl-Meyer Assessment (FMA) evaluates motor function in patients with ischemic stroke and comprises an upper-extremity motor subscore (0 to 66) and a lower-extremity motor subscore (0 to 34), for a total score range of 0 to 100. Per the protocol's total-score grading: 0-49 = severe, 50-84 = marked, 85-95 = moderate, 96-99 = mild motor impairment. Higher scores indicate better motor function. |
Week 13 (OLE baseline) and Weeks 17, 21, and 24 (open-label extension period)
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Datas de registro do estudo
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- ALT001-CN-IND-02002
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