scholarly journals Determination of Phase 3 Dose for X4P-001 in Patients with WHIM Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1102-1102
Author(s):  
David C Dale ◽  
Frank Caleb Firkin ◽  
Audrey Anna Bolyard ◽  
Merideth L. Kelley ◽  
Emily Dick ◽  
...  
Keyword(s):  
Viral Infections ◽  
Genetic Disorder ◽  
Primary Objective ◽  
Sampling Point ◽  
Phase 2 ◽  
Infection Rates ◽  
Cxcr4 Antagonist ◽  
Phase 3 ◽  
Whim Syndrome ◽  
Success Criteria

Abstract Background: WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) Syndrome is a serious, ultrarare genetic disorder caused by a gain-of-function mutation in CXCR4 that causes profound neutropenia and lymphopenia associated with increased rates of bacterial and viral infections. Long-term sequelae include hearing loss, bronchiectasis, and HPV-associated malignancies. The cancer risk in WHIM patients is estimated at 30% by age 40. There is currently no treatment that addresses the underlying mechanism of disease. G-CSF increases neutrophil counts but does not appear to reduce infection rates; use of parenteral gamma globulin has had mixed reports of benefit, but no controlled trials have been reported; Plerixafor, a CXCR4 antagonist, has been shown to increase leukocyte counts and reduce infection rates when absolute neutrophil counts (ANC)>600 mm-3 and absolute lymphocyte counts (ALC)>1000 mm-3, but is a parenteral agent that must be administered twice daily. X4P-001 is an orally available, allosteric inhibitor of CXCR4 that is being developed to treat WHIM. We report here the PK/PD data from the Phase 2 portion of Phase 2/3 trial X4P-001 MKKA (NCT03005327) in WHIM patients that led to selection of the dose for Phase 3 development. Methods: Study X4P-001 MKKA is a Phase 2/3 study. The primary objective of Ph2 portion was to assess the dose required to achieve a consistent increase in circulating neutrophils and lymphocytes. Adult patients with WHIM syndrome, with documented WHIM-associated genotype, and either ANC <400 mm-3 and/or ALC<650 mm-3 were treated with escalating doses of X4P-001. After at least 5 weeks on a dose, patients were hospitalized overnight for rich PK sampling. At each sampling point ANC and ALC were also determined. An area under the curve for ANC and ALC was calculated using the trapezoidal rule and normalized to AUCs assuming maintenance of the threshold values of 600 mm-3 for ANC and 1000 mm-3 for ALC over 24hr. Dose escalation was permitted for adjusted AUC value <0 cell/hours/μL. AUC values ≥0 were considered as having met the primary objective for Phase 2. Results: Eight patients were enrolled and were evaluable for efficacy. 6 of 8 were female, and the mean (SD) age was 35.5 (13.37). Two patients started treatment with 50 mg, then received, 100, 150, 300 and 400 mg; 2 started at 100 and then received 200 and 300 mg; 2 started at 200 mg; 1 escalated to 300 and 400 mg while the other terminated after 1 week due to an adverse event (AE). Two started at 300 mg and did not escalate. Doses of at least 300 mg/day were needed to achieve success criteria for ANC, while at doses ≥100 mg/day, 50-100% met success criteria for ALC. (Figure 1) Two patients discontinued: 1 due to an AE of grade 1 rash, and 1 voluntarily withdrew. No serious AEs were reported. One patient had unrelated cholecystitis (grade 3). All other AEs were grade 1 or 2. Conclusions: Treatment of WHIM patients with X4P-001 results in meaningful increases in ANC at doses ≥300 mg, and in ALC at doses ≥100 mg per day for at least 5 weeks. These doses are anticipated to be associated with clinically meaningful outcomes in terms of infections and warts. X4P-001 appeared to be safe and well-tolerated at doses of 50-400 mg per day.4 Disclosures Dale: Athelas, Inc.: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi-Aventi: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; Beheringer-Ingelheim: Consultancy; Coherus: Consultancy. Hartmann:Cetara: Employment; X4P Pharmaceuticals: Consultancy. Brown:Certara: Employment; X4P Pharmaceuticals: Consultancy. Ebrahim:X4Pharmaceuticals: Employment. Gorelick:X4 Pharma: Consultancy; PIN Pharma: Consultancy; Shire: Consultancy; NGN Capital: Consultancy, Other: Venture partner; IntraBio: Consultancy; Zymo Consulting Group LLC: Employment.

Idalopirdin bei Alzheimererkrankung: nicht besser als Plazebo

2018 ◽  
Vol 86 (08) ◽  
pp. 456-457
Keyword(s):  
Phase 2 ◽  
Phase 3 ◽  
Alzheimer Demenz

Die Blockade von Serotoninrezeptoren, insbesondere des Serotonin-Rezeptortyps 5-HT6, als Zusatztherapie in Kombination mit Cholinesterasehemmer, hat in experimentellen Versuchen sowie in einer Phase-2-Studie positive Effekte bei Demenz gezeigt. Im Rahmen eines Phase-3 Entwicklungsprogramms wurde nun die Effektivität des selektiven Serotoninrezeptor-Antagonisten Idalopirdin bei leichter bis mittelschwerer Alzheimer Demenz geprüft.

PENERAPAN MODEL QUANTUM LEARNING UNTUK MENINGKATKAN HASIL BELAJAR AUTOCAD SISWA KELAS X TEKNIK PEMESINAN SMK NEGERI 1 STABAT

2013 ◽  
Vol 5 (1) ◽  
Author(s):  
Abdul Hasan Saragih
Keyword(s):  
Positive Response ◽  
Phase 1 ◽  
First Grade ◽  
Learning Model ◽  
Second Phase ◽  
Phase 2 ◽  
Phase 3 ◽  
The Third ◽  
Third Phase ◽  
Quantum Learning

This classroom research was conducted on the autocad instructions to the first grade of mechinary class of SMK Negeri 1 Stabat aiming at : (1) improving the student’ archievementon autocad instructional to the student of mechinary architecture class of SMK Negeri 1 Stabat, (2) applying Quantum Learning Model to the students of mechinary class of SMK Negeri 1 Stabat, arising the positive response to autocad subject by applying Quantum Learning Model of the students of mechinary class of SMK Negeri 1 Stabat. The result shows that (1) by applying quantum learning model, the students’ achievement improves significantly. The improvement ofthe achievement of the 34 students is very satisfactory; on the first phase, 27 students passed (70.59%), 10 students failed (29.41%). On the second phase 27 students (79.41%) passed and 7 students (20.59%) failed. On the third phase 30 students (88.24%) passed and 4 students (11.76%) failed. The application of quantum learning model in SMK Negeri 1 Stabat proved satisfying. This was visible from the activeness of the students from phase 1 to 3. The activeness average of the students was 74.31% on phase 1,81.35% on phase 2, and 83.63% on phase 3. (3) The application of the quantum learning model on teaching autocad was very positively welcome by the students of mechinary class of SMK Negeri 1 Stabat. On phase 1 the improvement was 81.53% . It improved to 86.15% on phase 3. Therefore, The improvement ofstudent’ response can be categorized good.

The Efficacy and Safety of FMX101, Minocycline Foam 4%, for the Treatment of Acne Vulgaris: A Pooled Analysis of Phase 2 and Phase 3 Studies

2017 ◽  
Vol 1 ◽  
pp. s49
Author(s):  
Linda Stein Gold ◽  
Sunil Dhawan ◽  
Jonathan Weiss ◽  
Zoe D Draelos ◽  
Herman Ellman
Keyword(s):  
Acne Vulgaris ◽  
Pooled Analysis ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Phase 3

Abstract Not Available

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

scholarly journals Tenecteplase Thrombolysis for Acute Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3440-3451
Author(s):  
Steven J. Warach ◽  
Adrienne N. Dula ◽  
Truman J. Milling
Keyword(s):  
Ischemic Stroke ◽  
Intracranial Hemorrhage ◽  
Time Window ◽  
Large Vessel ◽  
Bolus Administration ◽  
Phase 2 ◽  
Qualitative Synthesis ◽  
Phase 3 ◽  
Symptomatic Intracranial Hemorrhage ◽  
Meta Analyses

Tenecteplase is a fibrinolytic drug with higher fibrin specificity and longer half-life than the standard stroke thrombolytic, alteplase, permitting the convenience of single bolus administration. Tenecteplase, at 0.5 mg/kg, has regulatory approval to treat ST-segment–elevation myocardial infarction, for which it has equivalent 30-day mortality and fewer systemic hemorrhages. Investigated as a thrombolytic for ischemic stroke over the past 15 years, tenecteplase is currently being studied in several phase 3 trials. Based on a systematic literature search, we provide a qualitative synthesis of published stroke clinical trials of tenecteplase that (1) performed randomized comparisons with alteplase, (2) compared different doses of tenecteplase, or (3) provided unique quantitative meta-analyses. Four phase 2 and one phase 3 study performed randomized comparisons with alteplase. These and other phase 2 studies compared different tenecteplase doses and effects on early outcomes of recanalization, reperfusion, and substantial neurological improvement, as well as symptomatic intracranial hemorrhage and 3-month disability on the modified Rankin Scale. Although no single trial prospectively demonstrated superiority or noninferiority of tenecteplase on clinical outcome, meta-analyses of these trials (1585 patients randomized) point to tenecteplase superiority in recanalization of large vessel occlusions and noninferiority in disability-free 3-month outcome, without increases in symptomatic intracranial hemorrhage or mortality. Doses of 0.25 and 0.4 mg/kg have been tested, but no advantage of the higher dose has been suggested by the results. Current clinical practice guidelines for stroke include intravenous tenecteplase at either dose as a second-tier option, with the 0.25 mg/kg dose recommended for large vessel occlusions, based on a phase 2 trial that demonstrated superior recanalization and improved 3-month outcome relative to alteplase. Ongoing randomized phase 3 trials may better define the comparative risks and benefits of tenecteplase and alteplase for stroke thrombolysis and answer questions of tenecteplase efficacy in the >4.5-hour time window, in wake-up stroke, and in combination with endovascular thrombectomy.

scholarly journals PSVI-3 Dietary supplementation with coated omega-3 fatty acids has positive effects on growth performance and nutrients digestibility in weaned pigs

2020 ◽  
Vol 98 (Supplement_3) ◽  
pp. 196-197
Author(s):  
Woo Jung Seok ◽  
Je min Ahn ◽  
Jing Hu ◽  
Dexin Dang ◽  
Yanjiao Li ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Growth Performance ◽  
Phase 1 ◽  
Dietary Supplementation ◽  
Basal Diet ◽  
Phase 2 ◽  
Omega 3 ◽  
Phase 3 ◽  
Linear Effect ◽  
Weaning Pigs

Abstract The objective of this study was to evaluate the effects of dietary supplementation of coated omega-3 fatty acid (n-3 CFA) by corn cob power silica on performance of weaning pigs. A total of 200 weaned pigs [(Landrace x Yorkshire) x Duroc, average initial body weight at 6.97 ± 1.22 kg] were randomly assigned to four experimental treatments in a 6-week experiment in 3 phases as follows: CON, basal diet; 2) 0.3CFA, CON + phase 1(0.3% n-3CFA), phase 2(0.2% n-3CFA), phase 3(0.1% n-3CFA); 3) 0.6CFA, CON + phase 1(0.6% n-3CFA), phase 2(0.4% n-3CFA), phase 3(0.2% n-3CFA); 4) 0.9CFA, CON + phase 1(0.9% n-3CFA), phase 2(0.6% n-3CFA), phase 3 (0.3% n-3CFA). Each treatment had 10 replicates with 5 pigs (three gilts and two barrows) per replicate. The data were analyzed using the GLM procedure of SAS as a randomized complete block design. Pen served as the experimental unit. Linear, quadratic and cubic polynomial contrasts were used to examine effect of dietary treatment with coated n-3FA in the basal diet. Variability in the data was expressed as the standard error of means and P&lt; 0.05 was considered to statistically significant. Increasing the level of n-3CFA in the diet linearly increased ADG and G/F of pigs (Table 1). Increasing the level of n-3CFA showed a linear increment in the digestibility of DM (83.59, 84.38, 85.13, 85.89 %) whereas nitrogen digestibility (81.79, 82.38, 82.96, 83.64 %) showed a trend (linear effect, p=0.0594) at the end of experiment. The fecal lactobacillus count was increased (7.22, 7.27, 7.33, 7.35 log10cfu/g) with the increase in the supplemental level of n-3CFA (linear effect; p&lt; 0.05). However, there were no differences in the concentration of serum haptoglobin, or fecal E. coli, Clostridium and Salmonella counts despite the increase in n-3CFA levels in the diet. Supplementation of the diet with coated n-3 fatty acids positively affected growth performance and digestibility of dry matter and nitrogen, and enhanced the count of lactobacillus in weaning pigs.

scholarly journals Dietary Inclusion of Blood Plasma with Yeast (Saccharomyces cerevisiae) Supplementation Enhanced the Growth Performance, Nutrient Digestibility, Lactobacillus Count, and Reduced Gas Emissions in Weaning Pigs

Animals ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 759
Author(s):  
Vetriselvi Sampath ◽  
Dong Heon Baek ◽  
Sureshkumar Shanmugam ◽  
In Ho Kim
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Phase 1 ◽  
Average Daily Gain ◽  
Nutrient Digestibility ◽  
Phase 2 ◽  
Phase 3 ◽  
Yeast Saccharomyces Cerevisiae ◽  
Yeast Phase ◽  
Weaning Pigs ◽  
Daily Gain

This experiment was performed to examine the hypothesis that blood plasma (BP) with yeast (Saccharomyces cerevisiae) supplement in the diet of weaning pigs could provoke the growth performance, nutrient digestibility, fecal microbial, and reduce harmful gas excretion. A total of one hundred and eighty healthy piglets were taken and assigned (complete random blocks) to three dietary treatments as: Phase 1: Treatment (TRT) 1-6% BP; TRT 2-3% BP + 3% yeast; TRT 3-6% yeast. Phase 2: TRT 1-3%; BP., TRT 2-1.5% BP + 1.5% yeast; TRT 3- 3% yeast. Phase 3: TRT 1- Control (CON) (Basal diet); TRT 2- CON; TRT 3- CON for six- weeks. Each treatment had twelve replicates and five (three gilts and two barrows) pigs per pen. Dietary inclusion of BP with yeast supplementation significantly increased the body weight of piglets during phase 2 (p = 0.003) and phase 3 (p = 0.032). In addition, TRT2 group piglets had a significant improvement in average daily gain at the end of each phase and overall (p = 0.047, 0.025, 0.018 and 0.012, respectively). At phase 3, TRT2 group piglets showed a significant improvement on nutrient digestibility of dry matter (p = 0.012) and nitrogen (p = 0.040). The fecal microbiota of TRT2 group piglets showed a tendency to increase the number of Lactobacillus counts at phase 1 (p = 0.07) and phase 2 (p = 0.06) as well as, a significant improvement at phase 3 (p = 0.021). In addition, TRT2 group piglets had trend to decrease NH3 (p = 0.074) and H2S (p = 0.069) during phase 2, and significantly reduced NH3 (p = 0.038) and H2S (p = 0.046) at phase 3. However, the fecal score of piglets remains unaffected during the entire trial. At the end of phase 1 piglets’ IgG (p = 0.008) was significantly increased with the inclusion of BP with yeast supplementation. Based on the positive effects on body weight, average daily gain, nutrient digestibility, Lactobacillus count, and reduced gas emission, we suggest that dietary supplement with BP and yeast in the diet of weaned piglet could serve as an excellent alternative to antibiotics growth promoters.

scholarly journals Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome

2021 ◽  
pp. 1-10
Author(s):  
Glenn M. Chertow ◽  
Gerald B. Appel ◽  
Sharon Andreoli ◽  
Sripal Bangalore ◽  
Geoffrey A. Block ◽  
...  
Keyword(s):  
Kidney Function ◽  
Alport Syndrome ◽  
Genetic Disorder ◽  
Geometric Mean ◽  
Genetic Diagnosis ◽  
Significant Loss ◽  
The European Union ◽  
Phase 3 ◽  
Double Blind ◽  
Histologic Diagnosis

<b><i>Introduction:</i></b> Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (&#x3c;5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. <b><i>Methods:</i></b> The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12–70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30–90 mL/min/1.73 m<sup>2</sup>, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values &#x3e;200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. <b><i>Results:</i></b> A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (<i>n</i> = 77) or placebo (<i>n</i> = 80). The average age at screening was 39.2 years, and 23 (15%) were &#x3c;18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m<sup>2</sup>, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was −4.9 mL/min/1.73 m<sup>2</sup> despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. <b><i>Discussion/Conclusion:</i></b> CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

scholarly journals Evaluating the Potential of Commercial Forest Inventory Data to Report on Forest Carbon Stock and Forest Carbon Stock Changes for REDD+ under the UNFCCC

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Danae Maniatis ◽  
Yadvinder Malhi ◽  
Laurent Saint André ◽  
Danilo Mollicone ◽  
Nicolas Barbier ◽  
...  
Keyword(s):  
Carbon Stock ◽  
Measurement Data ◽  
Forest Carbon ◽  
Phase 2 ◽  
Inventory Data ◽  
Ecological Data ◽  
Phase 3 ◽  
Forest Carbon Stock ◽  
Commercial Logging ◽  
Commercial Forest

In the context of the adoption at the 16th Conference of the Parties in 2010 on the REDD+ mitigation mechanism, it is important to obtain reliable data on the spatiotemporal variation of forest carbon stocks and changes (called Emission Factor, EF). A re-occurring debate in estimating EF for REDD+ is the use of existing field measurement data. We provide an assessment of the use of commercial logging inventory data and ecological data to estimate a conservative EF (REDD+ phase 2) or to report on EF following IPCC Guidance and Guidelines (REDD+ phase 3). The data presented originate from five logging companies dispersed over Gabon, totalling 2,240 plots of 0.3 hectares.We distinguish three Forest Types (FTs) in the dataset based on floristic conditions. Estimated mean aboveground biomass (AGB) in the FTs ranges from 312 to 333 Mg ha−1. A 5% accuracy is reached with the number of plots put in place for the FTs and a low sampling uncertainty obtained (± 10 to 13 Mg ha−1). The data could be used to estimate a conservative EF in REDD+ phase 2 and only partially to report on EF following tier 2 requirements for a phase 3.

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