Active-controlled Clinical Trial Research Articles

#386 Avacopan versus prednisone taper in newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis in the ADVOCATE trial

Abstract Background and Aims In granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), two types of antineutrophil cytoplasmic autoantibody-associated vasculitis, relapses are common, with 14–44% of patients experiencing a relapse at 18–36 months, depending on patient characteristics, duration of follow-up, and maintenance treatment [1]. In the phase 3 ADVOCATE trial, 69% of patients were newly diagnosed and 31% had relapsing GPA/MPA [2]. This post hoc subgroup analysis of ADVOCATE evaluates the safety and efficacy of avacopan compared with a prednisone taper in patients with newly diagnosed or relapsing GPA/MPA. Method ADVOCATE, a randomised, double-blind, double-dummy, active-controlled clinical trial, assigned eligible patients 1:1 to receive avacopan or a prednisone taper on a background of either cyclophosphamide (followed by azathioprine or mycophenolate mofetil) or rituximab. Data from patients with newly diagnosed (N = 229) or relapsing (N = 101) GPA/MPA were analysed. Key outcomes were the percentage of patients achieving remission at week 26 and sustained remission at week 52. Other outcomes included relapse rate, change in estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (UACR), glucocorticoid dose (prednisone-equivalent), Glucocorticoid Toxicity Index (GTI), health-related quality of life (HRQoL), and safety. Results Baseline characteristics were comparable between the avacopan and prednisone taper arms within each disease status group (Table 1). Efficacy outcomes are reported in Table 2. At week 26, similar proportions of patients with newly diagnosed GPA/MPA achieved remission in the avacopan and prednisone taper arms (66.1% vs 66.7%; difference [95% confidence interval (CI)]: −0.6% [−12.8, 11.7]). In the relapsed group, a numerically higher proportion of patients receiving avacopan than those receiving a prednisone taper achieved remission at week 26 (86.3% vs 78.0%; difference [95% CI]: 8.3% [−6.6, 23.1]). Compared with the prednisone taper arm, the proportion of patients who achieved sustained remission at week 52 with avacopan was similar in newly diagnosed GPA/MPA (60.9% vs 57.9%; difference [95% CI]: 3.0% [−9.7, 15.7]) and higher in relapsed GPA/MPA (76.5% vs 48.0%; difference [95% CI]: 28.5% [10.4, 46.6]). The relapse rate over 52 weeks after remission at any time was lower with avacopan than with a prednisone taper in both newly diagnosed (8.2% vs 18.2%) and relapsed (14.6% vs 27.7%) GPA/MPA. There was a larger improvement in eGFR over 52 weeks (newly diagnosed: 8.1 vs 5.3; relapsed: 5.0 vs 0.7) and earlier reduction in UACR at 4 weeks (newly diagnosed: −42% vs −1%; relapsed: −32% vs 3%) in the avacopan arm than in the prednisone taper arm. The total all-source median glucocorticoid dose was 625 mg in the avacopan arm compared with 3048 mg in the prednisone taper arm for newly diagnosed GPA/MPA, and 500 mg in the avacopan arm compared with 3139 mg in the prednisone taper arm for relapsed GPA/MPA. At week 26, the GTI cumulative worsening and aggregate improvement scores were lower (more favourable) with avacopan than with a prednisone taper in both arms. The change from baseline in both analysed HRQoL scales was numerically higher with avacopan than with a prednisone taper at week 52 in both groups (Table 2). Fewer adverse events per patient were reported with avacopan vs a prednisone taper in both disease status groups (Table 1). Conclusion In this post hoc subgroup analysis of the ADVOCATE trial, efficacy and safety outcomes in patients with newly diagnosed or relapsed GPA/MPA favoured avacopan compared with a prednisone taper, supporting the use of avacopan in these patient types. The observed clinical efficacy of avacopan especially in patients with relapsing GPA/MPA provides valuable insights into the treatment of this difficult-to-treat subgroup.

A randomized double-blind active-controlled clinical trial on the efficacy of topical basil (Ocimum basilicum) oil in knee osteoarthritis.

Basil is a widely used herb in Persian medicine and is gaining recognition as a functional food worldwide. This trial aimed to assess the effectiveness of a traditional formulation of basil oil in comparison with diclofenac gel in treating knee osteoarthritis, considering its established anti-inflammatory, anti-nociceptive, and anti-oxidative properties. One hundred eligible patients were equally randomized to the traditional basil oil (containing sesame oil) and diclofenac gel groups. They used their respective topical treatments thrice daily for 4weeks. Various measurements were taken at the beginning of the study, 2, and 4 weeks after starting the intervention, including the 8-m walk test, knee pain (based on visual analog scale), flexion angle of the knee joint, analgesic consumption, and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. No significant differences were observed between the basil oil and diclofenac gel groups in any of the measured outcomes. However, significant improvements were noted within each group for most variables. Topical application of the traditional formulation of basil oil appears to improve clinical symptoms and certain functional indicators of knee osteoarthritis to a similar extent as diclofenac gel. This suggests that basil oil could be considered an effective management option for this condition. Clinical Trial Registration: https://irct.behdasht.gov.ir/, identifier IRCT2017081711341N7.

A Randomised Active Controlled Clinical Trial to Evaluate the Efficacy of Vyoshadi Yoga versus Simethicone drop in Udarshula (Infantile Colic)

Background: Infantile colic is said to be the most common complaint among few weeks to 6 months of age babies and is characterised by continual sobbing. Acharya Kashyapa has portrayed a disease named ‘Udarshula,’ which shows the same clinical features as ‘Infantile colic. The present study aimed to evaluate the efficacy of ‘Vyoshadi Yoga in Udarshula. Material and Methods- This study belongs to Randomized Active controlled clinical trial which comprises total 40 patients of Udarshula randomly divided into two equal groups. Group A (Trial group) was treated with Vyoshadi Yoga two times a day after feeding with Honey and Group B (Control group) was treated with Simethicone drop administered two times a day after feeding for 14 days. Assessment of Udarshula was done by using the parameters of the FLACC scale, Subjective Criteria and Parent Questionnaire on 0,3rd ,7th, and 14th day. Results- Positive results were seen in both groups. After application of Wilcoxon Sign Rank test, it has been observed that both the formulation of Vyoshadi Yoga and Simethicone were found to be equally significant P-value=0.01<0.05 in both groups. On the 28th day, post follow-up showed both the group were reduced the symptoms of Infantile colic and improvement was seen. Conclusion- Significant results were noted in both the interventions. No ADR was reported. Further large sample studies with standard control would render better evidence in results with justification.

Clinical validation of a fast-acting acetaminophen: a randomized, active and placebo controlled dental pain study

Objectives To address the need for faster pain relief of over-the-counter (OTC) analgesic users, a novel drug delivery technology was developed to achieve faster absorption of orally administered acetaminophen with the goal of delivering earlier onset of pain relief. Previous development studies suggested that a 1000 mg dose of this fast-acting acetaminophen (FA-acetaminophen) formulation provided faster absorption and onset of action versus, commercially available OTC fast-acting analgesics, 1000 mg of extra-strength acetaminophen (ES-acetaminophen) or 400 mg of liquid-filled ibuprofen capsules (LG-ibuprofen). This study was designed as the definitive trial evaluating the onset of pain relief of FA-acetaminophen versus these same OTC comparators. Methods This single-dose, randomized, double-blind, placebo- and active-controlled clinical trial compared analgesic onset, overall efficacy, and safety of FA-acetaminophen 1000 mg, ES-acetaminophen 1000 mg, LG-ibuprofen 400 mg, and placebo over 4 h in a postsurgical dental pain model. Following removal of 3 to 4 impacted third molars, 664 subjects with moderate-to-severe pain were randomized in a 4:4:2:1 ratio to FA-acetaminophen (249), ES-acetaminophen (232), LG-ibuprofen (124), or placebo (59). Mean age was 18.9 years; 45.5% were male; 57.5% had severe baseline pain intensity. Subjects stopped a first stopwatch if/when they had perceptible pain relief and a second stopwatch if/when their pain relief became meaningful to them. Pain intensity difference (PID) and pain relief (PAR) were obtained using an 11-point numerical rating scale. Findings FA-acetaminophen 1000 mg had faster median time to onset of pain relief (15.7 min) compared to ES-acetaminophen 1000 mg (20.2 min, p = 0.035), LG-ibuprofen 400 mg (23.2 min, p < 0.001), and placebo (non-estimable), statistically greater mean PAR and PID scores than other treatment groups at 15 and 30 min, and a statistically greater percentage of subjects with confirmed perceptible pain relief at 15 and 20 min. At 25 min, FA-acetaminophen 1000 mg had a statistically significantly greater percentage of subjects with confirmed perceptible pain relief than LG-ibuprofen 400 mg and placebo. No clinically significant adverse events were reported. Conclusions This study supports previous studies, demonstrating faster onset of analgesia with FA-acetaminophen 1000 mg compared to OTC ES-acetaminophen 1000 mg and OTC LG-ibuprofen 400 mg. ClinicalTrials.gov Identifier NCT03224403 https://clinicaltrials.gov/ct2/show/NCT03224403

Safety of remimazolam in comparison with midazolam for colonoscopy: A systematic review and meta-analysis

Background Remimazolam is an ester-based ultra-short-acting benzodiazepine that efficiently achieves sedation within a short period and is now being assessed as a suitable alternative to midazolam. This meta-analysis aims to pool the available data assessing and focusing on the safety aspect of remimazolam compared with midazolam. Methods A multi-center randomized control trial for patients undergoing endoscopic procedures like colonoscopy was conducted, comparing remimazolam to placebo for the midazolam group as the intervention group. The safety of remimazolam was the primary endpoint of this meta-analysis. Results A total of 3 studies were included. The total study population was 697, including the placebo, remimazolam, and midazolam groups. The types of studies included are i. randomized, double-blind, parallel-group, active-controlled clinical trial ii. prospective, randomized, parallel-group study comparing remimazolam to placebo (blindly), RCT, and iii. prospective, double-blind, randomized, parallel-group study RCT.; Treatment-emergent adverse effects included vascular disorders (P=0.42), cardiac disorders (p=0.06), respiratory, thoracic, and mediastinal disorders (p=0.26), infections and infestations (0.88), hematologic abnormalities such as anemia (p=0.63), and derangements in Blood pressure (systolic p=0.47 and diastolic p=0.68 and respiratory parameters (p=0.34). Analysis of the reported data suggests that the remimazolam group had a significantly higher incidence of treatment-emergent adverse effects compared to the midazolam group (RR: 0.84; 95% CI [0.78, 0.91]; P &lt;0.00001; I2 = 5%). Conclusions In conclusion, this meta-analysis of three randomized controlled trials showed outcomes favoring both remimazolam and midazolam as successful sedatives, yet the higher requirement of top-up dosage and rescue sedatives in the midazolam group indicates that remimazolam can be used as its replacement, especially in colonoscopy procedures.

Comparing tocilizumab biosimilar BAT1806/BIIB800 with reference tocilizumab in patients with moderate-to-severe rheumatoid arthritis with an inadequate response to methotrexate: a phase 3, randomised, multicentre, double-blind, active-controlled clinical trial

Biosimilars provide an opportunity to address unmet medical need by expanding access to biological treatments. This study aimed to show equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles of a proposed tocilizumab biosimilar BAT1806/BIIB800, to reference tocilizumab, in participants with rheumatoid arthritis with an inadequate response to methotrexate. This phase 3, multicentre, randomised, double-blind, active-controlled, equivalence study comprised a 24-week initial treatment period (results reported here) and a 24-week secondary treatment period. Participants were recruited at 54 centres across five countries (China, Ukraine, Poland, Georgia, and Bulgaria). Patients with active rheumatoid arthritis with an inadequate response to methotrexate were randomly assigned (1:1:2) to receive reference tocilizumab up to week 48, or reference tocilizumab up to week 24 followed by BAT1806/BIIB800 up to week 48 (the two reference tocilizumab groups were analysed as a single group in this analysis), or BAT1806/BIIB800 up to week 48 (the BAT1806/BIIB800 group), administered by intravenous infusion once every 4 weeks at a starting dose of 8 mg/kg. The primary endpoint was the proportion of participants who had a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 (for the European Medicines Agency [EMA]) or week 24 (for the US Food and Drug Administration [FDA] and China National Medical Products Administration [NMPA]) using prespecified equivalence margins (95% CI -14·5 to +14·5 [EMA], 90% CI -12·0 to +15·0 [FDA], and 95% CI -13·6 to +13·6 [NMPA]). The International Council for Harmonisation E9(R1) estimand framework, with strategies for addressing intercurrent events, was implemented for the efficacy evaluations with expected differences as per the predefined equivalence margins. This trial is registered at ClinicalTrials.gov (NCT03830203) and EudraCT (2018-002202-31), and is closed to new participants. Between Dec 19, 2018, and Jan 5, 2021, we randomly assigned 621 participants: 309 to the reference tocilizumab group and 312 to the BAT1806/BIIB800 group. The mean age was 50·5 years (SD 12·0), 534 (86%) were women, 87 (14%) were men, and 368 (59%) were White. For the primary estimands, estimated ACR20 response rates were 64·8% in the reference tocilizumab group and 69·0% in the BAT1806/BIIB800 group (treatment difference 4·1% [95% CI -3·6 to 11·9]) at week 12, and 67·9% in the reference tocilizumab group and 69·9% in the BAT1806/BIIB800 group (treatment difference 1·9% [90% CI -4·0 to 7·9; 95% CI -5·2 to 9·1]) at week 24. All confidence intervals were contained within the predefined equivalence margins. Comparable pharmacokinetic and immunogenicity profiles were observed for the reference tocilizumab and BAT1806/BIIB800 groups. Adverse events were reported by 201 (65%) participants in the reference tocilizumab group and 206 (66%) in the BAT1806/BIIB800 group; 196 (63%) participants in the reference tocilizumab group and 201 (64%) participants in the BAT1806/BIIB800 group reported a treatment-emergent adverse event. Five participants had a fatal event (reference tocilizumab n=1; BAT1806/BIIB800 n=4). BAT1806/BIIB800 showed equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles as reference tocilizumab. Bio-Thera Solutions and Biogen.

Mortality and Morbidity Among Individuals With Hypertension Receiving a Diuretic, ACE Inhibitor, or Calcium Channel Blocker

The long-term relative risk of antihypertensive treatments with regard to mortality and morbidity is not well understood. To determine the long-term posttrial risk of primary and secondary outcomes among trial participants who were randomized to either a thiazide-type diuretic, calcium channel blocker (CCB), or angiotensin-converting enzyme (ACE) inhibitor with up to 23 years of follow-up. This prespecified secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a multicenter randomized, double-blind, active-controlled clinical trial, followed up with participants aged 55 years or older with a diagnosis of hypertension and at least 1 other coronary heart disease risk factor for up to 23 years, from February 23, 1994, to December 31, 2017. Trial participants were linked with administrative databases for posttrial mortality (N = 32 804) and morbidity outcomes (n = 22 754). Statistical analysis was performed from January 2022 to October 2023. Participants were randomly assigned to receive a thiazide-type diuretic (n = 15 002), a CCB (n = 8898), or an ACE inhibitor (n = 8904) for planned in-trial follow-up of approximately 4 to 8 years and posttrial passive follow-up for up to 23 years. The primary end point was mortality due to cardiovascular disease (CVD). Secondary outcomes included all-cause mortality, combined fatal and nonfatal (morbidity) CVD, and both mortality and morbidity for coronary heart disease, stroke, heart failure, end-stage renal disease, and cancer. A total of 32 804 participants (mean [SD] age, 66.9 [7.7] years; 17 411 men [53.1%]; and 11 772 Black participants [35.9%]) were followed up for all-cause mortality and a subgroup of 22 754 participants (mean [SD] age, 68.7 [7.2] years; 12 772 women [56.1%]; and 8199 Black participants [36.0%]) were followed up for fatal or nonfatal CVD through 2017 (mean [SD] follow-up, 13.7 [6.7] years; maximum follow-up, 23.9 years). Cardiovascular disease mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively, at 23 years after randomization (adjusted hazard ratio [AHR], 0.97 [95% CI, 0.89-1.05] for CCB vs diuretic; AHR, 1.06 [95% CI, 0.97-1.15] for ACE inhibitor vs diuretic). The long-term risks of most secondary outcomes were similar among the 3 groups. Compared with the diuretic group, the ACE inhibitor group had a 19% increased risk of stroke mortality (AHR, 1.19 [95% CI, 1.03-1.37]) and an 11% increased risk of combined fatal and nonfatal hospitalized stroke (AHR, 1.11 [95% CI, 1.03-1.20]). In this secondary analysis of a randomized clinical trial in an adult population with hypertension and coronary heart disease risk factors, CVD mortality was similar between all 3 groups. ACE inhibitors increased the risk of stroke outcomes by 11% compared with diuretics, and this effect persisted well beyond the trial period. ClinicalTrials.gov Identifier: NCT00000542.

Zibotentan in combination with dapagliflozin compared with dapagliflozin in patients with chronic kidney disease (ZENITH-CKD): a multicentre, randomised, active-controlled, phase 2b, clinical trial

In patients with chronic kidney disease, SGLT2 inhibitors and endothelin A receptor antagonists (ERAs) can reduce albuminuria and glomerular filtration rate (GFR) decline. We assessed the albuminuria-lowering efficacy and safety of the ERA zibotentan combined with the SGLT2 inhibitor dapagliflozin. ZENITH-CKD was a multicentre, randomised, double-blind, active-controlled clinical trial, done in 170 clinical practice sites in 18 countries. Adults (≥18 to ≤90 years) with an estimated GFR (eGFR) of 20 mL/min per 1·73 m2 or greater and a urinary albumin-to-creatinine ratio (UACR) of 150-5000 mg/g were randomly assigned (2:1:2) to 12 weeks of daily treatment with zibotentan 1·5 mg plus dapagliflozin 10 mg, zibotentan 0·25 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus placebo, as adjunct to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if tolerated. The primary endpoint was a change from baseline in log-transformed UACR (zibotentan 1·5 mg plus dapagliflozin vs dapagliflozin plus placebo) at week 12. Fluid retention was an event of special interest, defined as an increase in bodyweight of at least 3% (at least 2·5% must have been from total body water) from baseline or an increase of at least 100% in B-type natriuretic peptide (BNP) and either a BNP concentration greater than 200 pg/mL if without atrial fibrillation or BNP greater than 400 pg/mL if with atrial fibrillation. This trial is registered with ClinicalTrials.gov, NCT04724837, and is completed. Between April 28, 2021, and Jan 17, 2023, we assessed 1492 participants for eligibility. For the main analysis, we randomly assigned 449 (30%) participants, 447 (99%) of whom (mean age 62·8 years [SD 12·1], 138 [31%] female, 309 [69%] male, 305 [68%] White, mean eGFR 46·7 mL/min per 1·73 m2 [SD 22·4], and median UACR 565·5 mg/g [IQR 243·0-1212·6]) received treatment with zibotentan 1·5 mg plus dapagliflozin (n=179 [40%]), zibotentan 0·25 mg plus dapagliflozin (n=91 [20%]), or dapagliflozin plus placebo (n=177 [40%]). Zibotentan 1·5 mg plus dapagliflozin and zibotentan 0·25 mg plus dapagliflozin reduced UACR versus dapagliflozin plus placebo throughout the treatment period of the study. At week 12, the difference in UACR versus dapagliflozin plus placebo was -33·7% (90% CI -42·5 to -23·5; p<0·0001) for zibotentan 1·5 mg plus dapagliflozin and -27·0% (90% CI -38·4 to -13·6; p=0·0022) for zibotentan 0·25 mg plus dapagliflozin. Fluid-retention events were observed in 33 (18%) of 179 participants in the zibotentan 1·5 mg plus dapagliflozin group, eight (9%) of 91 in the zibotentan 0·25 mg plus dapagliflozin group, and 14 (8%) of 177 in the dapagliflozin plus placebo group. Zibotentan combined with dapagliflozin reduced albuminuria with an acceptable tolerability and safety profile and is an option to reduce chronic kidney disease progression in patients already receiving currently recommended therapy. AstraZeneca.

Evaluation of Safety and Anti-RBD IgG Sars Cov-2 after Indovac Administration in Depok

The WHO declared the COVID-19 pandemic on March 11, 2020, then several centres developed Covid-19 vaccines. The Indovac vaccine contains SARS-CoV-2 RBD antigen adjuvanted with Alum and CpG1018. This article reported Jakarta Centre Phase 1 trial results of the safety and immunogenicity of Indovac in Kota Depok. This study is a randomised, observer-blinded, active-control (Sinovac) clinical trial. The study included 175 healthy adults aged 18–70 and 75 participants were enrolled by the Jakarta centre. Two vaccine doses were given 28 days apart. Four vaccine formulas were tested. Safety evaluations included solicited and unsolicited adverse events (AE) up to 28 days post-injection. SARS-CoV-2 anti-RBD IgG was tested before, 14, and 28 days after second injection to determine immunogenicity. Most solicited AEs were injection site pain. Local pain was highest in the RLCL group after the first dose (38.62%) and RHCH after the second dose (23.08%). 13.33% and 6.67% of control group subjects experienced local pain after the first and second injections, respectively. RHCL has the highest seroconversion (100%) after two injections. Anti-RBD IgG responses increased (p&lt;0.005) in all groups and plateaued 28 days after the second dose injection. In conclusion, Indovac was safe and immunogenic in Jakarta.

Efficacy and safety of V1a receptor antagonists in autism spectrum disorder: A meta-analysis.

This meta-analysis has evaluated the efficacy and safety of V1a receptor antagonists in ASD compared to placebo. The reviewers extracted data from four relevant clinical trials after a literature search on databases and clinical trial registries. Quality assessment was done using the risk of bias assessment tool, and the random-effects model was used to estimate effect size. Subgroup analysis, meta-regression and sensitivity analysis were done. PRISMA guidelines were followed in the selection, analysis and reporting of findings. V1a receptor antagonists did not reduce Vineland II Adaptive behaviour composite score significantly (SMD: 0.14; 95% CI: -0.06-0.35; p= 0.16; PI: -0.44-0.73), communication domain subscale score and socialization domain subscale score. The change in daily living skills domain subscale score was significant and favourable for V1a receptor antagonists (SMD: 0.15; 95% CI: 0.03-0.26; p= 0.01). The subgroup analysis revealed a significant improvement in Vineland II Adaptive behaviour composite score with doses <10mg (SMD: 0.45; 95% CI: 0.11-0.78; p= 0.009). Meta-regression does not show a significant association between SMD of ASD symptom score reduction with the duration and dose of V1a receptor antagonist therapy. Treatment-emergent adverse effects were not serious and dose dependent. Low doses (<10mg) of V1a receptor antagonist may be effective in reducing the core symptoms of ASD compared to placebo; however, future active-controlled clinical trials are necessary to generate conclusive evidence.

Adapted vaccine strategy: facing the persistent challenges of COVID-19

Adapted vaccine strategy: facing the persistent challenges of COVID-19

The Caries-Arrest Effectiveness of Silver Diamine Fluoride Treatment with Different Post-Treatment Instructions in Preschool Children: A Study Protocol for a Randomized Controlled Trial.

In this 12-month randomized active-controlled clinical trial, we compare two post-treatment instructions for silver diamine fluoride (SDF) therapy in arresting dentine caries. The trial will include at least 254 kindergarten children with active dentine caries. The children will be randomized into two groups and receive a 38% SDF solution applied topically to their carious lesions. Children in Group A will rinse immediately, whereas those in Group B will refrain from rinsing, eating, and drinking for 30 min. One trained examiner will perform the dental examination at baseline and every six months. The primary outcome measurement will be the proportion of caries lesions that become arrested at the 12-month examination. Potential confounding factors and parents' satisfaction with SDF therapy at baseline and after 12 months will be collected using parental questionnaires. This trial will provide evidence-based information for clinical practitioners to give post-treatment instructions for SDF therapy. This study is registered at ClinicalTrial.gov (USA) (registration number: NCT05655286).

Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non–Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Naïve Patients

Prespecified analyses of the PRO2TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO2TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents. Phase 3, global, open-label, randomized, active-controlled clinical trial. Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD. Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa. The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACEplus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis). In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of≤10mL/min/1.73m2 in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of≤10mL/min/1.73m2 and who may not have had access to dialysis. Different regional treatment patterns of patients with NDD-CKD. The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.

Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non–Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Treated Patients

In the PRO2TECT trials, vadadustat was found to be noninferior to darbepoetin alfa in hematologic efficacy but not for major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction or stroke) in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). We investigated the regional differences in MACE in the PRO2TECT trials. Phase 3, global, open-label, randomized, active-controlled clinical trial. A total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD. 1:1 randomization to receive vadadustat or darbepoetin alfa. The primary safety end point was the time to first MACE. At baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (<90U/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of≥10g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region, P=0.07). In Europe, ESA rescue was associated with a higher risk of MACE in both groups. Several analyses are exploratory. In this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group. Akebia Therapeutics, Inc. ClinicalTrials.gov identifier: NCT02680574.

Effect of adjunct Vitamin D treatment in vitamin D deficient pulmonary tuberculosis patients: A randomized, double blind, active controlled clinical trial

BackgroundSince, Vitamin D [1α,25(OH)2D)] enhances antimicrobial activity of Innate immunity and modulate Adaptive immune responses, simultaneously, so it play a potential role for balanced immune activity against Mycobacterium tuberculosis and restricting tissue injuries within the TB patients.(Chun et al., 2011) 9 We aimed to determine the role of adjunct Vitamin D treatment on the outcome of pulmonary tuberculosis patients and evaluated the effect of Vitamin D administration on Differential Leucocyte Count, Erythrocyte Sedimentation Rate, serum Adenosine deaminase, serum C- reactive protein, Oxygen saturation (SpO2) and Body Weight in Vitamin D deficient pulmonary tuberculosis patients. MethodsWe conducted a prospective, interventional, randomized, double blind, parallel group, active controlled clinical trial. Newly diagnosed Vitamin D deficient pulmonary tuberculosis patients were randomly assigned to intervention group (received standard anti-tubercular treatment with adjunct Vitamin D3) and control group (received standard anti-tubercular treatment without adjunct Vitamin D3). Total four doses [each dose of 2.5 mg (100000 IU)] of Vitamin D3 were given, orally. First dose was given within 7 days of starting anti-tubercular treatment and second, third, fourth dose were given at 2, 4 and 6 weeks respectively. At the time of enrollment, we measured all baseline characteristics. During follow-up, we measured the study variables and monitored adverse events at 2, 4, 6, 8 and 12 weeks. Our safety parameter was serum corrected calcium level to assess the risk of hypercalcemia. ResultsTotal 130 pulmonary TB patients, 65 patients in each group, were analyzed. Our study results showed that decrease in Neutrophil count was statistically significant with small effect sizes at every time point of measurement and increase in Lymphocyte count was statistically significant with small and moderate effect sizes at 4, 6 and 8 week for intervention group than for control group. Decrease in erythrocyte sedimentation rate was statistically significant with small effect sizes at 6 and 8 week, decrease in serum adenosine deaminase and serum C- reactive protein was statistically significant with moderate effect sizes at 4, 6 and 8 week for intervention group than for control group. Increase in Oxygen saturation was statistically significant at 4 week with small effect size and increase in body weight was statistically significant with small effect sizes for intervention group than for control group. No case of hypercalcemia was reported. ConclusionOur findings suggest a potential role of adjunctive Vitamin D3 to accelerate resolution of inflammatory responses and improvement in clinical outcomes of pulmonary TB patients. Trial registrationThis trial is registered with Clinical Trials Registry - INDIA (http://ctri.nic.in) with CTRI Number - CTRI/2021/11/037914. Place of studyRoom Number 27, first floor out-patients department (OPD) and inpatient Wards, fourth floor, Department of Respiratory Medicine, Uttar Pradesh University of Medical Sciences, Saifai, Etawah (U.P.), INDIA.

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m2 and ≥60 mL/min per 1·73 m2) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Travere Therapeutics.

Efficacy and Safety of a Persian Medicine Formula on Functional Dyspepsia Symptoms: A Randomized Double-Blind Active-Control Clinical Trial

Introduction: Functional dyspepsia (FD) is one of the most frequent gastrointestinal disorders with a high burden. Although FD is a heterogeneous disorder without any standard therapy (treatment/treatment – repetition), there is a wide history of using herbal remedies for its treatment. Two of these herbal remedies quoted in various Persian medicine resources are celery and ajwain. Their effects have been investigated in recent clinical trials in FD patients. We aimed to compare the effect of celery and ajwain to that of domperidone in patients with postprandial distress syndrome. Methods: This is a randomized double-blind active-control clinical trial, conducted at Kerman, Iran in 2020. Participants of this study were 100 patients suffering from FD (postprandial distress syndrome subtype). The intervention group received 1 g of the combination of celery and ajwain (Apium graveolens L. and Trachyspermum copticum [L.] Link), while the control group received 30 mg of domperidone per day for 4 consecutive weeks. Primary outcomes were symptom severity and frequency, and secondary outcomes were quality of life (QoL) and safety. All outcomes were assessed at the end of the trial and also 4 weeks after the trial was finished. Results: No significant differences in symptom frequency were found between groups. However, differences in symptom severity were found at the end of the follow-up (week 8) (p = 0.001). The intragroup analysis showed a significant decrease in the symptoms severity and frequency at the end of week 4 in both groups (p < 0.001). QoL in the intervention group was higher compared to the control group at the end of the study (p < 0.001) and at the point of the follow-up (week 8; p < 0.001). No serious adverse events occurred in either group. Conclusion: The herbal mixture of celery and ajwain could be considered a safe and effective remedy, decreasing the severity of symptoms and increasing QoL in patients with postprandial distress syndrome. It is further suggested to confirm these findings in high-quality multi-center clinical trials.

A randomized trial of once daily versus twice daily dosing of oral iron in CKD

We investigated the effect of two dosing regimens of oral iron on iron status and hematological parameters in patients with CKD. In this single center, open label, randomized, active controlled clinical trial, stable adult patients with CKD stage G3–4 with percentage transferrin saturation (%TSAT) ≤ 30% and serum ferritin ≤ 500 ng/ml were eligible. Participants were randomized to receive either 100 mg of ferrous ascorbate once daily (OD group) or 100 mg of ferrous ascorbate twice daily (BD group, total daily dose 200 mg). The primary outcome was change in %TSAT between groups over 12 weeks. The secondary outcomes were changes in other iron status and hematological parameters, serum interleukin-6 (IL-6) and hepcidin. 80 participants were enrolled out of which 76 completed the study. Change in %TSAT was not significantly different between groups (β = − 1.43, 95% CI − 3.99 to 1.12, BD group as reference). The rise in serum ferritin was less in the OD group as compared to BD group (β = − 0.36, 95% CI − 0.61 to − 0.10) whereas MCHC increased in the OD group as compared to decrease in the BD group (β = 0.37, 95% CI 0.067–0.67). These observations need exploration to ascertain the impact of different oral iron dosing strategies in CKD.

Efficacy and safety of Lu AF35700 in treatment-resistant schizophrenia: A randomized, active-controlled trial with open-label extension

IntroductionTreatment resistance constitutes the highest burden of disease within schizophrenia. We hypothesized that the synergistic activity of Lu AF35700 at dopamine D1 and D2 receptors might provide superior antipsychotic effects versus first-line antipsychotic therapy in patients with treatment resistant schizophrenia (TRS), with a benign tolerability profile. MethodsThis was a randomized, double-blind, active-controlled clinical trial (NCT02717195) followed by a one year open-label safety extension (NCT02892422). Following prospective confirmation of treatment resistance, patients were randomized (1:1:1) to 10 weeks double-blind treatment with Lu AF35700 10 mg or 20 mg, or active comparator (risperidone or olanzapine). Results1628 patients were screened for TRS, of which 1092 entered the prospective confirmation period. Of these, 697 were randomized (Lu AF35700 10 mg n = 235, 20 mg n = 232, comparator n = 230) and 395 discontinued before randomization, including 264 (24 %) who responded to treatment. 586 patients completed the double-blind phase, of which 524 entered the open-label extension and 318 completed 1-year of open-label treatment. At the end of the double-blind phase, the mean ± SE change in positive and negative syndrome scale (PANSS) total score was −10.1 ± 0.96 for Lu AF35700 10 mg, −8.22 ± 0.98 for Lu AF35700 20 mg, and − 9.90 ± 0.97 for the comparator group. Treatment differences [95 % CI] versus comparator treatment were non-significant (−0.12 [−2.37; 2.13] and 1.67 [−0.59; 3.94], respectively). The most common adverse events with Lu AF35700 were increased weight and headache. Prolactin values decreased by ≥50 % in both sexes treated with Lu AF35700. ConclusionsDespite evidence of antipsychotic efficacy, treatment with Lu AF35700 failed to differentiate from conventional antipsychotic treatment for patients with TRS.

Efficacy and Safety of Ciprofloxacin Plus Fluocinolone Acetonide Among Patients With Acute Otitis Externa

Ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution seems to be efficacious and safe in treating acute otitis externa (AOE) compared with ciprofloxacin, 0.3%, or fluocinolone acetonide, 0.025%, otic solution alone. To evaluate the superiority of ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution compared with ciprofloxacin, 0.3%, or fluocinolone acetonide, 0.025%, otic solution alone in treating AOE. A phase 3 randomized, double-blind, active-controlled clinical trial was conducted between August 1, 2017, and September 14, 2018, at 36 centers in the US. The study population comprised 493 patients aged 6 months or older with AOE of less than 21 days' duration with otorrhea, moderate or severe otalgia, and edema, as well as a Brighton grading of II or III (tympanic membrane obscure but without systemic illness). Statistical analysis was performed from November 14, 2018, to February 14, 2019. Participants were randomly assigned to receive ciprofloxacin plus fluocinolone, ciprofloxacin, or fluocinolone twice daily for 7 days and were evaluated on day 1 (visit 1; baseline), days 3 to 4 (visit 2; conducted via telephone), days 8 to 10 (visit 3; end of treatment), and days 15 to 17 (visit 4; test of cure). The primary outcome was therapeutic cure (clinical and microbiological) at the end of the treatment period. The principal secondary end point was the time to end of ear pain. Efficacy analyses were conducted in the microbiological intent-to-treat population, clinical intent-to-treat population, and microbiological intent-to-treat population with Pseudomonas aeruginosa and Staphylococcus aureus. A total of 493 patients (254 female patients [51.5%]; mean [SD] age, 38.2 [23.1] years) were randomized (197 to receive ciprofloxacin plus fluocinolone, 196 to receive ciprofloxacin, and 100 to receive fluocinolone). Therapeutic cure in the modified intent-to-treat population with ciprofloxacin plus fluocinolone (63 of 103 [61.2%]) was statistically comparable to that of ciprofloxacin (49 of 91 [53.8%]; difference in response rate, 7.3%; 95% CI, -6.6% to 21.2%; P = .30) and fluocinolone (20 of 45 [44.4%]; difference in response rate, 16.7%; 95% CI, -0.6% to 34.0%; P = .06) at visit 3 and significantly superior to ciprofloxacin at visit 4 (90 of 103 [87.4%] vs 69 of 91 [75.8%]; difference in response rate, 11.6%; 95% CI, 0.7%-22.4%; P = .04). A statistically faster resolution of otalgia was achieved among patients treated with ciprofloxacin plus fluocinolone (median, 5.0 days [range, 4.2-6.3 days]) vs ciprofloxacin (median, 5.9 days [range, 4.3-7.3 days]; 95% CI, 4.3-7.3 days; P = .002) or fluocinolone (median, 7.7 days [range, 6.7-9.0 days]; 95% CI, 6.7-9.0 days; P < .001). Ciprofloxacin plus fluocinolone demonstrated statistical superiority in sustained microbiological response vs ciprofloxacin (94 of 103 [91.3%] vs 74 of 91 [81.3%]; difference in response rate, 9.9%; 95% CI, 0.3%-19.6%; P = .04) and fluocinolone (34 of 45 [75.6%]; difference in response rate, 15.7%; 95% CI, 2.0%-29.4%; P = .01) and in the microbiological outcome vs fluocinolone by visit 3 (99 of 103 [96.1%] vs 37 of 45 [82.2%]; difference in response rate, 13.9%; 95% CI, 2.1%-25.7%; P = .01) and ciprofloxacin by visit 4 (97 of 103 [94.2%] vs 77 of 91 [84.6%]; difference in response rate, 9.6%; 95% CI, 0.9%-18.2%; P = .02). Fifteen adverse events related to study medications were registered, all of which were mild or moderate. Ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution was efficacious and safe in treating AOE but did not demonstrate superiority vs ciprofloxacin, 0.3%, or fluocinolone acetonide, 0.025%, otic solutions alone in the main study end point of therapeutic cure. ClinicalTrials.gov Identifier: NCT03196973.