Rates Of Study Drug Discontinuation Research Articles

Abstract 12470: Sacubitril/Valsartan in Patients With Heart Failure and Deterioration of Kidney Function to Estimated Glomerular Filtration Rate Less Than 30ml/min/1.73m 2 : Insights From PARAGON-HF and PARADIGM-HF

Background: Sacubitril/valsartan is a foundational therapy for patients with heart failure (HF). Although current US FDA labeling does not identify threshold kidney function below which initiation or continuation of sacubitril/valsartan is precluded, guidelines generally identify eGFR<30mL/min/1.73m 2 as a contraindication to therapy. Methods: The RCTs PARAGON-HF and PARADIGM-HF assessed sacubitril/valsartan versus valsartan or enalapril in patients with HF. Patients with eGFR <30 (PARADIGM) or <25 mL/min/1.73 m 2 (PARAGON) at randomization were excluded. Discontinuation below this eGFR during follow-up was not mandated. We examined the effects of sacubitril/valsartan on efficacy and safety in patients experiencing progression of CKD to eGFR<30mL/min/1.73m 2 in follow-up. Results: Among 4,746 patients in PARAGON-HF and 8,346 patients in PARADIGM-HF (with eGFR>30ml/min/1.73m 2 at randomization), 613 (12.9%) and 691 (8.3%), respectively, had an eGFR<30mL/min/1.73m 2 at least once in follow-up. Patients with CKD progression had higher rates of study drug discontinuation and hyperkalemia (>5.5 mmol/L); however, rates remained similar between treatment groups. Patients with deterioration in kidney function to eGFR<30ml/min/1.73m 2 were at a higher risk of the primary composite outcome in both PARAGON-HF (RR 2.08; 95% CI: 1.72-2.52) and PARADIGM-HF (HR 2.32; 95% CI: 1.94-2.76). The incidence of the primary composite outcome was lower in patients treated with sacubitril/valsartan irrespective of deterioration in kidney function to eGFR<30mL/min/1.73m 2 in both PARAGON-HF (P int =0.74) and PARADIGM-HF (P int =0.50); Figure 1 . Conclusion: HF patients with progression of CKD to eGFR<30ml/min/1.73m 2 experience high risk of CV outcomes and continuation of sacubitril/valsartan was associated with persistent benefit. These data support potential continuation of sacubitril/valsartan, even among patients experiencing progression to advanced CKD.

Termination Based on Event Accrual in Per Protocol Versus Intention to Treat in the ROCKET AF Trial

BackgroundIn event‐driven clinical trials, study termination is based on accrual of a target number of primary efficacy events. For noninferiority trials in which superiority is conditionally examined, the ideal cohort in which to track event accrual is unclear. We used data from the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial to determine the effect of primary efficacy‐event tracking in the per‐protocol cohort during the on‐treatment period versus the intention‐to‐treat (ITT) cohort during the ITT period.Methods and ResultsROCKET AF was terminated after accruing 429 primary efficacy events (stroke or systemic embolism) in the per‐protocol cohort during the on‐treatment period for noninferiority. We identified the date on which 429 events occurred in the ITT cohort during the ITT period. We performed noninferiority and superiority analyses based on hypothetical study termination on this date. ROCKET AF would have terminated 226 days earlier if events were tracked during the ITT period. Similar to the main trial findings, rivaroxaban would have met noninferiority versus warfarin for the primary efficacy end point (hazard ratio [HR], 0.77; 95% CI, 0.62–0.96; P<0.001). In contrast to the main trial findings, rivaroxaban would have met superiority for the primary efficacy end point (HR, 0.82; 95% CI, 0.68–0.99; P=0.038). In both termination scenarios, rivaroxaban was associated with a lower risk of intracranial hemorrhage and similar risk of other safety end points.ConclusionsClinical trial termination based on event accrual in the ITT cohort versus the per‐protocol cohort may have important implications on trial results depending on rates of study drug discontinuation and event rates off treatment.

LEFAMULIN EFFICACY AND SAFETY IN ADULTS WITH COMMUNITY-ACQUIRED BACTERIAL PNEUMONIA: POOLED ANALYSIS OF THE LEFAMULIN EVALUATION AGAINST PNEUMONIA (LEAP) 1 AND LEAP 2 TRIALS BY AGE, INCLUDING IN PATIENTS AGED ≥85 YEARS

SESSION TITLE: Chest Infections Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Community-acquired bacterial pneumonia (CABP) is the most common cause of infectious death in US adults aged >65y. Worldwide, the aging population is increasing, and older patients (pts) with CABP are especially at risk, with higher hospitalization and mortality rates than younger pts. Those with advanced age are more vulnerable to having or developing CABP complications, and treatment is often more difficult in these pts (eg, due to multimorbidity, immunosenescence, polypharmacy). The efficacy/safety of lefamulin (LEF), a novel pleuromutilin approved for intravenous (IV) and oral use in adults with CABP, were shown in 2 noninferiority phase 3 trials, LEAP 1 and LEAP 2. Here, we report pooled LEAP 1 and 2 efficacy/safety outcomes by age group (18-64, 65-74, 75-84, and ≥85y). METHODS: In LEAP 1, adults with CABP (PORT risk class III–V) received IV LEF 150mg q12h for 5–7d or moxifloxacin (MOX) 400mg q24h for 7d, with optional IV-to-oral switch (LEF 600mg q12h or MOX 400mg q24h). In LEAP 2, adults with CABP (PORT II–IV) received oral LEF 600mg q12h (5d) or MOX 400mg q24h (7d). Both studies assessed early clinical response (ECR) at 96±24h after first study drug dose in the intent-to-treat (ITT) population (all randomized pts) and investigator assessment of clinical response (IACR) at test of cure (TOC; 5–10d after last dose) in the modified ITT (received ≥1 study drug dose) and clinically evaluable (met predefined evaluability criteria) populations. Treatment-emergent adverse events (TEAEs) were also assessed. RESULTS: In the pooled ITT population, 1289 pts were randomized to LEF (n=646) or MOX (n=643); 772 (59.9%) were aged 18–64y, 297 (23.0%) were 65–74y, 177 (13.7%) were 75–84y, and 43 (3.3%) were ≥85y. Older pts (ages 75–84y, ≥85y) were more likely to have comorbidities (eg, moderate/severe renal impairment, hypertension, arrhythmia) vs younger pts (ages 18–64y, 65–74y). For all age groups, high and similar ECR (LEF ≥88%; MOX ≥82%) and IACR success (LEF ≥82%; MOX ≥83%) rates were seen with each treatment, including in pts aged ≥85y (ECR: 88.5% [LEF] vs 82.4% [MOX]; IACR success: 88.5%-95.5% vs 88.2%-100%). The most common TEAEs were gastrointestinal, with generally similar rates across age groups for LEF (8.6%–15.0%) and MOX (5.9%–14.0%). With both treatments, rates of serious TEAEs and TEAEs leading to death were somewhat lower in younger (3.4%–5.3% and 0.5%–2.6%, respectively) vs older (5.9%–12.4% and 0%–4.5%) pts. Rates of study drug discontinuation due to TEAEs were similar for older (3.5%) and younger (3.0%) pts with LEF, while rates with MOX were higher in older (7.8%) vs younger (2.4%) pts. CONCLUSIONS: LEF efficacy was high across all age groups, including pts aged ≥85y. The AE profile and study drug discontinuation rates were similar across all age groups. CLINICAL IMPLICATIONS: LEF is a promising new option for treating CABP in pts with advanced age and comorbidities at risk of poor outcomes. DISCLOSURES: Employee relationship with Vir Biotech Please note: >$100000 Added 06/12/2020 by Elizabeth Alexander, source=Web Response, value=Salary Former Employee, Holds Stock relationship with Nabriva Therapeutics Please note: $1001 - $5000 Added 06/12/2020 by Elizabeth Alexander, source=Web Response, value=Company Stock Employee relationship with Nabriva Therapeutics Please note: >$100000 Added 06/01/2020 by Steven Gelone, source=Web Response, value=Salary Employee relationship with Nabriva Therapeutics Please note: >$100000 Added 06/01/2020 by Steven Gelone, source=Web Response, value=Ownership interest Employee relationship with Nabriva Therapeutics Please note: >$100000 Added 04/15/2020 by Lisa Goldberg, source=Web Response, value=Salary Employee relationship with Nabriva Therapeutics Please note: $20001 - $100000 Added 04/15/2020 by Lisa Goldberg, source=Web Response, value=Stock Employee relationship with Nabriva Therapeutics Please note: >$100000 Added 04/08/2020 by Andrew Meads, source=Web Response, value=Salary Employee relationship with Nabriva Therapeutics Please note: $5001 - $20000 Added 04/08/2020 by Andrew Meads, source=Web Response, value=Shareholder Consultant relationship with Allergan and Nabriva Therapeutics Please note: $1-$1000 Added 04/07/2020 by Christian Sandrock, source=Web Response, value=Consulting fee Removed 04/07/2020 by Christian Sandrock, source=Web Response Consultant relationship with Allergan Please note: $1-$1000 Added 04/07/2020 by Christian Sandrock, source=Web Response, value=Consulting fee Consultant relationship with Nabriva Therapeutics Please note: $1-$1000 Added 04/07/2020 by Christian Sandrock, source=Web Response, value=Consulting fee Employee relationship with Nabriva Therapeutics Please note: >$100000 Added 06/02/2020 by Jennifer Schranz, source=Web Response, value=Salary

Erratum to: Efficacy and Safety of Intravenous-to-oral Lefamulin, a Pleuromutilin Antibiotic, for the Treatment of Community-acquired Bacterial Pneumonia: The Phase III Lefamulin Evaluation Against Pneumonia (LEAP 1)Trial.

BACKGROUND Lefamulin, a pleuromutilin antibiotic, is active against pathogens commonly causing community-acquired bacterial pneumonia (CABP). The Lefamulin Evaluation Against Pneumonia (LEAP 1) study was a global noninferiority trial to evaluate the efficacy and safety of lefamulin for the treatment of CABP. METHODS In this double-blind study, adults with CABP of Pneumonia Outcomes Research Team risk class ≥III were randomized 1:1 to receive lefamulin at 150 mg intravenously (IV) every 12 hours or moxifloxacin at 400 mg IV every 24 hours. After 6 doses, patients could be switched to an oral study drug if prespecified improvement criteria were met. If methicillin-resistant Staphylococcus aureus was suspected, either linezolid or placebo was added to moxifloxacin or lefamulin, respectively. The US Food and Drug Administration primary endpoint was an early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug in the intent-to-treat (ITT) population (noninferiority margin, 12.5%). The European Medicines Agency co-primary endpoints were an investigator assessment of clinical response (IACR) 5-10 days after the last dose of the study drug in the modified ITT (mITT) and clinically evaluable (CE) populations (noninferiority margin, 10%). RESULTS There were 551 patients randomized (n = 276 lefamulin; n = 275 moxifloxacin). Lefamulin was noninferior to moxifloxacin for ECR (87.3% vs 90.2%, respectively; difference -2.9%, 95% confidence interval [CI] g -8.5 to 2.8) and IACR (mITT, 81.7% vs 84.2%, respectively; difference -2.6%, 95% CI -8.9 to 3.9; CE, 86.9% vs 89.4%, respectively; difference -2.5%, 95% CI -8.4 to 3.4). Rates of study drug discontinuation due to treatment-emergent adverse events were 2.9% for lefamulin and 4.4% for moxifloxacin. CONCLUSIONS Lefamulin was noninferior to moxifloxacin for the primary efficacy endpoints and was generally safe and well tolerated. CLINICAL TRIALS REGISTRATION NCT02559310.

Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF.

IntroductionPatient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation.MethodsROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up).ResultsA total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation.ConclusionsStudy drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes.ClinicalTrials.govNCT00403767.FundingThe ROCKET AF trial was funded by Johnson & Johnson and Bayer.Electronic supplementary materialThe online version of this article (10.1007/s40119-019-00146-6) contains supplementary material, which is available to authorized users.

Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome

BackgroundMore effective treatments are needed for patients with postinfectious, diarrhoea-predominant, irritable bowel syndrome (IBS-D). Accordingly, we conducted a randomised, double-blind, placebo-controlled, 8-week-long trial to assess the efficacy and safety of...

Abstract 078: Implications of Patient-Reported Treatment Satisfaction for Discontinuation of Rivaroxaban versus Warfarin in ROCKET-AF

Background: Patient-reported outcomes and satisfaction are important in both trials and clinical practice and may be associated with treatment adherence. Methods: ROCKET-AF was a randomized, double-blind trial of rivaroxaban versus warfarin for prevention of thromboembolism in patients with atrial fibrillation. In a substudy, we compared treatment satisfaction scores: Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). Patient-driven discontinuation included stopping study drugs due to withdrawal of consent, non-compliance, or loss to follow-up. Rates of discontinuation were calculated for participants above and below the median scores for each scale. Results: Of 14,264 patients in ROCKET AF, 1,181 (8.3%; median age 75 years; 34% women) patients completed both the ACTS and TSQM II questionnaires 4 weeks after starting the study drug. Over a median follow-up of 1.6 years, 450 premature study drug discontinuations occurred, 116 (26%) patient-driven. Patients less satisfied with treatment by the ACTS Benefits and Burdens and TSQM II scales had higher rates of study drug discontinuation ( Table ). Conclusions: Patient-reported satisfaction was lower in patients with study drug discontinuation, suggesting that collecting patient-reported outcomes early in clinical trials may guide interventions that improve adherence and clinical outcomes.

Abstract P4-14-14: Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab

Abstract BACKGROUND: Pertuzumab (P) in combination with trastuzumab (T) and docetaxel (D) is the approved first line SOC in patients with HER2 positive metastatic breast cancer and is approved neoadjuvantly in patients with HER2 positive stage Ib-IIIc breast cancer. Because of its role in heterodimerization with EGFR, P may cause adverse events associated with EGFR antagonists. Diarrhea is the most commonly reported AE due to P. Increased usage of P has generated clinical questions regarding the incidence and management of diarrhea. Here we report safety analyses of diarrhea from three P containing studies. METHODS: The safety population evaluated in this exploratory analysis included 804 patients from CLEOPATRA, 416 patients from NeoSphere, and 223 from TRYPHAENA. Diarrhea incidence, severity (NCI-CTCAE v3.0), and management in P containing arms were analyzed. RESULTS: The incidence and management of diarrhea in MBC (Table 1), EBC (Table 2): CLEOPATRA P+T+D n=408Pla+T+D n=396Incidence of Events n (%)All Grades279 (68)193 (49)≥ Grade 338 (9)20 (5)Median time to 1st event (days) all grades / Interquartile Range (IQR)8 (4,44)23 (6,82)Discontinuation of any study drug8 (0.2)2 (0.6)Treatment n (%)Antidiarrheal treatment164 (40)77 (19) NeoSphere X4 followed by adjuvant FECx3TRYPHAENANeoadjuvant tx followed by T up to 1 yearT+D n=107P+T+D n=107P+T n=108P+D n=94FEC+P+T x3→P+T+D x3 n=72FEC x3 →P+T+D x3 n=75TCH+P x6 n=76Incidence of Events n (%) (neoadjuvant + adjuvant exposure)All Grades41 (38)55 (51)46 (43)53 (56)46 (64)47 (63)55 (72)≥ Grade 34 (4)7 (7)3 (3)5 (5)3 (4)4 (5)9 (12)Median time to 1st event (days) all grades / Interquartile Range (IQR)7 (4,24)8 (3,26)19 (4,117)6 (3,21)9 (4,30)69 (64,82)6 (3,21)Discontinuation of any study drug0000000Treatment n (%)Antidiarrheal treatment13 (12)23 (22)20 (19)28 (30)23 (32)22 (29)31 (41)pertuzumab(P)+trastuzumab(T)+docetaxel(D) FEC= 5FU, epirubicin, cyclophosphamide TCH= docetaxel,(T)carboplatin(C), trastuzumab(H) The overall incidence of diarrhea events is greatest in the first cycle containing P: in CLEOPATRA (P+T+D) 43%, in NeoSphere (P+T+D) 34%, (P+T) 21%, and in TRYPHAENA (FEC+P+T→P+T+D) 40%, (FEC→P+T+D c4) 46%, and (TCH+P) 55%. Of patients experiencing diarrhea, the median number of events (all grades) for patients receiving P+T+D in CLEOPATRA and NeoSphere was 2 and 1 respectively, and 2 for patients receiving TCH+P in TRYPHAENA. CONCLUSIONS: Diarrhea was common in all P containing arms but events were mostly low grade and occurred more often with the first cycle. Events and management were similar in the EBC and MBC setting. Approximately half of patients required antidiarrheal treatment. However, rates of study drug discontinuation due to diarrhea were low. Studies of treatment associated diarrhea management are planned. Citation Format: Swain SM, Schneeweiss A, Gianni L, Stein A, McNally V, Heeson S, Portera C, Yoo B, Cortes JC, Baselga J. Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-14.

Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma

BackgroundThe combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.MethodsWe randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation–positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival.ResultsThe median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy.ConclusionsThe addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600–mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann–La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.)

A Randomized, Double-blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection

A Randomized, Double-blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection

A Randomized Trial of Colchicine for Acute Pericarditis

BackgroundColchicine is effective for the treatment of recurrent pericarditis. However, conclusive data are lacking regarding the use of colchicine during a first attack of acute pericarditis and in the prevention of recurrent symptoms.MethodsIn a multicenter, double-blind trial, eligible adults with acute pericarditis were randomly assigned to receive either colchicine (at a dose of 0.5 mg twice daily for 3 months for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg) or placebo in addition to conventional antiinflammatory therapy with aspirin or ibuprofen. The primary study outcome was incessant or recurrent pericarditis.ResultsA total of 240 patients were enrolled, and 120 were randomly assigned to each of the two study groups. The primary outcome occurred in 20 patients (16.7%) in the colchicine group and 45 patients (37.5%) in the placebo group (relative risk reduction in the colchicine group, 0.56; 95% confidence interval, 0.30 to 0.72; number needed to treat, 4; P<0.001). Colchicine reduced the rate of symptom persistence at 72 hours (19.2% vs. 40.0%, P=0.001), the number of recurrences per patient (0.21 vs. 0.52, P=0.001), and the hospitalization rate (5.0% vs. 14.2%, P=0.02). Colchicine also improved the remission rate at 1 week (85.0% vs. 58.3%, P<0.001). Overall adverse effects and rates of study-drug discontinuation were similar in the two study groups. No serious adverse events were observed.ConclusionsIn patients with acute pericarditis, colchicine, when added to conventional antiinflammatory therapy, significantly reduced the rate of incessant or recurrent pericarditis. (Funded by former Azienda Sanitaria Locale 3 of Turin [now Azienda Sanitaria Locale 2] and Acarpia; ICAP ClinicalTrials.gov number, NCT00128453.)

Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: Results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial

Patients with atrial fibrillation who are vitamin K antagonist (VKA)-naive may have a higher risk of thrombosis and/or bleeding than VKA-experienced patients. Using data from ARISTOTLE, we assessed baseline characteristics and the treatment effect of apixaban versus warfarin in the VKA-naive and VKA-experienced cohorts. We compared rates of study drug discontinuation and time-in-therapeutic range. Overall, 7,800 (43%) were VKA naive, and 10,401 were VKA experienced. At baseline, both groups were similar with respect to age and congestive heart failure, hypertension, age, diabetes, stroke score (CHADS2). Fewer VKA-naive patients had a history of prior stroke (18% vs 21%) or prior bleeding (10% vs 22%) and were more often female (39% vs 33%). The effect of apixaban on the primary efficacy and safety outcomes was similar in VKA-naive (stroke/systemic embolism: hazard ratio [HR] 0.86, 95% CI 0.67-1.11 and major bleeding: HR 0.73, 95% CI 0.59-0.91) and VKA-experienced populations (stroke/systemic embolism: HR 0.73, 95% CI 0.57-0.95, P value for interaction = 0.39 and major bleeding: HR 0.66, 95% CI 0.55-0.80, P value for interaction = 0.50). Permanent study drug discontinuation was numerically less likely in patients receiving apixaban whether they were VKA naive (HR for discontinuation: 0.87, 95% CI 0.79-0.95) or VKA experienced (HR for discontinuation: 0.93, 95% CI 0.85-1.02). Among patients receiving warfarin, the mean/median times in therapeutic range were lower in the VKA-naive group (VKA-naive: 57.5/61.4, VKA-experienced: 66.0/69.1, P < .001). The treatment effects of apixaban (vs warfarin) were not modified by VKA naivety. The rates of stroke/systemic embolism and major bleeding were numerically lower among the patients assigned to apixaban, irrespective of prior VKA use.

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) has durable efficacy and differentiated safety compared to atazanavir boosted by ritonavir plus emtricitabine/tenofovir DF at week 96 in treatment‐naïve HIV‐1‐infected patients

Purpose of the studyThe primary Week 48 analysis of this ongoing, randomized, double‐blind, double‐dummy, active‐controlled Phase 3 international trial of elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) in treatment‐naïve patients demonstrated that Quad was non‐inferior to atazanavir boosted by ritonavir (ATV/r) + FTC/TDF with a differentiated safety profile. We report the Week 96 interim data.MethodsKey eligibility criteria included HIV‐1 RNA≥5,000 c/mL and eGFR≥70 mL/min. Virologic success (HIV‐1 RNA &lt;50 c/mL) at Week 96 was assessed per snapshot algorithm. Adverse events and laboratory data were collected prospectively. Bone mineral density (BMD) was assessed by DEXA scan in a subgroup of patients.Results708 patients (90% male, 74% white, 41% with HIV‐1 RNA &gt;100,000 c/mL) were randomized and treated. At Week 48, Quad was non‐inferior to ATV/r+FTC/TDF (90% vs 87%, difference 3.0%, 95% CI −1.9% to 7.8%). High rates of virologic success were maintained at Week 96 (83% vs 82%, difference 1.1%, 95% CI −4.5% to 6.7%). Subgroup analysis revealed similar rates of virologic success in patients with baseline HIV‐1 RNA &gt;100,000 c/mL (82% vs 80%). Mean CD4 cell increases (cells/mm3) were 256 vs 261 at Week 96. Emergent resistance was infrequent (2% vs&lt;1%). Rates of study drug discontinuation due to adverse events (AEs) were low and comparable (4% vs 6%). Rates of study drug discontinuation due to renal reasons remained low and similar through Week 96 (3 [0.8%] vs 2 [0.6%]); since Week 48, 1 patient in each group discontinued study drug due to serum creatinine (Cr) increase without features of proximal renal tubulopathy. Median increases from baseline in serum Cr (µmol/L [mg/dL]) in Quad vs ATV/r+FTC/TDF at Week 96 (10.6 vs 7.1 [0.12 vs 0.08]) were similar to those at Week 48 (10.6 vs 7.1 [0.12 vs 0.08]). Quad continued to have smaller increases (mmol/L [mg/dL]) in triglycerides (0.06 vs 0.18 [5 vs 16], P=0.012); Quad had greater increases in total cholesterol (0.36 vs 0.21 [14 vs 8], P=0.046) at Week 96 only; changes in LDL and HDL cholesterol were similar. Quad had smaller mean decreases (%) in BMD (hip: −3.16 vs ‐4.19, P=0.069, spine: −1.96 vs −3.54, P=0.049).ConclusionsAt Week 96, Quad demonstrated high rates of virologic suppression with low rates of resistance and a differentiated safety and tolerability profile relative to ATV/r+FTC/TDF. These results support the durable efficacy and long‐term safety of Quad in HIV‐1 infected patients.

Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) has durable efficacy and differentiated safety compared to efavirenz/emtricitabine/tenofovir DF at week 96 in treatment‐naïve HIV‐1‐infected patients

Purpose of the studyThe primary Week 48 analysis of this ongoing, randomized, double‐blind, double‐dummy, active‐controlled Phase 3 trial of elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) in treatment‐naïve patients demonstrated that Quad was non‐inferior to efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF) with a differentiated safety profile. We report the Week 96 interim data.MethodsKey eligibility criteria included HIV‐1 RNA ≥5,000 c/mL and eGFR ≥70 mL/min. Virologic success (HIV‐1 RNA &lt;50 c/mL) at Week 96 was assessed per snapshot algorithm. Adverse events and laboratory data were collected prospectively.Results700 patients (89% male, 63% white, 33% with HIV‐1 RNA &gt;100,000 c/mL) were randomized and treated. At Week 48, Quad was non‐inferior to EFV/FTC/TDF (88% vs 84%, difference +3.6%, 95% CI ‐1.6% to 8.8%). High rates of virologic success were maintained at Week 96 (84% vs 82%, difference 2.7%, 95% CI ‐2.9% to 8.3%). Subgroup analysis revealed similar rates of virologic success in patients with baseline HIV‐1 RNA &gt;100,000 c/mL (81% vs 83%). Mean CD4 cell increase (cells/mm3) was 295 vs 273. Emergent resistance was infrequent (3% vs 3%). Rates of study drug discontinuation due to adverse events (AEs) were low and comparable (5% vs 7%). Rates of neuropsychiatric AEs were lower in Quad than in EFV/FTC/TDF (47% vs 66%, P&lt;0.001), as were rates of rash (21% vs 31%, P=0.006). Drug discontinuation due to renal reasons occurred in 7 (2%) vs 0 patients through Week 96; only two patients discontinued Quad since Week 48 due to serum creatinine (Cr) increase without features of proximal renal tubulopathy. Median changes in serum Cr (µmol/L [mg/dL]) at Week 96 in Quad vs EFV/FTC/TDF (11.5 vs 0.9 [0.13 vs 0.01]) were similar to those at Week 48 (12.4 vs 0.9 [0.14 vs 0.01]). Quad had smaller median increases (mmol/L [mg/dL]) in total (0.23 vs 0.47 [9 vs 18], P&lt;0.001) and LDL cholesterol (0.23 vs 0.41 [9 vs16], P=0.011), and similar increase in triglycerides (0.05 vs 0.09 [4 vs 8], P=0.41).ConclusionsAt Week 96, Quad demonstrated high rates of virologic suppression with low rates of resistance and a differentiated safety and tolerability profile relative to EFV/FTC/TDF. These results support the durable efficacy and long‐term safety of Quad in HIV‐1 infected patients.

Pharmacokinetics and 48 Week Efficacy of Adjusted Dose Indinavir/Ritonavir in Rifampicin-Treated HIV/Tuberculosis-Coinfected Patients: A Pilot Study

HIV/tuberculosis (HIV/TB)-coinfected patients intolerant/resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have limited treatment options. We evaluated the pharmacokinetics (PK)/safety/efficacy of an adjusted dose of indinavir/ritonavir (IDV/r) 600/100 mg plus two NRTIs in HIV/TB-coinfected Thais receiving rifampicin-based anti-TB treatment. This was a prospective, open-label study. Eighteen Thai, HIV/TB-coinfected patients between 18 and 60 years were recruited. IDV/r 600 mg/100 mg plus lamivudine and stavudine were administered every 12 h (bid). When rifampicin was stopped, IDV/r was reduced to 400/100 mg BID. Clinical outcomes, adverse events, and concomitant drugs were intensively collected. Intensive 12-h PK was performed after 2 weeks of IDV/r while on rifampicin. Samples were collected: predosing and 1, 2, 3, 4, 6, 8, 10, and 12 h after drug intake. The median body weight was 55 kg. The median CD4 was 26 cells/μl. The median HIV RNA was 5.05 log(10) copies/ml. Then 15/18 underwent intensive PK at week 2. The median time between initiating rifampicin and IDV/r was 4.5 months. The median duration of rifampicin during study (rifampicin/IDV/r together) was 15.6 weeks. All received a total of 9 months of antituberculous drugs. The geometric means (GM) of indinavir AUC(0-12) and C(12) were 8.11 mg*h/liter and 0.03 mg/liter, respectively. After stopping rifampicin and reducing IDV/r to 400/100 bid, the GM indinavir C(12) increased to 0.68 mg/liter (p=0.004). In all, 8/18 (44%) had asymptomatic ALT elevation and 2/18 (11%) had symptomatic hepatotoxicity requiring IDV/r discontinuation. All 13 patients who remained on IDV/r treatment had HIV RNA <50 copies/ml at 48 weeks. Concomitant use of rifampicin and IDV/r resulted in subtherapeutic indinavir concentrations. Although 44% of them developed asymptomatic Grade 3/4 transaminitis, the rate of study drug discontinuation due to hepatotoxicity was low. Despite good virological outcome in our cohort, prolonged exposure to subtherapeutic indinavir concentrations may lead to treatment failure.

Patient-Reported Quality of Life In Elderly, Newly Diagnosed Multiple Myeloma Patients Treated with Bortezomib-Based Regimens: Results From the Phase 3b UPFRONT Study

Patient-Reported Quality of Life In Elderly, Newly Diagnosed Multiple Myeloma Patients Treated with Bortezomib-Based Regimens: Results From the Phase 3b UPFRONT Study

Comparison of the Safety and Efficacy of Cyclosporine Minimization Versus Cyclosporine Elimination in De Novo Renal Allograft Patients Receiving Sirolimus

The safety and efficacy of concentration-controlled use of sirolimus (SRL) and cyclosporine (CsA) followed by CsA minimization (CsAm) or elimination (CsAe) beginning at week 13 was compared in a phase 4, open-label, randomized (1:1) trial of renal transplant recipients enrolled between March 2004 and November 2005. The primary endpoint was renal function, measured at 12 months using the Nankivell formula, in patients remaining on therapy. Though a total enrollment of 140 patients in each group was planned to provide an 80% power to detect a difference in means, only 207 subjects were enrolled in this study. Demographic characteristics were similar between groups, with 98.1% recipients of first grafts, 69.1% from living donors, and 7.2% diabetics. At 12 months, there were no differences in renal function (61.08 vs 65.24 mL/min, P = .132); incidence of biopsy-confirmed acute rejection (14.3% vs 22.5%, P = .152); and patient (89.5% vs 92.2%, P = .632), graft (87.6% vs 88.2%, P = .999), and death-censored graft (98.1% vs 94.1%, P = .166) survivals between CsAm and CsAe groups, respectively. There were no differences in the overall rate of study-drug discontinuation (32.4% vs 36.3%, P = .562) but more patients discontinued because of lack of efficacy/graft loss in the CsAe group (4.8% vs 14.7%, P = .018). This study was underpowered to demonstrate the superiority of one regimen over the other. In summary, SRL immunotherapy combined with CsA minimization or elimination showed comparative safety and efficacy. Both regimens offer potential treatment options for de novo renal allograft recipients.

Comparison of β-Blockers, Amiodarone Plus β-Blockers, or Sotalol for Prevention of Shocks From Implantable Cardioverter Defibrillators&lt;SUBTITLE&gt;The OPTIC Study: A Randomized Trial&lt;/SUBTITLE&gt;

Implantable cardioverter defibrillator (ICD) therapy is effective but is associated with high-voltage shocks that are painful. To determine whether amiodarone plus beta-blocker or sotalol are better than beta-blocker alone for prevention of ICD shocks. A randomized controlled trial with blinded adjudication of events of 412 patients from 39 outpatient ICD clinical centers located in Canada, Germany, United States, England, Sweden, and Austria, conducted from January 13, 2001, to September 28, 2004. Patients were eligible if they had received an ICD within 21 days for inducible or spontaneously occurring ventricular tachycardia or fibrillation. Patients were randomized to treatment for 1 year with amiodarone plus beta-blocker, sotalol alone, or beta-blocker alone. Primary outcome was ICD shock for any reason. Shocks occurred in 41 patients (38.5%) assigned to beta-blocker alone, 26 (24.3%) assigned to sotalol, and 12 (10.3%) assigned to amiodarone plus beta-blocker. A reduction in the risk of shock was observed with use of either amiodarone plus beta-blocker or sotalol vs beta-blocker alone (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.28-0.68; P<.001). Amiodarone plus beta-blocker significantly reduced the risk of shock compared with beta-blocker alone (HR, 0.27; 95% CI, 0.14-0.52; P<.001) and sotalol (HR, 0.43; 95% CI, 0.22-0.85; P = .02). There was a trend for sotalol to reduce shocks compared with beta-blocker alone (HR, 0.61; 95% CI, 0.37-1.01; P = .055). The rates of study drug discontinuation at 1 year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for beta-blocker alone. Adverse pulmonary and thyroid events and symptomatic bradycardia were more common among patients randomized to amiodarone. Despite use of advanced ICD technology and treatment with a beta-blocker, shocks occur commonly in the first year after ICD implant. Amiodarone plus beta-blocker is effective for preventing these shocks and is more effective than sotalol but has an increased risk of drug-related adverse effects.Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00257959.

Long-term oral platelet glycoprotein IIb/IIIa receptor antagonism with sibrafiban after acute coronary syndromes: Study design of the Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events post-acute cOroNary sYndromes (SYMPHONY) trial

Background Despite progress, atherosclerotic vascular disease remains a major cause of morbidity and mortality. Intravenous therapy with platelet glycoprotein (GP) IIb/IIIa receptor antagonists improves outcome in patients with acute coronary syndromes (ACS). Whether potent long-term antiplatelet therapy with oral GP IIb/IIIa antagonists will further improve outcome at a dose that is tolerable in long-term treatment is unknown. Trial Design SYMPHONY (Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events post-acute cOroNary syndromes) was a randomized, double-blind, aspirin-controlled trial with 2 concentration regimens of sibrafiban, an oral peptidomimetic GP IIb/IIIa antagonist, for long-term treatment instead of aspirin in patients after an ACS. Patients were eligible for SYMPHONY if they presented within 7 days of an ACS (≥20 minutes of ischemic symptoms), had been clinically stable for at least 12 hours, and met one of the following inclusion criteria: ST-segment depression or elevation of at least 0.5 mm or new left bundle branch block with the ACS or elevated creatinine kinase MB more than the upper limit of normal and >3% of total creatine kinase or, if creatine kinase MB was not measured, an elevated level of troponin T or I. Approximately 9000 patients post ACS were randomized 1:1:1 to treatment with either aspirin (80 mg every 12 hours) or high-dose or low-dose sibrafiban every 12 hours. Assignment of tablet strength (3, 4.5, or 6 mg) within the sibrafiban arms was based on body weight and renal function to achieve a target steady-state plasma concentration. The duration of study drug therapy was 90 days. Patients who had intracoronary stenting during the course of the study initially received a blinded stent medication assignment for 2 to 4 weeks based on their initial randomization as follows: aspirin/ticlopidine 250 mg twice daily, low-dose sibrafiban/ticlopidine placebo twice daily, and high-dose sibrafiban/ticlopidine placebo twice daily. After the second interim safety assessment by the Data and Safety Monitoring Board the stent regimen for the low-dose group was modified to include ticlopidine 250 mg twice daily. End Points The primary efficacy end point of SYMPHONY was the 90-day incidence of a composite of all-cause mortality, myocardial infarction or reinfarction, and severe recurrent ischemia. A clinical events classification committee was established to determine the end points of reinfarction and severe recurrent ischemia. The primary safety end points were the incidence of major bleeding or minor bleeding and the combined incidence of major and minor bleeding. Bleeding classification was done by computer algorithm. Tolerability was assessed by the rate of study drug discontinuation from bleeding. (Am Heart J 1999;138:210-8.)