NCT03368664 - A Study to Evaluate Efficacy, Safety, and Tolerability of Alemtuzumab in Pediatric Patients With RRMS With Disease Activity on Prior DMT | Crick

Eligibility

Sex: ALLMin age: 10 YearsMax age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria : * 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. Exclusion criteria: * 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.

Outcomes

Primary Outcomes

Brain Magnetic Resonance Imaging (MRI) Assessment: Adjusted Number of New or Enlarged T2 Lesions Per Month

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.

Time frame: Period 1: Month -4 up to Month 0, Period 2: Month up 4 to Month 8

Secondary Outcomes

Brain Magnetic Resonance Imaging Assessment: Number of Participants With New or Enlarged T2 Lesions

Number of participants with at least one new or enlarged T2 lesions was reported in this outcome measure. Number of new or enlarged T2 lesions 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.

Time frame: 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

EDSS was an ordinal scale in half-point increments that qualified disability in participants with MS. It consisted of 8 ordinal rating scales assessing seven functional systems (FS) (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and other). Ambulation scoring was done to conclude evaluation. EDSS steps 1.0 to 4.5 referred to participants with MS who were fully ambulatory, while EDSS steps 5.0 to 9.5 were defined by the impairment to ambulation. Individual FS scores were then used in conjugation with ambulation score to obtain total EDSS score which ranged from 0 (normal neurological examination) to 10 (death due to MS) in half-point increments, where higher scores indicated worst outcomes. Baseline for EDSS was defined as the last non-missing value prior to the first course of alemtuzumab.

Time frame: Baseline (Month 0), Months 4 and 8

Adjusted Annualized Relapse Rate (ARR) at Year 2

Adjusted ARR was defined as the total number of relapses that occurred during the alemtuzumab treatment phase divided by the total number of follow-up years and was estimated based on negative binomial regression. Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the neurologist and documented by the functional system scores.

Time frame: At Year 2

Change From Baseline in Cognition Test Score of Brief Visuospatial Memory Test - Revised (BVMT-R) Total Score

BVMT-R: tool to measure visuospatial learning and memory abilities across research and clinical settings. Visual display of 6 simple figures arranged in 2x3 matrix on separate pages was shown to participants for 3 consecutive 10-second trials. After each trial, participants drew as many designs as accurately as they could in correct location. They were asked to reproduce designs in exact layout after 25-minute delay filled with other distractor tasks. Forced-choice recognition trial was administered immediately after delayed memory trial. Optional copy trial was included at end of test where participants were asked to copy figure display accurately. Scoring of immediate, delayed recall and copy trials were based on accuracy of drawings and location of figures. Score range 0 to 12 per trial; total score: 0 to 36 for all 3 trials. Higher scores: better visuospatial memory. Change from baseline in total score is presented. Baseline:Month -4 for Period 1;Month 4 for Period 2.

Time frame: 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

The SDMT was used to assess cognitive impairment and involved a simple substitution task that normal children and adults could easily perform. Using a reference key, the examinee/participant had 90 seconds to pair specific numbers with given geometric figures. Responses were only in oral form for this study and administration time was just 5 minutes. The number of corrected substitutions and number of completed responses were recorded. The score for each was the number of correctly coded items ranging 0-110 in 90 seconds; higher scores indicated a better outcome. Change from baseline in number of completed responses and number of corrected substitutions by SDMT is presented. Baseline: Month -4 for Period 1; Month 4 for Period 2.

Time frame: 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

The PedsQL™ measurement model was a modular approach to measure health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. It included a child and teen self-report, and parents' report of children and teen. Each report consisted of 23 items and 4 scales (physical, emotional, social and school functioning). Each item used a 5-point rating scale (from 0='it is never a problem' to 4='it is almost always a problem'). Items are reverse scored and linearly transformed to a 0 (almost always) to 100 (never) scale. Total scores (0 to 100) for each report were mean of specific items where higher score indicated better HRQoL. Baseline: last non-missing value prior to first course of alemtuzumab.

Time frame: 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

Pediatric NeuroQoL was measurement system that evaluated and monitored physical, mental and social effects experienced by children living with neurological conditions. Physical effects (fatigue, pain) and mental effects (cognitive function, anxiety, depression) was assessed. Each domain had 8 to 10 items and participants indicated how often they experienced feelings and circumstances related to each domain on scale 1 to 5 (1='never' to 5='almost always'). This scale was reversed for cognitive function (1='very much' to 5='not at all'). Higher values: worse outcome for fatigue, pain, anxiety, depression, and better cognitive function. Raw scores were re-scaled to standardized scores with mean=50 and standard deviation=10. T-score range: 20 to 80. T-score \<30 indicated clinically significant impairment. Change from baseline in physical and mental effects scores by pediatric NeuroQoL is presented. Baseline: last non-missing value prior to first course of alemtuzumab.

Time frame: Baseline (Month 0) and Months 4, 8, 12, 18, 24, 36, 48 and 60

Serum Concentrations of Alemtuzumab Over Time

Blood samples were collected at the specified timepoints for measurement of serum concentrations of alemtuzumab.