Portable NIV for patients with moderate to severe COPD: two randomized crossover trials

Background Long-term non-invasive ventilation (NIV) is as an established treatment option for chronic hypercapnic COPD patients. Beneficial effects have also been shown during exercise, but this is restricted to rehabilitation programs. New portable NIV (pNIV) devices may now enable NIV application during walking at home. Study design and methods In two randomized crossover trials, the impact of pNIV on dyspnea and endurance capacity was investigated in patients with moderate to severe COPD. Participants performed a standardized 6-min walking test, with and without pNIV, using a pre-set inspiratory/expiratory positive airway pressure of 18/8 cmH2O. The first study was performed in NIV-naïve patients (Study I), while the second study was performed in those already established on long-term NIV (Study II). Results 38 patients (66.9 ± 7.4 years, mean FEV1: 30.3 ± 8%pred) and 23 patients (67.6 ± 8.7 years, mean FEV1: 29.8 ± 10.4%pred) participated in Study I and II, respectively. In Study I, the mean difference in the Borg Dyspnea Scale (BDS, primary outcome) score following walking was 3.2 (IQR 2–4) without pNIV, compared to 2.6 (IQR 1–4) with pNIV (ΔBDS 0.65, P = 0.04), while walking distance increased from 311.8 m (95%CI 276.9–346.6 m) to 326.3 m (95%CI 291.5–361.2 m) (P = 0.044) when pNIV was used. Accordingly, in Study II, the mean difference in BDS was 4.4 (IQR 3–6) without pNIV, compared to 4.5 (IQR 3–6) with pNIV (ΔBDS 0.09, P = 0.54), while walking distance decreased from 291.5 m (95%CI 246.1–336.9 m) to 258.4 m (95%CI 213–303.8 m) (P ≤ 0.001). Interpretation The use of a pNIV device during walking can improve dyspnea and walking distance in patients with moderate to severe COPD. Patients who do not already receive long-term NIV therapy are more likely to benefit compared to those undergoing long-term NIV. Careful patient selection is mandatory. Clinical Trial Register: DRKS00013203; DRKS00012913 registered October 20th 2017 and October 16th 2017; https://www.drks.de/drks_web/

Effects of CYP3A4 and P-glycoprotein inhibition or induction on the pharmacokinetics of ubrogepant in healthy adults: Two phase 1, open-label, fixed-sequence, single-center, crossover trials

Background: Ubrogepant is metabolized by cytochrome P450 3A4 (CYP3A4) and is a P-glycoprotein (P-gp) substrate. Objective: To assess effects of multiple-dose moderate-strong CYP3A4 and strong P-gp inhibitors and inducers on ubrogepant pharmacokinetic (PK) parameters. Methods: Two phase 1, open-label, fixed-sequence, single-center, crossover trials enrolled healthy adults to receive ubrogepant 20 mg with/without verapamil 240 mg (a moderate CYP3A4 inhibitor) or ketoconazole 400 mg (a strong CYP3A4 and P-gp transporter inhibitor) (Study A), or ubrogepant 100 mg with/without rifampin 600 mg (a strong CYP3A4 inducer and P-gp inducer) (Study B). Outcomes included ubrogepant PK parameters (area under plasma concentration-time curve, time 0 through infinity [AUC0-∞], peak plasma concentration [Cmax]), and safety (treatment-emergent adverse events [TEAEs]). PK parameters were compared between ubrogepant with/without coadministered medications using linear mixed-effects models. Cmax and AUC0-∞ least-squares geometric mean ratios (GMR) of ubrogepant with/without coadministration were constructed. Results: Twelve participants enrolled in Study A and 30 in Study B. AUC0-∞ and Cmax GMR (90% CI) were 3.53 (3.32–3.75) and 2.80 (2.48–3.15), respectively, for ubrogepant with verapamil; 9.65 (7.27–12.81) and 5.32 (4.19–6.76) with ketoconazole; and 0.22 (0.20–0.24) and 0.31 (0.27–0.36) with rifampin. TEAEs were predominantly mild; no treatment-related serious TEAEs or TEAE-related discontinuations occurred. Conclusion: The PK of ubrogepant were significantly affected by the concomitant use of CYP3A4 moderate-strong inhibitors and strong inducers.

Nocebo response in human models of migraine: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled, two-way crossover trials in migraine without aura and healthy volunteers

Background Human models of migraine have been used for the past 30 years to test putative ‘trigger’ molecules and ascertain whether they induce migraine attacks in humans. However, nocebo effects using this model have never been systematically explored. Objective To assess the nocebo response rate in randomised clinical trials conducted at the Danish Headache Center, and in which human models of migraine were used. Methods In this systematic review and meta-analysis, we searched PubMed for studies of human models of migraine with a randomised, double-blind, placebo-controlled, two-way crossover design that included data on the incidence of migraine attacks or headache after infusion of placebo. A total of 943 articles were screened by title and abstract. Of these, 27 studies met the inclusion criteria (published between 1994 and 2020) and were included in the qualitative and quantitative analysis. We performed a random effects meta-analysis for the incidence of migraine attacks or delayed headache after placebo infusion. Results Twenty-seven studies were eligible for inclusion: 12 studies reported data for adults with migraine (n = 182), whereas 16 studies reported data on healthy volunteers (n = 210). For adults with migraine, the incidence of migraine attacks after placebo was 8.1% (95% CI = 2.5–15.5%, I2 = 50.8%). The incidence of delayed headache was 25.9% (95% CI = 18.5–34.1%, I2 = 18.9%). For healthy volunteers, the incidence of migraine attacks after placebo was 0.5% (95% CI = 0.0–3.6%, I2 = 0.0%) while the incidence of delayed headache was 10.5% (95% CI = 4.8–17.6%, I2 = 45.2%). Conclusion The nocebo response in randomised, placebo-controlled two-way crossover trials with intravenous infusions with intravenous infusion of placebo in migraine is negligible. Future studies using human models of migraine can be conducted by assuming a nocebo response rate of 15.5%.

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article.