ACE-536 Increases Hemoglobin in Healthy Postmenopausal Women: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3194-3194
Author(s):  
Kenneth M Attie ◽  
Ingrid E Boyd ◽  
Dawn M Wilson ◽  
Mark J Allison ◽  
Matthew L Sherman
Keyword(s):  
Blood Pressure ◽  
Adverse Events ◽  
Phase 1 ◽  
Vital Signs ◽  
Ineffective Erythropoiesis ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Dose Study ◽  
The Mean ◽  
Dose Levels

Abstract Abstract 3194 Background: ACE-536 is a recombinant fusion protein consisting of a modified form of the extracellular domain of the human activin receptor type IIB (ActRIIB) linked to the human IgG1 Fc domain. ACE-536 acts as a ligand trap for members of the TGF-β superfamily involved in erythropoiesis. ACE-536 promotes late-stage erythrocyte precursor cell differentiation by inhibiting specific TGF-β family ligands. Studies of ACE-536 in wild type animals across several species demonstrated an erythroid response that was rapid in onset, robust, and sustained. ACE-536 was also shown to significantly improve hematologic parameters and correct ineffective erythropoiesis in mouse models of myelodysplastic syndromes (MDS) and β-thalassemia. This study is the first human clinical trial of ACE-536. Methods: This was a single-center, randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability, PK, and PD effects of ACE-536 in healthy, postmenopausal women. Screening and baseline hemoglobin values were to be between 11.0 and 14.5 g/dL. Sequential cohorts of 8 subjects each were randomized to receive either ACE-536 (n=6) or placebo (n=2) administered as SC injections on Day 1 and Day 15. ACE-536 dose levels tested (prior to halting dose escalation per protocol due to positive hemoglobin response) were 0.0625, 0.125 and 0.25 mg/kg. The study included pre-specified individual stopping rules for the Day 15 dose for increases in hemoglobin, changes in blood pressure, or ≥ grade 3 adverse events. From Day 1 through Day 57, subjects were assessed for safety by monitoring adverse events, clinical laboratory tests, ECG, vital signs and physical examination. Longer-term follow up visits occurred on Days 71 and 127. Results: A total of 32 subjects were enrolled. The mean (SD) age was 59.4 (5.8) yr (range: 49–71 yr). All subjects in the first cohort (0.0625 mg/kg or placebo) received both doses of ACE-536; all subjects in the second cohort (0.125 mg/kg or placebo) received only one dose of ACE-536 due to study interruption. This dose level was repeated for the third cohort in which subjects received 2 doses; 1 subject in that cohort did not receive the second dose due to elevated blood pressure. Four subjects in the fourth cohort (0.25 mg/kg or placebo) did not receive the second dose due to hemoglobin increase ≥ 1.0 g/dL and one additional subject did not receive the second dose due to an AE of papular rash. There were no serious adverse events or study discontinuations reported. The majority of AEs were considered mild in severity. No clinically meaningful abnormalities in laboratory measures, vital signs, physical exam, or ECG were observed, and no anti-drug antibodies were detected. The mean serum ACE-536 Cmax and AUC after the first dose increased in a dose-proportional manner, with mean time to Cmax 7.7–11.7 days and mean elimination T½ 15.5–18.5 days. The maximum hemoglobin increase from baseline at any timepoint for subjects in the 0.25 mg/kg cohort ranged from 0.6 to 2.0 g/dL (5 of 6 subjects increased ≥1.1 g/dL), with a mean maximum increase of 1.3 g/dL (p<0.001 vs placebo). Mean hemoglobin levels increased in that dose group by at least 0.6 g/dL from Day 8 through Day 57, compared with a mean decrease in the placebo group of up to 0.6 g/dL through Day 43 (see Figure). Small increases in mean reticulocyte count and EPO levels were seen in groups treated with higher doses of ACE-536 as compared with the placebo group. Conclusions: The preliminary results from this first-in-human phase 1 study show that ACE-536 is associated with a robust and sustained increase in hemoglobin levels in healthy subjects. Dose levels up to 0.25 mg/kg were generally safe and well-tolerated. The PK results support SC dosing of ACE-536 every 3 weeks. These data warrant further evaluation of ACE-536 in clinical trials in patients with disease-associated ineffective erythropoiesis and anemia, such as MDS and β-thalassemia. Disclosures: Attie: Acceleron Pharma, Inc.: Employment. Boyd:Acceleron Pharma, Inc.: Employment. Wilson:Acceleron Pharma, Inc.: Employment. Sherman:Acceleron Pharma, Inc.: Employment.

scholarly journals A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Jeremy J. Lim ◽  
Michael A. Derby ◽  
Yaping Zhang ◽  
Rong Deng ◽  
Richard Larouche ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Influenza B Virus ◽  
Influenza B ◽  
Double Blind ◽  
Double Blind Placebo ◽  
B Virus ◽  
Dose Study ◽  
Single Ascending Dose Study ◽  
Dose Proportional

ABSTRACT Influenza B can cause significant morbidity and mortality. MHAB5553A, a human monoclonal immunoglobulin G1 (IgG1) antibody that binds to a highly conserved region of the hemagglutinin protein of influenza B virus, is being examined as a novel therapeutic for the treatment of influenza B patients with severe disease. This phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A. Twenty-six healthy male and female volunteers of >18 years of age were randomized into five cohorts receiving a single intravenous (i.v.) dose of 120, 1,200, 3,600, 8,400, or 10,800 mg MHAB5553A or placebo (four active:one placebo, except for the 120-mg cohort [4:2]). Subjects were followed for 120 days after dosing. No subject discontinued the study, no dose-limiting adverse events or serious adverse events were reported, and a maximum tolerated dose (MTD) was not defined. The most commonly reported adverse events were cold symptoms and headache; most were mild and occurred at a similar rate across all cohorts. MHAB5553A showed no relevant time- or dose-related changes in laboratory values or vital signs compared to the placebo. The observed serum PK was linear and generally dose proportional, and the observed nasal PK was nonlinear and generally non-dose proportional. MHAB5553A is generally well tolerated in healthy volunteers up to at least a single i.v. dose of 10,800 mg and demonstrated linear serum PK consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (This study has been registered at ClinicalTrials.gov under registration no. NCT02528903.)

scholarly journals 1371. Safety, Tolerability, and Pharmacokinetics of Multiple Doses of TP-6076, a Novel, Fully Synthetic Tetracycline, in a Phase 1 Study

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S420-S420 ◽  
Author(s):  
Larry Tsai ◽  
Alison Moore
Keyword(s):  
Physical Examination ◽  
Bacterial Infections ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Geometric Mean ◽  
Vital Signs ◽  
Gastrointestinal Adverse Event ◽  
Double Blind ◽  
Dose Study

Abstract Background TP-6076 is a novel, fully synthetic tetracycline being developed for the treatment of serious bacterial infections, including those caused by multidrug-resistant Acinetobacter baumannii. TP-6076 has demonstrated potent activity in vitro against carbapenem-resistant strains of A. baumannii, with MIC90 64 times lower compared with tigecycline and 256 times lower compared with minocycline. We now report the results of a multiple ascending dose study in normal healthy volunteers. Methods This was a phase 1, single-site, randomized, double-blind, placebo-controlled dose-escalating, multiple dose study in healthy adults who met the inclusion/exclusion criteria and provided informed consent prior to any study procedure. Cohorts of eight subjects each (six active and two placebo) received daily doses of 6.0 to 40.0 mg TP-6076 or placebo for 7 days. Plasma and urine samples for pharmacokinetic (PK) analyses were collected starting immediately prior to dosing until 96 hours after the last dose. Safety was assessed through collection of adverse events (AEs), clinical laboratories, vital signs, ECG, and physical examination data. Results The geometric mean derived PK parameters for TP-6076 were: There were no serious or severe AEs reported. The most frequently reported AEs were gastrointestinal events, including nausea and vomiting, and localized infusion site reactions. There were no clinically significant changes in clinical laboratory values, ECG parameters, or physical examination findings. Conclusion Following multiple IV doses of TP-6076, plasma exposure increased as dose increased. Multiple IV doses of TP-6076 were generally well tolerated, with higher gastrointestinal adverse event rates in the higher dose groups. Disclosures L. Tsai, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary. A. Moore, Tetraphase Pharmaceuticals: Employee, Salary.

scholarly journals Phase 1/2 Double-Blind, Placebo-Controlled, Dose Escalation, Safety, and Pharmacokinetic Study of Pagibaximab (BSYX-A110), an Antistaphylococcal Monoclonal Antibody for the Prevention of Staphylococcal Bloodstream Infections, in Very-Low-Birth-Weight Neonates

2009 ◽  
Vol 53 (7) ◽  
pp. 2879-2886 ◽  
Author(s):  
Leonard E. Weisman ◽  
Helen M. Thackray ◽  
Joseph A. Garcia-Prats ◽  
Mirjana Nesin ◽  
Joseph H. Schneider ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Birth Weight ◽  
High Risk ◽  
Adverse Events ◽  
Dose Escalation ◽  
Very Low Birth Weight ◽  
Phase 1 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Vlbw Infants

ABSTRACT Staphylococcal sepsis is a major cause of morbidity and mortality in very-low-birth-weight (VLBW) infants. A human chimeric monoclonal antibody, pagibaximab, was developed against staphylococcal lipoteichoic acid. We evaluated the safety, tolerability, and pharmacokinetics of pagibaximab in VLBW neonates. A phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study was conducted in VLBW infants (700 to 1,300 g) 3 to 7 days old. Patients received two doses 14 days apart of intravenous pagibaximab (10, 30, 60, or 90 mg/kg of body weight) or placebo in a 2:1 ratio. Blood and urine samples were obtained pre- and postinfusion for analysis of safety and pharmacokinetics, and data on adverse events were gathered. Staphylococcal organisms causing sepsis were collected and evaluated. Fifty-three patients received at least one dose of pagibaximab or placebo. The average gestational age was 27.6 weeks; the average birth weight was 1,003 g. All serious adverse events were deemed unrelated or probably not drug related. Morbidity and mortality were similar across treatment groups. No evidence of immunogenicity of pagibaximab was detected. Pagibaximab pharmacokinetics was linear. The mean clearance (CL), volume of distribution, and elimination half-life of pagibaximab were independent of dose. The serum half-life was 20.5 ± 6.8 days. Pagibaximab enhanced serum opsonophagocytic activity. All staphylococci causing sepsis were opsonizable by pagibaximab. Two infusions of pagibaximab, administered 2 weeks apart to high-risk neonates appeared safe and tolerable, and pharmacokinetics were linear. Evaluation of more frequent doses, at the highest doses tested, in neonates at high-risk of staphylococcal sepsis, is warranted.

scholarly journals Efficacy of two siddha polyherbal decoctions, Nilavembu Kudineer and Kaba Sura Kudineer, along with standard allopathy treatment in the management of mild to moderate symptomatic COVID-19 patients—a double-blind, placebo-controlled, clinical trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Anurag Srivastava ◽  
Manickavasagam Rengaraju ◽  
Saurabh Srivastava ◽  
Vimal Narayanan ◽  
Vivek Gupta ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Placebo Group ◽  
Viral Load ◽  
Adverse Events ◽  
Hospital Stay ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Function Test ◽  
Stay Time ◽  
The Mean

Abstract Background and aim Globally, the ongoing pursuit in exploring an effective drug to combat severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has not met with significant success to date. Indian traditional medicines, especially polyherbal formulations like Nilavembu Kudineer (NVK) and Kaba Sura Kudineer (KSK) of the Siddha system of medicine, have been used as public health interventions for controlling viral epidemics like dengue and Chikungunya. These traditional therapies have been found safe, effective, and widely accepted. The current study evaluates the comparative efficacy of NVK and KSK as opposed to the placebo, in the management of mild to moderate COVID-19 disease. Methods The study was a double-blind, placebo-controlled comparative clinical trial, with the primary objective of determining the efficacy of KSK and NVK. Patients (n=125) diagnosed with mild to moderate COVID-19 symptoms were enrolled in the study over a period of 4 months (Aug 2020—Dec 2020). Participants were randomized into 3 arms; placebo-decaffeinated tea in Arm I, NVK in Arm II, and KSK in Arm III. Each arm received 60 ml of the respective treatment twice a day, post morning and evening meals, along with standard allopathy treatment for a maximum of 10 days. The main outcome measures of the study were the reduction in SARS-CoV-2 viral load, hospital stay, and time taken by the patients to become asymptomatic from symptomatic. Efficacy assessments included clinical symptoms (fever, cough, and breathlessness) each day and real-time reverse transcription-polymerase chain reaction (RT-PCR), liver function test (LFT), renal function test (RFT), and electrolytes and electrocardiogram (ECG) at baseline (day 0) and days 3, 6, and 10. Post-treatment, participants were followed up for 30 days via phone for adverse effects if any. Effects of drugs on inflammatory markers (IL6) at the end of treatment were also recorded. Adverse events (AE) were monitored throughout the study. Results The results revealed that when compared to patients in the placebo arm, those in NVK and KSK arms showed a statistically significant reduction in hospital stay time, reduction in viral load of SARS-CoV-2, and the time taken to become symptomatic from asymptomatic. Out of 125 COVID-19 patients recruited, 120 completed the study; two from the placebo group developed severe symptoms and were shifted to the intensive care unit (ICU) and three patients from Arms II and III withdrew from the study. The mean age of females (n=60) and males (n=60) enrolled was between 40.2 and 44.3 years, respectively. Results were more promising for all the patients in NVK and KSK arms as all enrolled participants (100%) under this group got discharged by day 6 as compared to only 42.5% (n=17) from the placebo group on that day. The hospital stay time for patients in Arm I was significantly longer (mean [SD]=8.4 [2.0] days) as compared to the Arms II and III (mean [SD]=4.7 [1.5] and 4.2 [1.5] days, respectively (Kruskal-Wallis test, P=0.0001). Patients in the three groups took a significantly different number of days to become asymptomatic. While Arm II and III patients took mean of 2.5 and 1.7 days, respectively, Arm I, patients took a mean of 4.2 days (Kruskal-Wallis test, P=0.0001). In all, two adverse events were recorded, one for vomiting and one for diarrhea lasting a day in Arm I and Arm II, respectively. The mean value of interleukin-6 (IL6) was significantly different in comparison to the placebo-decaffeinated tea arm (NVK=2.6 and KSK=2.2, placebo=4.0, P=0.02). The other blood biochemical parameters like C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, and D-dimer that were analyzed at the baseline and at the time of discharge from the hospital, were not significantly different in the three arms. Conclusion NVK and KSK arms showed a statistically significant reduction in hospital stay time, reduction in viral load of SARS-CoV-2, and time taken for patients to become asymptomatic from symptomatic, when compared to the placebo (decaffeinated tea). The primary outcome measures of the KSK arm were significantly better than those in the NVK arm.

scholarly journals 1099. Evaluation of the Safety and Pharmacokinetics (PK) following Administration of Single and Multiple Doses of Anti-Staphylococcal Lysin, LSVT-1701, in Healthy Adult Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S641-S641
Author(s):  
Mary Beth Wire ◽  
Soo youn Jun ◽  
In-Jin Jany ◽  
Jun Gi Hwang ◽  
David Huang
Keyword(s):  
Single Dose ◽  
Healthy Adult ◽  
Phase 1 ◽  
Vital Signs ◽  
Time Data ◽  
Serum Samples ◽  
Double Blind ◽  
Dose Study ◽  
Clinically Significant ◽  
New Treatments

Abstract Background LSVT-1701 is an anti-staphylococcal phage lysin being developed for treatment of MRSA infections in combination with SoC antibiotics. The safety and PK of single ascending doses of LSVT-1701 0.1 to 10 mg/kg in healthy adult volunteers were previously described (Jun, et.al, AAC 2017;61:e02629-16). We further evaluated the safety and PK of multiple ascending doses of LSVT-1701 in healthy adult subjects. Methods Study ITB-101-1b was a Phase 1, randomized, double-blind, placebo-controlled, multiple ascending dose study. 8 subjects were randomized 3:1 to active:placebo in each cohort. LSVT-1701 was administered as a 6 mg/kg single dose and twice daily (BID) doses of 1.5, 3.0, and 4.5 mg/kg for 4 days (24h between Doses 1-2, 12h between Doses 2-6). Study drugs were administered as a 1-hour IV infusion. Serial serum samples were collected over 24 hours following the first and last doses for measurement of LSVT-1701 concentrations by a validated ELISA method. PK analysis of LSVT-1701 concentration-time data was done using noncompartmental methods. Safety was assessed by AEs, clinical labs, vital signs, and ECG. Results 30/32 (94%) subjects completed the study. No subjects withdrew due to AEs, and there were no severe AEs, no serious AEs, and no deaths. AEs were of mild (97%) to moderate (3%) intensity and were reported by all subjects in the LSVT-1701 6 mg/kg single dose group and 1-3 (17-50%) of subjects receiving 1.5 to 4.5 mg/kg BID or placebo. The most common AEs of headache, chills, rigors, and fever generally lasted for ≤2 days with or without acetaminophen treatment, and no clinically significant changes in blood pressure, heart rate, ECG, or clinical labs (other than transient increases in CRP) were observed. Infusion site reactions (erythema, pain, induration, warmth) were observed with BID administration of LSVT-1701, but not with the single 6 mg/kg dose or placebo. LSVT-1701 exposure increased greater than in proportion to dose and t1/2 was concentration-dependent, increasing with higher doses. No accumulation in LSVT-1701 exposure was observed. Summary of LSVT-1701 PK Parameters Summary of LSVT-1701 PK Parameters Conclusion The safety and PK profile of LSVT-1701 is favorable for evaluation in patients with S. aureus infections, including bacteremia and infective endocarditis, for which new treatments are needed. Disclosures Mary Beth Wire, Pharm#, Lysovant (Consultant) Soo youn Jun, PhD, iNtRON Biotechnology (Consultant) In-Jin Jany, PhD, iNtRON (Consultant) Jun Gi Hwang, PhD, Lysovant (Consultant) David Huang, MD, PhD, Lysovant (Consultant)

scholarly journals Randomized, double-blind, placebo-controlled phase I dose escalation study of Dan Qi Tong Mai tablet in healthy volunteers

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhong-ping Gou ◽  
Wei Zhang ◽  
Xiu-fang Liang ◽  
Ying Wang ◽  
Ju-hong Mou ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Healthy Volunteers ◽  
Dose Escalation ◽  
Salvia Miltiorrhiza ◽  
Vital Signs ◽  
Active Ingredients ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Dose Study

Abstract Background This study aims to assess the tolerability and safety of DQTM tablet, which contains a complex mixture of Salvia miltiorrhiza salvianolic acids and Panax notoginseng saponins. Methods A double-blind, randomized, placebo-controlled phase I dose escalation study was conducted in 84 healthy volunteers. In a single ascending dose study, active ingredients were administered in various doses (90, 270, 540, 1080, 1800, 2880, 4320 or 5760 mg) to 60 subjects in cohorts 1–8. In a multiple ascending dose study, active ingredients were administered at doses of 360, 720 or 2160 mg twice daily to 24 subjects in cohorts 9–11 for 14 consecutive days. Safety was evaluated based on clinical symptoms, vital signs, physical examinations, electrocardiography, laboratory tests and adverse events. Results No serious adverse events or clinically significant changes in vital signs or electrocardiography were observed. One subject experienced mildly elevated levels of alanine aminotransferase and aspartate transaminase but recovered spontaneously. Five subjects experienced a small increase in the number of daily stools. Conclusions DQTM tablet was well tolerated at single doses of up to 5760 mg and twice-daily doses of up to 2160 mg for 14 consecutive days. The most frequent adverse event was an increase in the number of daily stools.

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