A Double-Blind, Randomized, Crossover Comparative Study for Evaluating the Clinical Safety of Ephedrine Alkaloids-Free Ephedra Herb Extract (EFE)

Ephedra Herb is an important crude drug; it is used in various Traditional Japanese Medicine (Kampo) formulations. Its significant pharmacological effects have been believed to be attributed to ephedrine and pseudoephedrine, which sometimes induce adverse effects. On the other hand, it has been reported that some of these pharmacological effects are not dependent on ephedrine or pseudoephedrine. Ephedrine alkaloids-free Ephedra Herb extract has been newly developed. It has been reported to have analgesic, anti-influenza, and antimetastatic effects. This clinical trial was aimed at verifying the noninferiority of EFE’s safety compared to that of Ephedra Herb extract (EHE) in humans. This was a single-institution, double-blinded, randomized, two-drug, two-stage, crossover comparative study. Twelve healthy male subjects were equally and randomly allocated into two groups: prior administration of EFE (EFE-P) and prior administration of EHE (EHE-P). In Stage 1, EFE and EHE were orally administered to the EFE-P and EHE-P groups, respectively, for six days. After a 4-week washout period, Stage 2 was initiated wherein the subjects were given a study drug different from Stage 1 study drug for six days. Eleven adverse events with a causal relationship to the study drugs (EHE: 8; EFE: 3) were noted; all events were mild in severity. With regard to the incidence of adverse events, EHE and EFE administration, respectively, accounted for 4 cases (out of 12 subjects, similarly below) and 1 case of increased pulse rate (p=0.32) and 3 cases and 1 case of insomnia (p=0.59). Further, there was one case of hot flashes (p=1.00) due to EFE administration and one case of dysuria (p=1.00) due to EHE administration. There were no significant differences in the incidences of adverse events between EHE administration and EFE administration. Therefore, we concluded that EFE is not inferior to EHE in terms of safety.

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Safety findings from CENTURION, a phase 3 consistency study of lasmiditan for the acute treatment of migraine

The Journal of Headache and Pain ◽

10.1186/s10194-021-01343-2 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

C Tassorelli ◽

S Bragg ◽

JH Krege ◽

EG Doty ◽

PA Ardayfio ◽

...

Keyword(s):

Adverse Events ◽

Acute Treatment ◽

Motor Vehicle ◽

Specific Treatment ◽

Study Drug ◽

Control Group ◽

Phase 3 ◽

Serious Adverse Events ◽

Double Blind ◽

Vehicle Accidents

Abstract Background Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). Methods Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. Results Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. Conclusion In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. Trial registration NCT03670810

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The Safety and Efficacy of Oral Magnesium Pidolate in Children with Hemoglobin SC Disease.

Blood ◽

10.1182/blood.v106.11.3777.3777 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3777-3777

Author(s):

Brigitta Ursula Mueller ◽

Marlen Dinu ◽

Susan Kurth ◽

Roz Bryant ◽

Elizabeth Mullen ◽

...

Keyword(s):

Adverse Events ◽

Sickle Cell ◽

Serum Magnesium ◽

Study Drug ◽

Laboratory Evaluation ◽

Controlled Study ◽

Serious Adverse Events ◽

Double Blind ◽

Efficacy Analysis ◽

Cellular Dehydration

Abstract An important characteristic of the Hb SC erythrocyte is its high intracellular Hb concentration, which is due to cell K+ loss and dehydration mediated by an abnormally active K-Cl co-transport. This pathologic state of cellular dehydration raises the intracellular concentration of Hb S, thereby increasing its tendency to polymerize. Previous studies in patients with sickle cell disease have shown that oral Mg supplements can increase erythrocyte Mg content, reduce the activity of K-Cl co-transport and diminish erythrocyte dehydration. We performed a randomized, double blind, placebo-controlled study with crossover design on oral Mg supplementation in children with HbSC disease. Methods: Two major pediatric sickle cell centers participated in this IRB-approved study: Texas Children’s Sickle Cell Center and The Children’s Hospital in Boston. Over 100 eligible patients were contacted and invited to participate. The enrolled patients or their parents/guardians gave informed consent. Patients were randomized to either receive oral Mg pidolate or placebo for 6 months followed by a wash-out period of 2 months, then followed by a 6 month period of the other agent (placebo/Mg pidolate) and 2 months wash-out. Patients were initially followed every 2 weeks, then every 4 weeks. Safety was assessed both by clinical assessment as well as laboratory evaluation, including serum magnesium levels. Results: Between January 2002 and December 2004 we enrolled 12 patients (7 males, 5 female, age range 3.9 to 16.8 years) with HbSC disease and at least one pain crisis within the last year. Only 5 patients are fully evaluable for efficacy assessment. Seven patients came off study for the following reasons: 3 for non-compliance, 2 for study violation (pharmacy dispensed wrong formulation), and 2 withdrew for personal reasons (no longer interested), but all of them were included in the safety assessment. There were 3 events that were considered probably related to study drug (or placebo): diarrhea, grade 2 once and headaches, grade 3, in 2 instances. There were 6 events possibly related to drug (or placebo): diarrhea in three patients (all grade 1) and headaches of grade 2 or 3 in three patients. All adverse events resolved without stopping the drug/placebo. The results of the intracellular Mg concentrations and thus efficacy analysis will be available after unblinding the study in September 2005. Conclusion: Mg pidolate appears to be safe and well-tolerated when used in children with HbSC disease. No serious adverse events occurred that were considered definitively related to the study drug(s). Efficacy results will be available at the time of the meeting. However, despite the fact that study was open at 2 major sickle cell centers and had relatively non-restrictive enrollment criteria, accrual was extremely slow, presumably due to the sporadic and rather low disease intensity of Hb SC disease, and several patients did not complete the study. This should be taken into consideration when designing larger studies for patients with HbSC disease exclusively.

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A Comparison of Proposed Biosimilar and Originator Filgrastim for the Prevention of Neutropenia in Patients with Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Phase III, Randomized, Double-Blind Trial (The PIONEER study)

Blood ◽

10.1182/blood.v124.21.5133.5133 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5133-5133 ◽

Cited By ~ 4

Author(s):

Kimberly Blackwell ◽

Vladimir Semiglazov ◽

Pedro Gascon ◽

Roumen Nakov ◽

Stefan Kramer ◽

...

Keyword(s):

Breast Cancer ◽

Treatment Group ◽

Adverse Events ◽

Lower Limit ◽

Study Drug ◽

Phase Iii ◽

Efficacy And Safety ◽

Double Blind ◽

Pioneer Study ◽

The Mean

Abstract Introduction: Biosimilars are biologics which have demonstrated highly similar safety, potency and purity to an originator product. Several biosimilars of recombinant human filgrastim, based on the originator Neupogen®, have become available in Europe since 2008 and are now in clinical use for the prevention of chemotherapy-induced neutropenia and hematopoietic stem cell mobilization. Filgrastim biosimilars are presently being developed for the U.S. market. Study design: A randomized, double-blind, four-group, multi-center phase III non-inferiority trial was performed with breast cancer patients treated with myleosuppressive chemotherapy. The two filgrastim products – proposed biosimilar, EP2006 (“biosimilar”) vs. originator (U.S.-licensed Neupogen®) - were compared regarding efficacy and safety. Patients included: women ≥18 years with histologically-proven breast cancer eligible for neoadjuvant or adjuvant treatment with docetaxel 75 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC regimen) given for 6 cycles. Other key inclusion criteria included: Eastern Cooperative Oncology Group performance status ≤2 and adequate bone marrow function. Eligible patients were randomized to 4 groups with 2 of these groups alternating between the biosimilar and the originator filgrastim at the end of each cycle: 1) EP: treatment with EP2006 in all cycles; 2) EPNEU: EP2006 in Cycle 1, alternating between Neupogen and EP2006 in the following cycles; 3) NEUEP: Neupogen in Cycle 1, alternating between EP2006 and Neupogen in the following cycles; 4) NEU: treatment with Neupogen in all cycles. Patients received either biosimilar or originator filgrastim subcutaneously (daily dose of 5 µg/kg body weight) starting on Day 2 of each chemotherapy cycle until the absolute neutrophil count (ANC) recovered to 10×109/L after nadir or up to 14 days. Total duration of the study was 25 weeks: 3 weeks screening, 18 weeks treatment (total 6 cycles, 3 weeks each) and a follow-up visit 4 weeks after the last study drug administration. Primary objective was to assess the efficacy of the biosimilar compared to the originator with respect to mean duration of severe neutropenia (DSN) following Cycle 1 chemotherapy. A one-sided 97.5% confidence interval (CI) for the difference in the mean DSN calculated using ANCOVA model with factors “treatment” and “kind of therapy” and covariates “baseline ANC” was to be considered non-inferior if lower limit of this CI lies entirely above non-inferiority margin of -1 day. All secondary efficacy endpoints and safety endpoints were analyzed descriptively by treatment group. The study was conducted between December 2011 and June 2013. Results: Enrolled were 258 patients in 27 centers, of which 218 patients were randomized to treatment. The baseline characteristics were balanced between different groups. The per-protocol set included 204 patients out of 218 randomized patients. The safety set included 214 patients who received at least one dose of study drug. On average each patient received treatment for 8-9 days per cycle. The mean DSN in Cycle 1 was 1.17±1.11 days (biosimilar) and 1.20±1.02 days (originator); the mean difference in DSN was 0.04 days (97.5% CI, lower limit -0.26 days). The pre-defined non-inferiority criteria were met and the biosimilar was considered non-inferior to the originator filgrastim. The incidence of febrile neutropenia over all 6 cycles chemotherapy was comparably low in all treatment groups (EP: 2/40, 5.0%, EPNEU: 5/45, 11.1%, NEUEP: 1/44, 2.3%, NEU: 0/46, 0.0%). There was no obvious difference in incidences of treatment emergent adverse events between the treatment arms. Twelve patients experienced serious adverse events (EP: 5/53, 9.4% patients; EPNEU: 4/54, 7.4%; NEUEP: 1/55, 1.8%; NEU: 2/52, 3.8%). None of them were study drug related, including one death (in the EP treatment group due to pulmonary embolism). No subjects developed anti-drug antibodies. Conclusion: This large clinical study showed that efficacy and safety of the biosimilar was comparable to the originator filgrastim in prevention of neutropenia in patients with breast cancer. Repeated switching between the biosimilar and the originator filgrastim did not impact efficacy, safety or immunogenicity. Acknowledgment: The authors acknowledge the other investigators of the PIONEER study and acknowledge Gabor Stiegler, Sandoz Biopharmaceuticals for the medical writing. Disclosures Blackwell: Sandoz Biopharmaceuticals: Consultancy. Semiglazov:Sandoz Biopharmaceuticals: Consultancy. Gascon:Sandoz Biopharmaceuticals: Consultancy. Nakov:Sandoz Biopharmaceuticals: Employment. Kramer:Sandoz Biopharmaceuticals: Employment. Schwebig:Sandoz Biopharmaceuticals: Employment. Harbeck:Sandoz Biopharmaceuticals: Consultancy.

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A phase I, randomized, single-dose pharmacokinetic study comparing sb8 (bevacizumab biosimilar) with reference bevacizumab in healthy volunteers

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-020-04144-7 ◽

2020 ◽

Vol 86 (4) ◽

pp. 567-575 ◽

Cited By ~ 1

Author(s):

Donghoon Shin ◽

Yoon Jung Lee ◽

Jihye Choi ◽

Dahyoung Lee ◽

Minjeong Park ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Healthy Volunteers ◽

Neutralizing Antibodies ◽

Study Drug ◽

The European Union ◽

Double Blind ◽

Time Curve ◽

Single Dose Study ◽

Primary Endpoints

Abstract Purpose To compare pharmacokinetics, safety, tolerability, and immunogenicity between SB8, a bevacizumab biosimilar, and the European Union (EU) and United States (US) reference products (bevacizumab-EU, bevacizumab-US). Methods In this randomized, double-blind, parallel-group, and single-dose study, healthy volunteers were randomized to receive a 3 mg/kg dose of SB8, bevacizumab-EU, or bevacizumab-US via intravenous infusion. Primary endpoints were area under the concentration–time curve from time zero to infinity (AUCinf) and to the last quantifiable concentration (AUClast), and maximum observed serum concentration (Cmax). Bioequivalence was achieved if 90% confidence intervals (CIs) for the ratios of the geometric least squares means (LSMeans) of primary endpoints were within the predefined bioequivalence margins of 80.00–125.00%. Safety and immunogenicity were also investigated. Results The 90% CIs for the geometric LSMean ratios of AUCinf, AUClast and Cmax were all within the prespecified bioequivalence margins. Geometric LSMean ratios for SB8/bevacizumab-EU, SB8/bevacizumab-US and bevacizumab-EU/bevacizumab-US were 88.01%, 88.48% and 100.54% for AUCinf, 88.65%, 89.08% and 100.49% for AUClast and 99.59%, 101.15% and 101.56% for Cmax, respectively. Incidence of treatment-emergent adverse events (TEAEs) across treatment groups was comparable (SB8: 50.0%, bevacizumab-EU: 37.5%, bevacizumab-US: 53.8%). Most TEAEs were mild and considered as not related to the study drug. No deaths or treatment discontinuations due to adverse events occurred. Incidence of anti-drug antibodies was also comparable between all groups and no neutralizing antibodies were detected. Conclusion This study demonstrated pharmacokinetic bioequivalence and similar safety and immunogenicity profiles of SB8 to both reference products, bevacizumab-EU and bevacizumab-US, and of bevacizumab-EU to bevacizumab-US. Clinicaltrials.gov identifier NCT02453672 (submitted date); EudraCT number: 2015-001,026-41.

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The safety of ceftolozane-tazobactam for the treatment of acute bacterial infections: a systemic review and meta-analysis

Therapeutic Advances in Drug Safety ◽

10.1177/20420986211027096 ◽

2021 ◽

Vol 12 ◽

pp. 204209862110270

Author(s):

Li-Ting Wang ◽

Wei-Ting Lin ◽

Chih-Cheng Lai ◽

Ya-Hui Wang ◽

Cheng-Hsin Chen ◽

...

Keyword(s):

Adverse Events ◽

Bacterial Infections ◽

Therapeutic Option ◽

Meta Analysis ◽

Study Drug ◽

Adult Patients ◽

Control Group ◽

Clinical Safety ◽

Acute Bacterial Infections ◽

And Control

Objective(s): The aim of this study was to conduct a meta-analysis to assess the clinical safety of ceftolozane-tazobactam for the treatment of acute bacterial infections in adult patients. Methods: The PubMed, Embase, and Cochrane databases were searched from their inception until May 2020 for relevant randomized controlled trials (RCTs). Only RCTs evaluating the risk of adverse events (AEs) for ceftolozane-tazobactam and comparative treatments for acute bacterial infections in adult patients were included. Results: Overall, four RCTs including a total of 2924 patients (1475 in the ceftolozane-tazobactam group and 1449 in the control group) were included in the meta-analysis. The rate of treatment-emergent AEs was 51.3% (748/1458) in the ceftolozane-tazobactam group, which was comparable to the control group, 49.9% [714/1430; odd’s ratio (OR), 1.06; 95% confidence interval (CI), 0.91–1.25; I2 = 0%]. In addition, no difference was observed between the ceftolozane-tazobactam and control groups in terms of the risk of serious AEs (OR, 1.22; 95% CI, 0.93–1.61; I2 = 15.5%) and the risk of discontinuing the study drug due to AEs (OR, 0.85; 95% CI, 0.55–1.33; I2 = 0%). The rate of all-cause mortality did not significantly differ between the ceftolozane-tazobactam and control groups (OR, 1.11; 95% CI, 0.82–1.50; I2 = 0%). The only exception was the risk of Clostridiodes difficile ( C. difficile) colitis, where ceftolozane-tazobactam treatment was associated with a significantly higher risk compared with the control group [0.72% (10/1376) versus 0.14% (2/1391), OR, 3.84; 95% CI, 1.23–11.97; I2 = 0%]. Conclusion: Ceftolozane-tazobactam treatment is as tolerable as comparative treatment options for acute bacterial infections in adult patients, however it has an increased risk of C. difficile infection. As a novel broad-spectrum antibiotic, ceftolozane-tazobactam could be a safe therapeutic option for use in common clinical practice. Plain language summary The safety of ceftolozane-tazobactam (an antibiotics) for the treatment of acute bacterial infections Objective(s): Ceftolozane-tazobactam is an effective antibiotic for the treatment of acute bacterial infections. This study conducts a meta-analysis to assess the clinical safety (side effects) of ceftolozane-tazobactam for the treatment of acute bacterial infections in adult patients compared with other drugs. Methods: We extracted data from four randomized controlled trials, including a total of 2924 patients (1475 in the ceftolozane-tazobactam group and 1449 in the control group). Results: The rate of treatment related adverse events (AEs) was similar in the ceftolozane-tazobactam group (51.3%) and control group (49.9%). There was also no difference in risk of serious adverse events, the risk of discontinuing the study drug due to AEs, and all-cause mortality. The only exception was the risk of Clostridiodes difficile colitis (a cause of antibiotic-associated diarrhea), where ceftolozane-tazobactam treatment was associated with a significantly higher risk compared with the control group. Conclusion: In conclusion, as a novel broad-spectrum antibiotic, ceftolozane-tazobactam could be a safe therapeutic option for use in clinical practice.

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DOUBLE BLIND RANDOMISED COMPARATIVE STUDY OF EFFICACY AND TOLERABILITY OF TELMISARTAN AND LISINOPRIL IN MALE PATIENTS OF STAGE 1 ESSENTIAL HYPERTENSION

Journal of Evolution of Medical and Dental Sciences ◽

10.14260/jemds/2015/2353 ◽

2015 ◽

Vol 4 (95) ◽

pp. 16094-16097

Author(s):

Srinivasa Rao R ◽

Prabhakar K R

Keyword(s):

Essential Hypertension ◽

Comparative Study ◽

Double Blind ◽

Male Patients ◽

Stage 1

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486 Timing and Duration of Adverse Events in a Clinical Trial of Lower-Sodium Oxybate in Participants With Narcolepsy With Cataplexy

SLEEP ◽

10.1093/sleep/zsab072.485 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A192-A192

Author(s):

Richard Bogan ◽

Nancy Foldvary-Schaefer ◽

Roman Skowronski ◽

Abby Chen ◽

Michael Thorpy

Keyword(s):

Adverse Events ◽

Study Drug ◽

Drug Dose ◽

Sodium Oxybate ◽

Open Label ◽

Double Blind ◽

Peak Incidence ◽

Safety Population ◽

Titration Period ◽

Treatment Naïve

Abstract Introduction This analysis evaluated treatment-emergent adverse events (TEAEs) during a double-blind, placebo-controlled, randomized withdrawal trial (NCT03030599) of lower-sodium oxybate (LXB; Xywav™), an FDA-approved treatment for excessive daytime sleepiness or cataplexy in narcolepsy. Methods At study entry, participants were taking sodium oxybate (SXB) alone, SXB with other anticataplectics, other anticataplectics alone, or were anticataplectic treatment-naive. Participants taking SXB transitioned to the same LXB dose (gram-for-gram); oxybate-naive participants initiated LXB (4.5 g/night). TEAEs were analyzed in the safety population (N=201, received ≥1 study drug dose) during a 12-week open-label optimized treatment/titration period (while other anticataplectics were tapered/discontinued) and subsequent 2-week stable-dose period (SDP). TEAE duration was defined as time from TEAE start to end date (or end of SDP, if TEAE end date was unrecorded). Results LXB-emergent TEAEs varied by treatment at entry. Anticataplectic treatment-naive participants reported TEAEs including headache (n=36/90, 40%; median duration [range]=1 [1–76] day), nausea (n=19/90, 21%; duration=9 [1–37] days), and dizziness (n=15/90, 17%; duration=10 [1–117] days); peak incidence was week 2 (n=8/89, 9%) for headache, week 3 (n=3/88, 3%) for dizziness, and week 1 (n=6/90, 7%) for nausea. Anticataplectic treatment-naive participants (n=13/90, 14%) also reported decreased appetite, with relatively long duration (58 [2–358] days). Participants taking SXB alone reported TEAEs including headache (n=17/52, 33%; duration=1 [1–122] day) and diarrhea (n=4/52, 8%; duration=41 [2–101] days); peak headache incidence was week 4 (n=4/52, 8%); diarrhea had no peak. Participants taking other anticataplectics alone reported TEAEs including headache (n=14/36, 39%; duration=1 [1–94] day), nausea (n=9/36, 25%; duration=3 [1–16] days), and dizziness (n=9/36, 25%; duration=4 [1–29] days); peak incidence was week 1 (n=3/36, 8%) for headache, week 6 (n=2/32, 6%) for nausea, and week 4 (n=3/33, 9%) for dizziness. One participant taking SXB with other anticataplectics (n=1/23, 4%) reported headache in weeks 1–2 and 4; one reported nausea (4%) persisting from week 1 to 8. Overall, study discontinuations attributed to TEAEs were 20/57 (35%). Conclusion Most TEAEs with LXB treatment occurred early, were consistent with the known SXB safety profile, and were relatively short-lived (except decreased appetite). Participants previously taking SXB reported fewer TEAEs than oxybate-naive participants. Support (if any) Jazz Pharmaceuticals, Inc.

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Safety, Pharmacokinetics, and Antiviral Activity of a Novel HIV Antiviral, ABX464, in Treatment-Naive HIV-Infected Subjects in a Phase 2 Randomized, Controlled Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00545-17 ◽

2017 ◽

Vol 61 (7) ◽

Cited By ~ 9

Author(s):

Jean-Marc Steens ◽

Didier Scherrer ◽

Paul Gineste ◽

P. Noel Barrett ◽

Supparatpino Khuanchai ◽

...

Keyword(s):

Adverse Events ◽

Safety Data ◽

Study Drug ◽

Primary Objective ◽

Controlled Study ◽

Double Blind ◽

Antiviral Effects ◽

Randomization Code ◽

Treatment Naïve ◽

Dose Ranging

ABSTRACT We investigated the safety and antiviral effects of an anti-HIV compound (ABX464) with a unique mechanism of viral replication inhibition. This was a randomized, double-blind, placebo-controlled, dose-ranging study in treatment-naive HIV-infected patients. Participants were assigned to eight groups; each group included eight subjects receiving either the study compound, ABX464 (n = 6), or the corresponding placebo (n = 2), according to a randomization code. The first dose administered was 25 mg, given once or 3 times a day over a 2- to 3-week period. Ascending doses of up to 150 mg were delivered after review of the safety data. The primary objective of the study was to assess the safety and tolerability of ABX464 after repeated oral administrations in subjects infected by HIV. Sixty-six subjects were enrolled and were randomized. Sixty-three subjects completed the study according to the study protocol. Twenty-one adverse events (AEs) were reported by 7 subjects out of 16 (44%) who received placebo, and 158 AEs were reported by 39 subjects out of 50 (78%) who received the study drug. In the ABX464 treatment group, all of these adverse events were mild to moderate. No subjects discontinued treatment due to drug-related AEs. Administration of ABX464 at up to 150 mg once a day was safe and well tolerated in HIV-infected subjects. An efficacy signal with respect to a reduction of the viral load by ABX464 was detected, mainly in subjects treated at the highest dose. Further studies will be required to demonstrate antiviral effects in HIV-infected subjects in combination with other antiretroviral therapies. (This study is registered on the ClinicalTrials.gov website under registration no. NCT02452242.)

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Randomized, Double-Blind, Placebo-Controlled, Dose and Schedule-Finding Study of AMG 531 In Chemotherapy-Induced Thrombocytopenia (CIT): Results of a Phase I/II Study.

Blood ◽

10.1182/blood.v116.21.1544.1544 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1544-1544 ◽

Cited By ~ 7

Author(s):

Saroj Vadhan-Raj ◽

Fredrick Hagemeister ◽

Luis E. Fayad ◽

Xiao Zhou ◽

Shana Sherril ORoark ◽

...

Keyword(s):

Study Drug ◽

High Dose Chemotherapy ◽

High Dose ◽

Severe Thrombocytopenia ◽

Open Label ◽

Double Blind ◽

Clinical Safety ◽

Exact Test ◽

Vein Thrombosis ◽

Before And After

Abstract Abstract 1544 AMG 531 is a peptibody that increases platelet production by stimulating thrombopoietin (TPO) receptors. Prior studies (Vadhan-Raj et al, JCO 2003) have shown the importance of schedule of recombinant TPO to overcome thrombocytopenia (TCP) caused by high dose chemotherapy (CT). RHyper-CVAD alternating with RArac-MTX is a highly effective regimen in the treatment of aggressive non-Hodgkin's lymphoma (NHL), including Mantle-cell lymphoma, with severe TCP as dose-limiting toxicity (86% grade 4 TCP in cycle-2). The objectives of this study were to evaluate the clinical safety and preliminary efficacy of AMG 531 in CIT. Cohorts of 12 evaluable patients were enrolled sequentially at each of the 3 dose levels (1, 3, or 10 mcg/kg). Patients at each dose level were randomized 1:1 into Arm A (pre/post dosing) or Arm B (post-dosing only). All pts received CT alone in cycle-1. In cycle-2, all pts received blinded study drug (2:1 AMG 531 or placebo). The study drug was administered SC as 2 doses given on days -5 and 5 (pre and post doses-Arm A), or on days 5 and 7 (only post-chemotherapy doses-Arm B). In subsequent cycles of CT (maximum total 6 cycles), all pts, including placebo group, received open-label AMG 531 by the same schedule. Of the 50 pts enrolled, 41 received at least one dose of AMG 531 and are evaluable for toxicity and 36 received the treatment with the study drug as per protocol and are evaluable for response. Treatment with AMG 531 was generally well tolerated, with some pts experiencing mild to moderate headache, myalgia, bone pain, and thrombocytosis and venous thromboembolism [4 pts; 2 deep vein thrombosis (DVT) and 2 pulmonary embolism (PE); both at 10 mcg/kg]. Four of the 9 pts who did not receive the study drug also experienced DVT (3 pts) or PE (1 pt). The platelet nadir was significantly higher and the duration of TCP was shorter, with a reduced need for the PLT transfusions on Arm A (pre and post-dosing) compared to placebo as shown in the table below. There was reduced TCP on Arm B (post-dosing) as compared to placebo, but not statistically significant. There were also fewer patients with bleeding episodes (all grades) on Arm A vs placebo (1/12 pts vs 6/12 pts, p = 0.07, Fisher's exact test) in the blinded-cycle. Using general-linear model, there was a difference in schedule (p=0.0466) and difference in doses (p=0.0162) on duration of TCP, and the lower doses (1 or 3 mcg/kg) appeared to have a better biologic activity than higher dose (10mcg/kg) as compared to the placebo. Conclusions: AMG 531 was generally well tolerated and significantly reduced severe thrombocytopenia when administered both before and after (pre and post dosing) CT in NHL pts. Future larger studies are needed to establish the safety and efficacy of AMG 531 in CIT. Disclosures: Vadhan-Raj: Amgen: Honoraria, Research Funding. Off Label Use: AMG 531 (Romiplostim) for chemotherapy-induced thrombocytopenia.

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Safety of everolimus (EVE) in Asian patients (pts) with advanced gastric cancer (AGC) enrolled in the phase III GRANITE-1 study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4081 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4081-4081

Author(s):

Kun-Huei Yeh ◽

Eric Van Cutsem ◽

Atsushi Ohtsu ◽

Lin Shen ◽

Jaffer A. Ajani ◽

...

Keyword(s):

Adverse Events ◽

Disease Progression ◽

Mammalian Target Of Rapamycin ◽

Study Drug ◽

Asian Population ◽

Best Supportive Care ◽

Phase Iii ◽

Double Blind ◽

Risk Of Death ◽

Grade 3

4081 Background: Previous subanalyses of the RECORD-1 (Jpn J Clin Oncol 2011;41:17-24) and RADIANT-3 (GICS 2011; abs. 289) studies of the oral mammalian target of rapamycin inhibitor EVE showed that incidences of stomatitis, rash, infections, and pneumonitis were greater in Asian pts; however, the number of Asian pts enrolled was small. GRANITE-1 provides an opportunity to evaluate EVE safety in a broader Asian population. Methods: In the randomized, double-blind, phase 3 GRANITE-1 study, pts aged ≥18 y with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to EVE 10 mg/d + best supportive care (BSC) or placebo + BSC. Randomization was stratified by region (Asia [China, Japan, Korea, Taiwan, Thailand, Hong Kong] vs rest of world [ROW]) and previous lines of chemotherapy (1 vs 2). Study drug was continued until disease progression or unacceptable toxicity. Adverse events (AEs) were collected throughout the study and for 28 d after final dose of study drug and assessed according to the Common Terminology Criteria for Adverse Events, v 3.0. Primary endpoint was overall survival. Safety was a secondary endpoint. Results: Of the 656 pts in the study, 363 (55%) were enrolled in Asia and received EVE (n=243) or placebo (n=120). EVE did not significantly reduce the risk of death in the overall (HR 0.90; 95% CI 0.75-1.08), Asian (HR 0.96; 95% CI 0.75-1.23), or ROW (HR 0.85; 95% CI 0.65-1.10) populations. The most common any-grade AEs among EVE-treated pts (Asia vs ROW) were decreased appetite (45% vs 51%), stomatitis (44% vs 35%), and fatigue (34% vs 35%). Among EVE-treated pts, rates of any-grade rash, infections, and pneumonitis (Asia vs ROW) were 22% vs 18%, 24% vs 28%, and 4% vs 2%, respectively; rates of grade 3/4 stomatitis, rash, infections, and pneumonitis (Asia vs ROW) were 4% vs 6%, 0% vs 0.5%, 6% vs 9%, and 0.4% vs 1%, respectively. No grade 4 pneumonitis was observed. Only 1 pt (from Asia) discontinued due to pneumonitis (grade 3). Conclusions: The safety profile of EVE in Asian pts with AGC was similar to that observed in ROW pts with AGC and with EVE in other cancers. No new safety signals were identified. Pneumonitis was relatively uncommon in Asian and ROW pts.

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