Double-blind Placebo-controlled Phase Research Articles

The Maternal Group B Streptococcus Alpha-Like Protein Subunit Vaccine GBS-NN Targets Homotypic and Heterotypic Strains, Confers Opsonophagocytic Killing and Prevents <i>in vitro</i> Invasion of Human Epithelial Cells

Maternal vaccination, resulting in transfer of protective IgG across the placenta, represents a promising strategy to prevent neonatal disease caused by group B Streptococcus (GBS). The prototype vaccine GBS-NN, a fusion protein consisting of the N-terminal domains of the alpha-like protein (Alp) family members AlphaC and Rib, has been shown to display a good safety profile and to elicit a strong antibody response against the intact GBS-NN protein in a randomized placebo-controlled double-blind phase 1 trial in healthy adult women. Here we show that the vaccinees achieve robust IgG and IgA responses against both AlphaC and Rib and that vaccination additionally gives rise to antibodies against the heterotypic Alp family members Alp1-3. Responses against the heterotypic N-domains were more variable between subjects and correlated strongly with levels of pre-existing antibodies. Postvaccination sera mediated opsonophagocytic killing that correlated strongly with IgG but not IgM responses elicited by the vaccine. These sera also consistently prevented bacterial invasion of human cervical epithelial cells. Like the vaccine-induced response, naturally acquired IgG against the N-domains of AlphaC and Rib was dominated by the IgG1 subclass. Consistent with the enhanced ability of IgG1 to cross the placenta, naturally acquired IgG against both domains accumulated in neonatal relative to maternal blood, as assessed in a separate group of non-vaccinated pregnant women and their babies.

Evaluation of the effect of curcumin and zinc co-supplementation on glycemic measurements, lipid profiles, and inflammatory and antioxidant biomarkers in overweight or obese prediabetic patients: a study protocol for a randomized double-blind placebo-controlled phase 2 clinical trial

BackgroundThe prevalence of prediabetes is increasing worldwide. Unfortunately, prediabetes is related to non-communicable diseases. A high risk of developing type 2 diabetes mellitus (T2DM) is reported in people with prediabetes. Curcumin, a polyphenol, might lead to its therapeutic role in obesity and some obesity-related metabolic diseases. Zinc is a trace element that plays a key role in the synthesis and action of insulin, carbohydrate metabolism, and decreasing inflammation. There has been no clinical trial of zinc and curcumin co-supplementation in patients with prediabetes. In previous studies, the single administration of zinc or curcumin has not been conducted on many of the studied markers in prediabetic patients.MethodsThe purpose of this randomized double-blind placebo-controlled clinical trial is to investigate the effect of curcumin and zinc co-supplementation on glycemic measurements, lipid profiles, and inflammatory and antioxidant biomarkers among 84 prediabetic patients with body mass index (BMI) between 25 and 35. Also, liver enzyme, serum zinc, urine zinc, blood pressure, anthropometric parameters, quality of life, adherence to co-supplementation, the side effects of co-supplementation, physical activity, and dietary intake will be assessed. Women or men (18–50 years old for men and 18 years to before menopause for women) will be followed for 3 months (90 days). This study will be conducted at Yazd Diabetes Research Clinic, Shahid Sadoughi University of Medical Sciences.DiscussionA diet rich in antioxidants, polyphenols, and phytochemicals has been shown to have a beneficial role in prediabetes. According to the beneficial properties of curcumin or zinc and inadequate evidence, RCTs are needed to assess the effect of curcumin and zinc co-supplementation in native prediabetes patients. We hope the results of the present trial, negative or positive, fill this gap in the literature and facilitate the approach for a much larger, multi-center clinical trial. In conclusion, a synergic effect of co-supplementation along with a weight-loss diet may delay the progression to type 2 diabetes mellitus.Trial registrationIranian Registry of Clinical Trials (IRCT) IRCT20190902044671N1. Registered on 11 October 2019

Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials.

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.

Azathioprine immunosuppression and disease modification in Parkinson’s disease (AZA-PD): a randomised double-blind placebo-controlled phase II trial protocol

IntroductionThe immune system is implicated in the aetiology and progression of Parkinson’s disease (PD). Inflammation and immune activation occur both in the brain and in the periphery, and a proinflammatory...

Topical Propranolol Improves Epistaxis Control in Hereditary Hemorrhagic Telangiectasia (HHT): A Randomized Double-Blind Placebo-Controlled Trial.

Epistaxis is a common debilitating manifestation in hereditary hemorrhagic telangiectasia (HHT), due to mucocutaneous telangiectases. The epistaxis can be difficult to control despite available treatments. Dysregulated angiogenesis has been shown to be associated with telangiectases formation. Topical propranolol has demonstrated antiangiogenic properties. We performed a two-phase study, i.e., a double-blind placebo-controlled phase, followed by an open-label phase. The aim of the study was assessment of safety and efficacy of nasal propranolol gel in HHT-related epistaxis. Twenty participants with moderate-severe HHT-related epistaxis were randomized to eight weeks of propranolol gel 1.5%, or placebo 0.5 cc, applied to each nostril twice daily; and continued propranolol for eight weeks in an open-label study. For the propranolol group, the epistaxis severity score (ESS) improved significantly (−2.03 ± 1.7 as compared with −0.35 ± 0.68 for the placebo group, p = 0.009); hemoglobin levels improved significantly (10.5 ± 2.6 to 11.4 ± 2.02 g/dL, p = 0.009); and intravenous iron and blood transfusion requirement decreased. The change in nasal endoscopy findings was not significant. During the open-label period, the ESS score improved significantly in the former placebo group (−1.99 ± 1.41, p = 0.005). The most common adverse event was nasal mucosa burning sensation. No cardiovascular events were reported. Our results suggest that topical propranolol gel is safe and effective in HHT-related epistaxis.

LBA15 Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC)

LBA15 Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC)

LBA28 A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial

LBA28 A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial

Early-start vs delayed-start donepezil against cognitive decline in Parkinson disease: a randomized clinical trial

ABSTRACT Background Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). Research design and methods The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. Results A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). Conclusions Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study).

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019).

Sodium taurocholate cotransporting polypeptide (NTCP) is a new and promising target for treatment of hypercholesterolemia: A proof of concept from a randomized double-blind placebo-controlled phase I trial

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019)

Efficacy and Safety of the Combination of Pravastatin and Sorafenib for the Treatment of Advanced Hepatocellular Carcinoma (ESTAHEP Clinical Trial).

Pravastatin has demonstrated anti-tumor activity in preclinical and clinical studies. This multicentric randomized double-blind placebo-controlled phase II study (NCT01418729) investigated the efficacy and safety of sorafenib + pravastatin combination on the overall survival (OS) and time to progression (TTP) of patients with advanced hepatocellular carcinoma (aHCC). A total of 31 patients were randomized. Median OS did not differ between both groups (12.4 months for the sorafenib + pravastatin group vs. 11.6 months for the control group). Of note, however, the radiological TTP was higher in patients treated with sorafenib + pravastatin than in the control group (9.9 months vs. 3.2 months; p = 0.008). Considering all the study population, the presence of portal vein thrombosis (PVT) was associated with worse OS, being lower in patients with PVT compared to patients without PVT (6.3 months vs. 14.8 months; p = 0.026). Data also showed a decrease in OS in patients with vascular invasion (VI) compared to patients who did not present it (6.3 months vs. 14.8 months; p = 0.041). The group of patients without dermatological events (DE) showed lower OS (6.9 months vs. 14.5 months; p = 0.049). In conclusion, combination of sorafenib + pravastatin was safe and well-tolerated, prolonging the TTP of patients with aHCC but not improving the OS compared to sorafenib + placebo. The absence of PVT and VI and the development of DE are positive prognostic factors of sorafenib response.

848-P: Totum-63 Lowers Fasting Glycemia in Subjects with Prediabetes: A Phase 2A Clinical Trial

Over 1 billion people worldwide suffer prediabetes, which is defined by increased fasting blood glucose (FBG), glucose intolerance and/or higher A1c hemoglobin. Prediabetes is considered a risk factor for type 2 diabetes (T2D). We have developed Totum-63, a plant-based product designed to reduce T2D risk factors. In a phase I/II clinical trial, Totum-63 had shown its safety, good tolerance and beneficial effects on post-prandial glucose control in healthy subjects. The aim of this multicentre, randomised and double-blind placebo-controlled phase IIA trial was to show the efficiency of Totum-63 in reducing FBG (primary endpoint) in 51 volunteers with prediabetes (defined by FBG ≥ 1.1 g/l and 2h OGTT glycemia ≥ 1.1 g/l). Secondary endpoints included blood glucose change following an oral glucose tolerance test (OGTT) and anthropometric parameters. Totum-63 (5g/day) or placebo was given to the participants for 6 months. At the end of the supplementation period, FBG was reduced in Totum-63 group compared to placebo group (difference from baseline: -0.04 ± 0.02 vs. +0.09 ± 0.04 g/l, p&amp;lt;0.05). Similarly, 2-hour OGTT glycemia was improved in Totum-63 group, vs. placebo (difference from pre-protocol value: -0.02 ± 0.07 vs. +0.32 ± 0.17 g/l, p&amp;lt;0.05). Moreover, Totum-63 had a significant lowering effect on body weight (-0.07 ± 0.42 vs. +1.83 ± 0.57 Kg; p&amp;lt;0.05) and waist circumference (-1.67 ± 0.73 vs. +2.81 ± 0.65 cm; p&amp;lt;0.001). To conclude, the primary endpoint of this clinical trial was reached, Totum-63 contributed to lower FBG in individuals with prediabetes. Moreover, the response to an OGTT was improved, as well as body weight and waist circumference, thus making Totum-63 a promising candidate for T2D risk prevention. Disclosure S. Peltier: Board Member; Self; Valbiotis. V. Chavanelle: Employee; Self; Valbiotis. Y.F. Otero: Employee; Self; Valbiotis. M. Bargetto: Employee; Self; Valbiotis. M. Cazaubiel: Board Member; Self; Valbiotis. B. Pereira: None. P. Sirvent: Board Member; Self; Valbiotis. J. Bard: Consultant; Self; Biofortis, Valbiotis. Stock/Shareholder; Self; Valbiotis.

Human urinary kallidinogenase in treating acute ischemic stroke patients: analyses of pooled data from a randomized double-blind placebo-controlled phase IIb and phase III clinical trial

ABSTRACTObjectives: Intravenous thrombolysis and thrombectomy are recommended for patients whose stroke onsets are within first 6 h, and very few options are available for patients whose stroke onset is more than 6 h, which includes most ischemic stroke patients. Human urinary kallidinogenase (HUK) showed potential clinical benefits in acute ischemic stroke patients. This study aims to investigate the safety and clinical benefits of HUK in ischemic stroke patients.Patients and methods: Patients were recruited for a multicenter double-blind, placebo-controlled phase II b and phase III trial. Neurophysiological outcomes were assessed by the European Stroke Scale (ESS) and the functional outcomes were assessed by the activity of daily living scale (ADL). Safety was monitored by recording adverse events.Results: The improvements in ESS scores and ADL scores in the HUK group were significantly greater than that in patients receiving placebo. Furthermore, HUK treatment was also associated with a lower rate of disable, according to ADL. HUK-related adverse events occurred at a low rate, in 1.73% of HUK-treated patients.Conclusion: HUK is safe and provides potential clinical benefits as a treatment for acute ischemic stroke. Further large post-marketing observational studies are needed.

Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event (RESTORE BRAIN study): a placebo controlled phase II study

BackgroundThe GABAA-α5 receptor antagonist S44819 is a promising candidate to enhance functional recovery after acute ischemic stroke (IS). S44819 is currently evaluated in this indication; RESTORE brain study started in Dec 2016 and was completed in March 2019.Methods/designThe study is a 3-month international, randomized, double-blind, parallel group, placebo-controlled phase II multicentre study. Patients in 14 countries who suffered an IS leading to a moderate or severe deficit defined by NIHSS score ranging from 7 to 20 and are aged between 18 to 85 years are included between 3 and 8 days after the stroke onset. Approximately 580 patients are to be included.The primary objective of the study is to demonstrate the superiority of at least one of the two doses of S44819 (150 or 300 mg bid) compared to placebo on top of usual care on functional recovery measured with the modified Rankin scale at 3 months. Comparisons between two doses of S44819 and placebo are assessed with ordinal logistic regression evaluating the odds of shifting from one category to the next in the direction of a better outcome at day 90. Secondary objectives include the evaluation of S44819 effects on neurological examination using the National Institute of Health Stroke Scale total score, activities of daily living using the Barthel Index total score, and cognitive performance using the Montreal Cognitive Assessment scale total score and Trail Making Test times. Safety and tolerability of the two doses of S44819 will also be analyzed.DiscussionThe RESTORE BRAIN study might represent the first proof of concept study of an innovative therapeutic approach that is primarily based on enhancing functional recovery after IS.Trial registrationRandomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event, an international, multi-centre, randomized, double-blind placebo-controlled phase II study. ClinicalTrials.gov, NCT02877615; Eudract 2016–001005-16. Registered 24 August 2016

One step closer to alleviating uraemic pruritus.

The KALM-1 randomized double-blind placebo-controlled phase III trial showed that intravenous difelikefalin, a selective κ-opioid receptor agonist, significantly reduces itch intensity in haemodialysis patients with uraemic pruritus. However, 49% of difelikefalin-treated patients showed no improvement. In light of the increasing number of patients with end-stage renal disease, additional treatments are sorely needed.

P515 Comparability of upadacitinib pharmacokinetics in Japanese and non-Japanese subjects with ulcerative colitis with the extended-release formulation

Abstract Background Upadacitinib (UPA), an oral selective JAK1 inhibitor, is being developed for treatment of patients with moderately-to-severely active ulcerative colitis (UC) in addition to several other inflammatory diseases. UPA has shown favourable efficacy and acceptable safety in UC in an 8-week double-blind placebo-controlled dose-ranging Phase 2b induction study in subjects with moderately-to-severely active UC (U-ACHIEVE trial). Methods Sparse blood samples were collected from subjects with UC who were enrolled in the U-ACHIEVE trial, which included Japanese and non-Japanese subjects. UPA plasma concentration vs. time after dose were summarised from the U-ACHIEVE trial. Additionally, data from U-ACHIEVE were pooled with data from UPA Phase 1 and other Phase 2 studies across different inflammatory diseases to characterise UPA population pharmacokinetics. The population pharmacokinetic model was used to estimate UPA plasma exposures from extended-release formulation (dose range 7.5 – 45mg QD) in 168 non-Japanese and 28 Japanese subjects with UC in U-ACHIEVE. Results UPA plasma exposures were approximately dose proportional over the evaluated dose range in Japanese subjects with UC. Observed dose-normalised plasma concentrations vs. time since the last dose (Figure 1) and dose-normalised model-estimated UPA exposures were comparable (within 25%) between Japanese and non-Japanese subjects with UC (Table 1). Conclusion UPA plasma exposures are similar between Japanese and non-Japanese subjects with UC. This is in agreement with prior assessments in healthy subjects and in subjects with RA which demonstrated comparable UPA exposures between Asian and Western subjects.

Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials

ObjectiveTo investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD).MethodsTwo multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with...

A double-blind placebo-controlled randomized phase II trial assessing the activity and safety of regorafenib in non-adipocytic sarcoma patients previously treated with both chemotherapy and pazopanib

BackgroundMetastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib. Patients and methodsThis double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours–based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743). ResultsFrom December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4–not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15–0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23–1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0). ConclusionThe present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.

Efficacy of Satralizumab (SA237) As Add-on Therapy in Pre-Specified Additional Analyses of Sakurasky, a Double-Blind Placebo-Controlled Phase 3 Study in Patients with Neuromyelitis Optica Spectrum Disorders (NMOSD)

A central role of interleukin-6 (IL-6) as key player in the pathophysiology of NMOSD, is strongly supported by the significant reduction in risk of relapse as previously demonstrated in the SAkuraSky study of the IL-6R inhibitor satralizumab for treatment of NMOSD as an add-on therapy. Here, we report the results of additional analyses (ClinicalTrials.gov number, NCT020728884). 83 patients meeting NMOSD diagnostic criteria with/without AQP4-Ab and at least two relapses in the last 2 years were randomly assigned to receive satralizumab 120 mg subcutaneously or placebo at week 0, 2 and 4 and every 4 weeks thereafter, added to stable immunosuppressant treatment. The primary endpoint was time to first protocol-defined relapse. Pre-specified additional analyses included efficacy in AQP4-Ab positive vs. negative subgroups, and effect on annualized relapse rate (ARR). Hazard ratios (HRs) were based on Cox proportional hazards model. Satralizumab added to baseline treatment significantly reduced risk of protocol-defined relapse by 62% vs placebo; HR, 0.38; 95% confidence interval (CI), 0.16 to 0.88; P=0.0184. Pre-specified additional analyses showed a 79% relapse risk reduction with satralizumab vs placebo in AQP4-Ab(+) patients (n=55; HR, 0.21; 95% CI, 0.06 to 0.75) and 34% in AQP4-Ab(-) patients (HR 0.66; 95% CI, 0.20 to 2.24). In the overall study population, ARR was 0.11 (95% CI, 0.05 to 0.21) when treated with satralizumab vs 0.32 (95% CI, 0.19 to 0.51) with placebo. Treatment with satralizumab as add-on to baseline immunosuppressant therapy significantly reduced relapse risk, particularly in AQP4-Ab(+) NMOSD patients.