A Study to Evaluate, Safety, Tolerability, and PK of AP-101 in Participants With ALS
A Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of AP-101 in Participants With Sporadic or SOD1-Associated ALS
The purpose of this study is to evaluate the safety, tolerability, PK, and PD of AP-101 in participants with fALS and sALS.
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Descrição detalhada
This Phase 2a, multicenter, randomized, double-blind, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamic markers of AP-101 in adults with sporadic ALS or SOD1-associated ALS. A total of 73 participants were randomized within each ALS cohort in a 2:1 ratio to receive AP-101 or placebo during a 24-week double-blind treatment period.
Participants assigned to AP-101 received a 500 mg intravenous loading dose on Day 1, a 2500 mg intravenous dose on Day 2, and 2500 mg intravenously every 3 weeks beginning on Day 22 through Week 24. Participants assigned to placebo received matching intravenous infusions on the same schedule. Stable use of locally approved ALS treatments was permitted.
Participants who completed the double-blind period could enter an optional 24-week open-label extension in which all participants received AP-101. To maintain the integrity of the double-blind period, the initial dose in the open-label extension remained blinded. Participants were followed for safety and pharmacokinetic assessments for up to 16 weeks after their final study dose.
The primary assessments evaluated adverse events, serious adverse events, immunogenicity, vital signs, clinical laboratory assessments, physical and neurological examinations, electrocardiograms, and changes in weight. Secondary assessments included serum pharmacokinetics, AP-101 concentrations in cerebrospinal fluid, and the neurofilament biomarkers phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL). Exploratory assessments included the ALS Functional Rating Scale-Revised, slow vital capacity, muscle strength, King's staging, survival and ventilation outcomes, quality of life, and cerebrospinal fluid total and misfolded SOD1.
Tipo de estudo
Inscrição (Real)
Estágio
- Fase 2
Contactos e Locais
Locais de estudo
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Berlin, Alemanha, 13353
- Charité
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Bonn, Alemanha, 53127
- Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)
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Hanover, Alemanha, 30625
- Hannover Medical School
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Ulm, Alemanha, 89081
- Ulm University Hospital
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Leuven, Bélgica, 3000
- Department of Neurology, University Hospitals
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Alberta
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Edmonton, Alberta, Canadá, AB T6G 1Z1
- ALS clinic at the Kaye Edmonton Clinic, University of Alberta
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Ontario
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London, Ontario, Canadá, ON N6A 5W9
- London Health Sciences Centre - Victoria Hospital
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Toronto, Ontario, Canadá, M4N 3M5
- ALS Research Sunnybrook Health Sciences Centre
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Quebec
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Montreal, Quebec, Canadá, H3A 2B4
- Montreal Neurological Institute and Hospital / Dr Genge
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Seoul, Coréia do Sul, 04763
- Hanyang University Medical Center
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California
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La Jolla, California, Estados Unidos, 92037
- UC San Diego, ACTRI
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Stockholm, Suécia, 113 61
- Studieenheten Akademiskt specialistcentrum, SLSO
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Umeå, Suécia, SE- 901 85
- Norrlands universitetssjukhus/ University Hospital of Northern Sweden (NUS)
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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:
- All participants must adhere to contraception restrictions
- Female participants of childbearing potential must adhere to contraception restrictions
- Have possible, clinically probable, clinically probable-laboratory supported or definite familial or sporadic ALS in accordance with the El-Escorial criteria or who have a diagnosis of ALS as defined by the Gold Coast Criteria; progressive motor impairment documented by history or repeated clinical examination, preceded by normal motor development, and presence of upper and lower motor neuron dysfunction in at least 1 body region or lower motor neuron dysfunction in at least 2 body regions and investigations excluding other conditions
- In familial ALS participants, a confirmed pathogenic superoxide dismutase 1 (SOD1) mutation
- Onset of symptoms (i.e, weakness) within past 24 months prior to screening, at the time of obtaining informed consent
- Have slow vital capacity (SVC) of greater than or equal to (> or =) 50 percentage (%) of predicted values. Participants with SVC of <50% of predicted values may be permitted to enter the open-label extension, based on the opinion of the investigator
- Absence of bilevel positive airway pressure (BiPAP)/proportional assist ventilation (PAV) > 4 hours for symptoms attributable to ALS. Use of a CPAP for pre-existing conditions will be allowed
- If on riluzole, must be on a stable dose.
- If on edaravone, must have completed 2 cycles and are expected to remain on the same dose throughout the study
- Able to provide informed consent which includes compliance with the requirements and restrictions
- Have venous access sufficient to allow for blood sampling
- Have clinical laboratory test results within the normal reference range for the population or study site, or results with acceptable deviations that are judged to be not clinically significant by the investigator
Exclusion Criteria:
- Have participated or currently participating in another clinical trial within 5 half-lives of baseline (Day 1)
- Have undergone a tracheostomy for ALS symptoms
- Are on nasal intermittent positive pressure ventilation (NIPPV) >4 hours per day for the treatment of ALS related symptoms
- Have other causes of neuromuscular weakness
- Have cognitive impairment, severe disease in the cardiovascular, hematological, renal system, neurodegenerative disease, pulmonary disorder, or psychiatric illness
- Pregnant or nursing women
- Have been exposed to any antisense treatment targeting SOD1 within 6 months of the baseline visit
- Have undergone stem cell therapy
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Dobro
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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Experimental: AP-101
AP-101 is administered by intravenous infusion (IV). |
Participants receive AP-101 by intravenous infusion (IV). |
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Comparador de Placebo: Placebo
Placebo is administered by intravenous infusion (IV). |
Participants receive placebo by intravenous infusion (IV). |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
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Participants With Treatment-Emergent Adverse Events (TEAE) and Treatment-Emergent Serious Adverse Events (TESAE) During the Double-Blind Period
Prazo: From the first dose through the 21-day follow-up after Week 24, approximately 27 weeks
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Treatment-emergent adverse events were adverse events that began or worsened after the first dose of randomized study treatment during the double-blind period. Treatment-emergent serious adverse events met the protocol-defined criteria for seriousness. Participants experiencing more than one event within a category were counted once in that category. Results are presented separately for the sporadic ALS and SOD1-associated ALS cohorts. |
From the first dose through the 21-day follow-up after Week 24, approximately 27 weeks
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Number of Participants With Abnormalities in Vital Signs, Clinical Laboratory Assessments, Physical and Neurological Examinations, and Electrocardiograms
Prazo: From the first dose through the 21-day follow-up after Week 24, approximately 27 weeks
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Number of participants with at least one abnormality in vital signs, clinical laboratory assessments, physical examinations, neurological examinations, or electrocardiograms during the double-blind period. Participants could be included in more than one category; therefore, categories were not mutually exclusive. Results are presented separately for the sporadic ALS and SOD1-associated ALS cohorts. |
From the first dose through the 21-day follow-up after Week 24, approximately 27 weeks
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Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs) During the Double-Blind Period
Prazo: From baseline through the 21-day follow-up after Week 24, approximately 27 weeks
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Serum samples were assessed for anti-drug antibodies to AP-101. Participants were evaluable for treatment-emergent anti-drug antibodies if they had at least one non-missing baseline result and at least one non-missing post-baseline result. One participant was anti-drug-antibody positive at baseline and subsequently tested negative; baseline positivity was not classified as treatment-emergent. Results are presented separately for the sporadic ALS and SOD1-associated ALS cohorts. ADA testing was not assessed in placebo participants. |
From baseline through the 21-day follow-up after Week 24, approximately 27 weeks
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Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
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Model-Derived Elimination Half-Life of AP-101 in Serum
Prazo: From the first AP-101 dose through 16 weeks after the final AP-101 dose, up to approximately 64 weeks
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The individual elimination half-life of AP-101 was estimated using empirical Bayes estimates from the final two-compartment population pharmacokinetic model. The model used pooled serum AP-101 concentration data from studies AP101-01 and AP101-02. This outcome summarizes participants from AP101-02 who were included in the final population pharmacokinetic model. |
From the first AP-101 dose through 16 weeks after the final AP-101 dose, up to approximately 64 weeks
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Model-Derived Area Under the Serum AP-101 Concentration-Time Curve
Prazo: AUC following the second active dose: Day 2 through Day 22; AUC at steady state: the 21-day dosing interval following the participant's final active AP-101 dose, which occurred up to approximately Week 48 of the study
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Individual AP-101 exposure was estimated using empirical Bayes estimates from the final two-compartment population pharmacokinetic model. Area under the concentration-time curve during the dosing interval was estimated following the second active AP-101 dose and at steady state. This outcome summarizes AP101-02 participants included in the final population pharmacokinetic model. |
AUC following the second active dose: Day 2 through Day 22; AUC at steady state: the 21-day dosing interval following the participant's final active AP-101 dose, which occurred up to approximately Week 48 of the study
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Model-Derived Maximum Serum AP-101 Concentration
Prazo: Cmax following the second active dose: Day 2 through Day 22; Cmax at steady state: during the 21-day dosing interval following the participant's final active AP-101 dose, which occurred up to approximately Week 48 of the study.
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Individual maximum serum AP-101 concentrations were estimated using empirical Bayes estimates from the final two-compartment population pharmacokinetic model. Maximum concentration was estimated following the second active AP-101 dose and at steady state. This outcome summarizes AP101-02 participants included in the final population pharmacokinetic model. |
Cmax following the second active dose: Day 2 through Day 22; Cmax at steady state: during the 21-day dosing interval following the participant's final active AP-101 dose, which occurred up to approximately Week 48 of the study.
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AP-101 Concentration in Cerebrospinal Fluid During the Double-Blind Period
Prazo: Week 12 and Week 24 of the double-blind period
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AP-101 concentrations were measured in cerebrospinal fluid to assess central nervous system exposure after repeated intravenous dosing. Samples were collected at Week 12 and Week 24 of the double-blind period and summarized by ALS cohort and visit among participants with quantifiable CSF AP-101 concentrations. Actual concentrations were reported rather than change from baseline because nearly all baseline concentrations were below the limit of quantitation. |
Week 12 and Week 24 of the double-blind period
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Change From Baseline in Cerebrospinal Fluid Phosphorylated Neurofilament Heavy Chain (pNfH) During the Double-Blind Period
Prazo: Baseline to Week 24 of the double-blind period
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Phosphorylated neurofilament heavy chain (pNfH) concentrations were measured in cerebrospinal fluid at baseline, Week 12, and Week 24. Results represent the mean change from baseline and are presented separately for the sporadic ALS and SOD1-ALS cohorts. Negative values indicate a decrease from baseline. |
Baseline to Week 24 of the double-blind period
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Change From Baseline in Serum Neurofilament Light Chain During the Double-Blind Period and 21-Day Follow-up
Prazo: Baseline through the 21-day follow-up after Week 24, approximately 27 weeks
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Neurofilament light chain (NfL) concentrations were measured in serum at baseline, Week 12, Week 24, and the 21-day follow-up after completion of double-blind treatment. Results represent the mean change from baseline and are presented separately for the sporadic ALS and SOD1-ALS cohorts. Negative values indicate a decrease from baseline. |
Baseline through the 21-day follow-up after Week 24, approximately 27 weeks
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Diretor de estudo: Study Director, AL-S Pharma AG
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Real)
Conclusão Primária (Real)
Conclusão do estudo (Real)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Real)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Termos MeSH relevantes adicionais
- Doenças do Sistema Nervoso Central
- Doenças do Sistema Nervoso
- Doenças Neuromusculares
- Doenças Metabólicas
- Doenças Neurodegenerativas
- Doenças da Medula Espinhal
- Proteinopatias TDP-43
- Deficiências de Proteostase
- Doença do neurônio motor
- Doenças Nutricionais e Metabólicas
- Esclerose Lateral Amiotrófica
- Esclerose lateral amiotrófica 1
Outros números de identificação do estudo
- AP101-02
- 2020-005971-11 (Número EudraCT)
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