A double-blind, randomized, placebo-controlled study was performed to assess the safety, tolerability, and pharmacokinetics of single oral doses of CHF 3381 in 56 young healthy male volunteers. The central nervous system effects of CHF 3381 were also evaluated, as well as the effect of food on the rate and extent of CHF 3381 absorption. Seven doses of CHF 3381 (25, 50, 100, 200, 300, 450, and 600 mg) were evaluated in an escalating order. At each dose level, 6 subjects were given CHF 3381, and 2 subjects were given placebo. Safety and tolerability evaluation included adverse events, physical examination, vital functions, electrocardiogram, laboratory tests, and 24-hour Holter (100-mg and 450-mg dose panels). Plasma and urinary concentrations of CHF 3381 and its two main metabolites (CHF 3567 and 2-aminoindane) were measured with a validated high-performance liquid chromatography method. Central nervous system effects were evaluated with the simple reaction time (SRT); learning memory task (LMT); Bond & Lader Visual Analog Scale for alertness, contentedness, and calmness; Addiction Research Center Inventory (ARCI); and electroencephalogram. There were no serious adverse events; the most frequent adverse events were dizziness, abnormal thinking, and asthenia. The number of adverse events with moderate intensity increased sharply with the dose, with no or few events up to 450 mg and 17 events with 600 mg. Therefore, 600 mg was defined as the maximum tolerated dose. There were no significant treatment effects on cardiovascular function and electrocardiogram parameters at any CHF 3381 dose or on oral temperature or laboratory tests. There were no clinically significant changes in laboratory variables. CHF 3381 was absorbed rapidly (tmax = 0.5-2 h) and cleared from plasma with a half-life of 3 to 4 hours. Plasma levels of CHF 3381 and its two major metabolites were found to be proportional to the dose. 2-Aminoindane formed slowly and reached much lower concentrations compared to the parent compound and the other metabolite (CHF 3567). Within 48 hours after dosing, 2% to 6% of the administered dose was found in the urine as unchanged drug, about 50% to 55% as the acid derivative (CHF 3567), and 2% to 3% as 2-aminoindane. Ingestion of food did not affect the extent of absorption of the drug, while the rate of absorption was considerably reduced (tmax = 4 h). No significant effects of CHF 3381 were observed on attention (SRT) or memory (LMT). Visual analog scales revealed a decreasing effect of CHF 3381 on alertness at 1 hour that reached statistical significance at 300 and 600 mg. EEG spectral analysis revealed minor decreasing effects of the 200-mg dose on total electric power measured at 2 hours. A stimulant effect was detected by the ARCI scale 24 hours after the 300-mg dose and might be related to the slow formation of the 2-aminoindane metabolite. In conclusion, this study has shown that the maximum tolerated dose of CHF 3381 after single oral administration in young healthy male volunteers is 600 mg. CHF 3381 displ...

What is already known about this subject • CHF 4227 is a selective oestrogen receptor modulator (SERM) that compares favourably in efficacy and potency with raloxifene in preventing bone loss and lowering serum cholesterol concentrations in OVX rats. • The compound prevented the development of DMBA‐induced mammary carcinoma in rats. • In preclinical studies, CHF 4227 differs from oestrogens and from others SERMs, such as levormeloxifene, in its lack of oestrogenic effects on uterine tissue. What this study adds • CHF 4227 is a well‐tolerated SERM for postmenopausal women dosed once daily for 28 days. It appears to effect beneficially bone tissue and serum lipids without inducing oestrogenic actions on the endometrium, negative effects on fibrinolytic system, and without worsening menopausal symptoms, in particular hot flushes. • CHF 4227 is a promising agent for the treatment of several conditions in postmenopausal women. Aims We evaluated the tolerability, adverse events profile, pharmacokinetics, and pharmacodynamics of CHF 4227, a new selective oestrogen receptor modulator (SERM), in healthy postmenopausal women. Methods Two phase I studies were conducted according to a double‐bind, placebo‐controlled design. Subjects were randomized to receive six single (5–400 mg) or five multiple oral doses of CHF 4227 for 28 days (5–100 mg). Results No vaginal bleeding and no changes in either endometrial thickness or the placenta protein 14 marker were found after 4 weeks of treatment. The compound did not induce negative effects on the fibrinolytic system. After 28 days of treatment, CHF 4227 decreased both total and LDL cholesterol concentrations (maximum decreases from baseline of 17.4% (95% CI 7.0, 27.7) and 27.6% (95% CI 9.0, 46.3), respectively). Decreases in both serum and urinary type‐I C‐terminal collagen telopeptide were also observed producing maximum changes of 40.6% (95% CI 29.5, 51.7), and 41.7% (95% CI 20.3, 56.8), respectively. CHF4227 (5 and 10 mg) induced near maximal oestrogen‐like effects on bone markers and serum lipids without causing hot flushes. The pharmacokinetics of CHF 4227 were characterized by a slow absorption, a long elimination half‐life (31–42 h after single administration) and dose linearity with respect to Cmax and AUC up to 100 mg. Conclusions CHF 4227 is a well‐tolerated SERM when administered once daily for 28 days. It is potentially active on bone resorption and serum lipids, without affecting the endometrium and without worsening hot flushes. CHF 4227 is a promising agent for the treatment of several conditions in postmenopausal women.

No abstract

No abstract

Introduction: Commonly accepted standardized sets of outcomes to be measured in clinical trials are still limited. In accordance, outcome measures vary widely between clinical trials even within defined hematological malignancy (HM) entities. Definition of a core outcome set (COS), which represents a standardized agreed set of outcomes that should be measured and reported in all trials for the respective disease of interest may improve this situation. Furthermore, respective COS should address the need of all stakeholders, i.e. not only the views of physicians and industry running the trials, but also the interests of patients and regulators. To perform a task like this, HARMONY - Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms in Hematology - a private-public partnership established in January 2017, including 53 partners and 43 associated partners in 18 different European countries and also 6 patient organizations, poses an optimal platform to define COS for HMs. Methods: To define COS for 5 selected HMs, it was decided to use the Delphi survey method provided by COMET initiative. Since HARMONY has members of several important stakeholder groups (clinicians, industry, health authorities and patient groups) it was decided to include all stakeholders to participate in the Delphi surveys. A pilot study was implemented for the COS for acute myeloid leukemia (AML) based on which additional Delphi surveys were developed for myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and chronic lymphocytic leukemia (CLL). As starting point preliminary outcome lists were generated based on published reports and available guidelines. Surveys were performed with representatives from each stakeholder group to agree within a pre-defined and iterative process on a COS for each HM. Conditions and criteria were defined in study protocols. Each outcome was rated into 3 categories (1-3 "not important", 4-6 "important but not critical" and 7-9 "critical"). A "consensus-in criterion" was defined if 70 % or more respondents scored the outcome as critically important (7-9) and 15% or fewer rated the outcome as limited important (1-3). To make sure that the patients' voice was heard within the consensus process, a special "patient-important criterion" had been implemented during data analysis. Outcomes ranked with a median of 7 or higher in the patient group were highlighted, showing these are really important for patients. According to a bottom-up-approach, an overarching COS was then created based on the individual survey results. Results: For the Delphi surveys a total of 365 individuals participated including 126 clinicians (35%), 46 EFPIA members (13%), 177 patients/patient advocates (48%) and 16 regulators (4%). While there was a large overlap of outcomes among HMs, there were also many disease specific outcomes such as leukemia-free survival (LFS) for AML, very good partial response (VGPR) for MM to name only few. In addition, there were sometimes major differences in the assessment of individual stakeholders within an outcome, e.g. between clinicians and patients. Finally, the general COS applicable to all HMs included core outcomes that met the consensus-in criterion for all HMs. Conclusion: Using Delphi surveys to define specific COS for HMs revealed meaningful results. Based on the bottom-up-approach not only disease specific HM COS could be defined, but also an overarching COS applicable to all HMs. This overarching COS will subsequently not only allow to compare results more easily within a distinct HM subgroup but also results across different HMs. To our knowledge, this is the first multidisciplinary approach to define COS across four different stakeholder groups. These COS should now be a starting point to further refine COS and to apply them within future clinical trials, thereby reducing inconsistencies and bias in outcome-reporting. Results of COS based clinical trials will simplify the development of novel clinical recommendations, which will improve future patient management and clinical patient care in the real-world setting. Figure 1 Figure 1. Disclosures Lang: Roche: Honoraria. Ossenkoppele: Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Döhner: Gilead: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Berlin-Chemie: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Astellas: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Pfizer: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Salles: Genmab: Consultancy; Incyte: Consultancy; Velosbio: Consultancy; Genentech/Roche: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Debiopharm: Consultancy; Allogene: Consultancy; Rapt: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Morphosys: Consultancy, Honoraria; Kite/Gilead: Consultancy; Ipsen: Consultancy; Takeda: Consultancy; Regeneron: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Dreyling: Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Sonneveld: Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Boccadoro: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Fenaux: Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Santini: Gilead: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Guillevic: BMS: Current Employment. Calado: Novartis: Current Employment. Sanz: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Hernández-Rivas: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Barbus: Abbvie: Current Employment. Schulze-Rath: Bayer: Current Employment. Bullinger: Menarini: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Bristol-Myers Squibb / Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Amgen: Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.