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Probiotic peanut oral immunotherapy versus oral immunotherapy and placebo in children with peanut allergy in Australia (PPOIT-003): a multicentre, randomised, phase 2b trial.
Loke, P, Orsini, F, Lozinsky, AC, Gold, M, O'Sullivan, MD, Quinn, P, Lloyd, M, Ashley, SE, Pitkin, S, Axelrad, C, et al
The Lancet. Child & adolescent health. 2022;(3):171-184
Abstract
BACKGROUND Oral immunotherapy is effective at inducing desensitisation to allergens and induces sustained unresponsiveness (ie, clinical remission) in a subset of patients, but causes frequent reactions. We aimed to investigate whether addition of a probiotic adjuvant improved the efficacy or safety of peanut oral immunotherapy. METHODS PPOIT-003, a multicentre, randomised, phase 2b trial, was conducted in three tertiary hospitals in Australia (Adelaide [SA], Melbourne [VIC], and Perth [WA]) in children aged 1-10 years, weighing more than 7 kg, with peanut allergy confirmed by a double-blind placebo-controlled food challenge (cumulative 4950 mg dose of peanut protein) and positive peanut skin prick test (≥3 mm) or peanut-specific IgE (≥0·35 kU/L). Children were randomly assigned (2:2:1) to receive probiotic and peanut oral immunotherapy (PPOIT), placebo probiotic and peanut oral immunotherapy (OIT), or placebo probiotic and placebo OIT (placebo) for 18 months, and were followed up until 12 months after completion of treatment. Oral immunotherapy consisted of increasing doses of peanut protein (commercially available food-grade 12% defatted peanut flour [50% peanut protein]) until a 2000 mg daily maintenance dose was reached. The probiotic adjuvant was a daily dose of 2 × 1010 colony-forming units of the probiotic Lactobacillus rhamnosus ATCC 53103. Placebo immunotherapy comprised maltodextrin, brown food colouring, and peanut essence, and placebo probiotic was maltodextrin. Dual primary outcomes were 8-week sustained unresponsiveness, defined as no reaction to a cumulative dose of 4950 mg peanut protein at treatment completion and 8 weeks after treatment completion, in the PPOIT versus placebo groups and the PPOIT versus OIT groups, analysed by intention to treat. Safety endpoints were adverse events during the treatment phase, and peanut ingestion and reactions in the 12-month post-treatment period. This study is registered with the Australian New Zealand Clinical Trials Registry, 12616000322437. FINDINGS Between July 4, 2016, and Sept 21, 2020, 201 participants were enrolled and included in the intention-to-treat analysis. 36 (46%) of 79 children in the PPOIT group and 42 (51%) of 83 children in the OIT group achieved sustained unresponsiveness compared with two (5%) of 39 children in the placebo group (risk difference 40·44% [95% CI 27·46 to 53·42] for PPOIT vs placebo, p<0·0001), with no difference between PPOIT and OIT (-5·03% [-20·40 to 10·34], p=0·52). Treatment-related adverse events were reported in 72 (91%) of 79 children in the PPOIT group, 73 (88%) of 83 children in the OIT group, and 28 (72%) of 39 children in the placebo group. Exposure-adjusted incidence of adverse events was 10·58 in the PPOIT group, 11·36 in the OIT, and 2·09 in the placebo group (ratio 0·92 [95% CI 0·85 to 0·99] for PPOIT vs OIT, p=0·042; 4·98 [4·11-6·03] for PPOIT vs placebo, p<0·0001; 5·42 [4·48-6·56] for OIT vs placebo, p<0·0001), with differences seen primarily in gastrointestinal symptoms and in children aged 1-5 years. During the 12-month post-treatment period, 60 (85%) of 71 participants in the PPOIT group, 60 (86%) of 70 participants in the OIT group, and six (18%) of 34 participants in the placebo group were eating peanut; rescue epinephrine use was infrequent (two [3%] of 71 in the PPOIT group, four [6%] of 70 in the OIT group, and none in the placebo group). INTERPRETATION Both PPOIT and OIT were effective at inducing sustained unresponsiveness. Addition of a probiotic did not improve efficacy of OIT, but might offer a safety benefit compared with OIT alone, particularly in preschool children. FUNDING National Health and Medical Research Council Australia and Prota Therapeutics.
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Proportions of circulating transitional B cells associate with MRI activity in interferon beta-treated multiple sclerosis patients.
Mimpen, M, Damoiseaux, J, van Doorn, W, Rolf, L, Muris, AH, Hupperts, R, van Luijn, MM, Gerlach, O, Smolders, J
Journal of neuroimmunology. 2021;:577664
Abstract
B-cells contribute to MS pathogenesis. The association of circulating B-cell phenotypes with combined unique active lesions (CUA) on MRI at 48 weeks follow-up was investigated in 50 interferon beta-treated MS patients. Transitional B-cell proportions were lower in participants with CUA at week 0 and 48 [p = 0.004, p = 0.002]. A decrease in circulating anti-EBNA-1 IgG levels between week 0 and 48 associated with absence of CUA [p = 0.047], but not with B-cell profiles. In a multi-factor model for CUA-risk, transitional B-cell proportions contributed independent from NK/T-cell ratio, change in anti-EBNA-1 IgG, and vitamin D supplementation. Transitional B-cells may predict treatment response in MS.
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A double-blind phase III trial of immunomodulating nutritional formula during adjuvant chemoradiotherapy in head and neck cancer patients: IMPATOX.
Boisselier, P, Kaminsky, MC, Thézenas, S, Gallocher, O, Lavau-Denes, S, Garcia-Ramirez, M, Alfonsi, M, Cupissol, D, de Forges, H, Janiszewski, C, et al
The American journal of clinical nutrition. 2020;(6):1523-1531
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Abstract
BACKGROUND In a previous phase II study an immunonutrient supplement was found to reduce severe acute toxicities for head and neck squamous cell cancer (HNSCC) patients treated with concomitant cisplatin and radiotherapy. OBJECTIVES The primary objective of the present study was to evaluate efficacy of the same immunonutrient supplement on severe mucositis. Secondary objectives included tolerance, compliance to oral supplementation, chemotherapy interruptions and delays, quality of life, and progression-free survival (PFS) and overall survival (OS) at 1, 2, and 3 y. METHODS Between November 2009 and June 2013, 180 HNSCC patients eligible for adjuvant chemotherapy after surgery with curative intent were included in our double-blind phase III multicenter trial. They were assigned to receive oral supplementation (3 sachets/d) of either a formula enriched with l-arginine and omega-3 (n-3) fatty and ribonucleic acids (experimental arm), or an isocaloric isonitrogenous control (control arm), for 5 d before each of 3 cycles of cisplatin. Intention-to-treat (ITT) and per-protocol (PP) analyses were undertaken, along with subgroup analyses of ≥75% compliant patients, to compare the incidence of acute mucositis (Radiation Therapy Oncology Group and WHO scales) and 36-mo survival. RESULTS At 1 mo after terminating chemoradiotherapy (CRT), no differences were observed in the incidence of grade 3-4 mucositis between treatment groups, in the ITT, PP (172 patients), and subgroup (≥75% compliance, n = 112) analyses. The immunomodulating supplement did not significantly improve survival in the ITT and PP analyses at 3 y after CRT. Among ≥75% compliant patients, however, OS at 3 y was significantly improved in the immunomodulating formula group (81%; 95% CI: 67%, 89%) compared with controls (61%; 95% CI: 46%, 73%; P = 0.034), as well as PFS (73%; 95% CI: 58%, 83% compared with 50%; 95% CI: 36%, 63%; P = 0.012). CONCLUSIONS Although this immunomodulating formula failed to reduce severe mucositis during CRT, the findings suggest that the long-term survival of compliant HNSCC patients was improved.This trial was registered at clinicaltrials.gov as NCT01149642.
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Combination Therapy of Adalimumab With an Immunomodulator Is Not More Effective Than Adalimumab Monotherapy in Children With Crohn's Disease: A Post Hoc Analysis of the PAILOT Randomized Controlled Trial.
Matar, M, Shamir, R, Turner, D, Broide, E, Weiss, B, Ledder, O, Guz-Mark, A, Rinawi, F, Cohen, S, Topf-Olivestone, C, et al
Inflammatory bowel diseases. 2020;(11):1627-1635
Abstract
BACKGROUND The PAILOT trial was a randomized controlled trial aimed to evaluate proactive vs reactive therapeutic drug monitoring in children with Crohn's disease (CD) treated with adalimumab. Our aim in this post hoc analysis of the PAILOT trial was to assess the efficacy and safety of adalimumab combination treatment in comparison with monotherapy at week 72 after adalimumab induction. METHODS Participants were children 6-17 years old, biologic naïve, with moderate to severe CD, who responded to adalimumab induction at week 4. Patients receiving immunomodulators at baseline maintained a stable dose until week 24; patients could then discontinue immunomodulators. At each visit, patients were assessed for disease index, serum biomarkers, fecal calprotectin, adalimumab trough concentration, and anti-adalimumab antibodies. RESULTS Out of the 78 patients (29% female; mean age, 14.3 ± 2.6 years), 34 patients (44%) received combination therapy. During the study period, there was no significant difference in the rates of sustained corticosteroid-free clinical remission (25/34, 73%, vs 28/44, 63%; P = 0.35) or sustained composite outcome of clinical remission, C-reactive protein ≤0.5 mg/dL, and calprotectin ≤150 µg/g (10/34, 29%, vs 14/44, 32%; P = 0.77) between the combination group and the monotherapy group, respectively. Clinical and biological outcomes did not differ between the proactive and reactive subgroups within the combination and monotherapy groups. Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but was numerically higher in the monotherapy group. CONCLUSIONS Combination therapy of adalimumab and an immunomodulator was not more effective than adalimumab monotherapy in children with CD (ClinicalTrials.gov No. NCT02256462).
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Study of immunotherapy in antibody positive psychosis: feasibility and acceptability (SINAPPS1).
Lennox, BR, Tomei, G, Vincent, SA, Yeeles, K, Pollard, R, Palmer-Cooper, E, Jones, P, Zandi, MS, Coles, A
Journal of neurology, neurosurgery, and psychiatry. 2019;(3):365-367
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Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.
Imel, EA, Glorieux, FH, Whyte, MP, Munns, CF, Ward, LM, Nilsson, O, Simmons, JH, Padidela, R, Namba, N, Cheong, HI, et al
Lancet (London, England). 2019;(10189):2416-2427
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Abstract
BACKGROUND X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING Ultragenyx Pharmaceutical and Kyowa Kirin International.
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A randomised trial of vitamin D in acute-stage allergic bronchopulmonary aspergillosis complicating asthma.
Dodamani, MH, Muthu, V, Thakur, R, Pal, A, Sehgal, IS, Dhooria, S, Aggarwal, AN, Garg, M, Chakrabarti, A, Agarwal, R
Mycoses. 2019;(4):320-327
Abstract
Vitamin D has been demonstrated to have an immunomodulatory role in cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA). Herein, we evaluate supplemental vitamin D in acute-stage ABPA complicating asthma. Thirty subjects were randomised to receive either prednisolone (n = 15, control) or prednisolone and oral vitamin D (n = 15, intervention arm). Serum vitamin D levels were significantly higher in the intervention versus the control arm, following therapy. The mean decline in total IgE at 2 months (primary outcome) was 10% higher in the intervention arm than the control arm; however, this was not statistically significant (48.6% vs 38.1%, P = 0.27). The percentage decline in total IgE after 4 and 6 months of randomisation was also similar in the two arms. There was no difference in asthma exacerbations (0 vs 2, intervention vs control; P = 0.16). No ABPA exacerbation occurred in either arm. The other outcomes including the Th2 (IL-4, IL-6 and IL-10) and Th17 (IL-17) cytokine levels were similar in the two groups. None of the participants experienced hypervitaminosis D. There was no significant improvement in the clinical or immunological outcomes following vitamin D supplementation. A larger trial is required to ascertain the role of vitamin D in ABPA complicating asthma [Clinicaltrials.gov: NCT03133299].
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Effects of combination of mizolastine and proteoglycan on chronic urticaria: a randomized controlled trial.
Xiong, X, Song, L, Chen, F, Ma, X
Archives of dermatological research. 2019;(10):801-805
Abstract
The present study aimed to observe the therapeutic effect of combined mizolastine and proteoglycan in chronic urticaria. The patients were randomly divided into the treatment group (n = 56) and the control group (n = 44). The treatment group was medicated with calcium gluconate (10 mg/ time, 1 time/day), vitamin D3 (intramuscular 10 mg/time, 1 time/week), mizolastine (10 mg/time, 1 time/day), and proteoglycan (1.2 g/time, 3 times/day), while the control group was administered with the same drugs except proteoglycan for 4 weeks. After treatment with combined mizolastine and proteoglycan, therapeutic effect with symptoms decline index (SDI) more than 60% was significant different (44 vs. 24, p = 0.000973) and the relapse rate after 2 months was significantly lower (17.9% vs. 38.6%, p = 0.0202). Using ELISA, we found that the IFN-γ (37.88 ± 4.27 pg/mL vs. 21.91 ± 4.95 pg/mL, p = 0.028) levels were specifically increased in the experiment group. The combination of mizolastine plus proteoglycan is effective in treating chronic urticaria with better therapeutic effect and lower relapse rate through promoting IFN-γ production.
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Immune function testing in sepsis patients receiving sodium selenite.
Guo, A, Srinath, J, Feuerecker, M, Crucian, B, Briegel, J, Boulesteix, AL, Kaufmann, I, Choukèr, A
Journal of critical care. 2019;:208-212
Abstract
PURPOSE We examined in a longitudinal study the role of sodium selenite in sepsis patients in strengthening the immune performance in whole blood samples using immune functional assays. MATERIALS AND METHODS This was a sub-study from a randomized, double blinded multicenter clinical trial (SISPCT) registered with www.clinicaltrials.gov (NCT00832039) and with data collected at our center. Full blood samples were incubated with various recall antigens and the supernatants were measured for their cytokine concentrations as markers for immune response. Data from days 0, 4, 7, 14, and 21 (from sepsis onset) were analyzed using a generalized least squares model in R to appropriately take the longitudinal structure and the missing values into account. RESULTS From the 76 patients enrolled in the study at our center, 40 were randomized to selenium therapy and 36 to placebo. The analyses of immune response assay data showed no statistical difference between the selenium and placebo groups at each of the time points. There was however an overall dampening of cytokine release, which tended to recover over time in both groups. CONCLUSION Selenium has long been an adjuvant therapy in treating sepsis. Recently, it was proven to not have beneficial effects on the mortality outcome. Using data from our center in this sub-cohort study, we identified no relative improvement in cytokine release of stimulated blood immune cells ex vivo from patients with selenium therapy over a three-week period. This offers a potential explanation for the lack of beneficial effects of selenium in sepsis patients.
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Effects of Immunonutrition in Advanced Human Immunodeficiency Virus Disease: A Randomized Placebo-controlled Clinical Trial (Promaltia Study).
Serrano-Villar, S, de Lagarde, M, Vázquez-Castellanos, J, Vallejo, A, Bernadino, JI, Madrid, N, Matarranz, M, Díaz-Santiago, A, Gutiérrez, C, Cabello, A, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;(1):120-130
Abstract
BACKGROUND While nutritional interventions with prebiotics and probiotics seem to exert immunological effects, their clinical implications in human immunodeficiency virus (HIV)-infected subjects initiating antiretroviral therapy (ART) at advanced HIV disease remain unclear. METHODS This was a pilot multicenter randomized, placebo-controlled, double-blind study in which 78 HIV-infected, ART-naive subjects with <350 CD4 T cells/μL or AIDS were randomized to either daily PMT25341 (a mixture of synbiotics, omega-3/6 fatty acids and amino acids) or placebo for 48 weeks, each in combination with first-line ART. Primary endpoints were changes in CD4 T-cell counts and CD4/CD8 ratio from baseline to week 48 and safety. Secondary endpoints were changes in markers of T-cell activation, bacterial translocation, inflammation, and α and β microbiota diversity. RESULTS Fifty-nine participants completed the follow-up with a mean CD4+ T-cell count of 221 ± 108 cells/μL and mean CD4/CD8 ratio of 0.26 ± 0.19. PMT25341 was well tolerated, without grade 3-4 adverse effects attributable to the intervention. While most of the assessed biomarkers improved during the follow-up in both arms, PMT25341-treated subjects did not experience any significant change, compared to placebo-treated subjects, in mean CD4+ T-cell count change (278 vs 250 cells/μL, P = .474) or CD4/CD8 ratio change (0.30 vs 0.32, P = .854). Similarly, we did not detect differences between treatment arms in secondary endpoints. CONCLUSIONS In HIV-infected patients initiating ART at advanced disease, the clear immunological benefits of ART were not enhanced by this nutritional intervention targeting the gut-associated lymphoid tissue and microbiota. CLINICAL TRIALS REGISTRATION NCT00870363.