scholarly journals Safety and Tolerability of Subcutaneous IgPro20 at High Infusion Parameters in Patients with Primary Immunodeficiency: Findings from the Pump-Assisted Administration Cohorts of the HILO Study

2021 ◽  
Author(s):  
John T. Anderson ◽  
Vincent R. Bonagura ◽  
Juthaporn Cowan ◽  
Connie Hsu ◽  
S. Shahzad Mustafa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Injection Site ◽  
Primary Immunodeficiency ◽  
Flow Rate ◽  
Immunoglobulin G ◽  
Randomized Study ◽  
Open Label ◽  
Serum Igg Levels ◽  
Trough Levels ◽  
Infusion Duration

Abstract Purpose To evaluate the safety and tolerability of subcutaneous IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) administered at high infusion parameters (> 25 mL and > 25 mL/h per injection site) in patients with primary immunodeficiency. Methods The Hizentra® Label Optimization (HILO) study was an open-label, parallel-arm, non-randomized study (NCT03033745) of IgPro20 using a forced upward titration design for infusion parameters. Patients experienced with pump-assisted IgPro20 infusions received weekly IgPro20 infusions at a stable dose in the Pump-Assisted Volume Cohort (N = 15; 25–50 mL per injection site) and in the Pump-Assisted Flow Rate Cohort (N = 18; 25–100 mL/h per injection site). Responder rates (percentage of patients who successfully completed ≥ 75% of planned infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. Results Responder rates were 86.7% (13/15, 25 mL) and 73.3% (11/15, 40 and 50 mL) in the Volume Cohort, and 77.8% (14/18, 25 and 50 mL/h), 66.7% (12/18, 75 mL/h), and 61.1% (11/18, 100 mL/h) in the Flow Rate Cohort. Infusion compliance was ≥ 90% in all patients in the Volume Cohort and in 83.3% of patients in the Flow Rate Cohort. The number of injection sites (Volume Cohort) and the infusion duration (Flow Rate Cohort) decreased with increasing infusion parameters. The rate of treatment-emergent adverse events per infusion was low (0.138 [Volume Cohort] and 0.216 [Flow Rate Cohort]). Serum IgG levels remained stable during the study. Conclusion Pump-assisted IgPro20 infusions are feasible at 50 mL and 100 mL/h per injection site in treatment-experienced patients, which may result in fewer injection sites and shorter infusion times. Trial Registration NCT03033745; registered January 27, 2017

scholarly journals Safety and Tolerability of Manual Push Administration of Subcutaneous IgPro20 at High Infusion Rates in Patients with Primary Immunodeficiency: Findings from the Manual Push Administration Cohort of the HILO Study

2020 ◽  
Author(s):  
Juthaporn Cowan ◽  
Vincent R. Bonagura ◽  
Patricia L. Lugar ◽  
Paul J. Maglione ◽  
Niraj C. Patel ◽  
...  
Keyword(s):  
Primary Immunodeficiency ◽  
Flow Rate ◽  
Flow Rates ◽  
Time In Treatment ◽  
Treatment Responder ◽  
Minimum Number ◽  
Local Reactions ◽  
Serum Igg Levels ◽  
Trough Levels ◽  
Infusion Duration

Abstract Purpose To evaluate the safety and tolerability of IgPro20 manual push (also known as rapid push) infusions at flow rates of 0.5–2.0 mL/min. Methods Patients with primary immunodeficiency (PID) with previous experience administering IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) were enrolled in the Hizentra® Label Optimization (HILO) study (NCT03033745) and assigned to Pump-assisted Volume Cohort, Pump-assisted Flow Rate Cohort, or Manual Push Flow Rate Cohort; this report describes the latter. Patients administered IgPro20 via manual push at 0.5, 1.0, and 2.0 mL/min/site for 4 weeks each. Responder rates (percentage of patients who completed a predefined minimum number of infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. Results Sixteen patients were treated; 2 patients (12.5%) discontinued at the 1.0-mL/min level (unrelated to treatment). Responder rates were 100%, 100%, and 87.5% at 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Mean weekly infusion duration decreased from 103–108 to 23–28 min at the 0.5- and 2.0-mL/min flow rates, respectively. Rates of treatment-related treatment-emergent adverse events (TEAEs) per infusion were 0.023, 0.082, and 0.025 for the 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Most TEAEs were mild local reactions and tolerability (infusions without severe local reactions/total infusions) was 100% across flow rate levels. Serum IgG levels (mean [SD]) were similar at study start (9.36 [2.53] g/L) and end (9.58 [2.12] g/L). Conclusions Subcutaneous IgPro20 manual push infusions at flow rates up to 2.0 mL/min were well tolerated and reduced infusion time in treatment-experienced patients with PID. Trial Registration NCT03033745

Pharmacokinetics, safety, and tolerability of four 28-day cycle intramuscular injections for risperidone-ISM 75 mg in patients with schizophrenia: A phase-2 randomized study (PRISMA-2)

2016 ◽  
Vol 33 (S1) ◽  
pp. s240-s241 ◽  
Author(s):  
L. Anta ◽  
J. Llaudó ◽  
I. Ayani ◽  
B. Gorostidi ◽  
M. Monreal ◽  
...  
Keyword(s):  
Injection Site ◽  
Drug Administration ◽  
Randomized Study ◽  
Deltoid Muscle ◽  
Study Medication ◽  
Open Label ◽  
Active Moiety ◽  
Intramuscular Injections ◽  
Competing Interest ◽  
Long Acting

IntroductionRisperidone-ISM is a new long acting intramuscular formulation of risperidone, for monthly administration without oral supplementation.ObjectiveTo characterize the pharmacokinetic of risperidone over multiple intramuscular injections in patients with schizophrenia.MethodA multicenter, open label, two-arm, parallel design clinical trial was performed. Each patient received 4 intramuscular injections of 75 mg of risperidone-ISM in either, gluteal or deltoid muscle at 28-day intervals.ResultsA total of 70 patients were randomized, 67 received at least one dose of study medication. Preliminary data show that mean Cmax of the active moiety was achieved 24-48 hours (Tmax) after each administration and ranged over four consecutive doses from 39.6-53.2 ng/mL and 54.1-61 ng/mL, when given in gluteal or deltoid, respectively. All subjects achieved therapeutic levels (> 7.5 ng/mL for the active moiety) between 2-8 hours after drug administration. The mean concentrations were maintained above therapeutic levels throughout the 4-week dosing period. No significance changes across the study were observed, either on Positive and Negative Syndrome Scale or Extrapyramidal Symptoms Scale. Overall, 63 subjects (94%) experienced at least 1 Treatment Emergent Adverse Event (TEAE) during the study. One serious TEAE (dystonia) was related to study treatment. One death not related to study medication was informed. The most frequently reported TEAEs were hyperprolactinaemia (57.7%) and injection site pain (32.8%).ConclusionsRisperidone-ISM achieved therapeutic levels from the first hours after drug administration and provided a sustained release throughout the 4-weeks dosing period over multiple intramuscular injections independently of the injection site. Risperidone-ISM was found to be safe and well tolerated.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Final analysis of a phase II, open label, randomized study of osimertinib versus osimertinib plus carboplatin/pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed with previous EGFR-TKI and whose tumours harbour a T790M mutation (LOGIK1604/NEJ032A).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21594-e21594
Author(s):  
Kentaro Tanaka ◽  
Hajime Asahina ◽  
Morihito Okada ◽  
Takahiro Uchida ◽  
Kana Watanabe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Randomized Study ◽  
Small Cell ◽  
Combination Group ◽  
Small Cell Lung ◽  
First Line ◽  
Open Label ◽  
T790m Mutation ◽  
Egfr Tki

e21594 Background: Osimertinib is now available not only as a second line treatment for the patients with EGFR and T790M-mutation positive non-small cell lung cancer (NSCLC) after initial tyrosine kinase inhibitors (TKIs) but as a first line treantment for those who are TKI-naive. The efficacy and the safety of osimertinib plus palatinum-based chemotherapy has not yet been evaluated. Methods: This phase 2, open-label, randomized study enrolled adult patients (pts) with clinical stage IIIB or IV, or postoperative recurrent NSCLC harbouring susceptible EGFR and T790M mutations after preceded EGFR-TKI failure. Pts were randomly assigned to receive either an osimertinib [80 mg/day 1-21; q3w] or a combination of osimertinib [80 mg/day 1-21] with carboplatin/pemetrexed (hereafter combination) [area under the curve (AUC) = 5 and 500 mg/m2 day 1; q3w]. The primary endpoint was progression-free survival (PFS). Secondary endpoints included incidence of adverse events, response rate and overall survival. As indiction of osimertinib was expanded to a first line, we amended the protocol to discontinue the enrollment and perform final analyses. Results: From October 2016 to January 2019, 62 pts were enrolled [31 pts osimertinib; 31 pts combination] (median age 68 (37-80); 53.2% male; 83.3% stage IV; 100% adenocarcinoma; 59.7% exon 19 deletion and 40.3% L858R; 45.2% never smoker). The rate of grade (G) ≥ 3 treatment-related adverse events was 32.2% in the osimertinib group and 83.9% in the combination group. Neutropenia, anemia and thrombocytopenia were more common in the combination group and the rates of G ≥ 3 were 0%, 0% and 6.4% in the osimertinib group and 38.7%, 25.8% and 29.1% in the combination group, respectively. Three episodes (9.7%) of G ≥ 3 infection and one episode (3.2%) of G ≥ 3 febrile neutropenia were uniquely observed in the combination group, however, these were well managed. Two episodes (6.5%) of G ≥ 3 pneumonitis was observed only in the osimertinib group. Exaggeration of adverse events specific for osimertinib or any unknown adverse event was not observed in the combination group. Final PFS analysis is to be demonstrated in the presentation. Conclusions: Combination of osimertinib with carboplatin and pemetrexed demonstrated safety in patients with EGFR and T790M mutation-positive NSCLC and the efficacy should be validated in the future phase 3 study. Clinical trial information: 000024438.

Safety of galcanezumab in patients with episodic migraine: A randomized placebo-controlled dose-ranging Phase 2b study

Cephalalgia ◽  
2018 ◽  
Vol 38 (6) ◽  
pp. 1015-1025 ◽  
Author(s):  
Tina Marie Myers Oakes ◽  
Vladimir Skljarevski ◽  
Qi Zhang ◽  
William Kielbasa ◽  
Michael E Hodsdon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Injection Site ◽  
Randomized Study ◽  
Injection Site Reaction ◽  
Episodic Migraine ◽  
Patient Treatment ◽  
Upper Respiratory Tract ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Humanized Monoclonal Antibody

Background Safety findings from a Phase 2b study of galcanezumab, a humanized monoclonal antibody against calcitonin gene-related peptide, for prevention of migraine (NCT02163993) are reported here. Methods Patients aged 18–65 years with episodic migraine were evaluated in this multicenter, double-blind, randomized study. After randomization, 410 patients were administered 5, 50, 120 or 300 mg of galcanezumab or placebo subcutaneously once every 4 weeks for 12 weeks, followed by a post-treatment off-drug period lasting 12 weeks. Results Treatment-emergent adverse events (TEAEs) were primarily rated as mild to moderate. Serious adverse events reported in galcanezumab dose groups were appendicitis, Crohn’s disease, suicidal ideation, and congenital ankyloglossia in an infant of a paternal pregnancy; each of these were reported by one patient. Adverse events leading to discontinuation with galcanezumab treatment were abdominal pain, visual impairment, and upper limb fracture, each reported by one patient. Treatment-emergent injection-site reactions were reported significantly more frequently ( p = 0.013) with galcanezumab (13.9%) than with placebo (5.8%). Injection-site pain was the most common injection-site reaction (galcanezumab 11.4%; placebo 2.9%, p = 0.004). Upper respiratory tract infection (galcanezumab 10.0%; placebo 8.8%) and nasopharyngitis (galcanezumab 7.0%; placebo 2.2%) also occurred more frequently with galcanezumab treatment. Potential hypersensitivity events were reported at similar frequencies in galcanezumab (3.3%) and placebo (5.1%) groups. Incidence of treatment-emergent anti-drug antibodies in galcanezumab dose groups (4.6% of patients during treatment period) did not appear to have any meaningful effects on safety, the pharmacokinetics of galcanezumab, or its ability to bind to the target ligand. Conclusion The results from this 3-month Phase 2b study support the initiation of larger Phase 3 trials of longer duration.

scholarly journals A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After ≥2 Prior TKIs

Blood ◽  
2021 ◽  
Author(s):  
Delphine Rea ◽  
Michael J Mauro ◽  
Carla Boquimpani ◽  
Yosuke Minami ◽  
Elza Lomaia ◽  
...  
Keyword(s):  
Adverse Events ◽  
Kinase Inhibitors ◽  
Randomized Study ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Primary Objective ◽  
Molecular Response ◽  
Open Label ◽  
Phase 3 ◽  
The Difference

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant or intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes due to disease biology and inadequate efficacy and/or safety of current therapies. Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with the potential to overcome resistance or intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. Two hundred and thirty-three patients were randomized to asciminib (n=157) or bosutinib (n=76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% CI, 2.19-22.30; 2-sided P=.029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and fewer adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant or intolerant to ≥2 prior TKIs. The trial is registered at www.ClinicalTrials.gov as NCT03106779.

scholarly journals Study design of a prospective, open-label study comparing increased infusion parameters of a 20% subcutaneous immunoglobulin (IgPro20) in patients with primary immunodeficiency

2019 ◽  
Author(s):  
Mikhail Rojavin ◽  
Jutta Hofmann ◽  
Michaela Praus
Keyword(s):  
United States ◽  
Injection Site ◽  
Primary Immunodeficiency ◽  
Flow Rate ◽  
Infusion Pump ◽  
The United States ◽  
Responder Rate ◽  
Prospective Clinical Study ◽  
Flow Rates ◽  
Study Results

Abstract Background: Immunoglobulin G (IgG) replacement therapy can be administered subcutaneously (SCIG) using an infusion pump or by manual push. Both methods have shown similar serum IgG trough levels for the same total weekly/monthly dose as well as safety and tolerability profiles. The currently approved infusion parameters for the SCIG Hizentra® (IgPro20, CSL Behring, King of Prussia, PA, USA) in primary immunodeficiency (PID) in the United States are volumes of ≤25 mL and flow rates of ≤25 mL/h per injection site. Previously, clinical studies and case reports had demonstrated use of higher infusion parameters than those approved, but safety and tolerability of these have not been systematically evaluated. In the absence of regulatory guidance, we have developed a novel prospective clinical study applying forced upward titration design to evaluate the safety and tolerability of high infusion parameters of IgPro20 in PID patients using pump-assisted and manual push techniques (NCT03033745). Results: A total of 45 patients were planned for inclusion. Primary endpoints were defined as the proportion of patients successfully infusing certain infusion parameters (responder rate). The study included three cohorts (n=15 planned per group): 1) Pump-assisted Volume Cohort with weekly infusions at volumes of 25, 40 and 50 mL per injection site; 2) Pump-assisted Flow Rate Cohort with weekly infusions at flow rates of 25, 50, 75 and 100 mL/h per injection site, and 3) Manual Push Flow Rate Cohort with 2 to 7 infusions at flow rates 30, 60 and 120 mL/h per injection site. Each infusion parameter level was tested for 4 weeks, after which those who successfully infused at the current level (responders) were switched to the next level. Responder rate, safety and tolerability were assessed. Study results will be available in early 2020. Conclusions: This study applied a novel and rigorous prospective evaluation of individual safety and tolerability levels of pump-assisted and manual push SCIG at higher infusion parameters than currently approved in the United States and demonstrated their safety and tolerability.

scholarly journals Timing of Onset of Adverse Events With Setmelanotide, an MC4R Agonist, in Patients With Severe Obesity Due to LEPR or POMC Deficiency

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A30-A31
Author(s):  
Karine Clément ◽  
Erica L T van den Akker ◽  
Gregory Gordon ◽  
Guojun Yuan ◽  
Peter Kühnen
Keyword(s):  
Adverse Events ◽  
Injection Site ◽  
Sexual Arousal ◽  
Special Interest ◽  
Leptin Receptor ◽  
Study Drug ◽  
Phase 2 ◽  
Open Label ◽  
Phase 3 ◽  
Open Label Phase

Abstract Introduction: Setmelanotide is a melanocortin 4 receptor agonist indicated for chronic weight management in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. This analysis aimed to assess the timing of the onset of adverse events (AEs) of special interest in patients with POMC/PCSK1 or LEPR deficiency obesity treated with setmelanotide. Methods: The timing of AE onset with setmelanotide was evaluated in a pooled set of patients with POMC/PCSK1 or LEPR deficiency who received setmelanotide in Phase 2 (RM-493-011 [NCT02507492]) or Phase 3 (RM-493-012 [NCT02896192] and RM-493-015 [NCT03287960]) clinical trials. Patients in the Phase 2 investigator-initiated trial (Charité Universitätsmedizin Berlin) received open-label setmelanotide for 12 to 13 weeks followed by an extension study for eligible patients. The Phase 3 trials included a 12-week open-label phase, an 8-week placebo-controlled phase, and a subsequent 32-week open-label phase, for a total treatment length of at least 1 year. AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). AEs of special interest were defined as those related to treatment-emergent AEs (TEAEs) commonly occurring with setmelanotide (hyperpigmentation disorders, disturbances in sexual arousal, nausea, vomiting, injection site reactions [ISRs]). Results: As of November 10, 2020, 35 patients (15 POMC, 2 PCSK1, 18 LEPR) were enrolled and included across the 3 trials; 2 patients in the Phase 2 trial were ongoing treatment as of the cutoff. Daily setmelanotide dose ranged from 0.25 to 3.0 mg. All patients experienced ≥1 TEAE, the most common being skin hyperpigmentation (85.7%), injection site erythema (68.6%), nausea (57.1%), and headache (51.4%). For AEs of special interest, hyperpigmentation disorders occurred in 85.7% of patients (30/35), disturbances in sexual arousal in 17.1% (6/35), nausea in 57.1% (20/35), vomiting in 28.6% (10/35), and ISRs in 88.6% (31/35). The onset of most hyperpigmentation disorder (34/53 events; 64.2%) and disturbances in sexual arousal (6/11 events; 54.6%) AEs were during Month 1 after starting setmelanotide. Onset of nausea and vomiting were most frequent during Month 1 of treatment (nausea: 12/34 events [35.3%]; vomiting: 6/19 events [31.6%]). ISRs occurred throughout the trial, with 41.6% (91/219 events) having an onset within Month 1 of treatment. Eighteen serious AEs occurred, none were interpreted as related to the study drug. Conclusions: In patients with POMC/PCSK1 or LEPR deficiency obesity who received setmelanotide treatment, the onset of AEs of special interest in any month was generally highest during Month 1 of treatment, with fewer events occurring during subsequent months. Apart from hyperpigmentation, all AEs occurred intermittently.

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