RESUMEN
Importance: Many pediatric patients with heterozygous familial hypercholesterolemia (HeFH) cannot reach recommended low-density lipoprotein cholesterol (LDL-C) concentrations on statins alone and require adjunct lipid-lowering therapy (LLT); the use of alirocumab in pediatric patients requires evaluation. Objective: To assess the efficacy of alirocumab in pediatric patients with inadequately controlled HeFH. Design, Setting, and Participants: This was a phase 3, randomized clinical trial conducted between May 2018 and August 2022 at 43 centers in 24 countries. Pediatric patients aged 8 to 17 years with HeFH, LDL-C 130 mg/dL or greater, and receiving statins or other LLTs were included. Following consecutive enrollment into dosing cohorts, 25 of 99 patients screened for dosing every 2 weeks (Q2W) failed screening; 25 of 104 patients screened for dosing every 4 weeks (Q4W) failed screening. A total of 70 of 74 Q2W patients (95%) and 75 of 79 Q4W patients (95%) completed the double-blind period. Interventions: Patients were randomized 2:1 to subcutaneous alirocumab or placebo and Q2W or Q4W. Dosage was based on weight (40 mg for Q2W or 150 mg for Q4W if <50 kg; 75 mg for Q2W or 300 mg for Q4W if ≥50 kg) and adjusted at week 12 if LDL-C was 110 mg/dL or greater at week 8. After the 24-week double-blind period, patients could receive alirocumab in an 80-week open-label period. Main Outcomes and Measures: The primary end point was percent change in LDL-C from baseline to week 24 in each cohort. Results: Among 153 patients randomized to receive alirocumab or placebo (mean [range] age, 12.9 [8-17] years; 87 [56.9%] female), alirocumab showed statistically significant reductions in LDL-C vs placebo in both cohorts at week 24. Least squares mean difference in percentage change from baseline was -43.3% (97.5% CI, -56.0 to -30.7; P < .001) Q2W and -33.8% (97.5% CI, -46.4 to -21.2; P < .001) Q4W. Hierarchical analysis of secondary efficacy end points demonstrated significant improvements in other lipid parameters at weeks 12 and 24 with alirocumab. Two patients receiving alirocumab Q4W experienced adverse events leading to discontinuation. No significant difference in adverse event incidence was observed between treatment groups. Open-label period findings were consistent with the double-blind period. Conclusions and Relevance: The findings in this study indicate that alirocumab Q2W or Q4W significantly may be useful for reducing LDL-C and other lipid parameters and be well tolerated in pediatric patients with HeFH inadequately controlled with statins. Trial Registration: ClinicalTrials.gov Identifier: NCT03510884.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Anticolesterolemiantes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Femenino , Niño , Masculino , LDL-Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Resultado del Tratamiento , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hipercolesterolemia/inducido químicamente , Hipercolesterolemia/tratamiento farmacológico , Método Doble Ciego , Anticolesterolemiantes/uso terapéuticoRESUMEN
OBJECTIVE: In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor. RESEARCH DESIGN AND METHODS: In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data. RESULTS: Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02-1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment-baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03-1.12; P = 0.0002) for incident type 2 diabetes. CONCLUSIONS: In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.
Asunto(s)
Anticolesterolemiantes , Diabetes Mellitus Tipo 2 , Anticuerpos Monoclonales Humanizados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Método Doble Ciego , Humanos , Lipoproteína(a) , Proproteína Convertasa 9 , Resultado del TratamientoRESUMEN
OBJECTIVES: Nonsteroidal anti-inflammatory drugs are efficacious for the treatment of acute and chronic pain; however, they have the potential for serious adverse events (AEs). The objective of this study was to evaluate the efficacy and safety of investigational, lower-dose, indomethacin submicron particle capsules compared with placebo in a study of patients with postsurgical pain. MATERIALS AND METHODS: This phase 2, multicenter, randomized, double-blind, single-dose, and placebo-controlled study enrolled 203 patients (18 to 50 y old) following extraction of ≥ 2 third molars who experienced moderate-to-severe pain intensity ≤ 6 hours after surgery. Patients received indomethacin submicron particle capsules (20 or 40 mg), celecoxib 400 mg, or placebo. The primary efficacy endpoint was the sum of total pain relief over 0 to 8 hours (TOTPAR-8) determined from the area under the curve for pain relief over 0 to 8 hours following administration of the study drug, where pain relief was measured on a 0 to 4 scale. Safety and tolerability were also assessed. RESULTS: Mean ± SE TOTPAR-8 scores were 10.8 ± 1.4 (indomethacin submicron particle capsules 20 mg), 12.6 ± 1.3 (indomethacin submicron particle capsules 40 mg), 14.8 ± 1.3 (celecoxib), and 3.0 ± 1.3 (placebo; P<0.001 for active treatments vs. placebo). Indomethacin submicron particle capsules treatment groups demonstrated better mean TOTPAR over 4 hours than placebo (P<0.001). Similar rates and profiles of treatment-emergent AEs were reported by patients across treatment groups. DISCUSSION: Lower-dose, indomethacin submicron particle capsules provide good overall pain relief in patients with postsurgical pain and are generally well tolerated. Indomethacin submicron particle capsules are a potentially promising option for treatment of acute pain and warrant further study.