Randomized Study Of Safety Research Articles

FrontMIND: A phase III, randomized, double-blind study of tafasitamab + lenalidomide + R-CHOP versus R-CHOP alone for newly diagnosed high-intermediate and high-risk diffuse large B-cell lymphoma.

TPS7590 Background: Up to 40% of patients relapse or are refractory (R/R) to R-CHOP, the current standard of care for diffuse large B-cell lymphoma (DLBCL), indicating an unmet need, particularly in patients with high-intermediate and high-risk disease (IPI 3–5). POLARIX (NCT03274492) evaluated a modified regimen substituting polatuzumab vedotin for vincristine (pola-R-CHP), demonstrating modest improvement in PFS with no OS benefit between treatment arms. The addition of lenalidomide (LEN) to R-CHOP improved both PFS and OS in the ECOG-ACRIN E1412 trial but not in the Phase III ROBUST study, in which a lower dose of LEN was used, despite a positive trend toward 2-year PFS in a subgroup analysis. The chemo-free immunotherapy tafasitamab + LEN has received accelerated approval in the United States (2020), and conditional marketing authorization in Europe and Canada (2021) in adult patients with R/R DLBCL ineligible for ASCT based on L-MIND (NCT02399085). The primary analysis of First-MIND (NCT04134936), a Phase Ib randomized safety study of R-CHOP + tafasitamab ± LEN in patients with previously untreated and newly diagnosed DLBCL, demonstrated that adding tafasitamab + LEN does not impair dosing and scheduling of R-CHOP, with toxicities similar to those expected with R-CHOP alone (ASH 2021; #3556). frontMIND (NCT04824092) will investigate the efficacy and safety of R-CHOP + tafasitamab + LEN vs R-CHOP alone in previously untreated patients with high-intermediate and high-risk DLBCL. Methods: frontMIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study. Approximately 880 patients are planned to be randomized at ̃350 centers in North and South America, Europe, and Asia-Pacific. Eligible patients aged 18‒80 years with previously untreated local biopsy-proven, CD20+ DLBCL with IPI score 3–5 (age-adjusted IPI 2–3 if ≤60 years), and ECOG PS 0–2 will be enrolled. Patients with transformed lymphoma (except double or triple hit lymphoma) are excluded. Patients will be randomized 1:1 to receive six 21-day (D) cycles of either R-CHOP + tafasitamab (12 mg/kg intravenously, D 1, 8, and 15) + LEN (25 mg orally, D1–10) or R-CHOP + tafasitamab and LEN placebos. Patients will be followed for up to 5 years after the end of treatment. The primary endpoint is investigator-assessed PFS. Secondary endpoints include investigator-assessed event-free survival, OS, safety, and tafasitamab serum concentration (trough and Cmax levels). Sensitivity and specificity of minimal residual disease for early detection of disease progression is an exploratory endpoint; further MRD parameters may also be investigated. The study is funded by MorphoSys AG and conducted with the scientific support of members of the Fondazione Italiana Linfomi and the German Lymphoma Alliance. Clinical trial information: NCT04824092.

A phase I randomized safety study of a single-size silicone rubber diaphragm used with or without a lactic-acid-containing diaphragm gel

ObjectivesTo evaluate a lactic-acid-containing diaphragm gel (Contragel®) approved outside the United States for use with a silicone rubber diaphragm (Caya®). The study gel is being evaluated as a safer alternative to nonoxynol-9 (N-9) gel, which has been associated with risk of increasing susceptibility to human immunodeficiency virus (HIV). Study designThis was a Phase I randomized, parallel study evaluating the safety of the novel diaphragm gel versus hydroxyethylcellulose (HEC) universal placebo gel delivered by the study diaphragm for two 7-day test cycles of daily use, without and with intercourse. The primary clinical safety endpoint was treatment emergent adverse events. Mucosal safety endpoints included colposcopic findings, anti-Escherichia coli activity of endocervical and vaginal fluid, immune mediators, Nugent score and ectocervical immune cell density. Endpoints were assessed prior to each test cycle and at day 7 of each test cycle. We compared the two independent groups and also evaluated paired changes from baseline in each gel cohort. ResultsTwenty-three participants used the study diaphragm with the novel gel (n=11) or with HEC (n=12). Use of either gel resulted in few genital AEs and no colposcopic findings. There were no differences in ectocervical histology and lymphocyte density or phenotype between the two cohorts at baseline or after each test cycle. We found no clinically important differences in the anti-microbial (anti Escherichia coli) activity of endocervical or vaginal fluid or concentrations of genital immune mediators (e.g. anti-inflammatory secretory leukocyte protease inhibitor (SLPI) or pro-inflammatory mediator RANTES) between the two gel cohorts at any visit. There were no important paired changes from baseline among participants using either gel in Nugent score, ectocervical histology or anti-microbial activity of genital secretions. ConclusionsWe found no clinically significant differences in clinical and mucosal safety endpoints between the two cohorts. The mucosal safety profiles of the study gel and HEC placebo gel were similar. ImplicationsOur data demonstrate no clinically important differences between the safety profiles of the lactic-acid-containing diaphragm gel versus HEC placebo gel when used with the study diaphragm. N-9 can no longer be used with contraceptive diaphragms in high HIV prevalence regions. Although larger studies are needed, the novel gel appears safe for use with the study diaphragm, which is the first over-the-counter, non-hormonal, diaphragm.

Plasma concentrations of levobupivacaine associated with two different intermittent wound infusion regimens following surgical ductus ligation in preterm infants.

Administration of local anesthetics by a surgically placed wound catheter has recently been shown to reduce the need for postoperative morphine administration in extremely preterm infants undergoing ductus ligation. The primary aim of this randomized safety study was to define the plasma levels of levobupivacaine (LB) following two different intermittent infusion regimens. Eighteen preterm infants 23-27 gestational weeks, median birthweight 721 g scheduled for ductus ligation were included in the study. All patients were anesthetized according to a standardized protocol based on high-dose fentanyl (25-50 μg·kg(-1) ). Before skin closure, a subcutaneous catheter was inserted into the wound. The patients were randomized to receive one of the two intermittent infusion regimens: Group BII: Initial bolus plus early start of the intermittent infusion or Group DII: No bolus plus delayed start (8 h) of the intermittent infusion. Blood samples for determination of LB plasma concentrations were obtained on six occasions during the 24-h postoperative observation period, as well as hourly postoperative pain assessments using the Echelle Douleur Inconfort Noveau (EDIN) pain scale. Plasma concentrations of LB ranged from 0.094 to 1.682 μg·ml(-1) and 0 to 0.549 μg·ml(-1) in group BII and DII, respectively. Both regimens were associated with low postoperative EDIN pain scores (24 h median of 0 and 1 in group BII and DII, respectively). No signs of systemic local anesthetic toxicity were noted. The two studied intermittent infusion regimens were associated with plasma levels below potentially toxic levels and were both associated with adequate postoperative pain scores.

Long-term, Randomized Safety Study of MP29-02 (a Novel Intranasal Formulation of Azelastine Hydrochloride and Fluticasone Propionate in an Advanced Delivery System) in Subjects With Chronic Rhinitis

MP29-02 is a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate (FP) in an advanced delivery system for the treatment of seasonal allergic rhinitis. The objective of this study was to evaluate the long-term safety of MP29-02 in subjects with chronic allergic (perennial) or nonallergic (vasomotor) rhinitis. This was a 1-year, randomized, open-label, active-controlled, parallel-group study in subjects with chronic allergic or nonallergic rhinitis. A total of 612 subjects were randomized in a 2:1 ratio to (1) MP29-02, one spray per nostril twice daily (total daily doses of azelastine hydrochloride and FP were 548 mcg and 200 mcg, respectively); or (2) FP, 2 sprays per nostril once daily (total daily dose 200 mcg). Safety and tolerability assessments were made at months 1, 3, 6, 9, and 12. The incidence of treatment-related adverse events was low with both MP29-02 (9.4%) and FP (11.1%), with no evidence of late-occurring adverse events. Nasal examinations showed no evidence of nasal mucosal ulcerations or septal perforations with MP29-02, and the overall incidence of adverse findings was reduced as the study progressed. There were no unusual or unexpected ocular examination findings and no clinically important laboratory findings or clinically important differences between groups in fasting AM serum cortisol levels after 12 months of treatment. MP29-02 was well tolerated. There were no safety findings that would preclude the long-term use of MP29-02 in the treatment of allergic rhinitis.

Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke–Enhanced Regimen Stroke Trial

In a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial. CLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score ≤1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression. Of 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01-1.40; P=0.053). At 90 days, 49.5% of the combination group had mRS ≤1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70-4.31; P=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51-3.76; P=0.52). The combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen. http://www.clinicaltrials.gov. Unique identifier: NCT00894803.

Stroke: Highlights of Selected Articles

<i>Stroke:</i> Highlights of Selected Articles

Juvéderm injectable gel: A multicenter, double-blind, randomized study of safety and effectiveness

A high concentration of crosslinked hyaluronic acid (HA) in a smooth, malleable formulation is the hallmark of the new Juvéderm dermal fillers. To determine the long-term effectiveness and safety of Juvéderm Ultra and Ultra Plus injectable gel. In the multicenter study approved by the Food and Drug Administration, subjects were randomized to treatment with Juvéderm Ultra or Ultra Plus in one nasolabial fold (NLF) and Zyplast collagen in the other. After optimal correction was achieved (treatment plus up to 2 touch-ups at 2-week intervals), effectiveness was assessed on a 5-point scale through the 6-month study period. An additional poststudy visit provided long-term effectiveness data. Safety was evaluated through subjects' daily diaries for 14 days after treatment. A total of 292 subjects were randomized and treated, 146 in each cohort. A total of 280 subjects completed the 6-month study, and 227 attended the poststudy visit. Clinically significant mean wrinkle correction (>or= 1 point improvement) was still in evidence at >9 months for both Juvéderm formulations but not for the Zyplast control. At >9 months, 75% of Juvéderm Ultra- and 81% of Juvéderm Ultra Plus-treated NLFs maintained a clinically significant correction. Moreover, 78% of NLFs treated with Juvéderm Ultra Plus still had a clinically significant improvement beyond 1 year. Local treatment site reactions were comparable for Juvéderm and Zyplast. These next-generation HA dermal fillers can be reliably expected to provide long-term correction, with Juvéderm Ultra lasting more than 9 months and Juvéderm Ultra Plus lasting for a year or more.

Intraocular pressure rise after primary posterior continuous curvilinear capsulorhexis with a fixed dorzolamide–timolol combination: Randomized safety study with intraindividual comparison using an angulated and a nonangulated intraocular lens

To assess the safety, in terms of the intraocular pressure (IOP), of cataract surgery with primary posterior continuous curvilinear capsulorhexis (PPCCC) and a postoperative dose of a fixed dorzolamide-timolol combination and evaluate the effect of intraocular lens (IOL) haptic angulation. Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. In this prospective randomized double-masked bilateral study, 88 eyes of 44 consecutive patients with age-related cataract were included in an intraindividual comparison study. All patients had standardized cataract surgery with PPCCC and IOL implantation in the capsular bag followed by a postoperative dose of a fixed dorzolamide-timolol combination. Patients were randomly assigned to receive an ACR6D SE IOL (Laboratoires Cornéal) in 1 eye and a Centerflex (C-flex) 570C IOL (Rayner Surgical GmbH) in the contralateral eye. The IOP was measured at baseline and postoperatively at 6 and 24 hours as well as 1 week. Intraindividual comparison showed statistically significantly higher IOP measurements in the C-flex 570C nonangulated IOL group than in the ACR6D SE angulated IOL group at 24 hours (P = .003) and 1 week (P = .043). The highest IOP spikes (34 mm Hg) were at 6 hours in 2 eyes with a C-flex 570C IOL. The ACR6D SE group had statistically significant changes in IOP between preoperative and all postoperative time points. In the C-flex 570C group, the only statistically significant change in IOP was between preoperatively and 6 hours postoperatively. Cataract surgery with PPCCC was safe in terms of the postoperative IOP course. Haptic angulation slightly decreased the overall IOP rise and the incidence of IOP rises above 30 mm Hg.

Fever as a Marker of Reactogenicity of an Acellular Pertussis-Containing Hexavalent Vaccine (HEXAVAC®) in a Large-Scale, Open, Randomized Safety Study in Healthy French Infants

Objective: New multivalent vaccines simplify childhood immunisation schedules and can increase vaccination coverage. However, they must have a reactogenicity profile which is acceptable and comparable with that of previously available vaccines. The objective of this trial was to assess the incidence of fever of 40.0°C or higher following vaccination with HEXAVAC® or concomitant PENTACOQ® and HBVAXPRO™.Study design: This was an open, randomised, pragmatic, post-licensure multicentre trial performed in France. Infants were randomly assigned to receive either a single injection of a hexavalent, aP-containing vaccine (HEXAVAC®) or separate injections of a pentavalent, wP-containing vaccine (PENTACOQ®) and Hepatitis B vaccine (HBVAXPRO™) at 2, 3 and 4 months of age. Both groups received a HEXAVAC® booster at 12-18 months of age. Results and discussion: 7151 infants were enrolled in 389 centres. During the combined 3-day periods following the primary series injections, the incidence of fever of 40.0°C or higher with HEXAVAC® was not greater than with [PENTACOQ® and HBVAXPRO™]. The incidence of fever at thresholds of 38.0°C, 38.5°C, 39.0°C and 39.5°C was significantly lower in the HEXAVAC group. The vaccine attributable risk for fever of 40.0°C following the booster injection with HEXAVAC® was statistically acceptable.Conclusion: The incidence of fever of 40.0°C higher in this study was very low and similar in both groups (HEXAVAC® or [PENTACOQ® + HBVAXPRO™] as a 3-dose primary series). Fever ≥ 38.0°C and ≤ 39.5°C was significantly less frequent following administration of HEXAVAC®. The incidence of fever of 40.0°C or higher following a HEXAVAC® booster dose was low in all infants studied.