Co-primary Efficacy Endpoints Research Articles

Efficacy, Tolerability, and Safety of DFN-15 (Celecoxib Oral Solution, 25 mg/mL) in the Acute Treatment of Episodic Migraine: A Randomized, Double-Blind, Placebo-Controlled Study.

ObjectiveThe objective of this study was to evaluate the efficacy, tolerability, and safety of 120 mg DFN‐15 vs placebo for the acute treatment of migraine.BackgroundCertain nonsteroidal anti‐inflammatory drugs (NSAIDs) are guideline‐recommended therapies for the acute treatment of migraine, but patients who use them may have issues with gastrointestinal tolerability. Celecoxib, a selective inhibitor of cyclooxygenase‐2, produces analgesia similar to nonselective NSAIDs. DFN‐15 is an oral, ready‐made liquid solution of celecoxib being investigated for the acute treatment of migraine.MethodsA randomized, double‐blind, placebo‐controlled, efficacy, tolerability, and safety study in adults with migraine was conducted. Subjects treated a single migraine attack with 120 mg DFN‐15 or placebo as soon as possible after the onset of pain of moderate to severe intensity. The 2 independent coprimary efficacy endpoints were the proportion of subjects with freedom from pain and the absence of the most bothersome symptom (MBS) at 2 hours postdose. A second double‐blind treatment period followed the first, but did not contribute to the primary outcomes and will be reported elsewhere.ResultsThere were 622 subjects randomized (1:1) to double‐blind treatment with either 120 mg DFN‐15 or placebo, and 567 (91.2%) treated a migraine with study drug (n = 285 DFN‐15; n = 282 placebo). Groups were balanced in demographic characteristics; the mean age was 40, and most subjects were female (87% [494/567]). At 2 hours postdose, DFN‐15 was significantly superior to placebo for pain freedom (35.6% [98/275] vs 21.7% [57/263], P < .001), with an odds ratio (95% CI) of 2.00 (1.36, 2.94) and for freedom from the MBS (57.8% [134/232] vs 44.8% [104/232], P = .007), with an odds ratio (95% CI) of 1.68 (1.17, 2.43). A total of 13.3% (38/285) of DFN‐15‐treated subjects and 8.9% (25/282) of placebo‐treated subjects reported a treatment‐emergent adverse event (TEAE). Study drug‐related TEAEs were reported by 9.1% (26/285) of DFN‐15 subjects and 6.0% (17/282) of placebo subjects, the most common of which were dysgeusia (4.2% [12/285] vs 1.4% [4/282]) and nausea (3.2% [9/285] vs 1.8% [5/282]). No subjects treated with DFN‐15 reported TEAEs that were severe or led to withdrawal, and no serious TEAEs or deaths were reported in the study.ConclusionsDFN‐15 was significantly more effective than placebo for the acute treatment of migraine, with a generally favorable tolerability and safety profile.

199 Efficacy and Safety With Andexanet Alfa in Traumatic Intracranial Hemorrhage: An ANNEXA-4 Substudy

Acute major bleeding secondary to trauma is a significant complication of anticoagulated patients. In patients taking Factor Xa (FXa) inhibitors, major bleeding events can be life-threatening in the absence of a specific reversal agent. ANNEXA-4 was a prospective, single-arm, open-label study evaluating the efficacy and safety of andexanet alfa in patients with acute major bleeding while taking FXa inhibitors. Eligible patients presented within 18 hours of their last FXa inhibitor dose. Co-primary efficacy endpoints were the percent change from baseline in anti-FXa activity, and the proportion of patients achieving excellent or good hemostatic efficacy over the first 12 hours after treatment, as determined by an independent adjudication committee. The criteria for hemostatic efficacy in patients with intracranial hemorrhage (ICH) were largely volume based; a 20 percent or lower increase in hematoma volume and/or thickness was considered excellent, a 20-35% increase was good, and a >35% increase was poor/none. Safety outcomes (including thrombotic events and death) were evaluated over 30 days. Among 352 patients enrolled in the study, 99 (28.1%) had an ICH associated with trauma. Mean age was 81.5 years. A total of 72 patients took apixaban, 22 rivaroxaban, 3 enoxaparin, and 1 edoxaban. Of the 99 ICH patients, 34 (34.3%) had bleeding in multiple compartments. The mean baseline hematoma volume in the 11 trauma patients with single-compartment intraparenchymal bleeding was 13.3 cc. Among 71 efficacy-evaluable ICH patients, 60 (84.5%) had excellent or good hemostatic efficacy. The median percent reduction in anti-FXa activity was 94.3% and 91.8% in ICH patients taking apixaban and rivaroxaban, respectively. The 30-day rates of thrombotic events and mortality were 7 of 99 (7.1%) and 10 of 99 (10.1%), respectively. In patients taking FXa inhibitors with ICH due to trauma, andexanet alfa resulted in a high rate of excellent or good hemostatic efficacy, with a relatively low occurrence of thrombotic events. These results are comparable to what was observed for ANNEXA-4 patients with spontaneous bleeding events and suggest that andexanet alfa could be a safe and effective treatment option in the traumatic ICH population.

LBA14_PR - IMvigor130: Efficacy and safety from a phase III study of atezolizumab (atezo) as monotherapy or combined with platinum-based chemotherapy (PBC) vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC)

LBA14_PR - IMvigor130: Efficacy and safety from a phase III study of atezolizumab (atezo) as monotherapy or combined with platinum-based chemotherapy (PBC) vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC)

A.07 Efficacy, safety, and tolerability of ubrogepant for the acute treatment of migraine: a single-attack phase 3 study, ACHIEVE I

Background: To evaluate efficacy, safety, and tolerability of ubrogepant, an oral CGRP receptor antagonist, for acute treatment of a single migraine attack. Methods: Multicenter, randomized, double-blind, placebo-controlled, parallel-group, single-attack, phase 3 study (NCT02828020). Patients randomized 1:1:1 to placebo, ubrogepant 50mg, or ubrogepant 100mg had 60 days to treat one migraine attack (moderate/severe pain intensity). Co-primary efficacy endpoints: pain freedom 2 hours post initial dose and absence of most bothersome migraine-associated symptom (MBS). Results: 1672 patients were randomized (safety population: n=1436; mITT population: n=1327). Mean age: 40.7 years; white (82.4%); female (87.5%). A significantly greater percentage of ubrogepant- than placebo-treated patients achieved pain freedom 2 hours post initial dose (50mg: 19.2%, adjusted P=0.0023; 100mg: 21.2%, adjusted P=0.0003; placebo: 11.8%). A significantly greater percentage of ubrogepant patients achieved absence of MBS (50mg: 38.6%, adjusted P=0.0023, 100mg: 37.7%, adjusted P=0.0023; placebo: 27.8%). The adverse event (AE) profile of ubrogepant was similar to placebo. The most common AEs (incidence ≥2% in any treatment group) within 48 hours of initial or optional second dose were nausea, somnolence, and dry mouth (all with incidence &amp;lt;5%). Conclusions: Both co-primary endpoints were met, with clinically meaningful effects on migraine headache pain and MBS. Ubrogepant was well tolerated, with no identified safety concerns.

P.010 Efficacy, safety, and tolerability of ubrogepant for the acute treatment of migraine: a single-attack phase 3 study, ACHIEVE II

Background: To evaluate efficacy, safety, and tolerability of ubrogepant for acute treatment of migraine attacks. Methods: Multicenter, double-blind, phase 3 study (NCT02867709). Randomized patients (1:1:1, placebo or ubrogepant 25mg or 50mg) had 60 days to treat one migraine attack (moderate/severe pain intensity). Co-primary efficacy endpoints (2 hours post initial dose): headache pain freedom and absence of most bothersome migraine-associated symptom (MBS). Secondary endpoints: pain relief, sustained pain relief, sustained pain freedom, and absence of migraine-associated symptoms. Results: 1686 patients were randomized (safety population: n=1465; mITT population: n=1355). Mean age: 41 years; white: 81%; female: 89%. Significantly greater proportions of ubrogepant- than placebo-treated patients achieved 2-hour pain freedom (placebo: 14.3%; 25mg: 20.7%, adjusted P=0.0285; 50mg: 21.8%, adjusted P=0.0129) and absence of MBS for 50mg (placebo: 27.4%; 50mg: 38.9%, adjusted P=0.0129). Secondary endpoints (except absence of nausea at 2h) met statistical significance versus placebo for ubrogepant 50mg. Absence of MBS and secondary outcomes were not significant for 25mg after multiplicity adjustment. Ubrogepant’s and placebo’s AE profiles were similar. Conclusions: Co-primary endpoints were met for ubrogepant 50mg. Ubrogepant 25mg was significantly superior to placebo for 2h pain freedom. Ubrogepant was well tolerated. Results support the efficacy, tolerability, and safety of ubrogepant for acute treatment of migraine attacks.

OR33-6 The Neurokinin 3 Receptor Antagonist, Fezolinetant, Is Effective in Treatment of Menopausal Vasomotor Symptoms: A Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging Study

Vasomotor symptoms (VMS; eg, hot flashes, night sweats) are caused by a loss of thermoregulatory control. The thermoregulatory center in the brain is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. The activity of KNDy neurons is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen negative-feedback. Declining estrogen levels at menopause disturb this balance, leading to VMS. Fezolinetant is an antagonist at NK3R that acts to moderate KNDy neuron function for the treatment of VMS (1). The aim of the current trial was to evaluate fezolinetant dose levels and treatment regimen in VMS. In this phase 2b, double-blind trial (NCT03192176), menopausal women age >40−65 y with moderate/severe VMS (≥50/wk) were randomized to one of the following: fezolinetant 15, 30, 60, or 90 mg BID or 30, 60, or 120 mg QD or placebo (PBO). Coprimary efficacy outcomes were frequency and severity of moderate/severe VMS at wk 4 and 12. Secondary efficacy outcomes included changes in moderate/severe VMS frequency and severity by study wk. Of 356 women randomized, 352 received ≥1 dose study drug (safety population; mean [SD] age: 54.6 [4.7] y; 73% white) and 287 (81%) completed the study: PBO: 37/44 (84%); fezolinetant: 250/312 (80%). The most common reasons for discontinuation were withdrawal of consent (6.7%) and AEs (5.9%). All fezolinetant dose groups demonstrated reductions in VMS frequency and severity at wk 4 and 12. Significant dose responses were observed in all coprimary efficacy endpoints. The differences from PBO in least squares (LS) mean changes from baseline in moderate/severe VMS frequency per day at wk 4 were −1.9, −3.0, −2.8, and −3.5 for 15, 30, 60, and 90 mg BID, respectively, and −2.3, −3.0, and −2.4 for 30, 60, and 120 mg QD, respectively, with a common SE of 0.8 (all P<.05). The differences from PBO in LS mean change from baseline in moderate/severe VMS frequency per day at wk 12 were −1.8, −2.1, −2.3, and −2.6 for 15, 30, 60, and 90 mg BID, respectively, and −2.1, −2.6, and −2.1 for 30, 60, and 120 mg QD, respectively, with a common SE of ~0.7 (all P<.05). Dose response was apparent in frequency and severity as early as at wk 1. The majority of TEAEs were mild or moderate in severity. There were no deaths or serious treatment-related TEAEs. This study demonstrates that fezolinetant is a safe and effective nonhormonal treatment for rapid reduction of moderate/severe menopausal VMS. 1Fraser GL, et al. Clinical evaluation of the NK3 receptor antagonist fezolinetant (a.k.a. ESN364) for the treatment of menopausal hot flashes [abstract OR16-5]. Endocr Rev. 2017;38(3).

Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study

AbstractRavulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor–naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), −4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (−76.8% vs −76.0%; difference [95% CI], −0.83% [−5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [−1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], −6.7% [−14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [−8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

Esmirtazapine treatment of postmenopausal vasomotor symptoms: two randomized controlled trials

Objectives: Two identical 12-week, randomized, double-blind, placebo-controlled, multi-arm, parallel-group Phase III studies (Study P012, NCT00560833; Study P013, NCT00535288) evaluated the efficacy and safety of esmirtazapine, an investigational medicine, for the treatment of moderate to severe vasomotor symptoms (VMS) in postmenopausal women.Methods: Participants were randomized to placebo or esmirtazapine (2.25, 4.5, 9.0, or 18.0 mg). Co-primary efficacy endpoints (daily frequency and severity of moderate to severe VMS, both at weeks 4 and 12) were based on participative LogPad daily diaries. Adverse events (AEs) were recorded.Results: In Studies P012 and P013, 942 and 946 participants were randomized, respectively. Compared with placebo, esmirtazapine significantly reduced the mean daily frequency by 1.4–2.2 moderate to severe VMS at weeks 4 and 12 (both ≥4.5 mg) and mean daily severity by 0.06–0.08 symptoms at weeks 4 (≥4.5 mg) and 12 (9.0 mg P012; 18.0 mg P013 only). Esmirtazapine was generally well tolerated with a more favorable safety profile at lower doses. Somnolence and fatigue were the most frequently reported AEs.Conclusions: Esmirtazapine reduced the frequency and severity of moderate to severe VMS associated with menopause and was generally well tolerated in the study population.

Trials in progress: IMagyn050/GOG 3015/ENGOT-OV39. A Phase III, multicenter, randomized study of atezolizumab versus placebo administered in combination with paclitaxel, carboplatin, and bevacizumab to patients with newly-diagnosed stage III or stage IV ovarian, fallopian tube, or primary peritoneal cancer.

There is mounting pre-clinical and clinical evidence that combinations of immunotherapy, specifically programed cell death-1 (PD-1) inhibition, with chemotherapy and anti-angiogenesis agents, such as bevacizumab, result in markedly improved outcomes across a variety of tumor types including endometrial cancer, renal cell cancer, and non-small cell lung cancer. IMagyn050/GOG 3015/ENGOT-OV39 is the first, randomized, phase III trial to evaluate the potential impact of this combination on both progression-free survival and overall survival in patients presenting with advanced epithelial ovarian cancer. The primary objective is to evaluate the efficacy of atezolizumab versus placebo in combination with paclitaxel + carboplatin + bevacizumab for front-line treatment of ovarian cancer among all patients and those with PD-L1+ tumors. This study will test the hypothesis that treatment with atezolizumab added to paclitaxel, carboplatin, and bevacizumab will prolong progression-free survival and overall survival compared with treatment with placebo plus paclitaxel, carboplatin, and bevacizumab. This is a randomized, phase III, placebo-controlled study. Eligible patients have a histologic diagnosis of advanced epithelial ovarain cancer, primary peritoneal, or fallopian tube cancer who either have residual disease after primary surgery or who are undergoing neoadjuvant chemotherapy with planned interval surgery. Ineligible patients include those who are cured with surgery alone or those for whom no gross residual disease remained following primary cytoreduction. There are two co-primary efficacy endpoints: investigator-assessed progression-free survival and overall survival. 1300 patients. April 2020. NCT03038100.

Biodegradable-Polymer Versus Polymer-Free Drug-Eluting Stents for the Treatment of Coronary Artery Disease.

Biodegradable-polymer (BP) and polymer-free (PF) drug eluting stents (DES) were developed to reduce the risk of delayed arterial healing observed with durable-polymer (DP) platforms. Although trials demonstrate BP-DES and PF-DES are non-inferior to DP-DES, there is limited data directly comparing these technologies. We performed a meta-analysis to assess the efficacy and safety of BP-DES versus PF-DES for the treatment of coronary artery disease. Electronic searches were performed identifying randomized trials comparing BP-DES with PF-DES. Co-primary efficacy endpoints were target vessel revascularization (TVR), target lesion revascularization (TLR) and angiographic in-stent late lumen loss (LLL). Co-secondary safety endpoints were all-cause death, myocardial infarction (MI) and stent thrombosis (ST). Of 208 studies, 5 met inclusion criteria including 1975 patients. At mean follow-up (14 ± 5 months), BP-DES were associated with significantly reduced rates of TVR (OR 0.58, 95%CI 0.37-0.92, p = 0.02), TLR (4.7% vs 9.5%) (OR 0.48, 95%CI 0.31-0.75, p = 0.001) and in-stent LLL (pooled mean difference -0.20 mm, 95%CI -0.24 to -0.16, p < 0.001). There was no difference in safety, including all-cause death (OR 1.24, 95%CI 0.68-2.28, p = 0.48), MI (OR 0.92, 95%CI 0.54-1.56, p = 0.75) or ST (OR 1.58, 95%CI 0.67-3.73, p = 0.30). These data suggests that BP-DES are more efficacious when compared with PF-DES for the treatment of CAD.

A Phase 3 Study of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria Naive to Complement Inhibitors: Results of a Subgroup Analysis with Patients Stratified By Baseline Hemolysis Level, Transfusion History, and Demographics

Background/Objective: Ravulizumab (ALXN1210) is an innovative C5 inhibitor with high C5 affinity and a half-life approximately 4 times longer than eculizumab. In the largest interventional clinical study of C5 inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH) to date, ravulizumab administered every 8 weeks (q8w) was shown to be noninferior to eculizumab (every 2 weeks [q2w]) across 2 coprimary endpoints and 4 key secondary endpoints, due to its ability to provide immediate, complete, and sustained inhibition of complement C5 (Lee et al, EHA-2018). Because PNH is a rare disease, prospective evaluation of new agents for the treatment of this disease, with the exception of ravulizumab, has been limited to small populations. As a result, assessing the effect of treatment in patients with unique disease characteristics and gaining a full understanding of the benefit-to-risk profile of new therapies, has been challenging. The objective of this protocol-specified analysis was to evaluate the relative efficacy of ravulizumab and eculizumab in adult patients with PNH based upon baseline hemolysis level, transfusion history, and demographics.Methods: In this phase 3, randomized, open-label, noninferiority, multicenter study (NCT02946463), patients ≥18 years of age with confirmed diagnosis of PNH, naive to complement inhibitor therapy, with lactate dehydrogenase (LDH) level ≥1.5 times upper limit of normal (xULN), and ≥1 PNH-related sign/symptom at screening received ravulizumab or eculizumab over a 183 day study period. Coprimary efficacy endpoints were transfusion avoidance and LDH normalization. Secondary endpoints were percent change in LDH, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, and proportion with stabilized hemoglobin levels. Subgroup analyses were performed on each of these endpoints, based on transfusion history (0, 1-14, or >14 units of packed red blood cells [pRBCs] in the year prior to the first dose of study drug), screening LDH levels (1.5-<3 or ≥3 xULN), sex, age, race, and geographical region. Descriptive statistics are provided with no formal hypothesis testing performed.Results: In total, 246 patients from countries across the Asia-Pacific region (n=124), Europe (n=91), North America (n=9), and South America (n=22) were randomized to ravulizumab (n=125) or eculizumab (n=121). For transfusion avoidance, the point estimates for 15/17 subgroups favored ravulizumab. The treatment effect favored ravulizumab irrespective of prior pRBC transfusion history and baseline LDH levels, as well as nearly all other demographic subgroups assessed (Panel A). With respect to LDH normalization, the point estimates for 11/17 subgroups favored ravulizumab. The treatment effect numerically favored ravulizumab among patients who received 1-14 and >14 pRBCs in the 12 months before randomization, both baseline LDH subgroups, and most of the demographic subgroups (Panel B). No sensitive subgroups were identified for either of the coprimary endpoints. Similarly, point estimates favored ravulizumab in the majority of patient subgroups across each of the key secondary endpoints, including: 8/17 of the subgroups on the assessment of percent change in LDH; 12/17 subgroups on the assessment of change in FACIT-Fatigue score; 13/17 subgroups on the assessment of breakthrough hemolysis; and 13/17 subgroups on the assessment of hemoglobin stabilization.Conclusions: Results of this prespecified analysis revealed point estimates favoring ravulizumab for the majority of the diverse subgroups of PNH patients analyzed. The consistency of these data across subgroups confirms the robustness of the results of this study. The benefit of ravulizumab in terms of transfusion avoidance and LDH normalization was retained across all subgroups. These results provide evidence supporting the use of ravulizumab for the treatment of complement inhibitor-naive patients with PNH regardless of transfusion history, baseline hemolysis level, sex, age, race, or geographic region. DisclosuresWeitz:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Kulagin:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Nakao:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Volles:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Damokosh:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Aguzzi:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Risitano:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy.

Lenalidomide, Adriamycin and Dexamethasone (RAD) Versus Bortezomib, Lenalidomide and Dexamethasone (VRD) in Newly Diagnosed Multiple Myeloma (MM) - Post-Induction Response and MRD Results By Flow Cytometry and NGS from a Phase 3 Randomized Controlled Clinical Trial (RCT)

Lenalidomide, Adriamycin and Dexamethasone (RAD) Versus Bortezomib, Lenalidomide and Dexamethasone (VRD) in Newly Diagnosed Multiple Myeloma (MM) - Post-Induction Response and MRD Results By Flow Cytometry and NGS from a Phase 3 Randomized Controlled Clinical Trial (RCT)

Pragmatic trial of multifaceted intervention (STROKE-CARD care) to reduce cardiovascular risk and improve quality-of-life after ischaemic stroke and transient ischaemic attack \u2013study protocol

BackgroundPatients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of future cardiovascular events. Despite compelling evidence about the efficacy of secondary prevention, a substantial gap exists between risk factor management in real life and that recommended by international guidelines. Moreover, stroke is a leading cause of disability and morbidity which partly emerges from post-stroke complications.Methods/designWe designed a block-randomised (2:1 ratio) open pragmatic trial [NCT02156778] with blinded outcome assessment comparing STROKE-CARD to usual post-stroke-patient care. STROKE-CARD is a multifaceted post-stroke disease management program with the objective of reducing recurrent cardiovascular events and improving quality of life in ischaemic stroke and TIA-patients. It combines intensified multi-domain secondary prevention, systematic detection and treatment of post-stroke complications, and patient self-empowerment. Enrolment of 2160 patients with acute ischaemic stroke or TIA (ABCD2-Score ≥ 3) is planned at two study centres in Austria. The co-primary efficacy endpoints are (i) the composite of major recurrent cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, and vascular death) occurring within 12 months after the index event and (ii) one-year health-related quality-of-life measured with the European Quality of Life-5 Dimensions (EQ-5D-3 L) questionaire. Secondary endpoints include all-cause mortality, functional outcome, and target-level achievement in risk factor management.DiscussionThis trial will provide evidence on whether the pragmatic post-stroke intervention program STROKE-CARD can help prevent cardiovascular events and improve quality-of-life within the setting of a high-quality acute stroke care system. In case of success, STROKE-CARD may be implemented in daily clinical routine and serve as a model for other disease management initiatives.Trial registrationClinicalTrials.gov: NCT02156778. (June 5, 2014, retrospectively registered).

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2 ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

A Phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease.

PurposeThe aim of this study was to evaluate the safety and efficacy of OTX-101, a clear nanomicellar aqueous solution of cyclosporine, in the treatment of dry eye disease (DED).Patients and methodsThis was a 12-week multicenter, randomized, prospective, double-masked, vehicle-controlled, dose-ranging clinical trial. Subjects were adults aged ≥18 years, with a total conjunctival staining score of ≥3 and ≤9, and global DED symptom score ≥40 (0–100 visual analogue scale). Following a 14-day vehicle run-in, subjects were randomized in a 1:1:1 ratio to twice daily treatment with OTX-101 0.09%, OTX-101 0.05%, or vehicle for 84 days. Co-primary efficacy end points were changes, from baseline to Day 84, in the total lissamine green conjunctival staining score in the designated study eye and in the global symptom score (both eyes). Secondary end points included total corneal fluorescein staining score, tear breakup time, and Schirmer’s test score.ResultsIn total, 455 subjects were randomized. Subjects treated with active drug experienced greater improvement in conjunctival staining than vehicle-treated patients (P<0.01 for both concentrations). All groups demonstrated improvements in global symptom score, but there were no differences among groups. Nominally significant differences were found between the active drug arms and vehicle for corneal staining scores and Schirmer’s test scores. Most treatment-emergent adverse events were mild in severity; no serious ocular adverse events were reported.ConclusionsBoth concentrations of OTX-101 met the co-primary sign end point (conjunctival staining) but not the co-primary symptom end point. OTX-101 0.09% demonstrated a notable impact on multiple signs of DED relative to vehicle and was well-tolerated.

Estradiol vaginal inserts (4 µg and 10 µg) for treating moderate to severe vulvar and vaginal atrophy: a review of phase 3 safety, efficacy and pharmacokinetic data

Objective: To review safety, efficacy and pharmacokinetic (PK) data from the phase 3 REJOICE trial, which evaluated a 17β-estradiol (E2) softgel vaginal insert approved in 2018 for moderate to severe dyspareunia associated with menopausal vulvar and vaginal atrophy (VVA).Methods: REJOICE (Clinicaltrials.gov: NCT02253173) was a randomized, double-blind, placebo-controlled trial in which women with moderate to severe dyspareunia due to menopausal VVA received 4 µg, 10 µg or 25 µg of an E2 vaginal insert or placebo for 12 weeks. The published data for the recently approved 4 µg and 10 µg doses of the E2 vaginal insert, including four co-primary efficacy endpoints (change from baseline to week 12 in percentages of superficial and parabasal cells, vaginal pH and severity of dyspareunia), safety and PK (which included serum E2 levels measured by gas chromatography and tandem mass spectrometry), are summarized here.Results: Women were randomized to receive the E2 vaginal insert (4 µg [n = 186] or 10 µg [n = 188]; Imvexxya) or placebo (n = 187) in the modified intention-to-treat population. The E2 vaginal insert (4 µg and 10 µg) significantly improved the percentages of superficial and parabasal cells (p < .0001), vaginal pH (p < .0001), and the severity score for dyspareunia (p < .05) from baseline to week 12 compared with placebo. The recently approved E2 vaginal insert was well tolerated, with no clinically significant differences in treatment-emergent or serious adverse events versus placebo. Systemic absorption of E2 with both doses was minimal.Conclusions: The recently FDA-approved E2 softgel vaginal insert (4 µg and 10 µg) was safe and effective over 12 weeks for treating moderate to severe dyspareunia due to menopausal VVA with minimal systemic E2 levels.

Abstract CT078: Tumor mutational burden (TMB) as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab (nivo) + ipilimumab (ipi) in first-line (1L) non-small cell lung cancer (NSCLC): identification of TMB cutoff from CheckMate 568

Abstract Background: Several studies have demonstrated the potential clinical utility of TMB as a biomarker of immune checkpoint blockade in multiple tumor types, including lung cancer. Prior analyses have been retrospective and exploratory, with varying cutoffs and methodologies used to assess TMB. The establishment of a clinically validated cutoff for nivo + ipi is required to confirm the clinical utility of TMB as a predictive biomarker in future studies. CheckMate 568 (NCT02659059) is a large, single-arm, phase 2 study of nivo + ipi in 1L NSCLC. TMB was assessed using Foundation One CDx™ (Foundation Medicine, Inc.) to identify an appropriate TMB cutoff to select patients for 1L nivo + ipi therapy. This cutoff was subsequently validated through a preplanned analysis in CheckMate 227, which evaluated progression-free survival in patients with high TMB as a co-primary endpoint (NCT02477826). Methods: In CheckMate 568, 288 patients with chemotherapy-naive stage IV NSCLC received nivo 3 mg/kg Q2W + ipi 1 mg/kg Q6W for up to 2 years. EGFR- and ALK-targetable NSCLC were excluded. The primary endpoint was objective response rate (ORR) as per independent review. ORR by TMB was a secondary endpoint. TMB was assessed using the validated FoundationOne® CDx assay (Foundation Medicine, Inc.). TMB classification performance with receiver operating characteristic (ROC) curves was used to determine an appropriate TMB cutoff associated with enhanced efficacy of nivo + ipi in 1L NSCLC. Prevalence analyses of TMB and PD-L1 were also conducted. Results: Baseline characteristics and efficacy were similar in both the all treated and TMB-evaluable populations. With a minimum follow-up of 3 months, ORR was 27% in all treated patients. ORR increased in patients with higher TMB, and plateaued with the threshold of ≥10 mutations (mut)/Mb (ORR: 4%, 10%, 44%, and 39% in patients with TMB &amp;lt;5, &amp;lt;10, ≥10, and ≥15 mut/Mb, respectively). ROC analysis of TMB vs ORR for nivo + ipi demonstrated optimal classification performance at 10 mut/Mb. The safety profile for nivo + ipi was consistent with previous reports and no new safety signals were observed. Conclusions: TMB ≥10 mut/Mb was associated with enhanced response to nivo + ipi regardless of PD-L1 expression, with ORRs &amp;gt;40%. This response rate, coupled with the known durability of responses to immuno-oncology agents, compares favorably to historical data with platinum-doublet chemotherapy. Therefore, a cutoff of ≥10 mut/Mb was chosen to define the TMB patient population for the co-primary efficacy endpoint in CheckMate 227. Citation Format: Suresh S. Ramalingam, Matthew D. Hellmann, Mark M. Awad, Hossein Borghaei, Justin Gainor, Julie Brahmer, David R. Spigel, Martin Reck, Kenneth J. O'Byrne, Luis Paz-Ares, Kim Zerba, Xuemei Li, William J. Geese, George Green, Brian Lestini, Joseph D. Szustakowski, Han Chang, Neal Ready. Tumor mutational burden (TMB) as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab (nivo) + ipilimumab (ipi) in first-line (1L) non-small cell lung cancer (NSCLC): identification of TMB cutoff from CheckMate 568 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT078.

Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial

ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer. We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. We assessed safety in all patients who were randomly assigned and received any amount of investigational product. This trial is registered with ClinicalTrials.gov, number NCT01901146 and Eudra, number CT 2012-004319-29. Of 827 patients enrolled, 725 were randomly assigned to receive ABP 980 (n=364) or trastuzumab (n=361). The primary endpoint was assessable in 696 patients (358 who received ABP 980 and 338 who received trastuzumab). Pathological complete response was recorded in 172 (48%, 95% CI 43-53) of 358 patients in the ABP 980 group and 137 (41%, 35-46) of 338 in the trastuzumab group (risk difference 7·3%, 90% CI 1·2-13·4; RR 1·188, 90% CI 1·033-1·366), with the upper bounds of the CIs exceeding the predefined equivalence margins of 13% and 1·318, respectively. Pathological complete response in the central laboratory assessment was seen in 162 (48%) of 339 patients assigned to ABP 980 at baseline and 138 (42%) of 330 assigned to trastuzumab at baseline (risk difference 5·8%, 90% CI -0·5 to 12·0, and RR 1·142, 90% CI 0·993 to 1·312). Grade 3 or worse adverse events during the neoadjuvant phase occurred in 54 (15%) of 364 patients in the ABP 980 group and 51 (14%) of 361 patients in the trastuzumab group, of which the most frequent grade 3 or worse event of interest was neutropenia, occurring in 21 (6%) patients in both groups. In the adjuvant phase, grade 3 or worse adverse events occurred in 30 (9%) of 349 patients continuing ABP 980, 11 (6%) of 171 continuing trastuzumab, and 13 (8%) of 171 who switched from trastuzumab to ABP 980, the most frequent grade 3 or worse events of interest were infections and infestations (four [1%], two [1%], and two [1%]), neutropenia (three [1%], two [1%], and one [1%]), and infusion reactions (two [1%], two [1%], and three [2%]). Two patients died from adverse events judged to be unrelated to the investigational products: one died from pneumonia while receiving neoadjuvant ABP 980 and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab. Although the lower bounds of the 90% CIs for RR and risk difference showed non-inferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that non-superiority was non-conclusive. In our sensitivity analyses based on central laboratory evaluation of tumour samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study. Amgen.

Efficacy and Safety of SER120 Nasal Spray in Patients with Nocturia: Pooled Analysis of 2 Randomized, Double-Blind, Placebo Controlled, Phase 3 Trials

SER120 desmopressin intranasal spray is the first U.S. Food and Drug Administration approved pharmacotherapy for nocturia. We evaluated its efficacy and safety in 2 randomized, double-blind, placebo controlled studies, DB3 and DB4. A total of 1,333 intent to treat patients 50 years old or older with 2.16 or more nocturic voids per night during a 2-week screening period were randomized equally to SER120 intranasal spray 1.66 or 0.83 mcg, or placebo for a 12-week treatment. Co-primary end points were the mean change from baseline in nocturic episodes per night and the percent of patients with a 50% or greater reduction in mean nocturic episodes per night. Secondary end points were the validated INTU (Impact of Nighttime Urination) quality of life questionnaire in DB4, time to the first nocturic void and the percent of nights with 1 or fewer nocturic voids. Each SER120 dose showed statistical significance vs placebo for the 2 co-primary end points, including the mean nocturic episodes per night (-1.4 with 0.83 mcg and -1.5 with 1.66 mcg vs -1.2 with placebo, each p <0.0001), the percent of patients with a 50% or greater reduction in mean nocturic episodes per night (37.9% with 0.83 mcg and 48.7% with 1.66 mcg vs 30.3% with placebo, p = 0.0227 and <0.0001, respectively) as well as for all secondary end points in the pooled analyses. The 1.66 mcg dose demonstrated significant improvements in the INTU score (p = 0.0255). The incidence of hyponatremia, defined as serum sodium 125 mmol/l or less regardless of symptoms or less than 130 mmol/l with symptoms, was 1.1%, 0% and 0.2% in the 1.66 and 0.83 mcg, and placebo groups, respectively. Other adverse events were similar across treatment groups. SER120 demonstrated significant improvements over placebo for co-primary and secondary efficacy end points that corresponded with quality of life improvements. SER120 at each dose had an acceptable safety profile.

PD64-01 THE WATER STUDY CLINICAL RESULTS – A PHASE III BLINDED RANDOMIZED TRIAL OF AQUABLATION VS. TURP WITH BLINDED OUTCOME ASSESSMENT FOR MODERATE-TO-SEVERE LUTS IN MEN WITH BPH

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Surgical Therapy & New Technology III1 Apr 2018PD64-01 THE WATER STUDY CLINICAL RESULTS – A PHASE III BLINDED RANDOMIZED TRIAL OF AQUABLATION VS. TURP WITH BLINDED OUTCOME ASSESSMENT FOR MODERATE-TO-SEVERE LUTS IN MEN WITH BPH Peter Gilling and Claus Roehrborn Peter GillingPeter Gilling More articles by this author and Claus RoehrbornClaus Roehrborn More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2973AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Early reports of Aquablation (robotic, high-velocity waterjet prostate resection) for lower urinary tract symptoms due to benign prostatic hyperplasia suggested efficacy similar to that of TURP. We aimed to compare the safety and efficacy of prostate ablation using Aquablation (A) vs TURP (T). METHODS In this randomized, blinded, multi-center phase III trial, men with moderate-to-severe LUTS related to BPH were assigned to TURP or Aquablation. The trial had a co-primary safety and efficacy endpoint designed to show non-inferiority regarding efficacy. The primary safety endpoint was the occurrence of persistent CD Grade 1 or Grade 2 or higher operative complications at 3 months. The primary efficacy endpoint was the reduction in IPSS score at 6 months. The 12 month data and the urodynamics sub-study results are presented. RESULTS The mean baseline IPSS score, demographic profile, and mean prostate volume (T: 52 mL vs. A: 54 mL, p=0.31) were similar in both arms. Mean operative time was equivalent between the two groups (T: 35.5 vs. A: 32.8 minutes, p=0.28), but mean 'resection' time was significantly lower in the Aquablation group (27 vs. 4 minutes, p<.0001). The primary safety endpoint occurred in 26% of Aquablation subjects and 42% of TURP subjects demonstrating superiority of Aquablation versus TURP. The difference in primary endpoint safety rate was driven mainly by retrograde ejaculation. Persistent retrograde ejaculation in the first 6 months occurred in 10% of Aquablation subjects and 38% of TURP subjects. Mean IPSS scores decreased from 22.9 at baseline to 5.9 and 22.2 to 6.8 at 6 months in the Aquablation and TURP groups, respectively. The IPSS change score at month 6 was 1.8 points larger after Aquablation demonstrating non-inferiority. Urodynamics studies were performed in 64 of the participating subjects at baseline and 6 month follow-up. At 6-month follow-up, [email protected] decreased by 36 and 37 cm H20 respectively (p<.0001 compared to baseline for both arms) with no significant difference in decrease between groups (p=.8919). The number of men urodynamically obstructed decreased from 75% to 22% in Aquablation and 100% to 23% in the TURP group. CONCLUSIONS In patients with moderate-to-severe LUTS due to BPH, surgical prostate ablation using a robotically guided waterjet showed non-inferior symptom relief compared to TURP but with a lower risk of retrograde ejaculation. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1219 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Peter Gilling More articles by this author Claus Roehrborn More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...