An Analysis of Potentially Prolactin-Related Adverse Events and Abnormal Prolactin Values in Randomized Clinical Trials with Paliperidone Palmitate

2012 ◽  
Vol 46 (10) ◽  
pp. 1322-1330 ◽  
Author(s):  
Thomas R Einarson ◽  
Michiel EH Hemels ◽  
Isaac Nuamah ◽  
Srihari Gopal ◽  
Danielle Coppola ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Descriptive Statistics ◽  
Paliperidone Palmitate ◽  
Serum Prolactin ◽  
Clinical Trial Database ◽  
Long Acting ◽  
Monthly Dose

Background: Paliperidone palmitate has been associated with serum prolactin elevations in some patients. However, few individuals with elevated prolactin levels (hyperprolactinomia) have symptomatic potentially prolactin-related adverse events (PPR-AEs). Objective: To quantify rates of hyperprolactinemia in subjects treated with the newly marketed paliperidone palmitate long-acting injection (PP-LAI) in randomized clinical trials, summarize rates of PPR-AEs in those trials by sex and dose, and determine how many PPR-AEs required treatment. Methods: Numbers and rates of investigator-reported hyperprolactinemia and PPR-AEs wore obtained from the sponsor's clinical trial database and have been included in regulatory filings. Results were tabulated for males, females, and overall, and by dose administered, using descriptive statistics. Those requiring treatment were described as well. Results: There were 3173 subjects (61.4% males) exposed to PP-LAI in 10 clinical trials; 2831 (89.2%) patients had recorded prolactin levels, including 1759 males (90, 3% of exposed males) and 1072 females (87.5% of exposed females). Overall, at any time, prolactin levels were elevated for 38.8% of the subjects (39.5% for males and 37.7% for females; p = 0.354 between sexes). However, them was no significant correlation between monthly dose and proportion of subjects with elevated prolactin levels (p = 0.109). There were 115 PPR-AEs in 107 patients (3.4%); 51 (44.3% of PPR-AEs) cases represented asymptomatic hyperprolactinemia. The remaining 64 symptomatic PPR-AEs affected 2.0% of the total number of subjects. Fifteen events in 13 participants (0.41% of patients or 4.7 events/1000 patients) required treatment. Conclusions: Clinicians should periodically assess patients on paliperidone palmitate for any PPR-AEs and carefully assess the benefits and risks when managing these effects.

scholarly journals Ixazomib Based Regimens in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis of Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Anum Javaid ◽  
Faryal Razzaq ◽  
Muhammad Ashar Ali ◽  
Muhammad Abu Zar ◽  
Atif Sohail ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trial ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Placebo Group ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Phase Ii Trial ◽  
Meta Analysis ◽  
Newly Diagnosed

Introduction: Multiple myeloma (MM) is an incurable malignancy, and clinical trials with newer agents have shown improved patient outcomes. Ixazomib (Ixa) is a proteasome inhibitor and induces apoptosis in cancer cells. It is commonly used with immunomodulators for the treatment of MM. We conducted a systematic review and meta-analysis to assess the efficacy of Ixazomib alone and in combination with other drugs for the treatment of newly diagnosed multiple myeloma (NDMM). Methods: A literature search was performed on PubMed, Cochrane, Embase, Web of Science, and clinicaltrials.gov. We used the following MeSH and Emtree terms; "ixazomib" AND "Multiple Myeloma" from inception till 06/05/2020. We screened 1,558 articles and included 3 randomized clinical trials (RCTs) (N=901) and 12 non-randomized clinical trials (NRCT) (N=632). We excluded case reports, case series, preclinical trials, review articles, observational studies, meta-analysis, and ongoing clinical trials that did not report interim efficacy outcomes. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In 15 clinical trials (N=1533), Ixa based regimens were used in patients with age range of 39-92 years. (Table 1) In 3 clinical trials (N=170), Ixa with Lenalidomide (Len) and dexamethasone (Dex) yielded a pooled overall response rate (ORR) of 90% (95% CI=0.82-0.94, I2=32%), a pooled complete response (CR) of 23% (95% CI=0.16-0.32, I2=24%) and a pooled ≥very good partial response and better (≥VGPR) of 39% (95% CI=0.24-0.57, I2 =76%) when used as induction therapy for NDMM patients. As consolidation therapy (N=88), pooled ORR was 91% (95% CI=0.79-0.97, I2=0), pooled CR was 36% (95% CI=0.27-0.47, I2=0) and pooled ≥VGPR was 70% (95% CI=0.53-0.84, I2=60%). (Fig 1-3) In 5 clinical trials (N=233), Ixa + cyclophosphamide (Cyc) + Dex yielded a pooled ORR, CR, and ≥VGPR of 76% (95% CI=0.70-0.81, I2 =0), 12% (95% CI=0.07-0.20, I2=44%), and 25% (95% CI=0.14-0.39, I2=78%), respectively. (Fig 1-3) The lower dose of Cyc 300mg/m2 had similar efficacy as 400mg/m2 with better safety profile in elderly patients. In a RCT (N=175) of Ixa with multiple combinations, Ixa + Dex yielded ORR 55% (95% CI=0.40-0.69), CR 14% (95% CI=0.07-0.28) and ≥VGPR 24% (95% CI=0.13-0.39). Ixa+ thalidomide (Thal) + Dex fostered ORR 82% (95% CI=0.70-0.90), CR 15% (95% CI=0.08-0.26), and VGPR 43% (95% CI=0.31-0.55). Ixa + bendamustine + Dex yielded ORR of 73% (95% CI=0.41-0.91), CR 9% (95% CI=0.01-0.44), and ≥VGPR 27% (95% CI=0.09-0.59). In one clinical trial (N=53), Ixa + melphalan (Mel) + prednisone (Pred) combination yielded pooled ORR, CR, and ≥VGPR of 66% (95% CI=0.52-0.77), 13% (95% CI=0.06-0.25), and 30% (95% CI=0.19-0.44), respectively. In a phase II trial (N=40), Ixa + daratumumab (Dara) + Len + Dex yielded an ORR, CR and ≥VGPR of 97% (95% CI=0.84-1), 15% (95% CI=0.07-0.28), and 35% (95% CI=0.22-0.51) respectively. (Fig 1-3) In a phase III RCT by Dimopholous et al. (N=656), Ixa maintenance therapy after stem cell transplant (SCT) yielded an ORR, CR, and ≥VGPR of 76%, 15%, and 54%, respectively. They observed 28% reduction in the risk of progression or death with Ixa vs. placebo, median progression free survival (mPFS) was 26.5 months (95% CI 23·7-33·8) vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). Second malignancies were 3% in both ixazomib and placebo group. 27% of the patients in ixazomib group and 20% patients in placebo group experienced serious adverse events. In a clinical trial on unfit and frail patients (N=46) treated with Ixa + daratumumab (Dara) + Dex, pooled ORR and ≥VGPR were 83% (95% CI=0.69-0.91, I2=0), and 33% (95% CI=0.21-0.47, I2=0), respectively. (Fig 1-3) In the phase II trial, ORR, CR, and VGPR with ixazomib and lenalidomide were 64%, 26%, and 53%, respectively. Conclusion: Ixa in combination with Len, Dex, Cyc, Dara, Mel, Pred is effective in the treatment of NDMM patients. In early phase trials, Ixa with Dara, Len, and Dexa showed the highest overall response as induction therapy. Ixazomib maintainance therapy prolongs PFS after SCT as compared to placebo and represents an additional option for post SCT maintainace therapy in NDMM patiens. The safety profile of Ixa was acceptable with most commonly encountered adverse events were hematological including neutropenia and thrombocytopenia. Additional multicenter, double-blind, randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

The Detection of Adverse Events in Randomized Clinical Trials: Can we Really Say New Medicines are Safe?

2013 ◽  
Vol 8 (2) ◽  
pp. 104-113 ◽  
Author(s):  
Izyan Wahab ◽  
Nicole Pratt ◽  
Lisa Kalisch ◽  
Elizabeth Roughead
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Randomized Clinical Trials

scholarly journals Recombinant Human Adenovirus-p53 Therapy for the Treatment of Oral Leukoplakia and Oral Squamous Cell Carcinoma: A Systematic Review

Medicina ◽  
2021 ◽  
Vol 57 (5) ◽  
pp. 438
Author(s):  
Jagadish Hosmani ◽  
Shazia Mushtaq ◽  
Shahabe Saquib Abullais ◽  
Hussain Mohammed Almubarak ◽  
Khalil Assiri ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Oral Cancer ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Oral Leukoplakia ◽  
Research Articles ◽  
Original Research ◽  
Therapeutic Effects ◽  
The World

Background and Objectives: Oral cancer is the 6th most common cancer in the world and oral leukoplakia is an oral potentially malignant disorder that could develop into oral cancer. This systematic review focusses on randomized clinical trials for recombinant adenovirus p-53 (rAD-p53) therapy for the treatment of oral leukoplakia and cancer. Materials and Methods: We searched for research articles on various databases such as Pubmed/Medline, Embase, CNKI (China National Knowledge Infra-structure), Springerlink, cochrane and Web of sciences from 2003 to 2020. MeSH (Medical Subject Headings) terms were used for the search. Inclusion criteria included original research, randomized clinical trials and articles only in English language. Exclusion criteria were any articles that were not research articles, not randomized trials, non-human studies, etc. The articles were further graded on the Jadad scale. Results: 578 articles were assessed from various databases; only 3 articles were found to be appropriate for this review. Thus, meta-analysis was not performed because of heterogeneity and lack of data. In the three studies, whether rAD-p53 was used as a standalone therapy or with other therapies, there was a beneficial effect of the therapy. Furthermore, there were no serious adverse events and the only adverse events reported were fever, pain at the local injection site, flu-like symptoms and lowered WBC count. Conclusions: Thus, we can conclude that this therapy has a potential for beneficial therapeutic effects and further clinical trials with more patients need to be performed to get better understanding of the effect of rAD-p53 therapy, which probably will pave the way to its approval in other parts of the world.

675 FUNDOPLICATION VERSUS ORAL PROTON PUMP INHIBITORS FOR GASTROESOPHAGEAL REFLUX DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Luca Schiliró Tristão ◽  
Francisco Tustumi ◽  
Guilherme Tavares ◽  
Letícia Nogueira Datrino ◽  
Maria Carolina Andrade Serafim ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Gastroesophageal Reflux Disease ◽  
Gastroesophageal Reflux ◽  
Adverse Events ◽  
Proton Pump ◽  
Reflux Disease ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Oral Intake

Abstract   Gastroesophageal reflux disease (GERD) is a widely studied and highly prevalent condition. However, few is reported about the exact efficacy and safety of fundoplication (FPT) compared to oral intake proton-pump inhibitors (PPI). This systematic review and meta-analysis of randomized clinical trials (RCT) aims to compare PPI and FPT in relation to the efficacy, as well as the adverse events associated with these therapies. Methods This systematic review was guided by PRISMA statement. Search carried out in June 2020 was conducted on Medline, Cochrane, EMBASE and LILACS. The inclusion criteria were (I) patients with GERD; (II) Randomized clinical trials, comparing oral intake PPI with FPT; (III) relevant outcomes for this review. The exclusion criteria were (I) reviews, case reports, editorials and letters (II) transoral or endoscopic FPT (III) studies with no full text. No restrictions were set for language or period. Certainty of evidence and risk of bias were assessed with GRADE Pro and with Review Manager Version 5.4 bias assessment tool. Results Ten RCT were included. Meta-analysis showed that heartburn (RD = −0.19; 95% CI = −0.29, −0.09) was less frequently reported by patients that underwent FPT. Furthermore, patients undergoing surgery had greater pressure on the lower esophageal sphincter than those who used PPI (MD = 7.81; 95% CI 4.79, 10.83). There was no significant difference between groups in the percentage of time with pH less than 4 in 24 hours, sustained remission and Gastrointestinal Symptom Rating Scale. Finally, FPT did not increase significantly the risk for adverse events such as postoperative dysphagia and impaired belching. Conclusion FPT is a more effective therapy than PPI treatment for GERD, without significantly increasing the risk for adverse events. However, before indicating a possible surgical approach, it is extremely important to correctly assess and select the patients who would benefit from FPT, such as those with severe erosive esophagitis, severe respiratory symptoms, low adherence to continuous drug treatment and patients with non-acid reflux, to ensure better results.

scholarly journals Clinical trial research on COVID-19 in Germany – a systematic analysis

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 913
Author(s):  
Julian Hirt ◽  
Abeelan Rasadurai ◽  
Matthias Briel ◽  
Pascal Düblin ◽  
Perrine Janiaud ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Research Agenda ◽  
Randomized Clinical Trials ◽  
Median Number ◽  
First Year ◽  
Industry Funding ◽  
Systematic Analysis ◽  
Clinical Trial Research ◽  
German Contribution

Background: In 2020, the COVID-19 pandemic led to an unprecedented volume of almost 3,000 clinical trials registered worldwide. We aimed to describe the COVID-19 clinical trial research agenda in Germany during the first year of the pandemic. Methods: We identified randomized clinical trials assessing interventions to treat or prevent COVID-19 that were registered in 2020 and recruited or planned to recruit participants in Germany. We requested recruitment information from trial investigators as of April 2021. Results: In 2020, 65 trials were completely (n=27) or partially (n=38) conducted in Germany. Most trials investigated interventions to treat COVID-19 (86.2%; 56/65), in hospitalized patients (67.7%; 44/65), with industry funding (53.8%; 35/65). Few trials were completed (21.5%; 14/65). Overall, 187,179 participants were planned to be recruited (20,696 in Germany), with a median number of 106 German participants per trial (IQR 40 to 345).  From the planned German participants, 13.4%  were recruited (median 15 per trial (IQR 0 to 44). Conclusions: The overall German contribution to the worldwide COVID-19 clinical trial research agenda was modest. Few trials delivered urgently needed evidence. Most trials did not meet recruitment goals. Evaluation and international comparison of the challenges for conducting clinical trials in Germany is needed.

scholarly journals Opportunities for selective reporting of harms in randomized clinical trials: Selection criteria for nonsystematic adverse events

2019 ◽  
Author(s):  
Evan Mayo-Wilson ◽  
Nicole Fusco ◽  
Hwanhee Hong ◽  
Tianjing Li ◽  
Joseph K. Canner ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Selection Criteria ◽  
Randomized Clinical Trials ◽  
Bipolar Depression ◽  
Selective Reporting ◽  
Journal Articles ◽  
Multiple Sources ◽  
Study Results ◽  
Meta Analyses

Abstract Background: Adverse events (AEs) in randomized clinical trials may be reported in multiple sources. Different methods for reporting adverse events across trials, or across sources for a single trial, may produce inconsistent and confusing information about the adverse events associated with interventions Methods: We sought to compare the methods authors use to decide which AEs to include in a particular source (i.e., “selection criteria”) and to determine how selection criteria could impact the AEs reported. We compared sources (e.g., journal articles, clinical study reports [CSRs]) of trials for two drug-indications: gabapentin for neuropathic pain and quetiapine for bipolar depression. We identified selection criteria and assessed how criteria affected AE reporting. Results: We identified 21 gabapentin trials and 7 quetiapine trials. All CSRs (6 gabapentin, 2 quetiapine) reported all AEs without applying selection criteria; by comparison, no other source reported all AEs, and 15/68 (22%) gabapentin sources and 19/48 (40%) quetiapine sources reported using selection criteria. Selection criteria greatly affected the number of AEs that would be reported. For example, 67/316 (21%) AEs in one quetiapine trial met the criterion “occurring in ≥2% of participants in any treatment group,” while only 5/316 (2%) AEs met the criterion, “occurring in ≥10% of quetiapine-treated patients and twice as frequent in the quetiapine group as the placebo group.” Conclusions: Selection criteria for reporting AEs vary across trials and across sources for individual trials. If investigators do not pre-specify selection criteria, they might “cherry-pick” AEs based on study results. Even if investigators pre-specify selection criteria, selective reporting of AEs will produce biased meta-analyses and clinical practice guidelines. Data about all AEs identified in clinical trials should be publicly available; however, sharing data will not solve all the problems we identified in this study. Keywords: Harms, adverse events, clinical trials, reporting bias, selective outcome reporting, data sharing, trial registration

scholarly journals Safety and Efficacy of Four Drug Versus Three Drug Regimens Among Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Saad Ullah Malik ◽  
Nazma Hanif ◽  
Priyanka Kumari ◽  
Khadija Noor Sami ◽  
Chase Warner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Standard Of Care ◽  
Drug Regimen ◽  
P Value ◽  
Newly Diagnosed ◽  
Drug Regimens ◽  
Grade 3

Introduction: During recent years there has been a boom in the availability of treatments for multiple myeloma (MM). Based on the status of disease (newly diagnosed or relapsed/refractory), several regimens have successfully improved progression free survival (PFS) and overall survival (OS) in these two types of patients. Triple drug regimen is considered the current standard of care for newly diagnosed MM patients. However, with the advent of four drug regimens, some studies demonstrated a significant improvement in PFS and OS compared to standard of care where as others showed marginal to no difference. Also, it remains unclear whether the benefits of using four drug regimen outweigh the risks. Thus, the aim of our meta-analysis was to compare the efficacy and safety of four drug versus three drug regimens among newly diagnosed multiple myeloma patients. Methods: We built a PICO based search strategy using keywords like "multiple myeloma", "randomized clinical trials" and ran literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov ranging from the date of inception till 16th July, 2020. A pre-validated data extraction sheet was used to extract data on PFS, OS and ≥Grade 3 hematologic adverse events at the longest follow-up. We included only randomized clinical trials (RCTs) comparing four versus three drug regimen in newly diagnosed MM patients. We excluded studies other than RCTs, studies conducted on relapsed refractory MM patients or other plasma cell dyscrasias. A generic variance weighted random effects model (DerSimonian and Laird) was used to derive hazard ratio estimates along with their 95% confidence intervals (CIs) for PFS and OS. Risk ratio along with its 95% CIs was estimated for Grade ≥3 hematologic adverse events. Heterogeneity was assessed with Cochrane Q -statistic and was quantified with I2 test (I2 >50% was consistent with a high degree of heterogeneity). A pre-specified sensitivity analysis was also performed for risk of adverse events. Cochrane Collaboration's tool was used to assess the quality of included RCTs and GRADE was used to rate the quality of evidence. Results: Initial search retrieved 7622 titles. After duplicate removal, 4880 articles were left. Following initial screening, 58 articles were considered for full text review. Of these only 3 studies (n=2277) met inclusion criteria. Four drug regimens included daratumumab, bortezomib, melphalan-prednisone (D-VMP), daratumumab, bortezomib, thalidomide-dexamethasone (D-VTd) and bortezomib and melphalan prednisone and thalidomide (VMPT-VT) respectively. Whereas, three drug regimens were bortezomib, melphalan-prednisone (VMP), bortezomib, thalidomide-dexamethasone (VTd) and bortezomib, melphalan and prednisone (VMP) respectively. There was a significant improvement in PFS when 4 vs 3 drug regimens were compared in patients with newly diagnosed MM (HR: 0.53, 95% CI: 0.46-0.62, p-value:<0.001, I2: 0%). Also, OS improved significantly in four drug regimen group (HR: 0.62, 95% CI: 0.51-0.76, p-value:<0.001, I2: 3.5%). There was no statistically significant difference in any grade ≥3 hematologic adverse events when 4 vs 3 drug regimens were compared (RR: 1.26, 95% CI: 0.93-1.73, p-value:0.14, I2: 93%). Sensitivity analysis after removing D-VTd regimen from any grade ≥3 hematologic adverse events revealed similar results (RR: 1.05, 95% CI: 0.97-1.13, p-value:0.23, I2: 23%) confirming the robustness of analysis. When each hematologic adverse event was looked at separately, there was no difference between 4 vs 3 drug regimen in rates of anemia (RR: 0.99, 95% CI: 0.76-1.28, p-value:0.92, I2: 0%), neutropenia (RR: 1.39, 95% CI: 1.00-1.94, p-value:0.05, I2: 85%) and thrombocytopenia (RR: 1.13, 95% CI: 0.92-1.39, p-value:0.24, I2: 33%). There was low risk of bias and strength of evidence was of moderate. Conclusion: Using four drug regimens, compared to three drug regimens, significantly improves PFS and OS among newly diagnosed multiple myeloma patients without any difference in the risk of ≥3 grade hematologic adverse events. Further randomized clinical trials are required to establish four drug regimen as standard of care for patients with newly diagnosed multiple myeloma. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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