P0500RESULTS OF A PHASE 1 TRIAL TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF BION-1301 IN HEALTHY VOLUNTEERS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jeannette Lo ◽  
Peter Van Zandvoort ◽  
Jos Van de Crommert ◽  
Aaron Endsley ◽  
Thomas Müller ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
Serum Levels ◽  
High Plasma ◽  
Double Blind ◽  
Phase 1 Trial ◽  
Review Team ◽  
Differentiation And Proliferation ◽  
Stage Renal Disease ◽  
To Receive

Abstract Background and Aims IgA nephropathy (IgAN), the leading cause of primary glomerulonephritis, is an autoimmune disease with no approved treatments. Slow progression to end-stage-renal disease occurs in up to 50% of patients with IgAN over approximately 20-25 years, resulting in the need for dialysis or kidney transplant. A critical step in IgAN pathogenesis is the production of galactose-deficient IgA1 (Gd-IgA1) leading to the generation of anti-Gd-IgA autoantibodies and the formation of immune complexes that result in kidney inflammation and damage. Patients with IgAN have elevated levels of A proliferation-inducing ligand (APRIL), which may contribute to IgAN pathogenesis by regulating differentiation and proliferation of B cells. In a study of patients with IgAN, those with high plasma APRIL levels had higher levels of Gd-IgA1 and proteinuria and lower estimated glomerular filtration rates compared to those with lower plasma APRIL levels. BION-1301 is a first-in-class humanized antagonistic antibody targeting APRIL. BION-1301 reduced serum levels of IgA, IgM, and IgG with no drug-related toxicity in nonhuman primates and was well-tolerated with no dose-limiting toxicities in a Phase 1/2 first-in-human clinical study in patients with late-stage multiple myeloma. The Phase 1 trial described here will characterize the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of BION-1301 in healthy volunteers (HV) and patients with IgAN. Methods The protocol for this study (NCT03945318) is comprised of 3 parts, of which only Parts 1 and 2 are complete. Parts 1 and 2 assess BION-1301 in HV, and Part 3 will assess BION-1301 in patients with IgAN. Parts 1 and 2 are double-blind, randomized, placebo-controlled single and multiple ascending dose designs, respectively. Part 3 will assess a multiple dose regimen in IgAN patients. Part 1 enrolled 36 HV in 5 dose cohorts, randomized in a 3:1 ratio to receive a single dose of BION-1301 or placebo delivered by IV infusion. Part 2 enrolled 27 HV in 3 dose cohorts, randomized in a 2:1 ratio to receive 3 doses of BION-1301 or placebo delivered by IV infusion once every two weeks over a one month period. Dose escalation decisions were made by a Safety Review Team based on safety, tolerability, and PK-related stopping criteria. Results To-date, BION-1301 continues to be well tolerated. Its biological activity in the study is characterized by free APRIL, IgA, IgG, and IgM levels; unblinded safety, PK, and PD results for Parts 1 and 2 in Healthy Volunteers will be presented. Conclusion BION-1301, a humanized anti-APRIL antibody, may provide a novel avenue for the potential treatment of IgAN that offers potential advantages compared to currently used antihypertensive or immunosuppressive therapies.

scholarly journals EXTENDED ABSORPTION OF LIOTHYRONINE FROM POLY-ZINC LIOTHYRONINE (PZL) IN HUMANS

2021 ◽  
Author(s):  
Alexandra Dumitrescu ◽  
Erin C Hanlon ◽  
Marilyn Arosema ◽  
Olga Duchon ◽  
Matthew Ettleson ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Drug Product ◽  
Phase 1 ◽  
Placebo Administration ◽  
Double Blind ◽  
Serum T3 ◽  
To Receive ◽  
Administration Methods ◽  
Hypothyroid Patients

Background: Liothyronine (LT3) has been increasingly used in combination with levothyroxine (LT4) in the treatment of hypothyroidism. A metal coordinated form of LT3, known as poly-zinc-liothyronine (PZL), avoided in rats the typical T3 peak seen after oral administration of LT3. Objectives: To evaluate in healthy volunteers (i) the pharmacokinetics of PZL-derived T3 after a single dose, (ii) the pharmacodynamics of PZL-derived T3, (iii) monitoring for the adverse events; (iv) exploratory analysis of the sleep patterns after LT3, PZL or placebo administration. Methods: 12 healthy volunteers 18 to 50 years of age were recruited for a Phase 1, double-blind, randomized, single-dose placebo-controlled, cross-over study to compare PZL against LT3 or placebo. Subjects were admitted three separate times to receive a randomly assigned capsule containing placebo, 50-mcg LT3, or 50-mcg-PZL, and were observed for 48h. A 2-week wash-out period separated each admission. Results: LT3-derived serum T3 levels exhibited the expected profile, with a Tmax at 2h and return to basal levels by 24-36h. PZL-derived serum T3 levels exhibited a ~30% lower Cmax that was 1 h delayed and extended into a plateau that lasted up to 6h. This was followed by a lower but much longer plateau; by 24 hours serum T3 levels still exceeded 1/2 of Cmax. TSH levels were similarly reduced indistinguishably in both groups. Conclusion: PZL possesses the necessary properties to achieve a much improved T3 pharma-cokinetic. Drug product development of PZL should improve the delivery of T3 even further. PZL is on track to provide hypothyroid patients with stable levels of serum T3.

scholarly journals Immunogenicity and Safety of a SARS-CoV-2 Inactivated Vaccine (KCONVAC) in Healthy Adults: Two Randomized, Double-blind, and Placebo-controlled Phase 1/2 Clinical Trials

2021 ◽  
Author(s):  
Hong-Xing Pan ◽  
Jian-Kai Liu ◽  
Bao-Ying Huang ◽  
Gui-Fan Li ◽  
Xian-Yun Chang ◽  
...  
Keyword(s):  
Antibody Response ◽  
Cellular Response ◽  
Phase 1 ◽  
Healthy Adults ◽  
Phase 2 ◽  
Double Blind ◽  
Live Virus ◽  
Phase 1 Trial ◽  
Phase 2 Trial ◽  
To Receive

Background The significant morbidity and mortality resulted from the infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for urgent development of effective and safe vaccines. We report the immunogenicity and safety of a SARS-CoV-2 inactivated vaccine, KCONVAC, in healthy adults. Methods Two phase 1 and phase 2 randomized, double-blind, and placebo-controlled trials of KCONVAC were conducted in Chinese healthy adults aged 18 through 59 years. The phase 1 trial was conducted in a manner of dosage escalation. The first 30 participants were randomized in a ratio of 4:1 to receive two doses of either KCONVAC at 5 μg per dose or placebo on Day 0 and Day 14, and the second 30 participants were randomized to receive either KCONVAC at 10 μg per dose or placebo following the same procedures. The participants in the phase 2 trial were randomized in a ratio of 2:2:1 to receive either KCONVAC at 5 μg or 10 μg per dose, or placebo on Day 0 and Day 14, or Day 0 and Day 28. In the phase 1 trial, the primary safety endpoint was the proportion of participants experiencing adverse reactions/events within 28 days following each vaccination. Antibody response and cellular response were assayed in the phase 1 trial. In the phase 2 trial, the primary immunogenicity endpoint was the seroconversion and titre of neutralization antibody, and the seroconversion of receptor binding domain (RBD)-IgG 28 days after the second dose. Findings In the phase 1 trial, 60 participants were enrolled and received at least one dose of 5-μg vaccine (N=24), 10-μg vaccine (N=24), or placebo (N=12). In the phase 2 trial, 500 participants were enrolled and received at least one dose of 5-μg vaccine (N=100 for 0/14 or 0/28 regimens), 10-μg vaccine (N=100 for each regimen), or placebo (N=50 for each regimen). In the phase 1 trial, 13 (54%), 11(46%), and 7 (58%) participants reported at least one adverse event (AE), of whom 10 (42%), 6 (25%), and 6 (50%) participants reported at least one vaccination-related AE after receiving 5-μg vaccine, 10-μg vaccine, or placebo, respectively. In the phase 2 trial, 16 (16%), 19 (19%), and 9 (18%) participants reported at least one AE, of whom 13 (13%), 17 (17%), and 6 (12%) participants reported at least one vaccination-related AE after receiving 5-μg vaccine, 10-μg vaccine, or placebo at the regimen of Day 0/14, respectively. Similar results were observed in the three treatment groups of Day 0/28 regimen. All the AEs were grade 1 or 2 in intensity. No AE of grade 3 or more was reported. One SAE (foot fracture) was reported in the phase 1 trial. KCONVAC induced significant antibody response. 87.5% (21/24) to 100% (24/24) of participants in the phase 1 trial and 83.0% (83/100) to 100% (99/99) of participants in the phase 2 trial seroconverted for neutralising antibody to live virus, neutralising antibody to pseudovirus, and RBD-IgG after receiving two doses. Across the treatment groups in the two trials, the geometric mean titres (GMTs) of neutralising antibody to live virus ranged from 29.3 to 49.1 at Day 0/14 regimen and from 100.2 to 131.7 at Day 0/28 regimen, neutralising antibody to pseudovirus ranged from 69.4 to 118.7 at Day 0/14 regimen and from 153.6 to 276.6 at Day 0/28 regimen, and RBD-IgG ranged from 605.3 to 1169.8 at Day 0/14 regimen and from 1496.8 to 2485.5 at Day 0/28 regimen. RBD-IgG subtyping assay showed that a significant part of RBD-IgG was IgG1. The vaccine induced obvious T-cell response with 56.5% (13/23) and 62.5% (15/24) of participants in 5-μg and 10-μg vaccine groups showed positive interferon-γ enzyme-linked immunospot responses 14 days after the second dose in the phase 1 trial, respectively. Interpretation KCONVAC is well tolerated and able to induce robust antibody response and cellular response in adults aged 18 to 59 years, which warrants further evaluation with this vaccine in the upcoming phase 3 efficacy trial. Funding Guandong Emergency Program for Prevention and Control of COVID-19 (2020A1111340002) and Shenzhen Key Research Project for Prevention and Control of COVID-19.

Safety evaluation of an antimalarial herbal product from Andrographis paniculata (AS201-01) in healthy volunteers

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Aty Widyawaruyanti ◽  
Arijanto Jonosewojo ◽  
Hilkatul Ilmi ◽  
Lidya Tumewu ◽  
Ario Imandiri ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Healthy Volunteers ◽  
Day Treatment ◽  
Phase 1 ◽  
Andrographis Paniculata ◽  
Control Group ◽  
Healthy Human ◽  
Double Blind ◽  
Random Blood Glucose ◽  
Significant Difference

Abstract Objectives Andrographis paniculata tablets (AS201-01) have previously been shown to have potent bioactivity as an antimalarial and to produce no unwanted side effects in animal models. Here, we present the phase 1 clinical trial conducted to evaluate the safety of AS201-01 tablets in healthy volunteers. Methods The study was a randomized, double-blind controlled cross-over, a placebo-controlled design consisting of a 4-day treatment of AS201-01 tablets. A total of 30 healthy human volunteers (16 males and 14 females) were divided into two groups, and each group was given 4 tablets, twice daily for 4 days. Group 1 received AS201-01, while group 2 received placebo tablets. Volunteers were given a physical examination before the treatment. The effects of AS201-01 on random blood glucose, biochemical, and hematological as well as urine profiles were investigated. Results There were no changes in observed parameters as a result of AS201-01 being administered. Statistical analysis showed no significant difference (p>0.05) between the test and control group regarding hematology profile, biochemical profile, and random blood glucose. Increased appetite and better sleep, which categorized as grade 1 adverse event was reported after treatment with AS201-01 tablet Conclusions The outcome supports our previous observation that the AS201-01 tablet, given twice a day for 4 days, is safe and nontoxic.

scholarly journals Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

2016 ◽  
Vol 60 (10) ◽  
pp. 6326-6332 ◽  
Author(s):  
David C. Griffith ◽  
Jeffery S. Loutit ◽  
Elizabeth E. Morgan ◽  
Stephanie Durso ◽  
Michael N. Dudley
Keyword(s):  
Plasma Clearance ◽  
Healthy Adult ◽  
Phase 1 ◽  
High Dose ◽  
Double Blind ◽  
Time Curve ◽  
Content Type ◽  
Multiple Doses ◽  
To Receive ◽  
Lactamase Inhibitor

ABSTRACTVaborbactam (formerly RPX7009) is a member of a new class of β-lactamase inhibitor with pharmacokinetic properties similar to those of many β-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single- and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort. Maximum concentrations for vaborbactam were achieved at the end of the 3-h infusion. Vaborbactam exposure (Cmaxand area under the concentration-time curve [AUC]) increased in a dose-proportional manner following multiple doses. There was no evidence of accumulation with multiple doses, consistent with the terminal half-life of ∼2 h. Both the volume of distribution (Vss) and plasma clearance were independent of dose. For the 2,000-mg dose, the plasma clearance was 0.17 ± 0.03 liters/h, the AUC from 0 h to infinity (AUC0–∞) was 144.00 ± 13.90 mg · h/liter, and theVsswas 21.80 ± 2.26 mg · h/liter. Urinary recovery was 80% or greater over 48 h across all dose groups. No subjects discontinued the study due to adverse events (AEs), and no serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among the vaborbactam- and placebo-treated subjects, with mild lethargy as the only unique AE reported with the high dose of vaborbactam. Overall, this study revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and formed the basis for advancement into patient studies in combination with meropenem, including treatment of patients with carbapenem-resistantEnterobacteriaceae(CRE) infections. (This study is registered at ClinicalTrials.gov under identifier NCT01751269.)

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