Open-label Study Research Articles

Clinical immunogenicity outcomes from GENEr8-1, a phase 3 study of valoctocogene roxaparvovec, an AAV5-vectored gene therapy for hemophilia A

Gene transfer therapies utilizing adeno-associated virus (AAV) vectors involve a complex drug design with multiple components that may impact immunogenicity. Valoctocogene roxaparvovec is an AAV serotype 5 (AAV5)-vectored gene therapy for treatment of hemophilia A that encodes a B-domain–deleted human factor VIII (FVIII) protein controlled by a hepatocyte-selective promoter. Following previous results from the first-in-human phase 1/2 clinical trial, we assessed AAV5 capsid– and transgene-derived FVIII-specific immune responses with 2 years of follow-up data from GENEr8-1, a phase 3, single-arm, open-label study in 134 adult men with severe hemophilia A. No FVIII inhibitors were detected following administration of valoctocogene roxaparvovec. Immune responses were predominantly directed toward the AAV5 capsid, with all participants developing durable anti-AAV5 antibodies. Cellular immune responses specific for the AAV5 capsid were detected in most participants by interferon-ᵧ enzyme-linked immunosorbent spot assay 2 weeks following dose administration and declined or reverted to negative over the first 52 weeks. These responses were weakly correlated with alanine aminotransferase elevations and showed no association with changes in FVIII activity. FVIII-specific cellular immune responses were less frequent and more sporadic compared with those specific for AAV5 and showed no association with safety or efficacy parameters.

Continuous subcutaneous levodopa/carbidopa infusion with ND0612 for Parkinson’s disease: Three-year data from the open-label BeyoND study

Continuous subcutaneous levodopa/carbidopa infusion with ND0612 for Parkinson’s disease: Three-year data from the open-label BeyoND study

Garadacimab for hereditary angioedema attack prevention: long-term efficacy, quality of life, and safety data from a phase 2, randomised, open-label extension study

Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long-term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema. This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double-blind, placebo-controlled) and a treatment period 2 (TP2: ≥44-week open-label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open-label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long-term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed. Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open-label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 39·0 years (IQR 27·0-53·0), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 87·9 weeks (IQR 50·0-106·6) in the garadacimab 200 mg group and 44·1 weeks (24·1-56·1) in the garadacimab 600 mg group. Median monthly attack rates were 0·0 (IQR 0·0-0·1) in the garadacimab 200 mg group and 0·1 (0·0-0·4) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run-in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths. Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long-term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema. CSL Behring.

Effectiveness and safety of a novel, collapsible pessary for management of pelvic organ prolapse

Pessaries are an effective treatment for pelvic organ prolapse, yet currently available pessaries can cause discomfort with removal and insertion. An early feasibility trial of an investigational, collapsible pessary previously demonstrated mechanical feasibility during a brief 15-minute office trial. Longer-term, patient-centered safety and efficacy data is needed. To assess the effectiveness and safety of the investigational vaginal pessary for pelvic organ prolapse at three months. This was a prospective, seven-center, open-label equivalence study with participants serving as their own controls. Subjects were current users of a Gellhorn or ring pessary with ≥ Stage II prolapse. Baseline subjective and objective data were collected for one month using their current pessary, and then data were collected through a three-month treatment phase with use of the study pessary. The primary outcome was change in Pelvic Floor Distress Inventory-20 score. Secondary outcome measures included objective assessment of prolapse support, changes in the Pelvic Floor Impact Questionnaire-7, and pain with insertion and removal measured on a Visual Analog Scale. Subjects fitted with study pessary were analyzed as intention to treat and those who dropped out were assigned scores at the upper limit of the predefined equivalence limits. Secondary per protocol analyses included subjects who completed treatment. The study was powered to 80% with a minimal important change equivalence limit of 18.3 points on the Pelvic Floor Distress Inventory-20 scale. Square root transformations were used for non-parametric data and p-values adjusted for multiple comparisons. Seventy-eight subjects were enrolled, though 16 withdrew prior to study pessary placement. Sixty-two subjects (50 ring and 12 Gellhorn pessary users) were fitted with the study pessary, and 48 (62%) completed the three-month intervention. The change in Pelvic Floor Distress Inventory-20 scores at three months demonstrated equivalence compared to the subjects' baseline scores, (mean difference -3.96 (improvement), 90% confidence interval (CI) [-11.99, 4.08], p=0.002). Per protocol analysis of the Pelvic Floor Distress Inventory-20, equivalence was not demonstrated with scores favoring the study pessary (mean difference -10.45, 90% CI, [-20.35, 0.54] (p=0.095)). Secondary outcomes included: objective measures of support which were similar, mean difference Ba=0.54 cm, Bp=0.04 cm, favoring study pessary; improvement in mean Pelvic Floor Impact Questionnaire-7 scores for those who completed the trial (pre=32.23, post=16.86, p=0.019); and pain with insertion and removal, which was lower with the study pessary compared to subject's own pessary (mean difference Visual Analogue Scale insertion=9.91 mm (p=0.019), removal=11.23 mm (p=0.019)). No serious adverse events related to the pessary were reported. Equivalence was demonstrated in the study pessary primary outcome compared to current non-collapsible pessaries for change in severity and bother of pelvic floor symptoms. In participants who completed the trial, the Pelvic Floor Impact Questionnaire-7 improved with the study pessary and change in Pelvic Floor Distress Inventory-20 scores were non-equivalent, favoring the study pessary. Subjects reported significantly lower pain scores with both pessary insertion and removal with the novel collapsible pessary compared with their standard pessary.

Phase 1 Study of Tivozanib Eye Drops in Healthy Volunteers and Patients with Neovascular Age-related Macular Degeneration

PurposeTo evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD). DesignThis multicenter, group-sequential dose escalation phase 1 study consisted of a placebo-controlled, double-masked study of healthy volunteers (Cohorts 1 and 2) and an open-label study of nAMD patients (Cohort 3). ParticipantsHealthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness ≥300 μm and best-corrected visual acuity score ≥23 letters in the study eye. MethodsIn the single-dose cohort of healthy men (Cohort 1: Steps 1–5), 1 or 2 tivozanib eye drops (30 μL/drop, 5-minute interval; 0.5, 1.0, and 2.0 w/v%) or placebo were administered in 1 eye once. In the multiple-dose cohort of healthy men (Cohort 2: Steps 1–6), 1 or 2 tivozanib eye drops (0.5, 1.0, and 2.0 w/v%) or placebo were administered 3 times daily (TID) in 1 eye for 21 days. In the multiple-dose cohort of nAMD patients (Cohort 3, Steps 1–3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered TID in 1 affected eye for 21 days. Main Outcome MeasuresThe safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, central subfield thickness (CST) was evaluated. ResultsIn total, 40, 48, and 28 participants were enrolled in Cohorts 1, 2, and 3, respectively. Serious AEs did not occur in Cohorts 1–3. The most frequent AE in multiple-dose cohorts was reversible punctate keratitis: placebo arm, 8.3% (healthy men, 1/12); tivozanib arm, 47.2% (healthy men, 17/36) and 14.3% (nAMD, 4/28). Serum tivozanib exposure increased dose-dependently and was similar in healthy men and patients with nAMD. In patients with nAMD, mean CST changes from baseline to Day 22 were −27.6 ± 54.88 (0.5 w/v%; 1 drop, TID), −35.6 ± 49.64 (1.0 w/v%; 1 drop, TID), and −43.7 ± 55.19 μm (1.0 w/v%; 2 drops, TID). ConclusionsTivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD.

EVALUATION OF THE EFFICACY AND TOLERABILITY OF A FIXED DOSE COMBINATION OF AMLODIPINE AND INDAPAMIDE IN PATIENTS OLDER THAN 55 YEARS

Objective: There is very limited real-life data on hypertension management in Bangladeshi population. Considering this fact, this study evaluated the effectiveness of treatment with an indapamide/amlodipine single-pill combination (SPC) in Bangladeshi patients over the age of 55 years, in an OPD setting with uncontrolled systolic hypertension in real-life clinical practice. Methods: This was a 3-month, multicenter, observational, open-label study conducted in 3 divisional cities of Bangladesh among patients with grade I or II hypertension who were either uncontrolled on previous antihypertensive treatment or treatment-naïve. The effectiveness of indapamide/amlodipine SPC was assessed by the change in office systolic blood pressure (SBP) and the rate of target SBP (&lt; 140 mmHg) achievement at 2 weeks, 1 month and 3 months, in four age groups: 55-59 years, 60-69 years, 70-79 years, and 80 years or older. Design and method: The COMBINE study recruited 213 patients, of whom 185 took indapamide/amlodipine 1.5/5 mg SPC fora full three-month course of therapy. Mean age was 62.4±7.4 years, 76 men [41.1%] and 109 women [58.9%]. The absolute decrease of SBP during 3 months of taking indapamide/amlodipine single-pill combination (SPC) was 29.3 mm Hg, DBP - 12.9 mm Hg. After 3 months of treatment significant SBP decreases from baseline were observed in each age group: ? 31.8 mmHg (from 156.7 to 124.9), ? 26.4 mmHg (from 152.7 to 126.3), ? 29.5 mmHg (from 152.8 to 123.3), and ? 25.8 mmHg (from 151.7 to 125.9) in the 55-59, 60-69, 70-79, and 80 years and older age groups, respectively. Leg edema was observed in 3 patients (1.62%), electrolyte imbalance was observed in 4 patients (2.16%) and 1 patients observed sudden fall of blood pressure. Conclusion: This COMBINE study results showed that indapamide/amlodipine SPC was associated with significant and rapid reductions in BP even in a different age range of Bangladeshi patients in routine clinical practice. This study result is consistent with already achieved data of this SPC globally.

Dual mTOR1/2 inhibitor sapanisertib (TAK-228) in combination with weekly paclitaxel in patients with previously treated metastatic urothelial carcinoma: a phase II open-label study.

BackgroundThe PI3K/AKT/mTOR pathway is frequently altered at genomic level in metastatic urothelial carcinoma (mUC). Since mTOR is the last protein in the PI3K signaling cascade, it may have the largest impact on the pathway and has been a focus of targeted therapies. Sapanisertib (TAK-228) is an oral highly selective mTOR1 and mTOR2 inhibitor. NFE2L2 mutations have been described as predictive biomarkers of response in patients with advanced squamous cell lung cancer treated with sapanisertib. Patients and methodsThis was an open-label, investigator-initiated phase II study evaluating safety and efficacy of sapanisertib plus paclitaxel in patients with mUC who had progressed to prior platinum therapy, and the correlation with NFE2L2 mutations in responders. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Patients were treated with weekly paclitaxel at dose of 80 mg/m2 on days 1, 8 and 15 in combination with sapanisertib 4 mg administered orally 3 days per week on days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle. NFE2L2 mutations were analyzed by Sanger sequencing in responders. Results22 patients were enrolled from May 2018 to April 2020; the trial was halted early due to slow accrual and the COVID-19 pandemic. ORR was 18.2% (N=4). Disease control rate was 50% (7 SD and 4 PR). Median PFS was 3.4 months (95% CI 1.8-6.1) and median OS was 6.1 months (95% CI 1.8-13.4). Adverse events (AE) of grade 3-4 were seen in 86% of patients, but no patients discontinued treatment due to AEs. NFE2L2 mutations were not found in responders. ConclusionsAlthough the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates. MicroAbstractThe mTOR pathway is frequently altered in UC and is crucial in regulating immune responses. This phase 2 trial investigated the role of the combination of sapanisertib (mTOR inhibitor) and paclitaxel in patients who progressed to standard therapies. 22 patients were enrolled. ORR was 18.2%. Median OS was 6.1 months (95% CI 1.8-13.4). 86% of patients had grade 3-4 adverse events (AE).

A phase I dose-escalation and -expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results

SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in pre- and post-menopausal women with ER+, HER2- advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. Patients and Methods Women aged 18 years or older with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, anti-tumor efficacy, pharmacokinetics, and impact on ESR1m circulating tumor (ct)DNA levels were assessed. By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events (TRSAEs) at doses ≤150 mg. Median tmax was achieved ∼2-4 hours post-dose at all doses investigated, with an estimated half-life of 20-23 hours. Efficacy was observed at all doses investigated, including in patients with prior CDK4/6 inhibitor and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. Camizestrant is a next-generation oral SERD and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75, 150 and 300 mg QD doses for Phase 2 testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study.

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.

Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Proline Henagliflozin in Chinese Subjects with Varying Degrees of Liver Dysfunction.

Proline henagliflozin, a novel selective inhibitor of sodium glucose cotransporter 2, is a treatment for type 2 diabetes mellitus. We designed a parallel-group, open-label, and multicenter study to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of henagliflozin in Chinese subjects with varying degrees of liver dysfunction. Thirty-two subjects were enrolled and divided into four groups based on liver function (normal liver function, mild, moderate, or severe liver dysfunction). The area under the plasma concentration from time zero to infinity of henagliflozin in subjects with mild liver dysfunction, moderate liver dysfunction, and severe liver dysfunction compared with normal liver function was increased by 137%, 197%, and 204%, respectively. The maximum plasma concentration was also increased by 123%, 129%, and 139%, respectively. PK parameters of three metabolites varied to different degrees in the liver dysfunction groups than in the normal liver function group. The mean accumulative excretion amounts and fraction of dose excreted in urine expressed as a percentage were all increased with the decrease of liver function. The PD parameters were significantly higher in liver dysfunction groups than those in the normal liver function group. However, the urine creatinine (UCr) was not significantly different among the groups. No notable adverse events or adverse drug reactions were observed. Due to the higher exposures in subjects with liver dysfunction, the benefit: risk ratio should be individually assessed because the long-term safety profile and efficacy have not been specifically studied in this population.

The effects of inhaled corticosteroids on healthy airways.

The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness. Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics. ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B-cell immunity (CD20, immunoglobulin heavy and light chains) and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.

The Role of a Cholecystokinin Receptor Antagonist in the Management of Chronic Pancreatitis: A Phase 1 Trial.

Chronic pancreatitis (CP) is a rare but debilitating condition with an 8-fold increased risk of developing pancreatic cancer. In addition to the symptoms that come from the loss of endocrine and exocrine function in CP, the management of chronic pain is problematic. We previously showed that the CCK-receptor antagonist called proglumide could decrease inflammation, acinar-ductal metaplasia, and fibrosis in murine models of CP. We hypothesized that proglumide would be safe and diminish pain caused by CP. A Phase 1 open-labeled safety study was performed in subjects with clinical and radiographic evidence of CP with moderate to severe pain. After a 4-week observation period, the subjects were treated with proglumide in 400 mg capsules three times daily (1200 mg per day) by mouth for 12 weeks, and then subjects returned for a safety visit 4 weeks after the discontinuation of the study medication. The results of three pain surveys (Numeric Rating Scale, COMPAT-SF, and NIH PROMIS) showed that the patients had significantly less pain after 12 weeks of proglumide compared to the pre-treatment observation phase. Of the eight subjects in this study, two experienced nausea and diarrhea with proglumide. These side effects resolved in one subject with doses reduced to 800 mg per day. No abnormalities were noted in the blood chemistries. A blood microRNA blood biomarker panel that corresponded to pancreatic inflammation and fibrosis showed significant improvement. We conclude that proglumide is safe and well tolerated in most subjects with CP at a dose of 1200 mg per day. Furthermore, proglumide therapy may have a beneficial effect by decreasing pain associated with CP.

Open-label observational study of effectiveness and tolerability of ipidacrine in treatment of patients with diabetic polyneuropathy (DIAMANT study)

Diabetic polyneuropathy (DPN) is one of the most common complications of diabetes mellitus, leading to the development of flaccid paresis, neuropathic pain syndrome, sensitive ataxia, as well as trophic disorders in the distal parts of the lower extremities.The purpose of the randomized, open-label, comparative, prospective study was to evaluate the effectiveness and tolerability of ipidacrine in the complex treatment of patients with DPN.Materials and methods. Patients with DPN (n = 60) were randomized into 2 groups. Both groups received basic therapy (alpha-lipoic acid, B vitamins, gabapentin); in the treatment of patients of the main group (n = 30), in addition, ipidacrine was used (Ipidacrine-SZ, North Star Co., Russia). We have analyzed the intensity of pain syndrome (VAS-P), the average daily dosage of gabapentin, and the results of the neuropathic dysfunctional scale (modified version, NDSm), Pittsburgh Sleep Quality Index, PSQI), Global Rating of Change Scale (GROC), the results of electroneuromyography (ENMG). The total duration of the observation and treatment period was 2 months.Results. After 2 months of therapy in the main group of patients, compared with the control group, there was significantly more complete pain control (VAS-P: 3.0 ± 0.9 vs 3.6 ± 0.8), a decrease in the average daily dosage of gabapentin (390 vs 500 mg/day), reduction in the severity of clinical manifestations of polyneuropathic syndrome (NDSm: 4.4 ± 1.0 vs 4.9 ± 1.0 points) and improvement in sleep quality (PSQI: 6.8 ± 1.3 vs 7.9 ± 1.7). According to ENMG data, patients in the main group showed a significant improvement in the neurophysiological parameters of both motor and sensory fibers, which was significantly more pronounced compared to the control group. A significantly larger proportion of patients in the main group assessed the improvement from the therapy as ‘pronounced’ (GROC: 10/33.3 % vs 6/20.0 %).Conclusions. The use of ipidacrine in complex therapy of patients with DPN can significantly reduce the clinical manifestations of disease and improve the neurophysiological parameters of the peripheral nerves of the lower extremities. Ipidacrine can be considered as a basic drug for the treatment of patients with neurological complications of diabetes mellitus.

Eculizumab in Adolescent Patients With Refractory Generalized Myasthenia Gravis: A Phase 3, Open-Label, Multicenter Study

BackgroundThis study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG). MethodsAdolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded. ResultsEleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were −5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and −2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. ConclusionsEculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.

A study of potency determination of 3C antimuonium crudum in the treatment of corn

Background: Planter skin is anatomically different from the normal skin of the body due to prominence of keratin filaments such as k6, k7, k9, k16 and k17. As per Hahnemann statement in chronic disease, Antimuonium crudum is basically the native ore (persulphuric of antimony) found in blocks of parallel block needle with a metallic lustre and are composed of twenty-eight parts of sulphur combined with 100 parts of metallic antimony. Methods: An observational comparative prospective open label study was conducted from September 2019 to September 2020. 32 patients were included in the study. Follow up of the cases were done after every 15 days where the size of the corn was measured using a vernier caliper. Height, width and diameter of the corn was also measured pre and post-treatment to analyse the results. Results: A total of 32 patients were studied. The size of the corn was considerably reduced after taking the medication. There was a significant reduction in the intensity of the pain due to corn after medication as well. Conclusions: There is a significant reduction of disease intensity score, after the homoeopathic treatment. Which shows the efficacy and potency of 3C Antimuonium crudum in the treatment of corn.

No evidence for an association of voxel-based morphometry with short-term non-motor outcomes in deep brain stimulation for Parkinson’s disease

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy in advanced Parkinson’s disease (PD). Motor and non-motor outcomes, however, show considerable inter-individual variability. Preoperative morphometry-based metrics have recently received increasing attention to explain treatment effects. As evidence for the prediction of non-motor outcomes is limited, we sought to investigate the association between metrics of voxel-based morphometry and short-term non-motor outcomes following STN-DBS in this prospective open-label study. Forty-nine PD patients underwent structural MRI and a comprehensive clinical assessment at preoperative baseline and 6-month follow-up. Voxel-based morphometry was used to assess associations between cerebral volume and non-motor outcomes corrected for multiple comparisons using a permutation-based approach. We replicated existing results associating volume loss of the superior frontal cortex with subpar motor outcomes. Overall non-motor burden, however, was not significantly associated with morphometric features, limiting its use as a marker to inform patient selection and holistic preoperative counselling.

Amino Acids Oral Treatment for the Amelioration of Skin, Hair, and Nails Conditions: An Open-Label Study

This study aimed at investigating the effect of a food supplement in ameliorating the skin, hair, and nails conditions. An open-label study on 21 women with mild-to-moderate aging all over the face (including wrinkles/fine lines, loss of skin firmness/elasticity, and normal to dry skin), acute telogen effluvium, and brittle/fragile nails was conducted. Skin (moisturization, elasticity, profilometry, and skin thickness), hair (pull test and phototricogram), and nails (clinical analysis of nail plate status) parameters were measured at baseline, and after 28 and 84 days of intake. The clinical analysis carried out by a board-certified dermatologist and the self-evaluation integrated the instrumental measurements. After 28 (D28) and 84 (D84) days of product intake the skin moisturization (superficial moisturization: +6.0% at D28 and +9.2% at D84; deep moisturization: +4.2% at D28 and +7.6 at D84), elasticity (R0 parameter: -11.5% at D28 and -19.3% at D84; R2 parameter: +7.8% at D28 and +11.9 at D84), profilometry (wrinkle depth: -9.5% at D28 and -14.5% at D84; skin smoothness: -4.9% at D28 and -7.7% at D84) and thickness (+0.11 mm at D28 and +0.24 mm at D84) were improved. At D84 the density of telogen hair was reduced by 9.5%; while at day 28 pull test was not indicative for telogen effluvium. The nail status was improved in most of the enrolled subjects. The instrumental measured effects were perceived by both the dermatologist and the enrolled subjects. Our results highlight the test product efficacy in improving the skin, hair, and nails conditions.

Add-on multiple submucosal injections of the RNA oligonucleotide GUT-1 to anti-TNF antibody treatment in patients with moderate-to-severe ulcerative colitis: an open-label, proof-of concept study

BackgroundCarbohydrate sulfotransferase 15 (CHST15) is an enzyme biosynthesizing matrix glycosaminoglycan that modulates tissue remodeling. We evaluated the efficacy of add-on submucosal injections of GUT-1, the RNA oligonucleotide inhibitor of CHST15, to ongoing anti-tumor necrosis factor (TNF) antibody treatment in patients with moderate-to-severe ulcerative colitis (UC).MethodsThis was an open-label study of 250 nM of GUT-1 by endoscopic submucosal injections at weeks 0, 2, 4 in five UC patients who lost response during maintenance treatment to anti-TNF antibodies. The primary endpoint was the rate of endoscopic improvement at week 6 and secondary endpoints included the rates of clinical remission by modified Mayo Score (mMS). Patients received follow-up observation with continuous maintenance treatment by the same anti-TNF antibody till the time of clinical recurrence or for overall 52 weeks.ResultsAt week 6, rates of endoscopic improvement and clinical remission were 80% (n = 4/5) and 60% (n = 3/5), respectively. The mean Endoscopy Subscore was reduced from 2.4 (95%CI: 1.7 to 3.1) at baseline, to 1.0 (95%CI: 0.1 to 1.9) at week 6. The mean mMS was reduced from 7.8 (95%CI: 6.2 to 9.4) to 1.3 (95%CI: 2.9 to 4.3). GUT-1 was well tolerated. Three patients did not show clinical recurrence for 52 weeks. All three corticosteroid-dependent patients showed no corticosteroid exposure for at least 24 weeks after achieving clinical remission. Multiple dosing was also well tolerated.ConclusionsAdd-on multiple injections of GUT-1 to ongoing anti-TNF antibody was able to induce rapid and durable clinical responses in UC patients who lost response to anti-TNF therapy.Trial registrationClinical trial Registration Number (Japan): UMIN000020900.

Precision synbiotics increase gut microbiome diversity and improve gastrointestinal symptoms in a pilot open-label study for autism spectrum disorder.

Autism spectrum disorder (ASD) is prevalent in 1 out of 36 children in the United States and contributes to health, financial, and psychological burdens. Attempts to identify a gut microbiome signature of ASD have produced varied results. The limited pre-clinical and clinical population sizes have hampered the success of these trials. To understand the microbiome associated with ASD, we employed whole metagenomic shotgun sequencing to classify microbial composition and genetic functional potential. Despite being one of the most extensive ASD post-synbiotic assessment studies, the results highlight the complexity of performing such a case-control supplementation study in this population and the potential for a future therapeutic approach in ASD.

Testing of symmetric biphasic stimulation in Vim-DBS ET patients: a randomized-controlled pilot study.

Symmetric biphasic pulses have been shown to increase the therapeutic window compared to standard cathodic pulses in ET Vim-DBS patients. Furthermore, three hours of stimulation with biphasic pulses caused less stimulation-induced ataxia compared to cathodic pulses. Therefore, an investigation of the longer-term safety of biphasic pulses is warranted. Seven ET patients were included in a randomized double-blind, cross-over design of one week home-use of symmetric biphasic stimulation (anodic phase first) versus cathodic stimulation. Amplitude was set in a double-blinded way, at the tremor arrest threshold. The primary outcome was safety assessed by documenting the adverse events. Secondary outcome parameters were stimulation amplitude, tremor (Fahn-Tolosa-Marin Tremor Rating Scale) and ataxia (International Cooperative Ataxia Rating Scale) severity, quality of life (Quality of Life in Essential Tremor Questionnaire) and cognition (Montreal Cognitive Assessment). Three patients continued in the open-label extension phase for 3 months, during which biphasic stimulation-only was further assessed by the same outcome parameters. During the 1 week testing, no adverse effects were reported. To obtain equivalent tremor control, the amplitude of the biphasic pulse was significantly higher compared to that of the cathodic pulse (p = 0.003). The other outcome parameters were not significantly different. During the open-label study, one patient used the remote control to increase the amplitude, leading to two falls caused by stimulation-induced ataxia. No other adverse effects occurred. In a small cohort, when tested for one week, symmetric biphasic pulses suggest to be safe, but require higher stimulation amplitudes. Further follow-up studies are needed to investigate long-term effects and safety.