TEAE-related Discontinuations Research Articles

Impact of presbyopia treatment pilocarpine hydrochloride 1.25% on night-driving performance

ABSTRACT Clinical relevance Patients prescribed pilocarpine ophthalmic solution are advised to be cautious when driving at night, but studies evaluating the effects of pilocarpine hydrochloride ophthalmic solution 1.25% (pilo), approved to treat presbyopia, on driving at night are lacking. Background This double-masked, crossover, phase 3b study evaluated night-driving performance with pilo or the placebo once daily. Methods Forty-three adults (40–55 years) with presbyopia impacting daily activities and mesopic, high-contrast, binocular distance-corrected near vision 6/12–6/30 were randomised to bilateral treatment with pilo followed by placebo or placebo followed by pilo (with a ≥7-day washout between interventions). Night-driving performance was evaluated at twilight at a closed-circuit course. Primary efficacy endpoint: overall composite night-driving performance Z score at the end of the 7–14-day intervention period, 1 hour post-instillation. Pilo was considered non-inferior if the lower limit of the 95% confidence interval (CI) for the least squares mean difference (LSMD, pilo minus placebo) was >–0.25. Other efficacy endpoints: individual components of the night-driving performance test (hazard avoidance rate; road sign recognition rate and distance; pedestrians recognition distance; overall driving and lane-keeping times) and night-driving experience questionnaire. Safety included treatment-emergent adverse events (TEAEs). Results The mean overall composite Z scores were −0.121 (pilo) and 0.118 (placebo). The LSMD (pilo minus placebo) was −0.224 (95% CI, −0.346, −0.103), with 3 of the 7 individual tasks being significantly better with the placebo. The questionnaire did not reveal significant differences between pilo and the placebo. There were no serious or severe TEAEs and no TEAE-related discontinuations. The most common ocular TEAEs were headache and visual impairment with pilo (both 27.9%), and dry eye (7.0%) with the placebo. Conclusion The overall performance of night driving was inferior with pilo, compared with placebo. The study findings are consistent with the current class labelling and provide evidence to inform regulators and assist clinicians considering prescribing pilo to adults who seek treatment of presbyopia symptoms and drive at night. ClinicalTrials.gov identifier: NCT04837482.

Efficacy and Safety of Add-on Parsaclisib to Ruxolitinib Therapy in Myelofibrosis Patients With Suboptimal Response to Ruxolitinib: Final Results From a Phase 2 Study

Background: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor and is effective in patients (pts) with myelofibrosis (MF). However, suboptimal or declining responses to RUX occur in a subset of pts, possibly due to persistent PI3K pathway activation with chronic JAK inhibitor therapy. Parsaclisib is a potent and highly selective next-generation PI3Kδ inhibitor. We conducted a phase 2 study (NCT02718300) evaluating add-on parsaclisib to stable doses of RUX, for pts with MF who experienced a suboptimal response to RUX (Yacoub A. HemaSphere 2021;5 Suppl 2:512). Here we report efficacy and safety results from the completed study. Methods: Eligible pts had primary or post-essential thrombocythemia/post-polycythemia vera MF with suboptimal response (palpable spleen >10 cm below left subcostal margin [LSM], or palpable splenomegaly 5-10 cm below LSM and presence of 1 symptom score ≥5 or 2 symptom scores ≥3 each using the Screening Symptom Form) after ≥6 months of RUX (5-25 mg twice daily; RUX stable dose, ≥8 wks). Pts remained on their stable RUX dose and were randomized to receive add-on parsaclisib 10 mg or 20 mg once daily (QD) for 8 wks and the same dose once weekly (QW) thereafter (QD/QW group), or parsaclisib 5 mg or 20 mg QD for 8 wks and 5 mg QD thereafter (all QD group) (Figure). Primary efficacy endpoint was change in spleen volume (SV) from baseline to wk 12 by MRI/CT scan. Key secondary endpoints included change in SV to wk 24, change in total symptom score (MFSAF-TSS, MPN-SAF-TSS), and safety. Results: Overall, 32 pts received parsaclisib QD/QW and 42 pts received parsaclisib all QD. Baseline median age was 68.0 (range 41.0-89.0) years and 47.3% of pts were male. The study has been completed. Median treatment duration was 336.5 days; median average daily dose was 5.0 mg/day for parsaclisib and 29.8 mg/day for RUX. Among all pts, 16 (21.6%) were rolled over to continue therapy in an open-label parsaclisib study after ending treatment in the present study. Other common reasons for pts discontinuing treatment were adverse events (13 [17.6%]) and progressive disease (10 [13.5%]); remainder discontinued for physician decision, pt decision, or "Other." Baseline median SV (cm3) was 2414.5 in QD/QW (n=29) and 1877.5 in QD (n=37); median MFSAF-TSS was 10.8 (n=28) and 16.3 (n=32) and median MPN-SAF-TSS was 25.5 (n=28) and 30.0 (n=37), respectively. Median percentage change in SV at wk 12 was −1.6 (n=28) in QD/QW and −15.4 (n=37) in QD, and at wk 24 was −2.5 (n=20) and −19.3 (n=29), respectively. Median percentage change in MFSAF-TSS at wk 12 was −14.0 (n=21) in QD/QW and −32.8 (n=24) in QD, and at wk 24 was −10.0 (n=16) and −44.4 (n=18), respectively. Median percentage change in MPN-SAF-TSS at wk 12 was −19.2 (n=20) in QD/QW and −39.8 (n=30) in QD, and at wk 24 was −43.3 (n=15) and −60.8 (n=26), respectively. Responder analysis for these 3 efficacy variables is shown in the Table. Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. Grade 3/4 nonhematologic TEAEs occurring in >1 pt overall were pneumonia (n=5; 3 QD/QW, 2 QD), fatigue, hypoxia (each n=2; each 1 QD/QW, 1 QD), dyspnea (n=2, all QD), fall, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hypocalcemia (each n=2; all QD/QW). New-onset grade 3 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 11/42 pts (26.2%) in QD; grade 4 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 3/42 pts (7.1%) in QD. TEAEs of special interest included grade ≥3 ALT and AST (each n=2; all QD/QW), grade ≥2 diarrhea (n=4) and rash (n=1) (all QD/QW), and any-grade herpes simplex (n= 4; 1 QD/QW, 3 QD) and VZV infection (n= 3; 1 QD/QW, 2, QD). No colitis was reported. TEAEs led to parsaclisib interruption in 16/32 pts in QD/QW and 22/42 pts in QD, and RUX interruption in 5/32 and 8/42 pts, respectively. TEAEs led to parsaclisib discontinuation in 5/32 pts in QD/QW and 4/42 pts in QD, and RUX discontinuation in 2/32 and 2/42 pts, respectively. Conclusion: Final results from the phase 2 study demonstrate improvement in symptoms and SV with add-on parsaclisib in patients with MF having a suboptimal response to ruxolitinib. All daily dosing regimens were more efficacious than daily/weekly dosing. Combination therapy was associated with limited grade 3/4 AEs and TEAE-related discontinuations. Phase 3 studies using 5 mg QD parsaclisib together with ruxolitinib in naive MF patients and ruxolitinib-experienced patients are in progress. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MPN-127: Add-On Parsaclisib (a PI3K5 Inhibitor) in Patients with Myelofibrosis and Suboptimal Response to Ruxolitinib: Interim Analysis from a Phase 2 Study

Context: Ruxolitinib is highly effective in myelofibrosis (MF), improving symptoms, reducing spleen size, and prolonging survival. However, suboptimal response may occur, potentially due to persistent PI3K/AKT pathway activation despite continued JAK inhibition. Objective: This phase 2 study (NCT02718300) evaluated optimal dosing, efficacy, and safety of add-on parsaclisib (INCB050465), a potent and highly selective next-generation PI3Kδ inhibitor, in patients with MF with a suboptimal response to ruxolitinib. Design: Patients had primary or secondary MF, ECOG performance status ≤2, and suboptimal response after ≥6 months of ruxolitinib (5–25 mg twice daily; stable dose ≥8 weeks). Patients remained on their stable ruxolitinib dose and were randomized to receive add-on parsaclisib 10 or 20 mg once daily (QD) for 8 weeks and the same dose once weekly (QW) thereafter (QD/QW group) or parsaclisib 5 or 20 mg QD for 8 weeks and 5 mg QD thereafter (all QD group). The primary endpoint was change in spleen volume from baseline to week 12. Results: At data cutoff (Aug 27, 2020) for this interim analysis, 32 patients had received parsaclisib QD/QW and 35 received parsaclisib all QD. Median percentage change in spleen volume at week 12 was –1.9 (n=29) in QD/QW and –13.0 (n=27) in QD and at week 24 was –3.5 (n=23) and –21.8 (n=17), respectively. Median percentage change in Myelofibrosis-Symptoms Assessment Form Total Symptom Score at week 12 was –14.0 (n=21) in QD/QW and –37.4 (n=17) in QD. Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. New-onset grade 3 and 4 thrombocytopenia were each observed in 6/32 (19%) patients in QD/QW and in 9/35 (26%) and 1/35 (3%) patients in QD, respectively. TEAEs of special interest included grade ≥2 diarrhea (n=4) and grade ≥2 rash (n=1) (all QD/QW). No colitis was reported. TEAEs led to parsaclisib discontinuation in 7/32 patients in QD/QW and 3/35 patients in QD and ruxolitinib discontinuation in 2/32 and 1/35 patients, respectively. Conclusions: Add-on parsaclisib showed preliminary efficacy in patients with MF experiencing suboptimal response to ruxolitinib; QD dosing appeared more efficacious than QD/QW dosing. Combination therapy was generally well tolerated with limited grade 3/4 AEs and TEAE-related discontinuations. Ruxolitinib is highly effective in myelofibrosis (MF), improving symptoms, reducing spleen size, and prolonging survival. However, suboptimal response may occur, potentially due to persistent PI3K/AKT pathway activation despite continued JAK inhibition. This phase 2 study (NCT02718300) evaluated optimal dosing, efficacy, and safety of add-on parsaclisib (INCB050465), a potent and highly selective next-generation PI3Kδ inhibitor, in patients with MF with a suboptimal response to ruxolitinib. Patients had primary or secondary MF, ECOG performance status ≤2, and suboptimal response after ≥6 months of ruxolitinib (5–25 mg twice daily; stable dose ≥8 weeks). Patients remained on their stable ruxolitinib dose and were randomized to receive add-on parsaclisib 10 or 20 mg once daily (QD) for 8 weeks and the same dose once weekly (QW) thereafter (QD/QW group) or parsaclisib 5 or 20 mg QD for 8 weeks and 5 mg QD thereafter (all QD group). The primary endpoint was change in spleen volume from baseline to week 12. At data cutoff (Aug 27, 2020) for this interim analysis, 32 patients had received parsaclisib QD/QW and 35 received parsaclisib all QD. Median percentage change in spleen volume at week 12 was –1.9 (n=29) in QD/QW and –13.0 (n=27) in QD and at week 24 was –3.5 (n=23) and –21.8 (n=17), respectively. Median percentage change in Myelofibrosis-Symptoms Assessment Form Total Symptom Score at week 12 was –14.0 (n=21) in QD/QW and –37.4 (n=17) in QD. Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. New-onset grade 3 and 4 thrombocytopenia were each observed in 6/32 (19%) patients in QD/QW and in 9/35 (26%) and 1/35 (3%) patients in QD, respectively. TEAEs of special interest included grade ≥2 diarrhea (n=4) and grade ≥2 rash (n=1) (all QD/QW). No colitis was reported. TEAEs led to parsaclisib discontinuation in 7/32 patients in QD/QW and 3/35 patients in QD and ruxolitinib discontinuation in 2/32 and 1/35 patients, respectively. Add-on parsaclisib showed preliminary efficacy in patients with MF experiencing suboptimal response to ruxolitinib; QD dosing appeared more efficacious than QD/QW dosing. Combination therapy was generally well tolerated with limited grade 3/4 AEs and TEAE-related discontinuations.

Long-Term Treatment With Extended-Release Methylphenidate Treatment in Children Aged 4 to

To investigate long-term (12-month) safety and symptom control of extended-release methylphenidate (MPH-MLR) in children aged 4 to <6 years after treatment optimization. A total of 90 children aged 4 to <6 years with attention-deficit/hyperactivity disorder (ADHD) were enrolled from 2 MPH-MLR studies. Treatment-emergent adverse events (TEAEs) and ADHD symptom control were assessed in the safety population (n = 89) and modeled with mixed model analyses. Most TEAEs (89.9%) were rated by investigators as of mild or moderate severity. One serious AE was reported (unrelated to study drug). Ten children discontinued because of TEAEs. Two discontinued because of weight loss; no significant increase in the rate of underweight children from baseline to endpoint was observed. Overall, 18% lost weight and 18% reported decreased appetite. Weight and height z scores and obesity rates decreased significantly from baseline to endpoint. Insomnia was reported (9%); none of these children discontinued. Sleep quality did not change significantly. Hypertension was reported (6.7%); none of these children dropped out. Diastolic, but not systolic, blood pressure increased significantly during the follow-up. Control of ADHD symptoms was maintained throughout follow-up. These data contribute to the understanding of the long-term safety of an extended-release stimulant in children 4 to <6 years of age. The observed risk of a TEAE-related discontinuation was ∼11%. TEAEs were not dose related, and most were of mild to moderate severity. Symptom control was maintained through the year-long study. A 12-Month Open Label Safety Study of Aptensio XR® in Children Ages 4-5 Years Diagnosed With ADHD (EF004); https://clinicaltrials.gov; NCT02677519.

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. Cmaxand 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 CmaxGMR (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.

Treatment of glioblastoma multiforme with \u201cclassic\u201d 4:1 ketogenic diet total meal replacement

IntroductionGlioblastoma (GBM) has poor survival with standard treatment. Experimental data suggest potential for metabolic treatment with low carbohydrate ketogenic diet (KD). Few human studies of KD in GBM have been done, limited by difficulty and variability of the diet, compliance, and feasibility issues. We have developed a novel KD approach of total meal replacement (TMR) program using standardized recipes with ready-made meals. This pilot study evaluated feasibility, safety, tolerability, and efficacy of GBM treatment using TMR program with “classic” 4:1 KD.MethodGBM patients were treated in an open-label study for 6 months with 4:1 [fat]:[protein + carbohydrate] ratio by weight, 10 g CH/day, 1600 kcal/day TMR. Patients were either newly diagnosed (group 1) and treated adjunctively to radiation and temozolomide or had recurrent GBM (group 2). Patients checked blood glucose and blood and urine ketone levels twice daily and had regular MRIs. Primary outcome measures included retention, treatment-emergent adverse events (TEAEs), and TEAE-related discontinuation. Secondary outcome measures were survival time from treatment initiation and time to MRI progression.ResultsRecruitment was slow, resulting in early termination of the study. Eight patients participated, 4 in group 1 and 4 in group 2. Five (62.5%) subjects completed the 6 months of treatment, 4/4 subjects in group 1 and 1/4 in group 2. Three subjects stopped KD early: 2 (25%) because of GBM progression and one (12.5%) because of diet restrictiveness. Four subjects, all group 1, continued KD on their own, three until shortly before death, for total of 26, 19.3, and 7 months, one ongoing. The diet was well tolerated. TEAEs, all mild and transient, included weight loss and hunger (n = 6) which resolved with caloric increase, nausea (n = 2), dizziness (n = 2), fatigue, and constipation (n = 1 each). No one discontinued KD because of TEAEs. Seven patients died. For these, mean (range) survival time from diet initiation was 20 months for group 1 (9.5–27) and 12.8 months for group 2 (6.3–19.9). Mean survival time from diagnosis was 21.8 months for group 1 (11–29.2) and 25.4 months for group 2 ( 13.9–38.7). One patient with recurrent GBM and progression on bevacizumab experienced a remarkable symptom reversal, tumor shrinkage, and edema resolution 6–8 weeks after KD initiation and survival for 20 months after starting KD.ConclusionTreatment of GBM patients with 4:1 KD using total meal replacement program with standardized recipes was well tolerated. The small sample size limits efficacy conclusions.Trial registrationNCT01865162 registered 30 May 2013, and NCT02302235 registered 26 November 2014, https://clinicaltrials.gov/

Integrated safety profile of atacicept: an analysis of pooled data from the atacicept clinical trial programme.

ObjectiveTo characterize the overall safety profile of atacicept, we conducted an integrated analysis of pooled safety data from all 17 clinical studies to date.MethodsThree data sets were used to investigate safety endpoints: a double-blind placebo-controlled set (n = 1568), an SLE set (n = 761) and a full analysis set (n = 1845; including all 17 studies).ResultsOf 1568 patients in the double-blind placebo-controlled-set, 30.8% received placebo, and 8.2, 24.5 and 36.5% received atacicept 25, 75 and 150 mg, respectively. Treatment-emergent adverse event (TEAE) rates (adjusted by treatment-exposure) were generally higher with atacicept vs placebo, but no consistent association was found between atacicept dose and specific TEAEs or mortality. Serious infection and serious TEAE rates were similar for atacicept and placebo. The TEAE-related discontinuation rates were higher with atacicept vs placebo (16.1 vs 10.9/100 patient-years). In the full analysis set, 11 deaths occurred during treatment. Across indications, exposure-adjusted mortality rates/100 patient-years (95% CI) were 3.60 (0.90, 14.38), 0.34 (0.05, 2.43) and 1.18 (0.49, 2.82) with atacicept 25, 75 and 150 mg, respectively, and 0.44 (0.06, 3.12) with placebo. In SLE patients, exposure-adjusted mortality rates were 1.45 (0.54, 3.87) with atacicept 150 mg and 0.78 (0.29, 2.07) across all atacicept-treated patients. No deaths occurred with atacicept 75 mg or placebo. In the SLE and double-blind placebo-controlled sets, pharmacodynamic effects of atacicept were not associated with increased infection rates.ConclusionThe results of this integrated safety analysis support further development and evaluation of atacicept in selected patients for whom potential benefits might outweigh risks.

Effectiveness and tolerability of THC:CBD oromucosal spray as add-on measure in patients with severe chronic pain: analysis of 12-week open-label real-world data provided by the German Pain e-Registry.

Objective: To evaluate effectiveness, tolerability and safety of an oromucosal spray containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), as add-on treatment in patients with severe chronic pain (SCP).Methods: Exploratory analysis of anonymized 12-week routine/open-label data provided by the German Pain e-Registry (GPR) on adult SCP patients treated with THC:CBD oromucosal spray in 2017.Results: Among those 30.228 cases documented in the GPR in 2017, 800 (2.6%; 57% female, mean ± SD age: 46.3±9.7 years) received a treatment with THC:CBD. All patients fulfilled the legislative preconditions for a treatment with cannabis as medicine as defined by the German Act Amending Narcotics and Other Regulations. THC:CBD-treatment was followed by an aggregated nine-factor symptom relief (ASR-9) improvement at end of week 12 vs baseline of 39.0±26.5% (95%-CI: 36.9–41.1, median: 42, range −41 to 85). A full ASR-9 response (ie, a 50%-improvement in all 9 factors) was found for 123 patients (15.4%), while 488 patients (56.0%) presented with an ≥50% improvement in at least 5 of 9 ASR factors. With a 54.9±17.2% (median: 56%, range: −6 to 85) improvement was significantly superior in the neuropathic pain subgroup (n=497, 62.1%) vs those with mixed (n=249, 31.1%; ASR-9: 18.2±12.0, median: 19, range: −12 to 42%) or nociceptive pain (n=54, 6.8%; ASR-9: −11.9±10.5, median: −11, range: −41% to 12%; p<0.001 for each). 159 patients (19.9%) reported at least one of 206 TEAEs, most of them of mild intensity (n=81.6%). Most frequently reported TEAEs were increased appetite (n=50, 6.3%) and dysgeusia (n=23, 2.9%). TEAE-related discontinuations were reported for 32 patients (4.0%). 113 (14.1%) patients discontinued due to inadequate pain relief, most of them with nociceptive pain (n=40, 74.1%), least with neuropathic pain (n=1, 0.2%; p<0.001).Conclusion: THC:CBD oromucosal spray proved to be an effective and well-tolerated add-on treatment for patients with elsewhere refractory chronic pain – especially of neuropathic origin.

Patient-reported outcomes in the single-tablet regimen (STaR) trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in antiretroviral treatment-naive adults infected with HIV-1 through 48 weeks of treatment

ABSTRACTThis 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naïve HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or ≥95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF.