Phase IV Studies: What Clinicians Need to Know!

Phase IV trials, also known as postmarketing safety and efficacy studies and postmarketing surveillance (PMS) studies, occur after a drug or medical device has received regulatory approval and is available in the market. These trials are designed to collect additional information regarding the product's safety, efficacy, and prolonged effects in a larger and more diverse patient population. The foremost goal of phase IV trials is to detect any rare or long-term adverse effects that may not have been identified during the prior phases of clinical development. During phase IV trials, pharmaceutical companies, academic institutions, or other research organizations conduct studies to evaluate various aspects of the product, including its real-world effectiveness, optimal use, and any potential safety concerns. The regulatory agencies play a role in overseeing these trials to ensure that they are conducted ethically and in compliance with good clinical practice (GCP) guidelines.

A non-entropy-based optimal multilevel threshold selection technique for COVID-19 X-ray images using chance-based birds' intelligence.

Recently, image thresholding methods based on various entropy functions have been found popularity. Nonetheless, entropic-based methods depend on the spatial distribution of the grey level values in an image. Hence, the accuracy of these methods is limited due to the non-uniform distribution of the grey values. Further, the analysis of the COVID-19 X-ray images is evolved as an important area of research. Therefore, it is needed to develop an efficient method for the segmentation of the COVID-19 X-ray images. To address these issues, an efficient non-entropy-based thresholding method is suggested. A novel fitness function in terms of the segmentation score (SS) is introduced, which is used to reduce the segmentation error. A soft computing approach is suggested. An efficient optimizer using the chance-based birds' intelligence is introduced to maximize the fitness values. The new optimizer is validated utilizing the benchmark test functions. The statistical parameters reveal that the suggested optimizer is efficient. It shows a quite significant improvement over its counterparts-optimization based on seagull/cuckoo birds. Precisely, the paper includes three novel contributions-(i) fitness function, (ii) chance-based birds' intelligence for optimization, (iii) multiclass segmentation. The COVID-19 X-ray images are taken from the Kaggle Radiography database, to the experiment. Its results are compared with three different state-of-the-art entropy-based techniques-Tsallis, Kapur's, and Masi. For providing a statistical analysis, Friedman's mean rank test is conducted and our method Ranked one. Its superiority is claimed in terms of Peak Signal to Noise Ratio (PSNR), Feature Similarity Index (FSIM) and Structure Similarity Index (SSIM). On the whole, an improvement of about 11% in PSNR values is achieved using the proposed method. This method would be helpful for medical image analysis.

Safety and efficacy of mycophenolate in COVID-19: a nonrandomised prospective study in western India.

Background: Antivirals and immunosuppressive agents are used with variable success in the treatment of COVID-19. Mycophenolate, an inhibitor of enzyme inosine monophosphate dehydrogenase, is an immunosuppressant used to prevent allograft rejection and other autoimmune diseases. Few laboratory studies have also reported antiviral properties of mycophenolate. The current study tried to assess the safety and efficacy of mycophenolate in patients hospitalised with COVID-19. Methods: This was a prospective non-randomised open label study with the objective to assess the effect of addition of mycophenolate to the standard of care on mortality due to COVID-19 and duration of hospital stay. The target study population was comprised of patients requiring inpatient treatment for COVID-19 during the period from Jan 15-April 15, 2021. The study was registered with Clinical Trial Registry of India (CTRI/2021/01/030477, registered on date-14/01/2021). Adult patients (n = 106) requiring hospitalisation for COVID-19 received mycophenolate, 360 mg, one tablet daily for one month. Mycophenolate was initiated within 48 h of the diagnosis of SARS-CoV-2 infection by RT‒PCR. While patients who did not consent for mycophenolate (n = 106), received only standard of care, and were considered as control group. The relevant clinical data including NEWS2 scores and high-resolution computed tomography of the thorax were collected and analysed. Findings: The mortality and hospital stay were significantly lower in the study group compared to the control group. Mycophenolate significantly reduced mortality after adjustment for other predictors (adjusted odds ratio: 0.082 with 95% CI: 0.012-0.567). Mycophenolate was an independent predictor of survival in patients hospitalised due to COVID-19. There was also no evidence of secondary bacterial infections and post-COVID complications. Interpretation: Mycophenolate administration is safe in COVID-19. Mycophenolate reduces mortality and duration of hospital stay in patients with COVID-19. Funding: Shri Janai Research Foundation, India.

A novel minimum generalized cross entropy-based multilevel segmentation technique for the brain MRI/dermoscopic images.

BACKGROUND: One of the challenging and the primary stages of medical image examination is the identification of the source of any disease, which may be the aberrant damage or change in tissue or organ caused by infections, injury, and a variety of other factors. Any such condition related to skin or brain sometimes advances in cancer and becomes a life-threatening disease. So, an efficient automatic image segmentation approach is required at the initial stage of medical image analysis. PURPOSE: To make a segmentation process efficient and reliable, it is essential to use an appropriate objective function and an efficient optimization algorithm to produce optimal results. METHOD: The above problem is resolved in this paper by introducing a new minimum generalized cross entropy (MGCE) as an objective function, with the inclusion of the degree of divergence. Another key contribution is the development of a new optimizer called opposition African vulture optimization algorithm (OAVOA). The proposed optimizer boosted the exploration, skill by inheriting the opposition-based learning. THE RESULTS: The experimental work in this study starts with a performance evaluation of the optimizer over a set of standards (23 numbers) and IEEE CEC14 (8 numbers) Benchmark functions. The comparative analysis of test results shows that the OAVOA outperforms different state-of-the-art optimizers. The suggested OAVOA-MGCE based multilevel thresholding approach is carried out on two different types of medical images - Brain MRI Images (AANLIB dataset), and dermoscopic images (ISIC 2016 dataset) and found superior than other entropy-based thresholding methods.

A prospective, multicenter, clinical Study to evaluate the Safety, Pharmacokinetics, and Efficacy of Bleed Outcomes, with HemoRel-A® in severe Hemophilia A Patients.

PURPOSE: To evaluate efficacy for an on-demand treatment of acute bleeding events, pharmacokinetics, safety, and tolerability of HemoRel-A® in severe hemophilia A. METHODS: A total of 44 male subjects with severe hemophilia A with an annualized bleed rate of 12 while on-demand treatment with factor VIII (FVIII) were enrolled in the study and received HemoRel-A® for bleed treatment. The efficacy of HemoRel-A® was evaluated based on a four-point scale (excellent, good, moderate, or none). Six-point pharmacokinetic (PK) assessment was performed following a single dose of 50 IU/kg in 12 subjects after a 7-day wash-out period. Safety evaluations were performed at each visit and inhibitor testing was performed in all patients at screening and end of study. RESULTS: Forty-four male subjects received at least a single dose of the study medication and were included in the intent-to-treat (ITT) analysis and safety outcome. In 23 (7.52%) out of the 306 bleeding events, HemoRel-A® efficacy was rated as excellent, in 272 (88.89 %) bleeds it was rated as good, and in 11 (3.68%) bleeding events it was rated as moderate. No failure of efficacy was noted in any of the bleeding events. Thus overall out of 306 bleeding events, 295 (96.41%) showed excellent or good efficacy. Pharmacokinetic assessment based on plasma FVIII activity measured by the chromogenic assay in 12 patients showed comparative results similar to FVIII preparations. A total of 12 adverse events (AEs) were reported in this study. There was no inhibitor development in this previously treated patients (PTP) cohort. CONCLUSION: HemoRel-A® was established to be efficacious and safe in the treatment of acute bleeding events in subjects with severe hemophilia A. TRIAL REGISTRATION NUMBER: CTRI/2018/05/013790. Registration date: 9th May 2018.

Randomised, Double-blind, Comparative Clinical Study of New Ranibizumab Biosimilar in Neovascular (Wet) Age-Related Macular Degeneration.

PURPOSE: The study was undertaken for regulatory purposes to establish clinical biosimilarity and interchangeability of a ranibizumab biosimilar with reference product. PATIENTS AND METHODS: A total of 159 subjects with neovascular (wet) age-related macular degeneration (AMD) were dosed with ranibizumab. Initial double blind period of 16 weeks was followed by open-label phase till week 24. Efficacy assessment was performed at weeks 1, 4, 8, 12, 16, 20 and 24 based on best corrected visual acuity. Change in central macular thickness was assessed by optical coherence tomography from baseline to week 24. Immunogenicity assessment was done in both arms at baseline, week 16 and week 24. Safety evaluation included clinical and ophthalmic examination, adverse events, vital signs, laboratory parameters and immunogenicity in both treatment arms. RESULTS: In the biosimilar test arm, 104 (98.11%) and 105 (99.06%) patients lost fewer than 15 letters in visual acuity at week 16 and week 24, respectively, compared with 53 (100%) at both follow-ups in reference arm. In the test arm, 27 (25.47%) and 34 (32.08%) patients gained at least 15 letters in visual acuity till week 16 and week 24 respectively, compared with 17 (32.08%) and 23 (43.30%) in the reference arm. In the test arm, mean change in central macular thickness at 24 weeks was -89.93 µm against -64.42 µm in the reference arm. Difference was statistically not significant for any endpoint at 16 and 24 weeks for the primary and secondary endpoints. CONCLUSION: The evaluation of efficacy, safety and immunogenicity was concluded to show no meaningful clinical difference for biosimilar ranibizumab with the reference product.

Randomized Comparative Clinical Study of First Global Omalizumab Biosimilar with Innovator Product in Moderate to Severe Persistent Asthma.

PURPOSE OF STUDY: Omalizumab the first anti-IgE antibody is proven with several real-world studies and meta-analyses as important adjuvant in severe allergic asthma. This study was undertaken for the first omalizumab biosimilar to establish clinical biosimilarity and interchangeability with originator product. MATERIALS AND METHODS: In this randomized, double-blind comparative study 105 subjects (70 subjects in the study group and 35 subjects in the reference group) were dosed up to week 16 as double blind phase and responders entered open label phase till week 24. All responders at week 16 received study product in open-label phase of the study as per their dosing schedule till week 24. The additional efficacy assessment visit was performed till week 24. Safety follow up visit was performed in responders at week 26. The pharmacokinetic (PK) and pharmacodynamic (PD) assessment was planned in 48 subjects after first dose of omalizumab. RESULTS: In double blind phase, 4 (5.80%) asthma exacerbations were reported in study arm compared to 1 (2.86%) asthma exacerbation in reference arm with no statistically significant difference (p>0.05). The time to first asthma exacerbation was 53 days in study arm compared to 62 days in reference arm. In study and reference arm, the mean change from baseline in forced expiratory volume in one second (FEV1%) was 7.51 and 5.98 at week 4; and 12.30 and 8.94 at week 16 respectively while mean change from baseline in forced expiratory volume in one second/forced vital capacity (FEV1/FVC%) was 4.20 and 4.06 at week 4 and 6.77 and 7.10 at week 16 respectively (no statistically significant difference, p>0.05). At week 16, 4 (5.80%) subjects in study arm had 50-75% inhaled corticosteroids (ICS) dose reduction compared to 2 (5.71%) subjects in reference arm. The proportion of subjects with meaningful improvement in Asthma Quality of Life Questionnaire (AQLQ) (improvement in overall AQLQ score ≥0.5), mean change in overall Asthma Control Questionnaire (ACQ) score and proportion of responders based on Global evaluation of treatment effectiveness (GETE) assessment also was similar at 16 weeks. A total of 101 adverse events were reported out of which 63 were reported in the study or biosimilar arm and 38 were reported in the reference or innovator arm. Two serious adverse events (SAEs) were reported, one in each arm. No deaths occurred during this study and the safety observations are consistent with the known safety profile of omalizumab. All the samples analysed in this study were negative for anti-omalizumab antibodies. There was no significant difference in the PK and PD evaluation. CONCLUSION: The evaluation of pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity was concluded to show no meaningful clinical difference of the biosimilar omalizumab with the reference product.

Comparative pharmacokinetics, efficacy, and safety of bevacizumab biosimilar to reference bevacizumab in patients with metastatic colorectal cancer.

OBJECTIVE: To establish clinical biosimilarity of BevaciRel™ bevacizumab biosimilar (study bevacizumab) with the reference innovator bevacizumab in terms of pharmacokinetics, efficacy, and safety in metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A total of 119 patients with mCRC were enrolled across 20 centers and randomized to receive study and reference bevacizumab in this Phase III clinical study. Of these, 116 patients were administered bevacizumab 5 mg/kg intravenously every 2 weeks with folinic acid, fluorouracil, and irinotecan regimen. The primary endpoint of the study was objective response rate (ORR) at week 25, and the secondary endpoints assessed were progression-free survival (PFS), overall survival (OS), and assessment of pharmacokinetics and safety along with immunogenicity in both treatment arms. RESULTS: The ORR was 60.53% in study bevacizumab and 66.67% in reference arm. The proportions of subjects showing CR and PR were comparable in both the arms. The median PFS at 1 year was 3.83 months in test arm and 4.6 months in reference arm. The mean OS was 10.91 months in test arm and 14.68 months in reference arm. The difference in ORR, median PFS, and OS was not statistically significant (P > 0.05). The median Tmaxwas 6.00 h in both the arms. The median t½ was 330.63 h and 226.14 h, respectively, for test and reference bevacizumab. The adverse event profile of both products was in line with the known profile of bevacizumab. CONCLUSION: The study biosimilar bevacizumab was found to be noninferior and clinically biosimilar to the reference bevacizumab, thereby meeting an unmet medical alternative need in mCRC.

A comparative phase III clinical study to evaluate efficacy and safety of TrastuRel™ (biosimilar trastuzumab) and innovator trastuzumab in patients with metastatic human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer.

INTRODUCTION: The present study for biosimilar trastuzumab was a multicentric, randomized, two-arm parallel-group, comparative phase III study in patients with metastatic breast cancer. MATERIALS AND METHODS: Stage I of the study was conducted among 42 participants with equal distribution in the study and reference arm. After a loading dose of 8 mg/kg trastuzumab was administered intravenously on day 1 of the first cycle; serum samples were obtained at 0, 1.5 (end of IP infusion), 3, 6, 8, 24, 96, 168, and 336 h after the first infusion for the first cycle only. Cmax and AUC0-336 were calculated for a single dose. Stage II enrolled a total of 106 patients across 20 centers who were randomized to receive biosimilar trastuzumab (study trastuzumab) or the reference trastuzumab with paclitaxel. The primary endpoint of the objective response rate (ORR) was analyzed after last the dosed participant had completed 25-week evaluation. The secondary outcome measures included time to tumor progression, progression-free survival and overall survival at week 48, and safety evaluation. RESULTS: For reference and study trastuzumab products, mean Cmax of 229.02 and 210.68 µg/mL and AUC0-336 of 24298.29 and 25809.33 (µg × h/mL), respectively, were obtained. The efficacy results demonstrated that study trastuzumab and reference trastuzumab had comparable ORR (48.44% vs. 44.44%). The proportions of participants showing complete response and partial response in each arm were found to be comparable. There were 56 (68.29%) participants in the study arm and 13 (59.09%) participants in the reference arm who had at least one adverse event during the study. Immunogenicity assessment also revealed no participants with positive antibody titer in any of the study arms. CONCLUSION: The pharmacokinetics, overall response rate at 25 weeks, and safety of the biosimilar trastuzumab was comparable to the reference trastuzumab.

An Open Label, Prospective, Single Centre Study to Evaluate the Efficacy and Safety of Fixed Dose Combination of Rabeprazole (Enteric-Coated, EC) 20 mg + Domperidone (Sustained Release, SR) 30 mg Capsule in Treatment of Patients with Laryngopharyngeal Reflux Disease.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg for treatment of laryngopharyngeal reflux disease (LPRD). DESIGN: A prospective, single centre, open-label, non-comparative, observational study SETTING: The study was conducted at an otolaryngology clinic in India between May 2012 and November 2012. PATIENTS: Patients (>18 yrs) with suspicious LPR-related symptoms, reflux symptom index (RSI) score >13 and reflux finding score (RFS) >7, willing to undergo rigid laryngoscopy and requiring fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule treatment according to the investigator's discretion were eligible for enrolment in the study. METHODS: Fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule treatment was given for a total duration of 90 days and efficacy was assessed by the change in RFS and RSI score at Day 90. The safety and tolerability of the study drug was assessed by monitoring adverse events, vital signs and physical examination. RESULTS: Overall, 50 patients were enrolled and completed the study. After 12 weeks of fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule treatment there was a significant change in mean RSI scores [mean (SD) RSI: 19.18 (3.24) at baseline to 2.52 (2.31) at end of study; (p<0.0001)] as well as mean RFS score [mean (SD) RFS: 12.62 (1.48) at baseline to 0.30 (0.51) at end of study; (p<0.0001)]. No adverse event was reported by any patient during the study period. CONCLUSION: Twelve weeks of treatment with combination of fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule significantly improved reflux symptoms in patients with LPR. The combination was found to be safe and well tolerated.

Efficacy and safety profile of combination of tramadol-diclofenac versus tramadol-paracetamol in patients with acute musculoskeletal conditions, postoperative pain, and acute flare of osteoarthritis and rheumatoid arthritis: a Phase III, 5-day open-label study.

OBJECTIVE: We aimed to evaluate the safety and efficacy of a fixed-dose combination (FDC) of tramadol and diclofenac versus a standard approved FDC of tramadol and paracetamol, in patients with acute moderate to severe pain. METHODS: A total of 204 patients with moderate to severe pain due to acute musculoskeletal conditions (n=52), acute flare of osteoarthritis (n=52), acute flare of rheumatoid arthritis (n=50), or postoperative pain (n=50) were enrolled in the study at baseline. Each disease category was then randomized to receive either of two treatments for 5 days: group A received an FDC of immediate-release tramadol hydrochloride (50 mg) and sustained-release diclofenac sodium (75 mg) (one tablet, twice daily), and group B received an FDC of tramadol hydrochloride (37.5 mg) and paracetamol (325 mg) (two tablets every 4-6 hours, up to a maximum of eight tablets daily). The primary efficacy end points were reductions in pain intensity from baseline at day 3 and day 5 as assessed by a Visual Analog Scale (VAS) score. RESULTS: Group A showed a significant reduction in the VAS score for overall pain from baseline on day 3 (P=0.001) and day 5 (P<0.0001) as compared with group B. The combination of tramadol-diclofenac resulted in few mild to moderate adverse events (nausea, vomiting, epigastric pain, and gastritis), which required minimal management, without any treatment discontinuation. The number of adverse events in group A was nine (8.82%) compared with 22 (21.78%) in group B, after 5 days of treatment. CONCLUSION: An FDC of tramadol-diclofenac showed a significantly greater reduction in pain intensity and was well tolerated compared with tramadol-paracetamol, resulting in better analgesia in patients suffering from moderate to severe pain due to acute musculoskeletal conditions, postoperative pain following orthopedic surgery, or acute flare of osteoarthritis and rheumatoid arthritis.

Efficacy and safety of methylcobalamin, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study.

BACKGROUND AND OBJECTIVE: To assess whether methylcobalamin and alpha lipoic acid (ALA) added to pregabalin provide additional benefit compared to pregabalin alone in type 2 diabetes mellitus associated peripheral neuropathy. SETTING AND DESIGN: An open label, randomized, controlled parallel-group pilot study. MATERIALS AND METHODS: Thirty adult patients with type 2 diabetes mellitus with symptoms of peripheral neuropathy for ≥6 months were randomized to receive pregabalin 75 mg, methylcobalamin 750 µg, and ALA 100 mg (PMA, n = 15); or pregabalin 75 mg (PG, n = 15) for 12 weeks. Assessment variables were numeric rating scale (NRS), sleep interference scores (SIS), response rate to pain, and global assessment for the usefulness of therapy. The nerve conduction velocity was assessed for sensory and motor nerves. Safety assessment included adverse events reported by the patients, clinical laboratory, and general medical, neurological examinations. STATISTICAL ANALYSIS: Efficacy analyses were done on per-protocol (PP) population, whereas safety analyses were done on intent-to-treat (ITT) population. RESULTS: Significant improvement was seen in pain and sleep interference in both groups. Mean nerve conduction velocity of left common peroneal nerve (CPN) showed significant improvement in PMA group at week 12 compared to baseline (P = 0.018). For right CPN both groups showed significant improvement. (PMA, P = 0.002, PG, P = 0.007). For sensory testing, at week 12, right superficial peroneal nerve showed reduction in nerve conduction velocity in PG group compared to baseline (P = 0.043). CONCLUSION: Methylcobalamine, ALA and pregabalin combination provides pain relief and improves sleep interference. Addition of methylcobalamin and ALA to pregabalin improves the nerve function. Due to small sample size, most of the efficacy parameters could not reach significant difference between groups; hence benefit of the 3-drug-combimation should be interpreted with reservation.

A Hall effect angle detector for solid-state NMR.

We describe a new method for independent monitoring of the angle between the spinning axis and the magnetic field in solid-state NMR. A Hall effect magnetic flux sensor is fixed to the spinning housing, so that a change in the stator orientation leads to a change in the angle between the Hall plane and the static magnetic field. This leads to a change in the Hall voltage generated by the sensor when an electric current is passed through it. The Hall voltage may be measured externally by a precision voltmeter, allowing the spinning angle to be measured non-mechanically and independent of the NMR experiment. If the Hall sensor is mounted so that the magnetic field is approximately parallel to the Hall plane, the Hall voltage becomes highly sensitive to the stator orientation. The current angular accuracy is around 10 millidegrees. The precautions needed to achieve higher angular accuracy are described.