The value of imaging and clinical outcomes in a phase II clinical trial of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease characterized by worsening dyspnea and lung function and has a median survival of 2–3 years. Forced vital capacity (FVC) is the primary endpoint used most commonly in IPF clinical trials as it is the best surrogate for mortality. This study assessed quantitative scores from high-resolution computed tomography (HRCT) developed by machine learning as a secondary efficacy endpoint in a 26-week phase II study of BMS-986020 – an LPA1 receptor antagonist – in patients with IPF. Methods: HRCT scans from 96% (137/142) of randomized subjects were utilized. Quantitative lung fibrosis (QLF) scores were calculated from the HRCT images. QLF improvement was defined as ⩾2% reduction in QLF score from baseline to week 26. Results: In the placebo arm, 5% of patients demonstrated an improvement in QLF score at week 26 compared with 15% and 27% of patients in the BMS-986020 600 mg once daily (QD) and twice daily (BID) arms, respectively [ versus placebo: p = 0.08 (600 mg QD); p = 0.0098 (600 mg BID)]. Significant correlations were found between changes in QLF and changes in percent predicted FVC, diffusing capacity for carbon monoxide (DLCO), and shortness of breath at week 26 ( ρ = −0.41, ρ = −0.22, and ρ = 0.27, respectively; all p < 0.01). Conclusions: This study demonstrated the utility of quantitative HRCT as an efficacy endpoint for IPF in a double-blind, placebo-controlled clinical trial setting. The reviews of this paper are available via the supplemental material section.

Duration of dual antiplatelet therapy and subsequent monotherapy type in patients undergoing drug-eluting stent implantation: a network meta-analysis

Aims To compare the safety and efficacy of very short (≤3 months), short (6 months), standard (12 months), and extended (&gt;12 months) dual antiplatelet therapy (DAPT), and of subsequent monotherapies, after coronary drug-eluting stent (DES) implantation. Methods and results Twenty-two randomized control trials (n = 110 059 patients/year) were selected and included in a Bayesian network meta-analysis. The primary efficacy endpoint (PEP) was a composite of cardiac death, myocardial infarction (MI), and stent thrombosis (ST), with each of the components of the PEP being a secondary efficacy endpoint. The primary safety endpoint was major bleeding rate. Compared to standard, we found a lower rate of MI [odds ratio (OR) 0.56, 95% confidence interval (CI) 0.44–0.77] in extended, a lower rate of major bleeding (OR 0.61, 95% CI 0.39–0.87) in very short, and a lower rate of any bleeding (OR 0.61, 95% CI 0.38–0.90) in short DAPT. All DAPT durations were comparable regarding the secondary efficacy endpoints. Very short DAPT followed by P2Y12 inhibition was the treatment of choice to reduce both major bleeding and MI. In the ACS subgroup, extended DAPT (as compared to standard) reduced PEP and ST rates (but not MIs). Conclusion The efficacy of short and very short is comparable with that of standard DAPT after DES implantation, whereas extended DAPT reduces MI rate. Very short DAPT is associated with lower haemorrhagic events and, followed by a P2Y12 inhibitor monotherapy, should be preferred in order to pursue a trade-off between major bleeding and ischaemic events.

Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy

Study Objectives Evaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB). Methods Adults aged 18–70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment. Results Efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (−0.49, 1.75) in the LXB group (p &lt; 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (−1.0, 1.0) in the LXB group (p &lt; 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%). Conclusions Efficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB. Clinical trial registration NCT03030599.

Efficacy and safety of a ready-to-drink bowel preparation for colonoscopy: a randomized, controlled, non-inferiority trial

Background: We performed a randomized, controlled, assessor-blinded, multicenter, non-inferiority (NI) study to compare the safety and efficacy of a ready-to-drink formulation of sodium picosulfate, magnesium oxide, and citric acid (SPMC oral solution) with a powder formulation (P/MC powder) for oral solution. Methods: Eligible participants (adults undergoing elective colonoscopy) were randomized 1:1 to split-dose SPMC oral solution or P/MC powder. The primary efficacy endpoint assessed overall colon-cleansing quality with the Aronchick Scale (AS), and the key secondary efficacy endpoint rated quality of right colon cleansing with the Boston Bowel Preparation Scale (BBPS). Assessments were performed by a treatment-blinded endoscopist. Tolerability was assessed using the Mayo Clinic Bowel Prep Tolerability Questionnaire. Safety assessments included adverse events and laboratory evaluations. Results: The study included 901 participants: 448 for SPMC oral solution; 453 for P/MC powder. SPMC oral solution demonstrated non-inferiority to P/MC powder {87.7% (393/448) responders versus 81.5% (369/453) responders [difference (95% confidence interval): 6.3% (1.8, 10.9)]}. The key secondary efficacy objective assessing the right colon was also met. According to the prespecified hierarchical testing, after meeting the primary and key secondary objectives, SPMC oral solution was tested for superiority to P/MC powder for the primary endpoint ( p = 0.0067). SPMC oral solution was well tolerated. Most common adverse events were nausea (3.1% versus 2.9%), headache (2.7% versus 3.1%), hypermagnesemia (2.0% versus 5.1%), and vomiting (1.3% versus 0.7%) for SPMC oral solution and P/MC powder, respectively. Conclusions: Ready-to-drink SPMC oral solution showed superior efficacy of overall colon cleansing compared with P/MC powder, with similar safety and tolerability. [ClinicalTrials.gov identifier: NCT03017235.]

Onabotulinum toxin-A injections for sleep bruxism

ObjectivesTo test the safety and efficacy of onabotulinum toxin-A (BoNT-A) injections into the masseter and temporalis muscles in patients with symptomatic sleep bruxism.MethodsParticipants 18 to 85 years old with clinically diagnosed sleep bruxism confirmed by polysomnography were enrolled in this randomized, placebo-controlled, 1:1, parallel-design trial with open-label extension. Participants were injected with BoNT-A 200 units (60 into each masseter and 40 into each temporalis) or placebo and were evaluated at 4 to 8 weeks after the initial treatment visit. The primary efficacy endpoint was clinical global impression (CGI), and the secondary efficacy endpoint was a visual analog scale (VAS) of change in bruxism and in pain at 4 to 8 weeks after injection. Exploratory endpoints included modified Montreal Bruxism Questionnaire, Headache Impact Test-6, total Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Self-Rated Anxiety Scale, and polysomnography data, including EMG recordings of the masseter and temporalis muscle bruxing events. Adverse events were recorded.ResultsThirty-one participants were recruited and 23 were randomized (19 female, age 47.4 ± 16.9 years). All 13 randomized to BoNT-A and 9 of 10 randomized to placebo completed the study. CGI (p < 0.05) and VAS of change (p < 0.05) favored the BoNT-A group. None of the exploratory endpoints changed significantly, but total sleep time and number/duration of bruxing episodes favored the BoNT-A group. Two participants randomized to BoNT-A reported a cosmetic change in their smile. No dysphagia or masticatory adverse events were reported.ConclusionsBoNT-A effectively and safely improved sleep bruxism in this placebo-controlled pilot trial. A large multicenter trial is needed to confirm these encouraging data.ClinicalTrials.gov identifierNTC00908050.Class of evidenceThis study provides Class II evidence that botulinum injections into the masseter and temporalis muscles improve subjective bruxism and painful symptoms associated with sleep bruxism.

A Phase 3, randomized, double-blind, placebo-controlled study of tasquinimod (TASQ) in men with metastatic castration-resistant prostate cancer (mCRPC), secondary endpoints.

239 Background: TASQ is an oral agent with immunomodulatory, anti-angiogenic and anti-metastatic properties that targets the tumor microenvironment. It was recently reported from this study that in chemotherapy-naïve men with mCRPC, single-agent TASQ statistically significantly improved rPFS, by both central (HR (95% CI) 0.64 (0.54-0.75)) and local review, as compared to PBO but no OS benefit was demonstrated (HR (95% CI) 1.10 (0.94-1.28)). In this abstract the results of secondary efficacy endpoint analyses are presented. Methods: Men with asymptomatic to mildly symptomatic chemotherapy-naïve mCRPC and evidence of bone metastases were assigned (2:1) to receive TASQ or PBO once daily until progression or toxicity. Randomization was stratified by KPS ( ≥ 90% vs < 90%), presence/absence of visceral disease, and geographic region. The secondary efficacy endpoints discussed here include a panel of radiological, PSA based and symptomatically assessed measures. Results: 1245 pts were randomized (TASQ, n = 832; PBO, n = 413) between 29 Mar 2011 and 7 Dec 2012 at 240 sites in 37 countries. Baseline characteristics were balanced between the 2 groups. In general, all radiology-based and PSA-based secondary endpoints showed statistically significant differences between TASQ and PBO in favor of TASQ. E.g. median time to radiological progression was 8.4 m for TASQ vs. 5.5 m for PBO, p < 0.001, HR (95% CI) 0.628 (0.534-0.739) by central assessment. However, symptomatically assessed endpoints in general showed statistically significant differences in favor of PBO. E.g. median time to symptomatic progression was 9.5 m for TASQ vs. 11.9 m for PBO, p = 0.031, HR (95% CI) 1.171 (1.014-1.353). Grade ≥ 3 TEAEs were more common with TASQ than PBO (42.8 vs 33.6%). Conclusions: Outcome of the radiological and PSA-based endpoints favor TASQ in contrast to the symptomatically assessed endpoints, which favor placebo. Overall survival was not improved, which may be due to limited efficacy of TASQ in the studied population, toxicity, or the differential use of effective life-prolonging agents post-TASQ/placebo. Clinical trial information: NCT01234311.

Efficacy and Safety Profile of Dabigatran Etexilate Compared with Enoxaparin in Primary Venous Thromboembolism Prevention after Total Knee or Hip Replacement Surgery in Patients Over 75 Years

The oral direct thrombin inhibitor, Dabigatran etexilate (Pradaxa®), was recently approved in Europe for the prevention of venous thromboembolism (VTE) in patients undergoing elective total knee replacement or total hip replacement surgery. Two pivotal clinical trials studied doses of 220 mg once daily and 150 mg once daily compared with 40 mg enoxaparin. A post hoc pooled analysis was performed in elderly patients (&gt;75 years) since the elderly, naturally lose renal function with aging. The efficacy and safety of once daily 220 mg and 150 mg dabigatran etexilate were compared with 40 mg subcutaneous enoxaparin using pooled data from the RE-MODEL (Eriksson BI et al. J Thromb Haemost2007; 5: 2178–2185) and RE-NOVATE (Eriksson BI et al. Lancet2007; 370: 949–956) pivotal trials. The primary efficacy endpoint was total VTE and all cause mortality and the primary secondary efficacy endpoint was major VTE and VTE related mortality. The primary safety endpoint was bleeding events, which were blindly adjudicated and categorized as major bleeding events (MBE), including surgical site bleeds. Of the patients treated with 220 mg dabigatran etexilate (1825), 150 mg dabigatran etexilate (1866) and enoxaparin (1848), 883 patients (16%) were above the age of 75, 73% of the elderly were evaluable for the primary efficacy endpoint, 75% were evaluable for the secondary efficacy endpoint, and all elderly patients were evaluable for safety including bleeding. The incidence of total VTE and all cause mortality was 20.8%, 22.6%, and 27.2% respectively in the three groups. A similar trend was observed for the secondary endpoint major VTE and VTE related mortality, with a descriptive statistical significant lower event rate in the 220 mg group (see table). MBEs occurred in 11 of the 295 elderly receiving 220 mg dabigatran etexilate (3.7%), 4 of the 282 elderly receiving 150 mg dabigatran etexilate (1.4%) and in 9 of the 306 elderly taking enoxaparin (2.9%). Notably, 6 of the 11 MBE in the dabigatran 220 mg group and 2 of the 4 MBE in the 150 mg group started before first oral treatment. In conclusion, in elderly patients (&gt;75 years) undergoing hip or knee replacement surgery, oral 150 mg dabigatran etexilate exhibited favourable bleeding profile with no difference in efficacy compared to 40 mg enoxaparin. Because safety is of paramount importance in the elderly who are at risk of any complications, the 150 mg once daily of dabigatran etexilate dose is currently recommended for this group. Table 1: Efficacy and bleeding endpoints in patients older than 75 years (p-value from Fisher’s exact test compared to Enoxaparin) Event Dabigatran etexilate 220 mg qd Dabigatran etexilate 150 mg qd Enoxaparin 40 mg qd Total VTE and all cause mortality 20.8% (44/212) (CI 15.5%–26.8%) p=0.14 22.6% (49/217) (CI 17.2%–28.7%) p=0.32 27.2% (58/213) (CI 21.4%–33.7%) Major VTE and VTE related mortality 1.9% (4/216) (CI 0.5%–4.7%) p=0.045 4.5% (10/221) (CI 2.2%–8.2%) p=0.53 6.0% (13/218) (CI 3.2%–10.0%) MBE 3.7% (11/295) (CI 1.9%–6.6%) p=0.65 1.4% (4/282) (CI 0.4%–3.6%) p=0.27 2.9%% (9/306) (CI 1.4%–5.5%)