The attributable estimand: A new approach to account for intercurrent events.

The term "intercurrent events" has recently been used to describe events in clinical trials that may complicate the definition and calculation of the treatment effect estimand. This paper focuses on the use of an attributable estimand to address intercurrent events. Those events that are considered to be adversely related to randomized treatment (eg, discontinuation due to adverse events or lack of efficacy) are considered attributable and handled with a composite estimand strategy, while a hypothetical estimand strategy is used for intercurrent events not considered to be related to randomized treatment (eg, unrelated adverse events). We explore several options for how to implement this approach and compare them to hypothetical "efficacy" and treatment policy estimand strategies through a series of simulation studies whose design is inspired by recent trials in chronic obstructive pulmonary disease (COPD), and we illustrate through an analysis of a recently completed COPD trial.

Budesonide/formoterol MDI with co-suspension delivery technology in COPD: the TELOS study.

TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219). Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and FEV1 area under the curve from 0-4 h (AUC0-4). Time to first and rate of moderate/severe exacerbations were assessed.BFF MDI 320/10 µg improved pre-dose trough FEV1versus FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV1 AUC0-4versus BD MDI (LSM 173 mL and 157 mL, respectively; both p<0.0001) at week 24. BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations versus FF MDI. Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD.

Randomized dose-ranging study of a budesonide metered-dose inhaler by using co-suspension delivery technology in asthma.

BACKGROUND: This is the first study of the inhaled corticosteroid, budesonide, delivered by metered-dose inhaler (BD MDI) using innovative co-suspension delivery technology in adults with asthma. OBJECTIVE: To characterize the effects of BD delivered by MDI on lung function and safety. METHODS: Randomized, double-blind, 4-week cross-over, placebo-controlled, phase IIb study of adults (18-65 years of age) with mild-to-moderate persistent asthma. The subjects received twice-daily BD MDI 320 µg, 160 µg, and placebo MDI, and either BD MDI 80 µg or 40 µg. The primary endpoint was change from baseline in morning trough forced expiratory volume in 1 second (FEV1) at the end of the treatment period (EOT). Secondary endpoints included change from baseline in morning and evening predose peak expiratory flow rate (PEFR), rescue medication use, and Asthma Control Questionnaire 5-question version (ACQ-5) score. Safety was also assessed. RESULTS: A total of 147 subjects were randomized. All doses of BD MDI improved morning trough FEV1 at EOT, and morning and evening predose PEFR in the last treatment week versus placebo (all p < 0.01), with improvements in trough FEV1 exceeding 100 mL for BD MDI 320 µg, and 160 µg only. Compared with placebo, all BD MDI doses reduced rescue medication use in the last week of treatment (p < 0.01) and improved ACQ-5 scores at EOT (all p < 0.01). All treatments were well tolerated. CONCLUSION: Analysis of the data demonstrated greater efficacy improvements for the higher doses of BD MDI (320 µg and 160 µg), with similar adverse event profiles compared with the lower doses. Hence, BD MDI 320 µg and 160 µg warrant further evaluation in subjects with persistent asthma.Clinical trial NCT02105012, www.clinicaltrials.gov.

Efficacy and safety of two doses of budesonide/formoterol fumarate metered dose inhaler in COPD.

Inhaled corticosteroid/long-acting ß2-agonist combination therapy is a recommended treatment option for patients with chronic obstructive pulmonary disease (COPD) and increased exacerbation risk, particularly those with elevated blood eosinophil levels. SOPHOS (NCT02727660) evaluated the efficacy and safety of two doses of budesonide/formoterol fumarate dihydrate metered dose inhaler (BFF MDI) versus formoterol fumarate dihydrate (FF) MDI, each delivered using co-suspension delivery technology, in patients with moderate-to-very severe COPD and a history of exacerbations. In this phase 3, randomised, double-blind, parallel-group, 12-52-week, variable length study, patients received twice-daily BFF MDI 320/10 µg or 160/10 µg, or FF MDI 10 µg. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 12. Secondary and other endpoints included assessments of moderate/severe COPD exacerbations and safety. The primary analysis (modified intent-to-treat) population included 1843 patients (BFF MDI 320/10 µg, n=619; BFF MDI 160/10 µg, n=617; and FF MDI, n=607). BFF MDI 320/10 µg and 160/10 µg improved morning pre-dose trough FEV1 at week 12 versus FF MDI (least squares mean differences 34 mL [p=0.0081] and 32 mL [p=0.0134], respectively), increased time to first exacerbation (hazard ratios 0.827 [p=0.0441] and 0.803 [p=0.0198], respectively) and reduced exacerbation rate (rate ratios 0.67 [p=0.0001] and 0.71 [p=0.0010], respectively). Lung function and exacerbation benefits were driven by patients with blood eosinophil counts ≥150 cells·mm-3. The incidence of adverse events was similar, and pneumonia rates were low (≤2.4%) across treatments. SOPHOS demonstrated the efficacy and tolerability of BFF MDI 320/10 µg and 160/10 µg in patients with moderate-to-very severe COPD at increased risk of exacerbations.

Efficacy, safety, and dose response of glycopyrronium administered by metered dose inhaler using co-suspension delivery technology in subjects with intermittent or mild-to-moderate persistent asthma: A randomized controlled trial.

OBJECTIVES: This randomized, double-blind, placebo-controlled, cross-over, Phase II dose-ranging study investigated the efficacy and safety of GP MDI (glycopyrronium administered by metered dose inhaler formulated using co-suspension delivery technology) compared with an open-label active comparator, salmeterol dry powder inhaler (SAL DPI), in subjects with intermittent or mild-to-moderate persistent asthma. METHODS: Subjects were randomized to receive five of seven treatments (GP MDI 28.8, 14.4, 7.2, 3.6, and 1.9 µg, placebo MDI, and SAL DPI 50 µg), each for a 14-day period. The primary endpoint was peak change from baseline in forced expiratory volume in 1 s (FEV1) on Day 15. Secondary endpoints included additional lung function parameters and symptoms (Asthma Control Questionnaire-5). Safety was monitored throughout. RESULTS: Of 248 subjects randomized, 211 completed the study. All doses of GP MDI resulted in significant improvements in the primary endpoint compared with placebo MDI in a dose-ordered fashion (range 85-155 mL, p < .0001), without appreciable differences between the two highest doses of GP MDI (28.8 and 14.4 µg) and SAL DPI 50 µg. Improvements in secondary lung function endpoints and symptoms were generally dose-ordered, with GP MDI 28.8 µg showing the greatest improvements. Similar results were observed when endpoints were analyzed based on subjects' background use of inhaled corticosteroids (yes/no). All GP MDI doses were well tolerated with no evidence of a dose-related effect on adverse events. CONCLUSIONS: The results of this study suggest that GP MDI could offer an important treatment option for maintenance therapy of asthma, and warrants further investigation in Phase III clinical trials.

Effectiveness and tolerability of a new lipid-altering agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol.

This study evaluated the efficacy and tolerability of gemcabene, a new lipid-altering agent, in a double-blind, randomized, dose-response study of 161 patients with high-density lipoprotein (HDL) cholesterol of <35 mg/dl and serum triglyceride (TG) levels of either >/=200 (n = 94) or <200 mg/dl (n = 67). After a 6-week, placebo, dietary lead-in period, patients were administered either 150, 300, 600, or 900 mg of gemcabene or placebo once daily for 12 weeks. In the TG >/=200 mg/dl stratum, gemcabene significantly increased serum HDL cholesterol by 18% with corresponding significant increases of 6% in both apolipoprotein A-I and A-II levels at the 150-mg dose. HDL cholesterol levels also increased 12% at the 300-mg dose; however, this did not reach statistical significance. Also, in the TG >/=200 mg/dl stratum, serum TG levels were significantly reduced by 27% and 39% at the 150- and 300-mg doses of gemcabene, respectively. No significant differences were found in serum HDL cholesterol or TG levels in the TG >/=200 mg/dl groups that received 600 or 900 mg of gemcabene, or in TG <200 mg/dl groups administered any dose of gemcabene. However, at these higher 600- and 900-mg doses, gemcabene significantly reduced serum low-density lipoprotein (LDL) cholesterol levels by 15% to 25%, respectively, in both TG strata, with proportionate decreases in the levels of apolipoprotein B. Gemcabene was well tolerated with a frequency of adverse events similar to that of placebo. In conclusion, at the lower doses, gemcabene significantly increased HDL cholesterol and reduced TG serum levels in patients with low HDL cholesterol and TG >/=200 mg/dl. At the higher doses, gemcabene significantly reduced LDL cholesterol levels in all patients with low HDL cholesterol.

Safety and immunogenicity of trivalent inactivated influenza vaccine in infants: a randomized double-blind placebo-controlled study.

BACKGROUND: Infants less than 6 months of age are at high risk for influenza disease and influenza-related complications, but no vaccine is licensed for this population. METHODS: A double-blind, randomized, placebo-controlled trial was conducted in 1375 healthy US infants 6 to 12 weeks of age. Subjects received 2 doses of trivalent inactivated influenza vaccine (TIV, Fluzone, sanofi pasteur; N = 915) or placebo (N = 460) 1 month apart in combination with indicated concomitant vaccines. Solicited adverse events were collected for 7 days following vaccination, and unsolicited adverse events for 28 days. Hemagglutination-inhibition antibodies to all 3 vaccine strains were measured following the second TIV/placebo dose. RESULTS: No significant differences were seen between TIV and placebo groups for any safety outcome. Fever > or =38 degrees C within 3 days of vaccination was seen in 11.2% versus 11.7% of TIV versus placebo recipients. Serious adverse events within 28 days were reported in 1.9% of TIV and 1.5% of placebo recipients. Antibody responses to childhood vaccines were similar in both groups. Increased influenza-specific antibody responses in TIV recipients compared with placebo recipients were seen against all 3 strains in TIV recipients (P < 0.001), with better responses to influenza A strains noted. Reciprocal geometrical mean titer to H1N1, H3N2, and B were 33, 95, and 11 in TIV recipients versus 7, 9, and 5 for placebo recipients. Over 90% of TIV recipients had antibody > or =1:40 for at least 1 vaccine strain and 49.6% for 2 strains, versus 16.4% and 0.9% in placebo-recipients. CONCLUSIONS: TIV administered to young infants beginning at 6 to 12 weeks of age is safe and immunogenic.

Trivalent inactivated influenza virus vaccine given to two-month-old children: an off-season pilot study.

BACKGROUND: Although children less than 6 months of age have the highest risk for hospitalization related to influenza infection, influenza vaccine is not approved for these children. METHODS: In an open-label, off-season study, healthy 6 to 12 week and 6-month-old children received 2 doses of the 2004 to 2005 trivalent inactivated influenza vaccine (TIV) administered 1 month apart along with other routine pediatric vaccines. Safety was assessed by parental diaries (n = 393). Immunogenicity analyses (n = 293) were performed on sera obtained before vaccination and 1 month after the second dose of TIV. Outcomes included the frequencies of subjects with injection site and systemic reactions and seroprotection rates to TIV antigens. RESULTS: Injection site reactions and fevers were generally mild and resolved within 3 days. Postvaccination seroprotection rates (titer > or = 1:40) in the 6- to 12-week-old and 6-month-old groups were 46% and 69% to A/New Caledonia (H1N1), 59% and 79% to A/Wyoming (H3N2), and 5% and 22% to B/Jiangsu (P < 0.001, all comparisons). For seronegative 6- to 12-week-olds whose mothers had not received TIV during pregnancy, postvaccination seroprotective titers to A/New Caledonia (H1N1) were achieved in 70% (38/54) and to A/Wyoming (H3N2) in 68% (23/34) of infants. CONCLUSIONS: TIV was well tolerated and safe when administered to children at both 6 to 12 weeks and 6 months of age. The antibody response was lower in the younger children, probably related to antibody suppression from passively acquired antibodies from mothers. In 6- to 12-week-olds without preexisting antibody, seroresponses to influenza A antigens approached those of 6-month-old children.