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Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: Results of the HINT 2 clinical trial.

ABSTRACT: BACKGROUND:The hygiene hypothesis suggests that microbial replacement may be therapeutic in allergic and autoimmune diseases. Nevertheless, the results of helminth treatment, including in multiple sclerosis (MS), have been inconclusive. OBJECTIVE:To assess safety and brain magnetic resonance imaging (MRI) activity in subjects with relapsing-remitting multiple sclerosis (RRMS) during oral administration of ova from the porcine whipworm, Trichuris suis (TSO). METHODS:A total of 16 disease-modifying treatment (DMT) naive RRMS subjects were studied in a baseline versus treatment (BVT) controlled prospective study. MRI scans were performed during 5?months of screening-observation, 10?months of treatment, and 4?months of post-treatment surveillance. RESULTS:No serious symptoms or adverse events occurred during treatment. For the cohort, there was a trend consistent with a 35% diminution in active lesions when observation MRIs were compared to treatment MRIs ( p?=?0.08), and at the level of individuals, 12 of 16 subjects improved during TSO treatment. T regulatory lymphocytes were increased during TSO treatment. CONCLUSION:TSO is safe in RRMS subjects. Potentially favorable MRI outcomes and immunoregulatory changes were observed during TSO treatment; however, the magnitude of these effects was modest, and there was considerable variation among the responses of individual subjects.

SUBMITTER: Fleming J

PROVIDER: S-EPMC5878983 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: Results of the HINT 2 clinical trial.

Fleming John J Hernandez Gianna G Hartman Leslie L Maksimovic Jane J Nace Sara S Lawler Benjamin B Risa Todd T Cook Thomas T Agni Rashmi R Reichelderfer Mark M Luzzio Christopher C Rolak Loren L Field Aaron A Fabry Zsuzsanna Z

Multiple sclerosis (Houndmills, Basingstoke, England) 20171024 1

<h4>Background</h4>The hygiene hypothesis suggests that microbial replacement may be therapeutic in allergic and autoimmune diseases. Nevertheless, the results of helminth treatment, including in multiple sclerosis (MS), have been inconclusive.<h4>Objective</h4>To assess safety and brain magnetic resonance imaging (MRI) activity in subjects with relapsing-remitting multiple sclerosis (RRMS) during oral administration of ova from the porcine whipworm, Trichuris suis (TSO).<h4>Methods</h4>A total ...[more]

PMID: 29064315

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Project description:BackgroundDaclizumab is a humanized monoclonal antibody against CD25 that modulates interleukin 2 signaling. The SELECT TRILOGY of clinical studies (SELECT/SELECTION/SELECTED) evaluated the safety and efficacy of daclizumab in patients with relapsing-remitting multiple sclerosis (RRMS). We report the long-term safety and efficacy of daclizumab 150 mg subcutaneous every 4 weeks in patients with RRMS in the SELECTED open-label extension study.MethodsAn interim intent-to-treat analysis of all enrolled patients was performed in January 2014 for this ongoing study.ResultsThe SELECTED study enrolled 90% of patients who completed SELECTION. In the safety and efficacy analysis (N = 410), median treatment time in SELECTED was 25 months (range, <1-45). Adverse events (AEs) were reported in 76% of patients, serious AEs (SAEs) excluding MS relapse in 16%, and treatment discontinuation due to AEs including multiple sclerosis (MS) relapse in 12%. AEs were primarily of mild to moderate severity, and common AEs (≥10%), excluding MS relapse, were nasopharyngitis (12%) and upper respiratory tract infection (12%). Most commonly reported SAEs (in ≥3 patients), excluding MS relapses, were increased serum hepatic enzymes, pneumonia, ulcerative colitis, and urinary tract infection (<1% each). Incidences of AE groups of interest include cutaneous events (28%), cutaneous SAEs (2%), gastrointestinal SAEs (2%), hepatic SAEs, (1%) and malignancies (1%). The incidence of AEs, SAEs, and treatment-related study discontinuations did not increase over time and no deaths were reported. The adjusted annualized relapse rate (95% confidence interval (CI)) analyzed at 6-month intervals was 0.15 (0.10-0.22) for weeks 97-120 and 0.15 (0.10-0.21) for weeks 121-144. In year 3, the adjusted mean (95% CI) number of new/newly enlarging T2 hyperintense lesions was 1.26 (0.93-1.72) and the mean (median) annualized change in brain volume was -0.32% (-0.34%).ConclusionsThe AE incidence did not increase with extension of therapy into year 3 in SELECTED; the safety profile was similar to that previously observed. The clinical efficacy of daclizumab was sustained over the 3 years comprising the SELECT TRILOGY, although potential selection bias cannot be excluded.Trial registrationClinicaltrials.gov NCT01051349; first registered January 15, 2010.

Project description:Background and objectivesAlemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation).MethodsParticipants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)].Results43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent.ConclusionSafety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course.Clinicaltrialsgov identifiersNCT00530348; NCT00548405; NCT00930553; NCT02255656.

Dataset Information

Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: Results of the HINT 2 clinical trial.

Publications

Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: Results of the HINT 2 clinical trial.

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