Long-term Safety Research Articles

Long-term follow-up of givosiran treatment in patients with acute intermittent porphyria from a phase 1/2, 48-month open-label extension study

BackgroundAcute hepatic porphyria is a group of multisystem disorders of which acute intermittent porphyria is the most common subtype. Givosiran, a subcutaneously administered RNA interference therapeutic targeting liver ALAS mRNA, is approved for treating these disorders. This Phase 1/2 open-label extension study (NCT02949830) evaluated the long-term safety and efficacy of givosiran in adults with acute intermittent porphyria, with follow-up of up to 48 months, which is the longest follow-up of givosiran treatment to date. Participants were adults aged 18–65 years who completed part C of the Phase 1 givosiran study (NCT2452372).MethodsEnrollees received givosiran for up to 48 months. Primary and secondary endpoints included the incidence of adverse events, changes in urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, annualized rate of porphyria attacks, and annualized hemin use. Quality of life was assessed using the EQ-5D-5L instrument as an exploratory endpoint.ResultsSixteen patients (median age: 39.5 years) participated. Common adverse events included abdominal pain, nasopharyngitis, and nausea (50% each), with injection-site erythema (38%) and injection-site pruritus (25%) noted as frequent treatment-related reactions. Givosiran therapy reduced annualized rates of porphyria attacks and hemin use by 97% and 96%, respectively. From months > 33 to 48, all patients were free from attacks requiring significant medical intervention and did not use hemin. There were substantial reductions in median urinary ALA and PBG of 95% and 98%, respectively. Additionally, a clinically meaningful improvement in quality of life was observed.ConclusionsIn the longest follow-up of givosiran-treated patients reported to date, the therapy maintained an acceptable safety profile and demonstrated sustained improvements in clinical outcomes over 4 years in patients with acute intermittent porphyria.

Long-term outcomes of catheter-directed sclerotherapy for ovarian endometrioma.

Although favorable results have been reported on catheter-directed sclerotherapy (CDS) for ovarian endometrioma, a thorough evaluation of its long-term efficacy is lacking. This study evaluates the long-term efficacy and safety of CDS with 99% ethanol for treatment of ovarian endometrioma. Between January 2020 and February 2022, data from 33 consecutive patients with symptomatic ovarian endometriomas who underwent CDS were retrospectively evaluated. All patients underwent pre-procedural and 6- and 12-month post-procedural ultrasonography. To assess the effect on ovarian reserve, serum anti-Müllerian hormone (AMH) levels were measured before and after the procedure. Procedure-related complications were also assessed. The mean volume of endometriomas decreased from 80.22 ± 66.43 to 0.73 ± 1.10 mL (P < 0.001), and the mean percentage of volume reduction was 98.99% ± 1.53%. No recurrences were observed during the follow-up period. In patients whose serum AMH levels were monitored for 1 year, no significant change in AMH level before and after CDS was observed (3.07 ± 1.81 vs. 2.72 ± 2.02 ng/mL, P = 0.190). One patient complained of moderate abdominal pain after CDS, which was conservatively managed. CDS remained safe and effective in treating ovarian endometrioma at the 1-year follow-up. Ovarian function after CDS was well preserved. CDS is a safe and effective treatment option for patients with ovarian endometrioma without compromising ovarian function.

Dapagliflozin's Role in Heart Failure: An Overview of Clinical Trial Evidence.

Heart failure (HF) has become a global health threat, necessitating the development of novel treatment options to address this crisis. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, such as dapagliflozin, may offer significant advantages in the treatment of HF, particularly in patients with reduced ejection fraction (HFrEF). This systematic review combines the findings from clinical studies to evaluate the safety and effectiveness of dapagliflozin in HF patients. The study results demonstrate dapagliflozin's consistent improvements in reducing adverse cardiovascular events, including cardiovascular death rates across different HF phenotypes. Mechanistically, dapagliflozin exerts diuretic and hemodynamic effects, along with its actions on myocardial metabolism, ion transporters, fibrosis, adipokines, and vascular function, which collectively contribute to its cardioprotective effects. This overview emphasizes dapagliflozin's key role in HF management, positioning it as one of the central pillars of the HF treatment regimen. Further studies are essential to fully understand dapagliflozin's long-term effectiveness, safety, and integration into routine clinical practice, ultimately improving patient outcomes in HF.

Transanal irrigation: a review of indications, key assessments, benefits, contraindications, complications, efficacy and safety

Transanal irrigation (TAI) is a therapeutic procedure designed to manage chronic bowel dysfunction, including constipation and faecal incontinence, particularly in individuals with neurogenic bowel dysfunction. TAI offers symptom relief and improves quality of life by providing autonomy in bowel management. This article explores the benefits, clinical indications and contraindications of TAI. The article also emphasises the importance of thorough patient assessments before initiating TAI, such as evaluating bowel function, manual dexterity and motivation. Furthermore, the review discusses the role of structured education programmes in ensuring long-term adherence and safety, particularly within the first 3 months. In addition, it covers the complications associated with TAI, such as bowel perforation and autonomic dysreflexia, and offers management strategies. Finally, the review outlines the conditions under which TAI should be discontinued and provides guidance on ensuring patient safety throughout the treatment.

The potential role of intracavernosal injection of platelet-rich plasma for treating patients with mild to moderate erectile dysfunction: A GRADE-Assessed systematic review and meta-analysis of randomized controlled trials.

Platelet-rich plasma (PRP) has shown positive effects on enhancing erectile function in animal studies. Human clinical trials are limited and provide contradictory results. This review aims to conduct a meta-analysis of the available Randomized controlled trials (RCT) to assess the efficacy of PRP in males with ED. A systematic review was carried out following the Cochrane Handbook of Intervention and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and registered in PROSPERO (CRD42023441655). A total of three RCTs were included in the analysis for a total of 221 patients with mild to moderate ED. The patients receiving PRP reported significantly better improvement of IIEFEF score during 1,3- and 6-months follow-up compared to the placebo group (mean difference [MD] 2.66, 95% confidence interval [CI] 1.48 to 3.83, p < 0.01; MD 2.11, 95%CI 0.13 to 4.09, p = 0.04; MD 2.99, 95%CI 1.79 to 4.19, p < 0.01). The pooled analysis indicated that attainment of minimally clinical important difference (MCID) was significantly higher in patients receiving PRP compared to the placebo group during one and 6-month follow-up (odds ratio [OR] 5.51, 95%CI 1.2 to 254, p = 0.03; OR 5.64, 95%CI 2.05 to 15.55, p < 0.01; respectively). Encouragingly, no major AEs were reported in all three trials in the PRP and placebo groups (p = 0.99). This review highlights the potential role of PRP in providing short-term improvement of erectile function parameters for up to 6 months in mild to moderate ED patients. Future RCTs with longer-duration follow-ups and more standardized treatment protocols are necessary to gain sufficient details on PRP's long-term effectiveness and safety.

Stereotactic radiosurgery for recurrent/residual nonfunctioning pituitary adenoma: a single-arm systematic review and meta-analysis.

Nonfunctioning pituitary adenomas (NFPAs) are a significant subtype of pituitary tumors, accounting for 30% of all pituitary tumors and 10-20% of intracranial tumors. The primary treatment for NFPAs is resection, but complete resection is often challenging due to the tumor's proximity to critical structures, leading to frequent recurrences. Stereotactic radiosurgery (SRS) has emerged as a viable treatment option for recurrent or residual NFPAs, but its long-term efficacy and safety profile require further investigation. This systematic review followed PRISMA guidelines and included studies published up to February 2024. We searched MEDLINE, Embase, and Cochrane databases for studies evaluating SRS for recurrent/residual NFPAs. Inclusion criteria focused on studies reporting outcomes and complications of SRS, while exclusion criteria omitted case reports, case series, and non-English studies. Data extracted included demographic details, dosimetry parameters, and follow-up durations. The risk of bias was assessed using the ROBINS-I tool, and statistical analyses were performed using single-arm meta-analyses. A total of 24 studies involving 3,781 patients were included. The mean follow-up duration was 60months. Tumor control was achieved in approximately 92.3% of patients. The risk of developing hypopituitarism post-SRS was 13.62%, while the risk for panhypopituitarism was 2.55%. New visual field deficits occurred in 3.94% of patients. Cranial nerve deficits were rare, with event rates below 1% for CN III, CN V, and CN VI. SRS is effective in managing recurrent or residual NFPAs, achieving high tumor control rates. However, the risk of hypopituitarism remains a significant concern, necessitating regular endocrinological monitoring. While generally safe, the potential for new visual field deficits and other cranial nerve deficits must be considered. SRS remains a valuable treatment option, but clinicians should be aware of its potential complications.

Long-term safety and subjective satisfaction of Bonebridge and Vibrant Soundbridge in congenital unilateral conductive hearing loss.

The objective of this study was to assess and compare the long-term safety and subjective satisfaction levels of Bonebridge (BB) and Vibrant Soundbridge (VSB) in patients with congenital unilateral conductive hearing loss (UCHL). The hearing effectiveness was measured using sound field hearing threshold (SFHT) and word recognition score (WRS). Long-term safety and subjective satisfaction levels were measured by questionnaires, including Speech, Spatial, and Qualities of Hearing Scale-12 (SSQ-12) and Abbreviated Profile of Hearing Aid Benefit (APHAB). Both BB and VSB were effective in improving the hearing of patients with congenital UCHL. Four of the 20 patients discontinued wearing the device postoperatively, and no complications were reported by long-term users. Patients experienced an overall improvement in their hearing experience across most subscales of SSQ-12 and a lower hearing problem rate across most subscales of the APHAB after implantation. However, the 'quality of hearing' subscale in the SSQ-12 did not show any improvement, and the aversiveness subscale in the APHAB exhibited a relatively higher percentage of reported problems after BB or VSB implantation. No significant differences were observed in SFHT, WRS, SSQ-12, and APHAB between the two groups. Both BB and VSB are effective in improving the hearing of UCHL patients, with high subjective satisfaction and low complication rates in the long-term postoperative period, with no significant difference between the two devices. Follow-up device fitting is essential, especially to address increased device sound or noise after surgery, reduce non-usage rates and achieve higher subjective satisfaction levels.

195 - Long-term safety and efficacy of low-dose desmopressin for nocturnal polyuria in men aged over eighty

195 - Long-term safety and efficacy of low-dose desmopressin for nocturnal polyuria in men aged over eighty

Long-term efficacy and safety of cannabidiol in patients with tuberous sclerosis complex: 3-year results from the cannabidiol expanded access program.

The cannabidiol (CBD) Expanded Access Program provided compassionate access to CBD for patients with treatment-resistant epilepsy, including tuberous sclerosis complex (TSC), at 35 US epilepsy centers. Here, we present the long-term efficacy and safety outcomes for add-on CBD treatment in patients with TSC. Patients received plant-derived, highly purified CBD (Epidiolex® 100 mg/mL, oral solution), increasing from 2 to 10 mg/kg/d to tolerance or maximum of 25-50 mg/kg/d. Efficacy endpoints were percentage change from baseline in median monthly convulsive, focal, and total seizure frequency and ≥ 50%, ≥75%, and 100% responder rates across 12-week visit windows through 144 weeks. Adverse events (AEs) are reported through 233 weeks. Thirty-four patients with confirmed TSC were included. Mean age was 12.4 years (range, 1.8-31.2), and patients were receiving a median of 3 (range, 1-7) antiseizure medications (ASMs) at baseline. Median CBD dose was 25-28 mg/kg/d for 36 weeks and then 20-50 mg/kg/d through 228 weeks. Dose reduction from baseline occurred for most ASMs, except topiramate. Median reduction in the frequency of convulsive, focal, and total seizures was 44%-81%, 51%-87%, and 44%-87%, respectively, through 144 weeks. Responder rates (≥50%, ≥75%, and 100% reduction) were 43%-71%, 14%-58%, and 0%-25% for convulsive seizures; 52%-75%, 35%-60%, and 7%-32% for focal seizures; and 46%-79%, 26%-65%, and 0%-13% for total seizures. A total of 94% of patients experienced ≥1 AE; 47% had serious AEs, considered treatment unrelated by the investigator. Treatment-related AEs (TRAEs) occurred in 71% of patients. The most frequently reported TRAEs were somnolence, diarrhea, and ataxia. Two patients experienced AEs leading to discontinuation. There were no deaths. Long-term add-on CBD use was associated with reduced seizure frequency through 144 weeks. The safety profile was consistent with previous reports. In this study, we evaluated efficacy and safety of cannabidiol (CBD) treatment in patients with tuberous sclerosis complex receiving CBD in addition to other antiseizure treatments in an Expanded Access Program. After starting CBD, 46%-79% of patients had at least 50% reduction and 26%-65% had at least 75% reduction in the number of seizures per month; up to 13% had no seizures through 144 weeks. Safety results were similar to prior studies; sleepiness and diarrhea were common treatment-related side effects. These results show that long-term CBD treatment was associated with fewer seizures and mild/moderate side effects.

Continuous Subcutaneous Foslevodopa-Foscarbidopa in Parkinson's Disease: A Mini-Review of Current Scope and Future Outlook.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, primarily because of the impairment of dopaminergic neurons. Long-term use of levodopa, the standard PD treatment, often results in fluctuating therapeutic effects and dyskinesia, necessitating alternative therapies. This review aims to synthesize current insights and clinical experiences with foslevodopa-foscarbidopa, focusing on its pharmacokinetics, efficacy, and safety profile, to evaluate its potential in transforming PD therapy. A systematic literature search was conducted up to November 2023 using databases PubMed, Web of Science, and Cochrane Library. The search yielded eight eligible articles, including pharmacological studies, case reports, observational studies, and controlled trials. No language restrictions were applied. Foslevodopa and foscarbidopa, as prodrugs of levodopa and carbidopa, exhibited excellent chemical stability and solubility, facilitating continuous subcutaneous infusion. Clinical trials demonstrated that these prodrugs maintain stable levodopa levels, thereby addressing the limitations of oral levodopa therapy. Phase 1 and 3 studies indicated significant improvements in motor function and quality of life in advanced PD patients. However, a higher incidence of treatment-emergent adverse events, mainly infusion site reactions, was observed compared to oral therapies. Foslevodopa-foscarbidopa emerges as a promising alternative for advanced PD treatment, offering sustained symptom control. Its efficacy in managing motor fluctuations and dyskinesia makes it a viable option in the PD therapeutic spectrum. Future research should focus on long-term safety, economic impact, and broader accessibility. Foslevodopa-foscarbidopa is now commercially distributed in many countries in Europe and in Japan.

Pimozide-loaded nanostructured lipid carriers: Repurposing strategy against lung cancer.

This study aimed to repurpose pimozide (PMZ) by incorporating it into nanostructured lipid carriers (NLC) using a modified melting emulsion ultrasonication method. We employed stearic and oleic acids in a 1:1 ratio as lipids, with Tween 80 and PEG 4000 as surfactants. The formulation was analyzed for particle size, zeta potential, and encapsulation efficiency. Transmission electron microscopy (TEM) was used to confirm the spherical shape of the particles. The release profile of PMZ-NLC was evaluated under different pH conditions, and anticancer activity was tested on A549 cell lines. The PMZ-NLC exhibited an average particle size of 136 ± 2.9 nm, a zeta potential of -25.1 ± 0.9 mV, and an encapsulation efficiency of 86% ± 11. TEM confirmed the spherical shape of the NLCs. PMZ release from PMZ-NLC was pH-sensitive, enhancing tumor targeting. IC50 values were 16.5 μM for free PMZ and 12.9 μM for PMZ-NLC after 72 h. PMZ-NLC demonstrated improved anticancer activity compared to free PMZ, suggesting that encapsulation enhances the drug's effectiveness. The pH-sensitive release profile supports its potential for targeted therapy in lung cancer. PMZ-NLC showed potential as a safe and effective strategy for lung cancer treatment. Further investigation is warranted to evaluate its in vivo efficacy, long-term safety, and clinical application.

Tocilizumab plus Nintedanib for progressive interstitial lung disease in systemic sclerosis: a one-year observational study.

Randomized controlled trials have recently shown that both the IL-6 inhibitor Tocilizumab and the antifibrotic Nintedanib are efficacious for Systemic Sclerosis (SSc)-associated progressive interstitial lung disease (ILD). Since real-world clinical data on Tocilizumab/Nintedanib combination are lacking, we report on their long-term safety and efficacy. Consecutive patients who received off-label Tocilizumab for SSc plus Nintedanib for progressive ILD were retrospectively studied. Adverse events, and changes in Forced Vital Capacity (FVC), Diffucing Capacity for Carbon Monoxide (DLCO) and high resolution chest tomography (HRCT) between baseline and 6 and 12 months were assessed. Tocilizumab/Nintedanib combination was well tolerated by all 20 patients [aged 52 ± 13 years (mean ± SD), 14 women, 15 diffuse SSc, disease duration of 5.7 ± 4.9 years]; 7 of 20 patients received concomitant mycophenolate mofetil safely. No serious adverse events or laboratory abnormalities were noted. Five patients developed persistent diarrhea and 2 of them reduced dosage of Nintedanib. Baseline FVC (74%±12%) and DLCO (45%±10%) remained overall stable both at 6 months (73.5%±13% and 46%±11%, respectively) and 12 months (73%±14% and 45%±11%, respectively), regardless of disease duration. The extent of fibrotic reticular pattern in available pairs of HRCTs (n = 12) remained also stable at 12 months, whereas proportion (%) of ground glass opacities decreased from 29%±16to21%±14% (p = 0.048); improvement in HRCTs by almost 75% was noted in 2 of these12 patients. Tocilizumab/Nintedanib combination for one year was safe and stabilized lung function in real-world SSc patients with progressive ILD. Additional studies of this combination treatment in SSc-ILD are warranted.

Long-Term Safety and Efficacy of Pegcetacoplan in Patients with C3 Glomerulopathy or Primary Immune-Complex Membranoproliferative Glomerulonephritis: The Long-Term VALE Extension Study

Long-Term Safety and Efficacy of Pegcetacoplan in Patients with C3 Glomerulopathy or Primary Immune-Complex Membranoproliferative Glomerulonephritis: The Long-Term VALE Extension Study

PHYOX3: Long-Term Safety and Efficacy of Nedosiran in Patients with Primary Hyperoxaluria Type 1

PHYOX3: Long-Term Safety and Efficacy of Nedosiran in Patients with Primary Hyperoxaluria Type 1

TCT-315 Acute and Long-Term Safety and Efficacy of IVUS-Guided Drug Coated Balloon Treatment for Carotid In-Stent Restenosis

TCT-315 Acute and Long-Term Safety and Efficacy of IVUS-Guided Drug Coated Balloon Treatment for Carotid In-Stent Restenosis

[Artículo traducido] Eficacia y seguridad del risankizumab en pacientes con psoriasis en el mundo real: un estudio retrospectivo, multicéntrico y no intervencionista

Background and objectiveRisankizumab – a humanized monoclonal antibody that targets the p19 subunit of IL-23 – has been recently approved to treat moderate-to-severe plaque psoriasis. Real-world data based on a representative pool of patients are currently lacking. ObjectiveTo assess the mid- and long-term safety and efficacy profile of risankizumab in patients with moderate-to-severe psoriasis in the routine clinical practice. MethodsThis was a retrospective and multicenter study of consecutive psoriatic patients on risankizumab from April 2020 through November 2022. The primary endpoint was the number of patients who achieved a 100% improvement in their Psoriasis Area and Severity Index (PASI) (PASI100) on week 52. ResultsA total of 510 patients, 198 (38.8%) women and 312 (61.2%) men were included in the study. The mean age was 51.7±14.4 years. A total of 227 (44.5%) study participants were obese (body mass index [BMI] >30kg/m2). The mean baseline PASI score was 11.4±7.2, and the rate of patients who achieved PASI100 on week 52, 67.0%. Throughout the study follow-up, 21%, 50.0%, 59.0%, and 66% of the patients achieved PASI100 on weeks 4, 16, 24, and 40, respectively. The number of patients who achieved a PASI ≤2 was greater in the group with a BMI ≤30kg/m2 on weeks 4 (P=.04), 16 (P=.001), and 52 (P=.002). A statistically significantly greater number of patients achieved PASI100 in the treatment-naïve group on weeks 16 and 52 (P=.001 each, respectively). On week 16 a significantly lower number of participants achieved PASI100 in the group with psoriatic arthropathy (P=.04). Among the overall study sample, 22 (4.3%) patients reported some type of adverse event and 20 (3.9%) discontinued treatment. ConclusionsRisankizumab proved to be a safe and effective therapy for patients with moderate-to-severe psoriasis in the routine clinical practice.

Long-term efficacy and safety of dose-dense and dose-intense ABVD without consolidation radiotherapy in patients with advanced Hodgkin lymphoma: A 15-year follow-up of the ABVDDD-DI phase II study.

We demonstrated that dose-densified and dose-intensified ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine; ABVDDD-DI) was safe and effective. Here, we present a post hoc long-term analysis of the 82 patients enrolled in the original study. The median observation time was 175 months (IQR 159-197). At 15 years, progression-free and overall survival rates were 81.2% (95% CI, 69.9%-88.7%) and 92.7% (95% CI, 82.6%-97.0%), respectively. Four patients with multiple cardiovascular risk factors experienced delayed G3 cardiac events. The cumulative incidence of second malignancies at 20 years was 6.1%. Fertility and childbearing potential were unaffected. Data support an ongoing benefit for ABVDDD-DI without uneven late toxicities.

Long-Term Efficacy and Safety of Lumasiran in Patients with Primary Hyperoxaluria Type 1: Final Analysis of the ILLUMINATE-A Trial

Long-Term Efficacy and Safety of Lumasiran in Patients with Primary Hyperoxaluria Type 1: Final Analysis of the ILLUMINATE-A Trial

S1454 Long-Term Efficacy and Safety of Intravenous (IV) Tulisokibart in Patients With Ulcerative Colitis (UC): Results From the Open-Label Extension (OLE) Period of the Phase 2 ARTEMIS-UC Study

S1454 Long-Term Efficacy and Safety of Intravenous (IV) Tulisokibart in Patients With Ulcerative Colitis (UC): Results From the Open-Label Extension (OLE) Period of the Phase 2 ARTEMIS-UC Study

Pegloticase-Induced Rapid Uric Acid Lowering and Kidney and Cardiac Health Markers in Youth-Onset Type 2 Diabetes: A Pilot Clinical Trial

Rationale & ObjectiveElevated serum uric acid (SUA) is a risk factor for incident hypertension and diabetic kidney disease in young persons with type 2 diabetes (T2D), particularly men. The acute benefit of aggressively lowering SUA on kidney and cardiovascular function in this population remains underexplored. This study was conducted to investigate the impact of a single pegloticase infusion on kidney and cardiovascular function. Study DesignAn open-label pilot trial. Setting & ParticipantsThe study involved 10 young adult males with youth-onset T2D and SUA levels ≥5 mg/dL. Intervention(s)Participants received a single infusion of pegloticase (8 mg). Evaluations were conducted using iohexol-based measured glomerular filtration rate (mGFR) and cardiac/kidney MRI before and one week after infusion. OutcomesThe primary outcomes were changes in SUA and mGFR one week after pegloticase infusion. ResultsNine participants (mean [±SD] age 22±5 years, HbA1c 8.6±3.3%, BMI 40.1±11.0 kg/m2, SUA 6.7±1.1 mg/dL) completed the pegloticase infusion and were included in the analysis. One week after the infusion, median [p25,p75] SUA concentrations dropped from 6.4 [5.6,7.6] to 0.5 [0.5,4.6] mg/dL (p=0.01). Mean mGFR increased from 113±20 to 122±19 ml/min per 1.73 m2 (p=0.004). Among responders (SUA reduction ≥3 mg/dL), an increase in mGFR correlated with an increase in renal artery blood flow (r:0.60, p=0.24) and decrease in SUA (r:-0.79, p=0.05). Mean MRI peak longitudinal cardiac strain additionally decreased from 15.4±2.2 to 13.1±2.2 % (p=0.03) in these responders. LimitationsThe pilot nature of the study and the small sample size limit the generalizability of the findings. ConclusionsIn young adult males with T2D, a single pegloticase infusion decreased SUA levels, which increased mGFR and was strongly associated with increased renal blood flow and impaired cardiac global longitudinal strain. Further research is required to assess the long-term efficacy and safety of pegloticase in patients with T2D.