Predefined Equivalence Margin Research Articles

Influence of Simulated Pre-Hospital Transport, Time to Analysis, and Storage Temperature on S100 Calcium-Binding Protein B Values.

According to in-hospital guidelines, the biomarker, S100 calcium-binding protein B (S100B), is used to rule out intracranial lesions in mild-moderate traumatic brain injury (TBI). It is currently investigated whether S100B is applicable in a pre-hospital setting. The aim was to compare S100B values and hemolysis index in blood samples drawn and stored under simulated pre-hospital conditions to standardized blood samples. Thirty patients undergoing craniotomy at Department of Neurosurgery, Aarhus University Hospital (Aarhus, Denmark) each had six blood samples drawn. Two samples, drawn in in-hospital standardized Beckton Dickinson tubes and pre-hospital Monovette tubes, respectively, were stored as references at 21°C for 30 min. Two samples were stored at 15°C and 29°C, respectively, one sample was stored at prolonged time (60 min), and one sample was transported for 30 min before centrifugation. S100B values were compared by equivalence test with a pre-defined equivalence margin of ±8.5%. There was no clinically relevant difference between samples stored in different tubes, at various temperatures, or time to analysis compared to reference samples. Transported samples had an 11.5% (90% confidence interval [CI], 6.55; 16.61) higher median S100B value and a 430% (95% CI, 279.6; 661.4) higher median hemolysis index compared to reference samples. Three of 30 (10%) patients had an S100B value above guideline cutoff in the transported sample, which was not found in reference samples (false positive). There were no false negatives. In conclusion, S100B values were not influenced by different tubes, temperatures, and time to analysis. Transported samples had higher median S100B values and hemolysis, icterus, and lipemia index compared to reference samples.

Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer.

Bevacizumab is a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) and used for treatments of various cancers. Due to the high costs of bevacizumab treatments, a biosimilar provides an affordable alternative therapy for cancer patients. In this randomized, double-blind, multicenter, phase 3 study, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor were enrolled and randomized (1:1) into IBI305 or bevacizumab groups. Patients received 6 cycles of paclitaxel/carboplatin plus IBI305 or bevacizumab 15 mg/kg intravenously followed by IBI305 or bevacizumab 7.5 mg/kg maintenance until disease progression, unacceptable toxicity or death. The primary endpoint was confirmed objective response rate (ORR) by an independent radiological review committee (IRRC) and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. A total of 450 NSCLC patients were enrolled (224 in IBI305 group and 226 in bevacizumab group). ORRs were 44.3% for IBI305 and 46.4% for bevacizumab, and the ORR ratio was 0.95 (90% CI: 0.803 to 1.135), within the predefined equivalence margin of 0.75 to 1.33. No significant difference in PFS (7.64 vs. 7.77 m, P=0.9987) was observed between the 2 groups. Serious adverse events (AEs) occurred in 33.5% (75/224) of patients in the IBI305 group and 37.6% (85/226) in the bevacizumab group. AEs ≥ grade 3 were similar in the IBI305 and bevacizumab groups [84.4% (189/224) vs. 89.8% (203/226), P=0.085]. IBI305 is similar to bevacizumab in terms of efficacy and safety. Clinicaltrials.org Identifier: NCT02954172. Registered on 3 November 2016. Https://clinicaltrials.gov/.

FKB327, an adalimumab biosimilar, versus the reference product: results of a randomized, Phase III, double-blind study, and its open-label extension

ObjectiveTo compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA).MethodsPatients were randomized 1:1 in a double-blind study (NCT02260791), received 40 mg of FKB327 or RP by subcutaneous injection every other week for 24 weeks (Period I), then re-randomized 2:1, remaining on the same study drug or switching to the other up to week 54 in an open-label extension (Period II, NCT02405780). Efficacy was evaluated using American College of Rheumatology (ACR20) response rate difference at week 24 with equivalence margins of ± 13% and − 12% to + 15% using 95% and 90% confidence intervals (CIs), respectively. Efficacy, serum drug concentrations, immunogenicity, and safety were compared at week 54.ResultsA total of 730 patients were randomized in Period I (n = 367 FKB327, n = 363 RP), and 645 transitioned to Period II (n = 216 FKB327–FKB327, n = 108 FKB327–RP, n = 108 RP–FKB327, n = 213 RP–RP). At week 24, ACR20 response rates were 74.1% with FKB327 versus 75.7% with RP. 95% and 90% CI of the response rate difference were − 7.9 to 4.7% and − 7.3 to 3.6%, respectively, meeting predefined equivalence margins. The ACR20 response rate remained over 70% of patients to week 54 with all treatment sequences. In Period I, mean trough serum drug concentrations were slightly higher for patients receiving FKB327 than those receiving RP. Mean concentrations were stable over time and reflected steady state in Period II. The proportions of patients with samples positive for neutralizing antidrug antibodies (ADAs) were comparable (57.7% with FKB327 vs. 55.5% with RP) at week 24, and no consistent difference in ADA were seen between continuous and switched treatments in Period II. Efficacy was slightly reduced in the small proportion of patients with high ADA titers in all treatment groups. No clinically significant differences were observed in the incidence of commonly reported treatment-emergent adverse events between the treatments across Periods I and II.ConclusionFKB327 was equivalent to RP in clinical efficacy and demonstrated comparable safety and immunogenicity in patients with moderate-to-severe RA. No effect of switching between FKB327 and RP was observed.Trial registrationClinicalTrials.gov, NCT02260791, Registered 29 July 2014.ClinicalTrials.gov, NCT02405780, Registered 17 July 2015.

1565P - A phase III study comparing SB8, a proposed bevacizumab biosimilar, and reference bevacizumab in patients with metastatic or recurrent non-squamous NSCLC

BackgroundSB8 is a proposed biosimilar of the reference bevacizumab (BEV). This study compared the efficacy, safety, pharmacokinetics (PK), and immunogenicity of SB8 to BEV in patients with metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC). MethodsIn this randomised, double-blind, multicentre study, patients were randomised (1:1) to receive SB8 or BEV with paclitaxel and carboplatin Q3W followed by SB8 or BEV maintenance therapy until disease progression, unacceptable toxicity, death, or 1 year from the randomisation of the last patient. The primary endpoint was the best overall response rate (ORR) by 24 weeks of chemotherapy; risk ratio was analyzed in the full analysis set (FAS) and risk difference was analyzed in the per-protocol set (PPS). Secondary endpoints were progression free survival (PFS), overall survival (OS), duration of response (DOR), safety, PK, and immunogenicity. ResultsA total of 763 patients (SB8, n=379; BEV, n=384) were randomized. Baseline characteristics were balanced between SB8 and BEV. In the FAS, the best ORR was 47.6% in SB8 and 42.8% in BEV; the risk ratio was 1.11 and its 90% CI was [0.975, 1.269], which was within the pre-defined equivalence margin of [0.737, 1.357]. In the PPS, the best ORR was 50.1% in SB8 and 44.8% in BEV; the risk difference was 5.3% and its 95% CI was [−2.2%, 12.9%], of which the lower margin was contained within and the upper margin was outside the pre-defined equivalence margin of [−12.5%, 12.5%]. The secondary efficacy endpoints in the FAS were comparable between SB8 vs BEV: median PFS (8.50 vs 7.90 months), median OS (14.90 vs 15.80 months), and median DOR (5.60 vs 5.85 months). The overall incidence of treatment-emergent adverse events (TEAEs) was comparable between SB8 vs BEV (92.1% vs 91.1%). The most frequently occurring TEAEs were alopecia, anaemia, and nausea. PK parameters (Ctrough and Cmax) and the incidence of overall anti-drug antibodies (16.1% vs 11.0%) were comparable between SB8 vs BEV. ConclusionsThis study demonstrated equivalence between SB8 and BEV in terms of best ORR risk ratio. Other efficacy endpoints, safety, PK, and immunogenicity were comparable between SB8 and BEV. Clinical trial identificationNCT02754882. Legal entity responsible for the studySamsung Bioepis Co., Ltd. FundingSamsung Bioepis Co., Ltd. DisclosureM. Reck: Honoraria (self), Advisory / Consultancy: Samsung Bioepis Co., Ltd.; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche. J. Choi: Full / Part-time employment: Samsung Bioepis Co., Ltd. D. Shin: Full / Part-time employment: Samsung Bioepis Co., Ltd. All other authors have declared no conflicts of interest.

In vivo accuracy of tooth surface reconstruction based on CBCT and dental MRI-A clinical pilot study.

Guided implant surgery (GIS) requires alignment of virtual models to reconstructions of three-dimensional imaging. Accurate visualization of the tooth surfaces in the imaging datasets is mandatory. In this prospective clinical study, in vivo tooth surface accuracy was determined for GIS using cone-beam computed tomography (CBCT) and dental magnetic resonance imaging (dMRI). CBCT and 3-Tesla dMRI were performed in 22 consecutive patients (mean age: 54.4±15.2years; mean number of restorations per jaw: 6.7±2.7). Altogether, 92 teeth were included (31 incisor, 29 canines, 20 premolars, and 12 molars). Surfaces were reconstructed semi-automatically and registered to a reference standard (3D scans of stone models made from full-arch polyether impressions). Reliability of both methods was assessed using intraclass correlation coefficients. Accuracy was evaluated using the two one-sided tests procedure with a predefined equivalence margin of ±0.2mm root mean square (RMS). Inter- and intrarater reliability of tooth surface reconstruction were comparable for CBCT and dMRI. Geometric deviations were 0.102±0.042mm RMS for CBCT and 0.261±0.08mm RMS for dMRI. For a predefined equivalence margin, CBCT and dMRI were statistically equivalent. CBCT, however, was significantly more accurate (p≤.0001). For both imaging techniques, accuracy did not differ substantially between different tooth types. Cone-beam computed tomography is an accurate and reliable imaging technique for tooth surfaces in vivo, even in the presence of metal artifacts. In comparison, dMRI in vivo accuracy is lower. Still, it allows for tooth surface reconstruction in satisfactory detail and within acceptable acquisition times.

Measurement equivalence of the English, Chinese and Malay versions of the World Health Organization quality of life (WHOQOL-BREF) questionnaires

BackgroundThe WHOQOL-BREF is a widely used questionnaire for measuring quality of life. It is important to establish the measurement equivalence of various language versions of WHOQOL-BREF so that scores from different language versions may be pooled together. The primary aim of this article was to evaluate the measurement equivalence of the English, Chinese and Malay versions of the WHOQOL-BREF.MethodsWe analysed data from the previously published, cross-sectional, WONDERS study and used linear regression models to adjust for potential confounding variables. Based on equivalence clinical trial methods, measurement equivalence was assessed by comparing 90% confidence interval (CI) of differences in scores across language versions with a predefined equivalence margin of 0.3 SD. Equivalence was achieved if the 90% CI fell within 0.3 SD. Data from 1203 participants, aged above 21 years, were analysed.ResultsParticipants who completed the different language versions of WHOQOL-BREF expectedly differed in age, ethnicity, highest education level, marital status, smoking status and Body Mass Index (BMI). The English and Malay language versions were definitely equivalent for all domains. The English and Chinese language versions were definitely equivalent for physical and environmental domains but inconclusive for psychological and social domains. Likewise, for Chinese and Malay versions.ConclusionThe English, Chinese and Malay language versions of the WHOQOL-BREF questionnaire may be considered equivalent, with evidence being more robust for some domains than the others. Given the large number of people who speak/ read Chinese and Malay, this study has widespread relevance.

Abstract P4-16-14: Meta-analysis of Phase I pharmacokinetic/pharmacodynamic results of proposed biosimilar pegfilgrastim

Abstract Background The long-acting granulocyte colony-stimulating factor (G-CSF) pegfilgrastim is widely used to prevent chemotherapy-induced neutropenia (CIN). Biosimilars could potentially improve sustainability of cancer care. Sandoz proposed biosimilar pegfilgrastim is under development and has been evaluated in Phase I and III studies.1,2 The current meta-analysis uses data from two Phase I studies in healthy volunteers (HVs) comparing pharmacokinetic (PK)/pharmacodynamic (PD) properties of Sandoz proposed biosimilar and EU-reference (Neulasta®) pegfilgrastim. Methods Data from two studies were included: a single-dose, double-blind, parallel-group study (study 1, data on file) and a single-dose, double-blind, crossover study (study 2),3 both in HVs randomized to receive proposed biosimilar or reference biologic (PK/PD analysis populations: study 1, n=93 per arm; study 2, n=169 per arm). Primary PK and PD parameters were AUC0–inf, AUC0–last, Cmax and ANC AUEC0–last, ANC Emax, respectively. For each parameter, geometric mean ratios and confidence intervals (CIs) for treatment comparisons (proposed biosimilar vs reference biologic) from the two studies were combined using meta-analytical techniques with a fixed-effects model. The 90% (PK) or 95% (PD) CIs were calculated and PK/PD biosimilarity was demonstrated if all CIs fell within equivalence margins of 80% to 125%. Non-baseline corrected PD parameters were used. Results The combined CIs of the geometric mean ratios for primary PK and PD parameters were all contained within the predefined equivalence margins. Safety, tolerability and immunogenicity were found to be similar between proposed biosimilar and EU-reference biologic in HVs (data not shown). Combined geometric mean with 90% (PK)/95% (PD) CICombined ratio with 90% (PK)/95% (PD) CI Proposed biosimilarEU-referenceProposed biosimilar vs EU-referencePK parametersAUC0–last (ng×h/mL)N93+16993+169 Geometric mean 90% CI6823 [6122, 7603]6034 [5404, 6738]1.1385 [1.0606, 1.2221]AUC0–inf (ng×h/mL)N92+168a93+168a Geometric mean 90% CI6973 [6268, 7757]6183 [5560, 6876]1.1335 [1.0570, 1.2156]Cmax (ng/mL)N93+16993+169 Geometric mean 90% CI196 [178, 216]180 [163, 198]1.0994 [1.0265, 1.1774]PD parametersAUEC0–last (109×h/L)N93+16993+169 Geometric mean 95% CI4986 [4855, 5121]4952 [4816, 5093]1.0119 [0.9959, 1.0281]Emax (109/L)N93+16993+169 Geometric mean 95% CI36.4 [35.3, 37.5]36.2 [35.1, 37.2]0.9981 [0.9790, 1.0175]AUC=area under serum-concentration curve; AUEC=area under effect curve; CI=confidence interval; Cmax=maximum observed serum concentration; Emax=maximum effect attributable to investigational medicinal product; PD=pharmacodynamic; PK=pharmacokinetic. aOne subject in study 2 had AUC0–inf extrapolated >20% and was excluded from AUC0–inf analysis Conclusions This meta-analysis of two Phase I studies supports PK/PD similarity of Sandoz proposed biosimilar to EU-reference pegfilgrastim. Also, no clinically meaningful differences in safety, tolerability and immunogenicity were found. Sandoz proposed biosimilar pegfilgrastim presents as a sustainable option to manage CIN in patients with cancer. References 1Blackwell et al. Oncologist 2016;21:789–94 2Harbeck et al. Future Oncol 2016;12:1359–67 3Nakov et al. Cancer Res 2018;78:P3-14-10 Citation Format: Nakov R, Wang J, Chen Y, Bellon A, Gattu S, Krendyukov A, Li Y. Meta-analysis of Phase I pharmacokinetic/pharmacodynamic results of proposed biosimilar pegfilgrastim [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-14.

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.

Abstract P5-20-14: Cardiotoxicity in 1 year of treatment with reference trastuzumab and its biosimilar candidate CT-P6 in HER2 positive early stage breast cancer (EBC) patients

Abstract Background CT-P6 is a proposed biosimilar to reference trastuzumab. This trial (NCT02162667) evaluated the similarity of CT-P6 and reference trastuzumab for both efficacy and safety in HER2 positive EBC patients. The primary endpoint, pathological complete response (pCR) rate was entirely within the pre-defined equivalence margin (Stebbing et al., Lancet Oncology 2017). Efficacy and safety were similar between the two treatment groups. We aimed to investigate the cardiotoxicity in the 1 year treatment and follow-up period. Methods A total of 549 patients with HER2 positive EBC were randomized to receive CT-P6 (n=271) or reference trastuzumab (n=278) in combination with docetaxel (Cycles 1-4) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC, Cycles 5-8) in the neoadjuvant setting. CT-P6 or reference trastuzumab was administered at 8 mg/kg (Cycle 1 only) followed by 6 mg/kg every 3 weeks. After surgery, patients received monotherapy of CT-P6 or reference trastuzumab up to 10 cycles in the adjuvant setting. Left ventricular ejection fraction (LVEF) was evaluated by ECHO or MUGA at baseline, every 3 or 4 cycles during treatment and every 6 months thereafter. If LVEF decreased by ≥10 points from baseline and <50%, a reassessment was performed within 3 weeks and the patient was withdrawn from the study treatment if the cardiac toxicity was confirmed. Results Median follow-up period was 19 months. In total, 96% of patients completed 8 cycles of taxane and anthracycline combination therapy during the neoadjuvant period and 90% of patients in each group received 1-year treatment of CT-P6 or reference trastuzumab. The relative dose intensity of study drug was similar, indicating good tolerability of CT-P6 and reference trastuzumab (97.5% and 97.3% during the neoadjuvant period; 98.5% and 98.8% during the adjuvant period). Docetaxel and FEC combination therapies were administered approximately 96% of dose intensity in the two groups. All patients had normal LVEF (≥55%) at baseline. Mean LVEF value was maintained more than 60% during 1-year treatment and follow-up period. Heart failure cases with LVEF decrease (≥10 points from baseline and <50%) were reported to be similar between two groups. Three patients in each group were withdrawn due to LVEF decrease. Adverse events of cardiac disorders were reported to be similar between two groups. All cases were mild or moderate except two cases. Table 1. Summary of heart failure with LVEF decrease and cardiotoxicity CT-P6 (N=271)Reference Trastuzumab (N=278)LVEF decrease ≥ 10 points and below 50%9 (3.3%)7 (2.5%)- Asymptomatic9 (3.3%)6 (2.1%)- Symptomatic01 (0.4%)- Confirmed2 (0.7%)4 (1.4%)- Withdrawn3 (1.1%)3 (1.1%)Cardiac disorder by AEs31 (11.4%)38 (13.7%)- Grade 1 to 230 (11.0%)37 (13.3%)- Grade 3 to 51 (0.4%)11 (0.4%)21 Grade 3 of Adams-Strokes syndrome occurring 5 months after the completion of 1-year treatment; 2 Grade 5 of acute myocardial infarction occurring 10 days after Cycle 1 of the neoadjuvant therapy Conclusions Combination therapy of CT-P6 with taxane/anthracycline and monotherapy of CT-P6 over 1 year period were well tolerated and cardiotoxicity was similar to reference trastuzumab. Citation Format: Esteva FJ, Chung HC, Royce ME, Lee SY, Lee SJ, Stebbing J. Cardiotoxicity in 1 year of treatment with reference trastuzumab and its biosimilar candidate CT-P6 in HER2 positive early stage breast cancer (EBC) patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-14.

Evaluating manufacturing process profile comparability with multivariate equivalence testing: Case study of cell-culture small scale model transfer.

This article studies the Generalized Mahalanobis Distance (GMD) approach proposed by Hoffelder which measures the dissimilarity of two multivariate Gaussian distributions with arbitrary covariance matrices and unequal sample sizes. This investigation demonstrated that, with appropriate adjustment, the GMD approach can achieve the targeted nominal Type I error and provide sufficient power for testing equivalence between two profile populations. The adjusted GMD approach was applied to examine the equivalence of harvest profiles between a 12L small scale model and 2000L manufacturing scale in a transfer study performed at Sanofi Specialty Care Framingham Biologics. The harvest profiles were evaluated based on three critical parameters (Productivity, Lactate Production, and Total Cell Density) and deemed practically equivalent using a pre-defined equivalence margin per the adjusted GMD approach. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:187-195, 2018.

A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer.

509 Background: SB3, a proposed biosimilar to the originator trastuzumab (TRZ), demonstrated similarity to its originator in terms of biological activities and pharmacokinetic (PK) equivalence. This study compared SB3 to TRZ in terms of efficacy, safety, PK, and immunogenicity in patients treated by neoadjuvant therapy for HER2 positive early breast cancer (NCT02149524). Methods: Phase III, randomized, double blind, multicenter study compared neoadjuvant SB3 or TRZ for 8 cycles concurrently given with chemotherapy (docetaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide). Then patients underwent surgery followed by 10 cycles of SB3 or TRZ. The primary endpoint was breast pathologic complete response (bpCR) rate. Equivalence was declared if the 90% confidence interval (CI) of the ratio or the 95% CI of the difference of the bpCR rates in the per-protocol set (PPS) were contained within the pre-defined equivalence margins (0.785, 1.546) and (-13%, 13%), respectively. Secondary endpoints were total pathologic complete response (tpCR), overall response rate (ORR), event-free survival, PK, immunogenicity, and safety. Results: 800 patients were included in PPS. The bpCR rates were 51.7% for SB3 and 42.0% for TRZ. The ratio of bpCR rate was 1.259 and its 90% CI was 1.112-1.426, within the pre-defined equivalence margin. The difference of bpCR rate was 10.70% and its 95% CI was 4.13-17.26; the lower margin was contained within, the upper margin was outside the pre-defined equivalence margin. Secondary endpoints were comparable between SB3 vs TRZ: tpCR rate (45.8% vs 35.8%); ORR (96.3% vs 91.2%). Safety was comparable between SB3 vs TRZ during neoadjuvant period: incidence of treatment-emergent adverse events (96.6% vs 95.2%), most commonly neutropenia, alopecia, and nausea; incidence of serious adverse events (10.5% vs 10.7%). PK equivalence was demonstrated and immunogenicity between SB3 vs TRZ was comparable (0.7% vs 0.0%). Conclusions: Equivalence was demonstrated between SB3 and TRZ based on the ratio of bpCR rates. Safety, PK, and immunogenicity were similar. Complete safety and survival data will follow. Clinical trial information: NCT02149524.

A Randomized Phase I Pharmacokinetic Study Comparing Biosimilar Candidate SB3 and Trastuzumab in Healthy Male Subjects

PurposeThis first-in-human study with SB3 was designed to evaluate the pharmacokinetic (PK) equivalence between SB3 and trastuzumab sourced in the European Union (EU trastuzumab), between SB3 and trastuzumab sourced in the United States (US trastuzumab), and between EU and US trastuzumab (NCT02075073). MethodsIn this randomized, double-blind, parallel group, single-dose comparative PK study, 109 healthy male subjects were randomized to receive a single 6-mg/kg IV dose of SB3, EU -trastuzumab, or US trastuzumab. The PK parameters were calculated using noncompartmental methods. The PK equivalence in terms of AUC0-–∞), AUC0–last, and Cmax for the pairwise comparisons (SB3 vs EU trastuzumab, SB3 vs US trastuzumab, and EU trastuzumab vs US trastuzumab) were determined using the predefined equivalence margin of 0.8 to 1.25. FindingsBaseline demographic characteristics for the randomized subjects were similar across the 3 groups. The 90% CIs for the geometric least square means of the AUC0–∞, AUC0–last, and Cmax were completely contained within the margin of 0.8 to 1.25. The proportions of subjects who experienced adverse events related to the study drug were 36.1%, 44.4%, and 61.1% in the SB3, EU trastuzumab, and US trastuzumab groups, respectively. The most frequently reported adverse events related to the study drug was infusion-related reactions. No subjects had positive results for antidrug antibodies after a single dose of SB3, EU trastuzumab, or US trastuzumab. ImplicationsThis study revealed PK equivalence between SB3 and EU trastuzumab, between SB3 and US trastuzumab, and between EU trastuzumab and US trastuzumab. SB3 is well tolerated without tolerability concerns after single-dose administration in healthy male subjects.

Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin.

LBA503 Background: Trastuzumab has revolutionized treatment of HER2+ breast cancer. Globally accessible alternatives are a critical need. We evaluated Myl-1401O, a proposed trastuzumab biosimilar, as treatment for HER2+ metastatic breast cancer (MBC), based on physicochemical analyses, nonclinical, pharmacokinetic and pharmacodynamic studies*. Methods: Heritage is a double-blind, randomized clinical trial designed to evaluate comparative efficacy and safety of Myl-1401O vs Herceptin. Eligible patients (pts) had centrally confirmed, measurable HER2+ MBC without prior chemotherapy or trastuzumab for metastatic disease. Pts were randomized to receive either Myl-1401O or Herceptin with docetaxel or paclitaxel for a minimum of 8 cycles. Trastuzumab was continued until progression. The primary endpoint was overall response (ORR) at Week 24 by blinded central evaluation using RECIST 1.1. Secondary endpoints include progression free survival (PFS), overall survival, and safety. A sample size of 456 pts was calculated to demonstrate equivalence in ORR at Week 24 for MYL-1401O vs Herceptin, defined as a 90% confidence interval (CI) for the ratio of best ORR within the equivalence margin (0.81, 1.24). Results: 500 pts were randomized, 458 were evaluable for efficacy. 44% had hormone receptor positive MBC, 84% received docetaxel. Week 24 ORR was 69.6% for Myl-14010 compared to 64% for Herceptin. The ratio of ORR was 1.09; both 90% CI (0.974-1.211) and 95% CI (0.954-1.237) were within the pre-defined equivalence margin. Median PFS is not yet reached (41 events for MYL-1401O vs 48 events for Herceptin). Safety was comparable; serious adverse events (primarily neutropenia related) occurred in 38% (MYL-1401O) vs 36% (Herceptin), with 4 fatal events in each arm. There was no significant change in cardiac function from baseline to Week 24 in either arm. Conclusions: MYL-1401O was equivalent to Herceptin, given in combination with a taxane as first-line therapy for MBC, as measured by 24 week ORR. Safety was comparable. The proposed trastuzumab biosimilar MYL-1401O could be a new treatment option for HER2+ MBC. * Presented at: British Pharmacological Society, Pharmacology Meeting; 2015 Dec 15-17; London, UK. Clinical trial information: 2011-001965-42.

Accelerometer-determined Step Counts In Simulated Free-living Activities In Children And Adolescents

PURPOSE: To evaluate step counting accuracy of the ActiGraph GT3X+ accelerometer in waist- and wrist-worn locations during simulated free-living activities among children and adolescents. METHODS: 123 children and adolescents (6-20 years) performed simulated free-living activities (i.e., seated watching a movie and basketball skill development activity) while concurrently wearing accelerometers on their waist and non-dominant wrist. Each activity was performed for 5 minutes and visually tallied steps served as the criterion (steps/min). Accelerometer data were processed using two filters: 1) normal (NF), and 2) low-frequency extension (LFE). Confidence intervals (95%) for the difference (criterion-test method) were generated using the non-parametric bootstrap (n = 5000 replicates) and used within an equivalence testing framework to evaluate accuracy relative to the pre-defined equivalence margins of ± 3 and ± 10 steps/min for movie watching and basketball, respectively. RESULTS: Compared to visually tallied steps (steps/min), both waist and wrist-worn accelerometers over-counted steps taken during movie watching (waist: NF = 0.02 [0, 0.05], LFE = 0.37 [0.23, 0.54]; wrist: NF = 0.50 [0.37, 0.64], LFE = 2.2 [1.64, 2.81]); however, all confidence intervals were completely contained within the pre-defined equivalence margin. Conversely, waist and wrist-worn accelerometers under-counted steps while performing a simulated basketball skill development activity (waist: NF = -36.51 [-40.31, -33.23], LFE = -11.87 [-15.37, -8.95]; wrist: NF = -28.85 [-32.64, -25.51], LFE = -17.43 [-21.19, -14.11]) with none of the associated confidence intervals falling completely within the pre-defined equivalence margin. CONCLUSION: In agreement with direct observation, the ActiGraph GT3X+ detected few false steps during movie watching with the waist-worn location and NF combination performing best. All combinations of wear location and filter choice underestimated step counts during a simulated basketball activity. Given these limited data, applying the LFE filter to a waist-worn device may provide the best overall free-living step count estimates for children and adolescents. Supported by NIH NCHID 1R21HD073807-01A1

A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy

ObjectivesTo compare the efficacy, safety, immunogenicity and pharmacokinetics (PK) of SB2 to the infliximab reference product (INF) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate therapy.MethodsThis is...

A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy

ObjectivesTo compare the efficacy and safety of SB4 (an etanercept biosimilar) with reference product etanercept (ETN) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate (MTX) therapy.MethodsThis is...

Efficacy and safety data of subsequent entry biologics pertinent to nephrology practice: a systematic review.

BackgroundSubsequent entry biologics (SEBs) may soon be a reality in Canadian nephrology practice. Understanding the worldwide experience with these agents will be valuable to Canadian clinicians.ObjectivesTo compare the efficacy and safety data between SEBs used in nephrology practice and their reference biologic.DesignSystematic review.Sources of informationOvid MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of s of Review of Effects, Cochrane Central Register of Controlled Trials.PatientsAdult patients with chronic kidney disease (CKD).MethodsOur systematic review follows the process outlined by Cochrane Reviews. For efficacy data, all randomized controlled trials (RCTs), quasi-RCTs and observational trials in nephrology practice were included. For safety data, case series, case reports, review articles in nephrology practice and pharmacovigilance programs were included as well.ResultsOnly epoetin SEBs trials were published in the literature. Ten studies involving three different epoetin SEBs (epoetin zeta, HX575 and epoetin theta) were included. The mean epoetin dose used did not differ significantly between the SEBs and the reference product. For epoetin zeta and epoetin theta, the mean hemoglobin levels achieved in the studies were similar between the SEBs and the reference epoetin. The HX 575 studies reported a mean absolute change in hemoglobin within the predefined equivalence margin, when compared with the reference biologic. In terms of safety data, 2 cases of pure-red-cell aplasia were linked to the subcutaneous administration of HX 575. Otherwise, the rate of adverse drug reactions was similar when epoetin SEBs were compared with the reference biologic.LimitationsOur analysis is limited by the paucity of information available on SEB use in nephrology with the exception of epoetin SEBs. Methodological flaw was found in one of the epoetin zeta studies which accounted for 45% of pooled results.ConclusionsLittle clinical difference was found between epoetin SEBs and the reference product. Although not deemed clinically important, the financial implication of a possible dose difference between epoetin zeta and reference product should be considered in pharmacoeconomic studies. Ongoing trials are expected to address the risk of pure-red-cell aplasia with HX 575.

Dalteparin versus Enoxaparin for the prevention of venous thromboembolic events in trauma patients.

The use of low-molecular-weight heparin (LMWH) for the chemoprophylaxis of venous thromboembolism (VTE) in trauma patients is supported by Level-1 evidence. Because Enoxaparin was the agent used in the majority of studies for establishing the efficacy of LMWH in VTE, it remains unclear if Dalteparin provides an equivalent effect. To compare Dalteparin to Enoxaparin and investigate their equivalence as VTE prophylaxis in trauma. Trauma patients receiving VTE chemoprophylaxis in the Surgical Intensive Care Unit of a Level-1 Trauma Center from 2009 (Enoxaparin) to 2010 (Dalteparin) were included. The primary outcome was the incidence of clinically significant VTE. Secondary outcomes included heparin-induced thrombocytopenia (HIT), major bleeding, and drug acquisition cost savings. Equivalence margins were set between -5 and 5%. A total of 610 patient records (277 Enoxaparin, 333 Dalteparin) were reviewed. The two study groups did not differ significantly: blunt trauma 67 vs. 62%, p=0.27; mean Injury Severity Score (ISS) 17±10 vs. 16±10, p=0.34; Acute Physiology and Chronic Health Evaluation (APACHE) II score 17±9 vs. 17±10, p=0.76; time to first dose of LMWH 69±98 vs. 65±67h, p=0.57). The rates of deep venous thrombosis (DVT) (3.2 vs. 3.3%, p=1.00), pulmonary emboli (PE) (1.8 vs. 1.2%, p=0.74), and overall VTE (5.1 vs. 4.5%, p=0.85) did not differ. The absolute difference in the incidence of overall VTE was 0.5% [95% confidence interval (CI): -2.9, 4.0%, p=0.85]. The 95% CI was within the predefined equivalence margins. There were no significant differences in the frequency of HIT or major bleeding. The total year-on-year cost savings, achieved with 277 patients during the switch to Dalteparin, was estimated to be $107,778. Dalteparin is equivalent to Enoxaparin in terms of VTE in trauma patients and can be safely used in this population, with no increase in complications and significant cost savings.

Is clinically indicated replacement of peripheral catheters as safe as routine replacement in preventing phlebitis and other complications?

BackgroundPeripheral intravenous catheterisation is the most commoninvasive procedure in hospitalized patients. In a significantpercentage of patients it can be associated with minorcomplications such as phlebitis and infiltration. Seriouscomplications such as catheter-related bloodstream infec-tions (CRBSI) are fortunately rare, occuring in about 0.1 %of intravenous catheters [1]. A regular removal andreplacement of peripheral intravenous catheters (IVC) hasbeen recommended by the US Centers for Disease Controland Prevention (CDC) to reduce the risks of such com-plications [2].However, such approach may lead to discomfort forpatients requiring additional needdlesticks and increasedworkload for clinical staff. Furthermore, it can be a sig-nificant contributor to health-care costs. For these reasons,IVC are already frequently left in place beyond the cur-rently recommended 72–96 h for appropriate reasons suchas a treatment soon to be completed, poor veins, or noavailable staff to cannulate [3].Small randomized clinical trials showed that IVCreplacement based on clinical indication is safe in terms ofdevelopment of phlebitis and other complications as com-pared to IVC routine replacement every 72–96 h [4, 5].Despite this evidence, the 2011 CDC guidelines designateclinically indicated replacement of IVC as an unresolvedissue, indicating that more research is needed [2].SummaryIn a multicentre, non blinded, randomized controlledequivalence trial Rickard and colleagues [6] investigate thesafety, effectiveness and possible benefits of clinicallyindicated replacement of IVC as compared to routinereplacement. Patients were considered eligible if they wereat least 18 years old and they were scheduled or expectedto have a peripheral IVC in situ for 4 days or more. Theexclusion criteria were current bacteraemia, plannedremoval of IVC within 24 h, IVC already in situ for morethan 72 h, IVC inserted in an emergency. 3,283 patientswere enrolled in three university-affiliated hospitals inAustralia and randomized either to IVC replacement everythird calendar day or to a replacement only after thedevelopment of phlebitis, infusion failure or completion oftherapy (clinically indicated IVC replacement). 1,593patients were assigned to the clinically indicated replace-ment group, 1,690 patients were randomized to the routinereplacement group.The primary endpoint was phlebitis during catheterisa-tion or within 48 h after removal; there were several sec-ondary outcomes, including bloodstream infection,infusion failure and mortality. The routine replacement andclinically indicated replacement of IVC were consideredequivalent if the limits of the two-sided 95 % confidenceinterval (CI) for the absolute risk difference were includedinside the predefined equivalence margin of 3 %.

The Short Form 36 English and Chinese versions were equivalent in a multiethnic Asian population

ObjectiveThe primary aim of this article was to evaluate measurement equivalence of the English and Chinese versions of the Short Form 36 version 2 (SF-36v2) and Short Form 6D (SF-6D). Study Design and SettingIn this cross-sectional study, health-related quality of life (HRQoL) was measured from 4,973 ethnic Chinese subjects using the SF-36v2 questionnaire. Measurement equivalence of domain and utility scores for the English- and Chinese-language SF-36v2 and SF-6D were assessed by examining the score differences between the two languages using linear regression models, with and without adjustment for known determinants of HRQoL. Equivalence was achieved if the 90% confidence interval (CI) of the differences in scores, due to language, fell within a predefined equivalence margin. ResultsCompared with English-speaking Chinese, Chinese-speaking Chinese were significantly older (47.6 vs. 55.5 years). All SF-36v2 domains were equivalent after adjusting for known HRQoL. SF-6D utility/items had the 90% CI either fully or partially overlap their predefined equivalence margin. ConclusionThe English- and Chinese-language versions of the SF-36v2 and SF-6D demonstrated equivalence.