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PURPOSE: Stereotactic body radiotherapy (SBRT) boost is a promising treatment for cervical cancer patients who are ineligible for intracavitary brachytherapy (ICBT). The aim of this multicenter, single-arm, phase I/II study was to prospectively evaluate the efficacy and toxicity of SBRT boost. MATERIALS AND METHODS: ICBT-ineligible patients with untreated cervical cancer were enrolled. Patients underwent whole-pelvic radiotherapy (45 Gy in 25 fractions) with SBRT boost to the primary lesion. In the phase I dose-escalation cohort (3 + 3 design), patients were treated with SBRT boost of 21 or 22.5 Gy in three fractions. Although dose-limiting toxicity was not confirmed, a dose of 21 Gy was selected for the phase II cohort because it was difficult to reproduce the pelvic organs position in two patients during the phase I trial. The primary endpoint was 2-year progression-free survival. RESULTS: Twenty-one patients (phase I, n = 3; phase II, n = 18) were enrolled between April 2016 and October 2020; 17 (81%) had clinical stage III-IV (with para-aortic lymph node metastases) disease. The median (range) follow-up was 40 (10-84) months. The initial response was complete response in 20 patients and partial response in one patient. The 2-year locoregional control, progression-free survival, and overall survival rates were 84%, 67%, and 81%, respectively. Grade ≥ 3 toxicity was confirmed in one patient each in the acute (diarrhea) and late (urinary tract obstruction) phases. CONCLUSION: These findings suggested that a SBRT boost is more effective than the conventional EBRT boost and can be an important treatment option for ICBT-ineligible patients with cervical cancer. STUDY REGISTRATION: This study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN000036845).
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Braquiterapia , Radiocirugia , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/radioterapia , Radiocirugia/métodos , Anciano , Persona de Mediana Edad , Braquiterapia/métodos , Estudios Prospectivos , Anciano de 80 o más Años , Dosificación Radioterapéutica , Adulto , Resultado del TratamientoRESUMEN
AIM: This Phase I study evaluated the safety and early efficacy of an aldosterone synthase inhibitor (BI 690517) in people with diabetes and albuminuric chronic kidney disease. METHODS: Double-blind, placebo-controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once-daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25-50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug-related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR. RESULTS: Fifty-eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug-related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo. CONCLUSIONS: BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease.
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Albuminuria , Insuficiencia Renal Crónica , Humanos , Método Doble Ciego , Masculino , Femenino , Persona de Mediana Edad , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Albuminuria/tratamiento farmacológico , Anciano , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Adulto , Resultado del Tratamiento , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Eplerenona/uso terapéutico , Eplerenona/efectos adversos , Nefropatías Diabéticas/tratamiento farmacológico , Tasa de Filtración Glomerular/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicacionesRESUMEN
AIMS: To investigate the pharmacokinetic/pharmacodynamic properties of once-weekly insulin icodec in individuals with type 1 diabetes (T1D). MATERIALS AND METHODS: In this randomized, open-label, two-period crossover trial, 66 individuals with T1D (age 18-64 years; glycated haemoglobin ≤75 mmol/mol [≤ 9%]) were to receive once-weekly icodec (8 weeks) and once-daily insulin glargine U100 (2 weeks) at individualized fixed equimolar total weekly doses established during up to 10 weeks' run-in with glargine U100 titrated to pre-breakfast plasma glucose (PG) of 4.4-7.2 mmol/L (80-130 mg/dL). Insulin aspart was used as bolus insulin. Blood sampling for icodec pharmacokinetics was performed from the first icodec dose until 35 days after the last dose. The glucose infusion rate at steady state was assessed in glucose clamps (target 6.7 mmol/L [120 mg/dL]) at 16-52 h and 138-168 h after the last icodec dose and 0-24 h after the last glargine U100 dose. Icodec pharmacodynamics during 1 week were predicted by pharmacokinetic-pharmacodynamic modelling. Hypoglycaemia was recorded during the treatment periods based on self-measured PG. RESULTS: Icodec reached pharmacokinetic steady state on average within 2-3 weeks. At steady state, model-predicted daily proportions of glucose infusion rate during the 1-week dosing interval were 14.3%, 19.6%, 18.3%, 15.7%, 13.1%, 10.6% and 8.4%, respectively. Rates and duration of Level 2 hypoglycaemic episodes (PG <3.0 mmol/L [54 mg/dL]) were 32.8 versus 23.9 episodes per participant-year of exposure and 33 ± 25 versus 30 ± 18 min (mean ± SD) for icodec versus glargine U100. CONCLUSIONS: The pharmacokinetic/pharmacodynamic properties of icodec suggest its potential to provide basal coverage in a basal-bolus insulin regimen in people with T1D.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Hipoglucemia , Insulina de Acción Prolongada , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Insulina Glargina/efectos adversos , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Hipoglucemia/tratamiento farmacológico , Glucemia , Glucosa/uso terapéuticoRESUMEN
AIM: To assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of CPL207280, a new G-protein-coupled receptor 40 agonist developed to treat type 2 diabetes (T2D). METHODS: The phase 1 study in healthy volunteers (White, age 18-55 years, body mass index 18.5-29.9 kg/m2 ) was performed after single (24 subjects, 5-480 mg) and multiple (32 subjects, 60-480 mg) once-daily administration of CPL207280. The effect of food intake and interaction with metformin were evaluated in additional cohort (12 subjects, 120 mg). The primary objective was the safety and tolerability of CPL207280. Secondary objectives included PK and pharmacodynamic (PD) characteristics (glucose, insulin, C-peptide, proinsulin, glucagon levels) observed during the 14-day treatment period. RESULTS: No deaths or serious adverse events (AEs) were reported. All reported AEs were classified as unrelated to the study product. No clinically significant differences in safety parameters were observed between cohorts and no food or metformin effect on safety parameters was identified. The ascending dose of CPL207280 caused an increase in the PK parameters maximum observed plasma concentration (Cmax ) or area under the plasma concentration-time curve up to 24 h. However, dose-normalized Cmax decreased with ascending dose. There was no relationship between the CPL207280 dose or prandial state and terminal elimination half-life and terminal elimination rate constant. No clear relationship between CPL207280 dose and PD area under the effect curve values was observed. CONCLUSIONS: CPL207280 was found to be safe and well tolerated by healthy volunteers (with a low risk of hepatotoxicity) for up to 14 days of administration. The PK profile of CPL207280 supports single-daily administration and justifies further development of this therapy for patients with T2D.
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Caproatos , Diabetes Mellitus Tipo 2 , Metformina , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Ácidos Grasos no Esterificados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Voluntarios Sanos , Área Bajo la Curva , Metformina/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble CiegoRESUMEN
AIMS: To test, for the first time in latent autoimmune diabetes in adults (LADA), the effects of autoantigen-specific immunotherapy by intralymphatic administration of aluminium-formulated recombinant human glutamic acid decarboxylase 65 (GAD-alum); specifically, to test if this treatment is safe, to test whether it induces a strong immunological response akin to a similar protocol in type 1 diabetes and to look for associations with preserved beta-cell function. MATERIALS AND METHODS: Three GAD-alum injections, 4 µg each, were administered 1 month apart into an inguinal lymph node in 14 people with newly diagnosed LADA (age 30-62 years) presenting with high levels of antibodies against glutamic acid decarboxylase (GADA). Adverse effects, immunological variables and beta-cell function were monitored, with detailed measurements at 5 and 12 months from baseline. RESULTS: Clinical adverse effects were minor and transient and measured laboratory variables were unaffected. All participants completed the study. Treatment raised levels of GADA, elicited strong effects on reactivity of peripheral blood mononuclear cells to GAD and raised cytokine/chemokine levels. Beta-cell function appeared stable preferentially in the seven participants carrying human leukocyte antigen (HLA) haplotypes DR3DQ2, as assessed by C-peptide glucagon tests (P < 0.05 vs. seven non-carriers). CONCLUSION: Intralymphatic treatment with GAD-alum in LADA is without clinical or other safety concerns over a 12-month period. As in a similar protocol used in type 1 diabetes, treatment exerts a strong immunological impact and is compatible with protection of beta-cell function preferentially in HLA-DR3DQ2 LADA patients. These findings pave the way for a randomized controlled trial in this important subgroup of LADA patients.
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Diabetes Mellitus Tipo 1 , Intolerancia a la Glucosa , Glutamato Descarboxilasa , Diabetes Autoinmune Latente del Adulto , Adulto , Humanos , Persona de Mediana Edad , Autoanticuerpos , Diabetes Mellitus Tipo 1/terapia , Intolerancia a la Glucosa/tratamiento farmacológico , Glutamato Descarboxilasa/efectos adversos , Glutamato Descarboxilasa/uso terapéutico , Inyecciones Intralinfáticas , Diabetes Autoinmune Latente del Adulto/tratamiento farmacológico , Leucocitos Mononucleares , Proyectos PilotoRESUMEN
AIM: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA) in healthy participants. MATERIALS AND METHODS: This was a double-blind, placebo-controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 40 kg/m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single-dose orforglipron, with four cohorts receiving escalating doses (0.3-6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2-24 mg). RESULTS: Ninety-two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract-related. Pharmacokinetics were approximately dose proportional, and the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3-6 mg). On Day 28, the mean t1/2 was 48.1 to 67.5 hours across the dose range (2-24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron-treated participants, compared to a reduction of 2.4 kg with placebo (P < 0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28. CONCLUSIONS: Orforglipron's long half-life (25-68 hours) allows once-daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP-1RAs, which supports continued clinical development.
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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Adulto , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/uso terapéutico , Voluntarios Sanos , Glucemia , Método Doble CiegoRESUMEN
AIM: To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: This was a double-blind, placebo-controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel-arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12 weeks. Eligible participants with T2D were aged 18 to 70 years and had glycated haemoglobin (HbA1c) levels ≥53.0 mmol/mol (7.0%) and ≤91.3 mmol/mol (10.5%). RESULTS: A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4 kg. The most common adverse events were gastrointestinal-related, and occurred early in treatment, similar to findings with other GLP-1RAs. At Week 12, mean t1/2 ranged from 29 to 49 hours. Mean HbA1c change ranged from -1.5% to -1.8% across orforglipron doses, versus -0.4% with placebo, and body weight change was -0.24 to -5.8 kg across orforglipron doses, versus 0.5 kg with placebo. CONCLUSIONS: Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP-1RAs. Orforglipron may provide a safe and effective once-daily oral treatment alternative to injectable GLP-1RAs or peptide oral formulations without water and food restrictions.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inducido químicamente , Hipoglucemiantes/efectos adversos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hemoglobina Glucada , Péptidos/efectos adversos , Peso Corporal , Péptidos Similares al Glucagón/uso terapéutico , Método Doble Ciego , Resultado del TratamientoRESUMEN
AIMS: Albuminuria is associated with abnormalities in the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate pathway. We assessed safety and efficacy of the NO-independent sGC activator BI 685509 in patients with diabetic kidney disease and albuminuria. MATERIALS AND METHODS: In this Phase Ib trial (NCT03165227), we randomized patients with type 1 or 2 diabetes, estimated glomerular filtration rate (eGFR) 20-75 mL/min/1.73 m2 and urinary albumin:creatinine ratio (UACR) 200-3500 mg/g to oral BI 685509 (1 mg three times daily, n = 20; 3 mg once daily, n = 19; 3 mg three times daily, n = 20, after final titration) or placebo (n = 15) for 28 days. Changes from baseline in UACR in first morning void (UACRFMV ) and 10-hour (UACR10h ) urine (3 mg once daily/three times daily only) were assessed. RESULTS: Baseline median eGFR and UACR were 47.0 mL/min/1.73 m2 and 641.5 mg/g, respectively. Twelve patients had drug-related adverse events (AEs; 16.2%: BI 685509, n = 9; placebo, n = 3), most frequently hypotension (4.1%: BI 685509, n = 2; placebo, n = 1) and diarrhoea (2.7%: BI 685509, n = 2; placebo, n = 0). Four patients experienced AEs leading to study discontinuation (5.4%: BI 685509, n = 3; placebo, n = 1). Placebo-corrected mean UACRFMV decreased from baseline in the 3-mg once-daily (28.8%, P = 0.23) and three-times-daily groups (10.2%, P = 0.71) and increased in the 1-mg three-times-daily group (6.6%, P = 0.82); changes were not significant. UACR10h decreased by 35.3% (3 mg once daily, P = 0.34) and 56.7% (3 mg three times daily, P = 0.09); ≥50.0% of patients (UACR10h 3 mg once daily/three times daily) responded (≥20% UACR decrease from baseline). CONCLUSIONS: BI 685509 was generally well tolerated. Effects on UACR lowering merit further investigation.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Humanos , Guanilil Ciclasa Soluble/farmacología , Guanilil Ciclasa Soluble/uso terapéutico , Albuminuria/tratamiento farmacológico , Albuminuria/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Tasa de Filtración Glomerular , Método Doble CiegoRESUMEN
AIM: Pramlintide improves postprandial glucose but requires additional injections. We investigated the pharmacokinetics/pharmacodynamics, efficacy and safety of ADO09, pramlintide/insulin A21G co-formulation, in type 1 diabetes (T1D). MATERIALS AND METHODS: This double-blinded, randomized, two-period cross-over study compared prandial administration of ADO09 or insulin aspart over 24 days in T1D using either ≤40 U bolus insulin per day [low-dose group (LD), n = 28] or 40-75 U [high-dose group (HD), n = 16]. Glycaemic responses through continuous glucose monitoring, and pharmacokinetics/pharmacodynamics profiles following mixed-meal-tolerance tests were evaluated at baseline and at the end of treatment. RESULTS: Glucose increments from 0 to 4 h after mixed-meal-tolerance test (primary endpoint) were 39% (not statistically significantly) lower with ADO09 in the low-dose group and 69% lower in the high-dose group. Mean continuous glucose monitoring glucose during ambulatory treatment was lower with ADO09 than with aspart (LD: -8.2 ± 7.9 mg/dl, p = .0001; HD: -7.0 ± 10 mg/ml, p = .0127), and time-in-range (70-180 mg/dl) improved (LD: +4%, p = .0134; HD: +4%, p = .0432). Body weight declined significantly with ADO09 (LD: -0.8 kg; HD: -1.6 kg). Hypoglycaemic events were slightly more frequent with ADO09 versus aspart (LD: 142 vs. 115; HD: 96 vs. 79). Gastrointestinal events occurred more frequently with ADO09 but were generally transient, and no other safety signals were identified. CONCLUSIONS: In comparison with aspart, ADO09 was well tolerated and effective in T1D across a wide range of dosage, significantly improving the average blood glucose level and body weight during 24 days of ambulatory treatment. Meal test profiles confirmed improvement of glycaemic patterns and other responses with ADO09.
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Diabetes Mellitus Tipo 1 , Insulina , Adulto , Humanos , Insulina/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Insulina Aspart/efectos adversos , Glucosa/uso terapéutico , Automonitorización de la Glucosa Sanguínea , Estudios Cruzados , Glucemia , Hipoglucemiantes/efectos adversos , Insulina Regular Humana/uso terapéutico , Peso Corporal , Periodo PosprandialRESUMEN
AIMS: To study the oral 11 beta-hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibitor BI 187004 (NCT02150824), as monotherapy and in combination with metformin, versus placebo in patients with type 2 diabetes mellitus (T2DM) affected by overweight or obesity. MATERIALS AND METHODS: This Phase II, randomized controlled trial investigated multiple rising doses of BI 187004 as monotherapy (Arm 1: 20, 80 or 240 mg) and in combination with metformin (Arm 2: 240 mg), in adults with T2DM and a body mass index of 28-40 kg/m2 . RESULTS: In total, 103 patients (Arm 1: n = 62, Arm 2: n = 41) were included in this study. BI 187004 was rapidly absorbed and exposure increased approximately dose-dependently. Target engagement of 11ß-HSD1 was observed with near-full inhibition of 11ß-HSD1 in the liver [decreased (5α-tetrahydrocortisol + 5ß-tetrahydrocortisol)/tetrahydrocortisone ratio]; hypothalamic-pituitary-adrenal axis activation was also seen (increased total urinary corticosteroids). No clinically relevant changes from baseline with BI 187004 treatment were observed for bodyweight or meal tolerance test parameters, or in most efficacy endpoints testing glucose and lipid metabolism; a significant increase was observed in weighted mean plasma glucose (p < .05 for 80 and 240 mg BI 187004) but not fasting plasma glucose. Drug-related adverse events were reported for 14 patients (22.6%) in Arm 1 and 10 patients (24.4%) in Arm 2, most frequently headache, diarrhoea, flushing and dizziness. A dose-dependent increase in heart rate was seen with BI 187004 treatment. CONCLUSIONS: BI 187004 was generally well tolerated in patients with T2DM. Despite complete 11ß-HSD1 inhibition, no clinically relevant effects were observed with BI 187004.
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Diabetes Mellitus Tipo 2 , Metformina , Adulto , Humanos , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Glucemia , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Sistema Hipotálamo-Hipofisario/metabolismo , Metformina/efectos adversos , Obesidad/complicaciones , Sobrepeso/complicaciones , Sistema Hipófiso-Suprarrenal/metabolismo , Tetrahidrocortisol/uso terapéuticoRESUMEN
BACKGROUND: Nedaplatin and nab-paclitaxel are each efficacious in the treatment of squamous cell lung cancer. PATIENTS AND METHODS: Eligibility criteria were: no prior chemotherapy, advanced squamous cell lung cancer; performance status 0-1, age > 20 years but < 75 years, and adequate hematologic, hepatic and renal function. Patients received escalating doses of nab-paclitaxel under a fixed dose of nedaplatin (100 mg/m2, day 1) every 3 weeks in phase I. The initial nab-paclitaxel dose was 100 mg/m2 on days 1 and 8 (level 1), and the next dose was 100 mg/m2 on days 1, 8, and 15 (level 2). In phase II, patients received the recommended doses. The primary endpoint was tumor response rate. RESULTS: In phase I, three patients at level 1 experienced no dose-limiting toxicities (DLTs) and two patients at level 2 experienced DLTs. Level 1 was thus determined as the recommended dose. Twenty-three patients were enrolled in phase II. The 3 patients in level 1 and 23 patients in phase II were included together for analyses. Three of these 26 patients were excluded from response analysis due to pneumonia and patient refusal. Response rate was 91.3% (95% confidence interval, 72.0-98.9%). Toxicities observed during all cycles were tolerable. CONCLUSIONS: The recommended dose for this combination was nedaplatin at 100 mg/m2 on day 1 and nab-paclitaxel at 100 mg/m2 on days 1 and 8 every 3 weeks. The combination of nedaplatin and nab-paclitaxel appears safe and efficacious in patients with untreated advanced squamous cell lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Adulto Joven , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Paclitaxel/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/etiología , Células Epiteliales/patologíaRESUMEN
AIM: To evaluate the ability of ladarixin (LDX, 400 mg twice-daily for three cycles of 14 days on/14 days off), an inhibitor of the CXCR1/2 chemokine receptors, to maintain C-peptide production in adult patients with newly diagnosed type 1 diabetes. MATERIALS AND METHODS: A double-blind, randomized (2:1), placebo-controlled study was conducted in 45 males and 31 females (aged 18-46 years) within 100 days of the first insulin administration. The primary endpoint was the area under the curve (AUC) for C-peptide in response to a 2-hour mixed meal tolerance test (AUC[0-120 min] ) at week 13 ± 1. Secondary endpoints included C-peptide AUC(15-120 min) , HbA1c, daily insulin requirement, severe hypoglycaemic events (SHE), the proportion of subjects achieving HbA1c less than 7.0% without SHE and maintaining a residual beta cell function. Follow-up assessments were scheduled at weeks 13 ± 1, 26 ± 2 and 52 ± 2. RESULTS: In total, 26/26 (100%, placebo) and 49/50 (98%, LDX) patients completed week 13. The mean change from baseline to week 13 in C-peptide AUC(0-120 min) was -0.144 ± 0.449 nmol/L with placebo and 0.003 ± .322 nmol/L with LDX. The difference was not significant (0.149 nmol/L, 95% CI -0.04 to 0.33; P = .122). At week 26, the proportion of patients with HbA1c less than 7.0% without SHE was transiently higher in the LDX group (81% vs. 54%, P = .024). Otherwise, no significant secondary endpoint differences were noted. Transient metabolic benefit was seen at week 26 in favour of the LDX group in the prespecified subpopulation with fasting C-peptide less than the median value at screening. CONCLUSIONS: In newly diagnosed patients with type 1 diabetes, short-term LDX treatment had no appreciable effect on preserving residual beta cell function.
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Diabetes Mellitus Tipo 1 , Adulto , Péptido C , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Método Doble Ciego , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/efectos adversos , Insulina/uso terapéutico , Masculino , Receptores de Interleucina-8 , Sulfonamidas , Resultado del TratamientoRESUMEN
AIM: To assess the feasibility of a prototype insulin infusion set (IIS) for extended wear in adults with type 1 diabetes. MATERIALS AND METHODS: The prototype Capillary Biomedical investigational extended-wear IIS (CBX IIS) incorporates a soft, flexible, reinforced kink-resistant angled nylon-derivative cannula with one distal and three proximal ports to optimize insulin delivery. Twenty adult participants with type 1 diabetes established on insulin pump therapy used the CBX IIS for two 7-day test periods while wearing a Dexcom G5 continuous glucose monitor. RESULTS: Participants were able to wear the CBX IIS for an average of 6.6 ± 1.4 days. Eighty-eight percent (36 of 41) of sets were worn for 7 days. No serious adverse events were reported. Five infusion sets failed prematurely because of: unresolvable hyperglycaemia (three); hyperglycaemia with elevated ketones (one); or infection (one). Median time in range (3.9-10.0 mmol/L) was 62% (54-76). Average glucose levels per day of infusion set wear showed a statistically significant increase over time (p < .001). CONCLUSIONS: Our preliminary observations confirm the tolerability of the prototype CBX IIS for extended wear, albeit with a deterioration in glucose control after the third day.
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Diabetes Mellitus Tipo 1 , Hiperglucemia , Adulto , Glucemia , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Estudios de Factibilidad , Humanos , Hiperglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Insulina/efectos adversos , Sistemas de Infusión de Insulina/efectos adversosRESUMEN
AIM: To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tirzepatide in Japanese participants with type 2 diabetes (T2D). METHODS: This phase 1, double-blind, placebo-controlled, parallel-dose, multiple-ascending dose study randomized participants to once-weekly subcutaneous tirzepatide or placebo. The tirzepatide treatment groups were: 5 mg (5 mg, weeks 1-8), 10 mg (2.5 mg, weeks 1-2; 5 mg, weeks 3-4; 10 mg, weeks 5-8), and 15 mg (5 mg, weeks 1-2; 10 mg, weeks 3-6; 15 mg, weeks 7-8). The primary outcome was tirzepatide safety and tolerability. RESULTS: Forty-eight participants were randomized. The most frequently reported treatment-emergent adverse events (AEs) were decreased appetite and gastrointestinal AEs, which were generally dose-dependent and mild in severity. The plasma tirzepatide concentration half-life was approximately 5 days. After 8 weeks of treatment, fasting plasma glucose decreased from baseline with tirzepatide versus placebo; the least squares (LS) mean decrease compared with placebo (95% confidence interval [CI]) was 52.7 (35.9-69.6), 69.1 (52.3-85.9), and 68.9 (53.2-84.6) mg/dL in the 5-, 10-, and 15-mg treatment groups, respectively (P < .0001 for all treatment groups). Tirzepatide also resulted in LS mean decreases from baseline versus placebo at 8 weeks in HbA1c up to 1.6% (95% CI 1.2%-1.9%; P < .0001 for all treatment groups) and body weight up to 6.6 kg (95% CI 5.3-7.9; P < .0001 for all treatment groups). CONCLUSIONS: All tirzepatide doses were well tolerated. The safety, tolerability, PK, and PD profiles of tirzepatide support further evaluation of once-weekly dosing in Japanese people with T2D.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Polipéptido Inhibidor Gástrico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/efectos adversos , JapónRESUMEN
AIM: To show pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence between Myxredlin, a novel, ready-to-use regular human insulin 1 U/mL formulation (BAX-HI), and Novolin R 100 U/mL concentrate diluted to 1 U/mL (NOVO-HI). MATERIALS AND METHODS: This phase 1, double-blind, randomized, two-way crossover study compared the PK and PD properties of BAX-HI and NOVO-HI. A total of 58 healthy males received 0.36 U/kg of each study drug, administered intravenously over a 6-hour period, concurrent with an 8-hour euglycaemic clamp at two treatment periods separated by a washout period of 7-10 days. The primary PK endpoint was the area under the insulin concentration-time curve at steady state (SS) measured from 300 to 360 minutes (AUCINS-SS 300-360 min ). The primary PD endpoint was the area under the glucose infusion rate-time curve at SS measured from 300 to 360 minutes (AUCGIR-SS 300-360 min ). RESULTS: All subjects completed the first treatment period and 54 subjects completed both treatment periods. Bioequivalence between BAX-HI and NOVO-HI was shown for the primary endpoints as the 90% confidence interval (CI) of the geometric least-squares (LS) mean ratio for AUCINS-SS 300-360 min , and the 90% CI and 95% CI of the geometric LS mean ratio for AUCGIR-SS 300-360 min were entirely contained within the prespecified limits of 80%-125%. Safety profiles were comparable for both study drugs and there were no serious adverse events. CONCLUSIONS: The study showed bioequivalence between BAX-HI and NOVO-HI in terms of PK and PD characteristics in healthy males.
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Insulina , Cloruro de Sodio , Estudios Cruzados , ADN Ribosómico , Humanos , Masculino , Equivalencia TerapéuticaRESUMEN
Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066 :TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066 :TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066 :TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066 :TRPCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066 :TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.
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Hiperandrogenismo , Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Anhídridos , Método Doble Ciego , Femenino , Humanos , Hiperandrogenismo/tratamiento farmacológico , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Sorbitol/análogos & derivadosRESUMEN
AIM: To investigate the glucosuric, renal and haemodynamic effects of licogliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, in patients with chronic kidney disease (CKD). METHODS: This multiple-dose, parallel-group, phase II mechanistic study randomized 53 participants (aged 18-78 years, body mass index ≤ 50 kg/m2 ) with varying degrees of CKD or normal renal function to treatment with licogliflozin (50 mg once daily) or placebo for 7 days. The effects of licogliflozin on 24-h urinary glucose excretion (UGE24 ), renal function, haemodynamics, pharmacokinetics and safety were assessed. RESULTS: Licogliflozin treatment for 7 days significantly (p < .01) increased UGE24 from baseline in participants with normal renal function (adjusted mean change: 41.8 [33.6, 49.9] g) or with mild (32.6 [24.1, 41.0] g), moderate A (35.7 [28.6, 42.9] g) or moderate B (20.3 [13.1, 27.5] g) CKD, but not in severe (6.2 [-0.71, 13.18] g) CKD. Licogliflozin reduced urinary electrolytes (sodium, potassium and chloride), blood pressure and urinary volume to varying extents among different groups. Significant increases in renin (p < .05), angiotensin II (p < .05) and aldosterone (p < .01) levels were observed. Adverse events were generally mild, and most commonly included diarrhoea (94%), flatulence (68%) and abdominal pain (21%). CONCLUSION: Licogliflozin treatment results in significantly increased UGE and favourable changes in urinary electrolytes and haemodynamics in patients with varying degrees of CKD (estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2 ).
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Diabetes Mellitus Tipo 2 , Insuficiencia Renal Crónica , Adolescente , Adulto , Anciano , Anhídridos , Tasa de Filtración Glomerular , Glucosa , Hemodinámica , Humanos , Riñón/fisiología , Persona de Mediana Edad , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Sodio , Transportador 2 de Sodio-Glucosa , Sorbitol/análogos & derivados , Adulto JovenRESUMEN
AIM: To investigate the tolerability, pharmacokinetics (PK) and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5-hydroxytryptamine-2c (5-HT2c ) agonist in subjects with overweight/obesity and apply mechanistic population pharmacokinetic-pharmacodynamic modelling to identify a plausible drug mechanism of action. MATERIALS AND METHODS: This phase 1, single-centre, double-blind, randomized, placebo-controlled, four-period, two-alternating cohorts study evaluated single escalating oral doses ranging from 5 to 130 mg of LY2140112 (LY) in subjects with overweight/obesity (body mass index: 27-39 kg/m2 ). Postprandial TG response (total TG, chylomicrons and very low-density lipoprotein particles [VLDL]-V6) following a high-fat meal were assessed for 11 h postmeal for each dose level. The PK profile was assessed for 96 h postdose. Drug exposure and TG concentrations in chylomicrons and VLDL-V6 were used to characterize the drug mechanism of action using non-linear mixed-effect modelling. RESULTS: Seventeen subjects entered the study and 16 subjects received at least one dose of LY. LY2140112 was generally well tolerated up to 75 mg. The PK of LY were described by a two-compartment model with first-order elimination. The 100 and 130 mg dose levels of LY significantly reduced the postprandial TG of VLDL-V6 by approximately 50%, while total TG and chylomicrons were not significantly different from placebo. The application of a published lipokinetic model successfully described the postprandial TG response in this study and indicated that LY reduced the conversion of TGs from chylomicron to VLDL-V6. CONCLUSIONS: LY significantly reduced the postprandial TG of VLDL-V6 following a single dose, when food consumption was controlled. The data indicate that a selective 5-HT2c agonist alters lipid metabolism, beyond the reported reduction in satiety. The application of a semi-physiological lipokinetic model enabled identification of a plausible drug mechanism of action of LY.
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Lipoproteínas VLDL , Serotonina , Quilomicrones , Humanos , Periodo Posprandial , TriglicéridosRESUMEN
AIM: To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS). MATERIALS AND METHODS: Individuals aged 12 years and older with BBS received once-daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes. RESULTS: From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was -5.5% (90% CI, -9.3% to -1.6%; n = 8); change from baseline was -11.3% (90% CI, -15.5% to -7.0%; n = 8) at 6 months and -16.3% (90% CI, -19.9% to -12.8%; n = 7) at 12 months. All participants reported at least one treatment-emergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points. CONCLUSIONS: Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.