A Multi-center, Open-label, Single-arm, Before and After Switch Study to Evaluate the Efficacy, Safety and Tolerability of Alemtuzumab in Paediatric Patients With Relapsing Remitting Multiple Sclerosis (RRMS) With Disease Activity on Prior Disease Modifying Therapy (DMT)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 16
- 试验地点
- 29
- 主要终点
- Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan
研究概览
简要总结
Primary Objective:
To evaluate the efficacy, safety, and tolerability of alemtuzumab intravenously (IV) in pediatric participants from 10 to less than (<) 18 years of age with Relapsing Remitting Multiple Sclerosis (RRMS) who have disease activity on prior DMT.
Secondary Objective:
To assess the pharmacokinetics (PK), pharmacodynamics (PD), anti-drug antibody (ADA) formation, and potential effects of alemtuzumab on other multiple sclerosis (MS) disease characteristics such as cognition and quality of life (QoL).
详细描述
The duration of study per participant was approximately 5 years and 5 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 10 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants with RRMS aged from 10 years to <18 years at study entry was eligible. Participants must meet the criteria of diagnosis of MS as defined by the International Pediatric MS Study Group (IPMSSG) criteria for pediatric MS and the criteria of MS based on 2010 McDonald criteria.
- •Signed written informed consent/assent obtained from participant and participant's legal representative (parent or guardian) according to local regulations.
- •Expanded Disability Status Scale (EDSS) score of 0.0 to 5.0 (inclusive) at screening.
- •At least 2 recorded MS attacks and at least 1 MS attack (relapse) in the last year during treatment with a beta interferon therapy (IFNB) or glatiramer acetate (GA) after being on that therapy for at least 6 months, and was currently still taking the same therapy.
- •At least 1 of the following:
- •>=1 new or enlarging T2 hyperintense lesion or gadolinium enhancing lesion while on that same prior therapy (IFNB or GA), or
- •Two or more relapses in the prior year, or
- •Tried at least 2 MS DMTs.
排除标准
- •Any progressive or non-relapsing forms of MS.
- •Conditions/situations such as:
- •Impossibility to meet specific protocol requirements.
- •Current participation in another interventional clinical study. Participants who were treated with a comparator agent approved for screening inclusion (INF or GA) may be considered for this trial.
- •Participant was the Investigator or any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol.
- •Uncooperative participant or any condition that could make the participant potentially non-compliant to the study procedures in the opinion of the Investigator.
- •Mental condition rendering the participant or parent/guardian unable to understand the nature, scope, and possible consequences of the study.
- •Clinically relevant cardiovascular, hepatic, neurological, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult or that would put the participant at risk by participating in the study in the opinion of the Investigator.
- •History of drug or alcohol abuse.
- •History of known human immunodeficiency virus (HIV) positivity.
- •Pregnant or breast-feeding female participants or those who had planned to become pregnant during the study.
- •Unwilling to agree to use a highly effective contraceptive method when receiving a course of alemtuzumab treatment and for 4 months following that course of treatment (fertile participants only).
- •Female participants who have commenced menstruating (i.e., are of childbearing potential) and are unwilling or unable to be tested for pregnancy.
- •Previous treatment with alemtuzumab.
- •Treatment with natalizumab, daclizumab, fingolimod, methotrexate, azathioprine, cyclosporine, or mycophenolate mofetil in the last 6 months prior to screening, or determined by the treating physician to had residual immune suppression from these or other MS treatments.
- •Treatment with teriflunomide in the last 12 months except if the participant underwent the recommended elimination procedure as per Summary of Product Characteristics (SmPC).
- •Previous treatment with mitoxantrone, cyclophosphamide, cladribine, rituximab, ocrelizumab, leflunomide, or any cytotoxic therapy.
- •Previous treatment with any investigational medication (drug that had not been approved at any dose or for any indication). Use of an investigational medication that is subsequently licensed and nonstandard use of a licensed medication (e.g., using a dose other than the dose that is stated in the licensed product labeling or using a licensed therapy for an alternative indication) was not exclusionary. Prior treatment with herbal medications or nutritional supplements was also permitted.
- •Intolerance of pulsed corticosteroids, especially a history of steroid psychosis.
- •History of malignancy.
- •Prior documented history of thrombocytopenia, or platelet count at screening < lower limits of normal (LLN).
- •Any disability acquired from trauma or another illness that, in the opinion of the Investigator, could interfere with evaluation of disability due to MS.
- •Participants with known Type 1 hypersensitivity or anaphylactic reactions to the active substances or any of the excipients, or intolerance of acyclovir or its therapeutic equivalent.
- •Major systemic disease or other illness that would, in the opinion of the Investigator, compromise participant safety or interfere with the interpretation of study results, e.g., current peptic ulcer disease, or other conditions that might predispose to hemorrhage, immune cytopenias, rheumatoid arthritis, systemic lupus erythematosus, other connective tissue disorders, vasculitis, inflammatory bowel disease, severe psoriasis.
- •Medical, psychiatric, cognitive, or other conditions that, in the Investigator's opinion, compromise the participant's ability to understand the participant information, to give informed consent, to comply with the trial protocol, or to complete the study.
- •Major psychiatric disorder that is not adequately controlled by treatment in the opinion of the Investigator.
- •Epileptic seizures that are not adequately controlled by treatment.
- •Magnetic resonance imaging (MRI)-related conditions: conditions that could interfere with MRI acquisition and/or interpretation of MRI results (eg, claustrophobia, orthopedic implants/treatments, orthodontic treatments etc).
- •Known bleeding disorder (e.g., dysfibrinogenemia, factor IX deficiency, hemophilia, Von Willebrand's disease, disseminated intravascular coagulation, fibrinogen deficiency, clotting factor deficiency).
- •Prior history of invasive fungal infections.
- •Active infection, eg, deep-tissue infection, that the Investigator considers sufficiently serious to preclude study participation.
- •In the Investigator's opinion, participant is at high risk for infection (e.g., indwelling catheter, dysphagia with aspiration, decubitus ulcer, history of prior aspiration pneumonia or recurrent urinary tract infection).
- •The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
研究组 & 干预措施
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Glatiramer acetate (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Methylprednisolone (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Ranitidine (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Dexchlorpheniramine (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Paracetamol (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Acyclovir (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Prednisolone (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Beta-Interferon (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Ceterizine (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Diphenydramine (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Other H1 antagonist (Drug)
Alemtuzumab
- alemtuzumab - Dose 1 (initial course) of alemtuzumab will be administered intravenously on 5 consecutive days, followed by Dose 2 (second course) on 3 consecutive days administered 12 months after initial course. Pre-medications (methylprednisolone, prednisolone, H1 antagonist [antihistamine], H2 antagonist, paracetamol, acyclovir) will be administered prior alemtuzumab administration. - Type: Experimental
干预措施: Alemtuzumab GZ402673 (Drug)
结局指标
主要结局
Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI Scan
时间窗: Period 1: Month -4 up to Month 0, Period 2: Month 4 to Month 8
Number of new or enlarged T2 lesions per scan was defined as the total number of new or enlarged T2 lesion that occurred during a specified period divided by the total number of scans performed during that specified period.
Brain Magnetic Resonance Imaging (MRI) Assessment: Adjusted Number of New or Enlarged T2 Lesions Per Month
时间窗: Period 1: Month -4 up to Month 0, Period 2: Month up 4 to Month 8
Number of new or enlarged T2 lesions per month was defined as the total number of new or enlarged T2 lesion that occurred during the study divided by the total number of follow-up months until the end of each period and was estimated based on negative binomial regression.
次要结局
- Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Months 4 and 8(Baseline, Months 4 and 8)
- Area Under the Plasma Concentration-Time Curve (AUC) of Alemtuzumab(Up to 5 years)
- Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Participants With New or Enlarged T2 Lesions Per MRI Scan(Period 1: Month -4 up to Month 0, Period 2: Month 4 to Month 8)
- Change From Baseline in Cognition Test Scores of Brief Visuospatial Memory Test - Revised (BVMT-R)(Up to 5 years)
- Maximum Serum Concentration Observed (Cmax) of Alemtuzumab(Up to 5 years)
- Terminal Half-life (T1/2z) of Alemtuzumab(Up to 5 years)
- Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAE)(Up to 5 years)
- Annualized Relapse Rate (ARR)(Up to 5 years)
- Change From Baseline in Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Questionnaire Score(Up to 5 years)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alemtuzumab(Up to 5 years)
- Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Alemtuzumab(Up to 5 years)
- Assessment of Lymphocyte Phenotyping(Up to 5 years)
- Change From Baseline in Cognition Test Scores of Symbol Digit Modality Test (SDMT)(Up to 5 years)
- Change From Baseline in Quality of Life (QoL) Measures of Pediatric Quality of Life (PedsQL) Questionnaire Score(Up to 5 years)
- Serum Concentrations of Alemtuzumab Over Time(Up to 5 years)
- Percentage of Participants With Incidence of Antidrug Antibodies (ADA)(Up to 5 years)
- Brain Magnetic Resonance Imaging Assessment: Number of Participants With New or Enlarged T2 Lesions(Period 1: Month -4 up to Month 0, Period 2: Month 4 to Month 8)
- Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Months 4 and 8(Baseline (Month 0), Months 4 and 8)
- Adjusted Annualized Relapse Rate (ARR) at Year 2(At Year 2)
- Maximum Observed Serum Concentration (Cmax) of Alemtuzumab(Pre-dose on Day 1, end of infusion on Day 5, Day 14 of Month 0; Months 1 and 2; pre-dose on Day 1, end of infusion on Day 3, Day 12 of Month 12; Months 13 and 14)
- Change From Baseline in Cognition Test Score of Brief Visuospatial Memory Test - Revised (BVMT-R) Total Score(Period 1: Baseline (Month -4) and Month 0, Period 2: Baseline (Month 4) and Month 8)
- Change From Baseline in Cognition Test Score of Symbol Digit Modality Test (SDMT): Number of Completed Responses and Corrected Substitutions(Period 1: Baseline (Month -4) and Month 0, Period 2: Baseline (Month 4) and Month 8)
- Change From Baseline in Pediatric Quality of Life (PedsQL) Questionnaire Score(Child and teen report: Baseline (Month 0) and Months 4, 8, 12, 18, 24, 36, 48 and 60; Parent report for children and teens: Baseline (Month 0) and Months 4, 8, 12, 18, 24 and 36)
- Change From Baseline in Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Questionnaire Score(Baseline (Month 0) and Months 4, 8, 12, 18, 24, 36, 48 and 60)
- Serum Concentrations of Alemtuzumab Over Time(Pre-dose on Day 1, end of infusion on Day 5, Day 14 of Month 0; Months 1 and 2; pre-dose on Day 1, end of infusion on Day 3, Day 12 of Month 12; Months 13 and 14)
- Time to Reach Maximum Observed Serum Concentration (Tmax) of Alemtuzumab(Pre-dose on Day 1, end of infusion on Day 5, Day 14 of Month 0; Months 1 and 2; pre-dose on Day 1, end of infusion on Day 3, Day 12 of Month 12; Months 13 and 14)
- Area Under the Cumulative Serum Concentration-Time Curve (AUC) of Alemtuzumab(Pre-dose on Day 1, end of infusion on Day 5, Day 14 of Month 0; Months 1 and 2; pre-dose on Day 1, end of infusion on Day 3, Day 12 of Month 12; Months 13 and 14)
- Area Under the Cumulative Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Alemtuzumab(Pre-dose on Day 1, end of infusion on Day 5, Day 14 of Month 0; Months 1 and 2; pre-dose on Day 1, end of infusion on Day 3, Day 12 of Month 12; Months 13 and 14)
- Terminal Half-Life (T1/2z) of Alemtuzumab(Pre-dose on Day 1, end of infusion on Day 5, Day 14 of Month 0; Months 1 and 2; pre-dose on Day 1, end of infusion on Day 3, Day 12 of Month 12; Months 13 and 14)
- Change From Baseline in Lymphocytes: Cluster of Differentiation 19 (CD19), CD3, CD3-/16+56, CD4 and CD8(Baseline (Month 0); Months 1, 4, 8, 12, 13, 15, 18, 21, 24, 36, 48 and 60)
- Change From Baseline in Lymphocytes: CD4/CD8(Baseline (Month 0); Months 1, 4, 8, 12, 13, 15, 18, 21, 24, 36, 48 and 60)
- Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)(Prior DMT Phase: From signing of informed consent form (0-28 days before Month -4) to Month 0, approximately 5 months; Alemtuzumab Treatment Phase+Safety Monitoring Phase: From first alemtuzumab dose at Month 0 to end of study, approximately 60 months)
- Number of Participants With Infusion-Associated Reactions (IARs) in the Alemtuzumab Treatment Phase(Up to 24 hours post-infusion, at Months 0 and 12)
- Percentage of Participants With Incidence of Antidrug Antibodies (ADA)(Months 1, 3, 12, 13, 15, 24, 36, 48 and 60)