A Randomized, Double-Blind, Single-Dose Phase 1 Comparative Pharmacokinetic Study Comparing SB12 (Eculizumab Biosimilar) with Reference Eculizumab in Healthy Volunteers

Background: SB12 has been developed as a biosimilar of the reference product (RP) eculizumab. Eculizumab is a humanized monoclonal antibody (IgG2/4 kappa immunoglobulin) that binds to the human C5 complement protein with high affinity. Binding to this protein blocks its cleavage into C5a and C5b, thereby inhibiting terminal complement-mediated intravascular haemolysis. It is currently indicated for the treatment of patients with paroxysmal nocturnal haemoglobinuria, atypical haemolytic uremic syndrome (aHUS), refractory generalized Myasthenia Gravis (gMG) and Neuromyelitis Optica Spectrum Disorder (NMOSD). Objectives: To demonstrate pharmacokinetic (PK) equivalence and evaluate pharmacodynamic (PD), safety, tolerability, and immunogenicity profiles between SB12 and the RP eculizumab. Methods: This was a double-blind, three-arm, parallel group, and single-dose study in healthy subjects, between 18-55 years of age, randomized in a ratio of 1:1:1 to receive a single 300 mg dose of either SB12, European Union (EU) sourced eculizumab, or United States of America (US) sourced eculizumab via intravenous (IV) infusion for 35 minutes. Blood samples for PK and PD analysis were collected over 64 days. The primary objective of this study was to demonstrate PK similarity between the investigational products (IPs), as assessed by area under the concentration-time curve from time zero to infinity (AUC inf). Secondary PK endpoints included area under the concentration-time curve from time zero to the last quantifiable concentration (AUC last) and maximum observed concentration (C max). Equivalence for the primary endpoint (AUC inf) was determined if 90% confidence intervals (CIs) for the ratio of geometric least squared means (LSMeans) of SB12 to EU sourced eculizumab, SB12 to US sourced eculizumab, and EU sourced eculizumab to US sourced eculizumab was within the equivalence margin of 80.00% to 125.00%, respectively. Other objectives for the study were to evaluate safety, tolerability, immunogenicity, and PD profiles for the IPs. Results: A total of 240 subjects (80 in each treatment group) were enrolled. Back transformation provided the geometric LSMean ratio for the comparison of SB12/EU sourced eculizumab, SB12/US sourced eculizumab and EU sourced eculizumab/US sourced eculizumab for AUC inf were 99.1 % (95.41,102.85), 95.1 % (91.40, 99.04), and 96.0 % (92.16, 100.10), respectively. The corresponding 90% CI was within the pre-defined equivalence margin of 80.00-125.00%, indicating that the each of two treatments are bioequivalent. The profiles of mean terminal complement activity and mean change from baseline of complement activity were superimposable following administration of SB12, EU sourced eculizumab, and US sourced eculizumab. There was a rapid decrease in the complement activity at the end of infusion and then a slow restoration. There was no non-responder in the aspect of the measured complement activity after treatment. There were no deaths or discontinuation of IP due to treatment-emergent adverse events (TEAEs) during the study. Two serious adverse events (SAEs) (renal colic in the SB12 treatment group and back pain in the US eculizumab treatment group) were reported, in 2 subjects. Both events were considered not related to the IP. The proportion of subjects who experienced TEAEs were similar between the SB12, EU sourced eculizumab, and US sourced eculizumab treatment groups (70.0%, 65.0%, and 71.3% of subjects, respectively). The overall incidence of subjects with post-dose anti-drug antibodies (ADA) to eculizumab was 2 (2.5%), 1 (1.3%), and 0 (0.0%) subjects in the SB12, EU sourced eculizumab, and US sourced eculizumab treatment groups, respectively. There was no significant difference between treatment groups. None of the subjects with post-dose ADA to eculizumab had a positive result for neutralizing antibodies. Conclusion: The Phase I study demonstrated PK bioequivalence and showed comparable PD, safety, immunogenicity between SB12 and the RP eculizumab. Disclosures Lee: Samsung Bioepis, Co., Ltd.: Current Employment. Jang: Samsung Bioepis, Co., Ltd.: Current Employment. Kim: Samsung Bioepis, Co., Ltd.: Current Employment. Jeong: Samsung Bioepis, Co., Ltd.: Current Employment. Lee: Samsung Bioepis, Co., Ltd.: Current Employment. Jung: Samsung Bioepis, Co., Ltd.: Current Employment. Demichelis: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol/Celgene: Consultancy, Speakers Bureau; AMGEN: Consultancy, Speakers Bureau; ASH: Research Funding; Jazz: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Abbvie: Consultancy, Speakers Bureau.

Score equivalence of paper-, tablet-, and interactive voice response system-based versions of PROMIS, PRO-CTCAE, and numerical rating scales among cancer patients

Background The study tests the effects of data collection modes on patient responses associated with the multi-item measures such as Patient-Reported Outcomes Measurement System (PROMIS®), and single-item measures such as Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Numerical Rating Scale (NRS) measures. Methods Adult cancer patients were recruited from five cancer centers and administered measures of anxiety, depression, fatigue, sleep disturbance, pain intensity, pain interference, ability to participate in social roles and activities, global mental and physical health, and physical function. Patients were randomized to complete the measures on paper (595), interactive voice response (IVR, 596) system, or tablet computer (589). We evaluated differential item functioning (DIF) by method of data collection using the R software package, lordif. For constructs that showed no DIF, we concluded equivalence across modes if the equivalence margin, defined as ± 0.20 × pooled SD, completely surrounds 95% confidence intervals (CI's) for difference in mean score. If the 95% CI fell totally outside the equivalence margin, we concluded systematic score difference by modes. If the 95% CI partly overlaps the equivalence margin, we concluded neither equivalence nor difference. Results For all constructs, no DIF of any kind was found for the three modes. The scores on paper and tablet were more comparable than between IVR and other modes but none of the 95% CI’s were completely outside the equivalence margins, in which we established neither equivalence nor difference. Percentages of missing values were comparable for paper and tablet modes. Percentages of missing values were higher for IVR (2.3% to 6.5% depending on measures) compared to paper and tablet modes (0.7% to 3.3% depending on measures and modes), which was attributed to random technical difficulties experienced in some centers. Conclusion Across all mode comparisons, there were some measures with CI’s not completely contained within the margin of small effect. Two visual modes agreed more than visual-auditory pairs. IVR may induce differences in scores unrelated to constructs being measured in comparison with paper and tablet. The users of the surveys should consider using IVR only when paper and computer administration is not feasible.

What to make of equivalence testing with a post-specified margin?

In order to determine whether or not an effect is absent based on a statistical test, the recommended frequentist tool is the equivalence test. Typically, it is expected that an appropriate equivalence margin has been specified before any data are observed. Unfortunately, this can be a difficult task. If the margin is too small, then the test's power will be substantially reduced. If the margin is too large, any claims of equivalence will be meaningless. Moreover, it remains unclear how defining the margin afterwards will bias one's results. In this short article, we consider a series of hypothetical scenarios in which the margin is defined post-hoc or is otherwise considered controversial. We also review a number of relevant, potentially problematic actual studies from the clinical trials research, with the aim of motivating a critical discussion as to what is acceptable and desirable in the reporting and interpretation of equivalence tests.

A multi-centre phase 3 study comparing efficacy and safety of Bemfola® versus Gonal-f® in women undergoing ovarian stimulation for IVF

Bemfola (follitropin alfa) (Finox AG, Switzerland), a new recombinant FSH, has a comparable pharmacological profile to that of Gonal-f (Merck Serono, Germany), the current standard for ovarian stimulation. A randomized, multi-centre, Phase 3 study in women undergoing IVF or intracytoplasmic sperm injection (n = 372) showed Bemfola yielding similar efficacy and safety profiles to Gonal-f. Women aged 20–38 years of age were randomized 2:1 to receive a single, daily, subcutaneous 150 IU dose of either Bemfola or Gonal-f. This study tested equivalence in the number of retrieved oocytes using a pre-determined clinical equivalence margin of ±2.9 oocytes. Compared with Gonal-f, Bemfola treatment resulted in a statistically equivalent number of retrieved oocytes (Bemfola 10.8 ± 5.11 versus Gonal-f 10.6 ± 6.06, mean difference: 0.27 oocytes, 95% confidence interval: -1.34–1.32) as well as a similar clinical pregnancy rate per embryo transfer in first and second cycles (Bemfola: 40.2% and 38.5%, respectively; Gonal-f: 48.2% and 27.8%, respectively). No difference in severe ovarian hyperstimulation syndrome was observed between treatment groups (Bemfola: 0.8%; Gonal-f: 0.8%). This study demonstrates similar clinical efficacy and safety profiles between Bemfola and Gonal-f, and suggests that Bemfola can be an appropriate alternative in ovarian stimulation protocols.

POS0612 EXPLORING EQUIVALENCE BETWEEN BIOSIMILAR SB4 AND REFERENCE ETANERCEPT BY ASSESSING EFFECTIVENESS IN RHEUMATOID ARTHRITIS PATIENTS TREATED IN ORDINARY CLINICAL PRACTICE

Background:Biosimilar drugs follow a tailored approval pathway that usually includes a Phase III comparative efficacy randomized controlled trial with a high internal but low external validity. Therefore, observational studies with high external validity are important to reassure patients and physicians that there are no clinically meaningful differences in effectiveness between a biosimilar and its reference drug. A EULAR Task Force systematic review and others have noted that recent comparative effectiveness studies often do not disclose applied analytical methods in sufficient detail, with many studies not adjusting for confounders nor accounting for attrition or missing data. 1,2Objectives:To apply the EULAR Points to Consider for Comparative Effectiveness Research (CER) in an analysis of reference etanercept (ETN) and SB4 biosimilar ETN in patients with rheumatoid arthritis (RA) treated in ordinary clinical practice in Norway.Methods:ETN-naÏve patients with RA starting ETN treatment between January 2010 and July 2018 at five centres in Norway were followed for at least 1 year; the 2 cohorts remained on either ETN or SB4 throughout. The primary outcome was DAS28 at Week 52. This CER has been designed to formally assess equivalence for DAS28, based on the accepted equivalence margin of 0.6.3 Conventional regression and propensity score (PS) models have been applied for the primary outcome evaluation of DAS28 at Week 52. Based on clinical knowledge, the confounders adjusted for in the step-wise PS model were age, gender, DAS28, order of biologics, and concomitant conventional synthetic disease-modifying anti-rheumatic drugs. A standardized difference (d) of <0.1 indicates a good match.Results:In the unmatched sample, there were 575 patients treated with reference ETN and 299 treated with SB4. Before PS matching, baseline mean (SD) DAS28 was different between the ETN and SB4 groups, 4.3 (1.2) vs 4.0 (1.3), (d) = 0.25. After PS matching, there were 176 RA patients in each group; baseline mean (SD) DAS28 was 4.1 (1.2) vs 4.1 (1.3), (d) = 0.05. At Week 52, the difference (mean [95% confidence interval (CI)]) between reference ETN and SB4 for primary outcome DAS28 at Week 52 was -0.02 (-0.33 to 0.29) in the unmatched analysis. Since the entire 95% CI is within the pre-defined equivalence margin of 0.6, equivalence at Week 52 has formally been shown. The analysis of the PS matched groups to Week 52 is ongoing and results will be presented in the poster.Conclusion:Our results show the importance of adopting proper analytical techniques when comparing a biosimilar with its reference product. A conventional regression model may not fully account for differences in key clinical measures (in this instance, disease activity) between the two groups at baseline, and therefore the Week 52 results might be biased. The propensity score matched model ensures comparability of the groups at baseline and therefore the validity of the Week 52 results should be more robust.References:[1]Cantini F and Benucci M. Mandatory, cost-driven switching from originator etanercept to its biosimilar SB4: possible fallout on non-medical switching. Ann Rheum Dis 2020; 79: e13.[2]Lauper K KJ, De Wit M, Fautrel B, et al. A Systematic Review to Inform the EULRA Points to Consider When Analysing and Reporting Comparative Effectiveness Research With Observational Data in Rheumatology. Annals of the Rheumatic Diseases 2020; 79:[3]Fransen J and van Riel PL. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 2005; 23: S93-99.Acknowledgements:The authors wish to acknowledge Janet Addison and Ulrich Freudensprung of Biogen for their intellectual contributions to this abstract and Bjørg Tilde Fevang for providing data from Haukeland University Hospital in Bergen. Editorial support for the preparation of this abstract was provided by Excel Scientific Solutions (Fairfield, CT, USA); funding was provided by Biogen International GmbH.Disclosure of Interests:Glenn Haugeberg Grant/research support from: Biogen, Gunnstein Bakland: None declared, Erik Rødevand: None declared, Inger Johanne Widding Hansen: None declared, Andreas Diamantopoulos: None declared, Are Hugo Pripp: None declared

In Vivo Comparison of Chlorine-Based Antiseptics versus Alcohol Antiseptic for Surgical Hand Antisepsis

Despite being commonly used as effective preparation for surgical hand antisepsis, alcohol solutions have major drawbacks, such as drying effect, emergence of hand eczema, and other diseases. This study aimed to demonstrate the effectiveness of sodium hypochlorite (NaOCl) and hydrogen peroxide (H2O2) as antiseptic in comparison to single sodium hypochlorite and 70% ethanol. In 5-day tests, the effects of 3 antiseptics were established according to standard test methods. The antiseptics were applied to the hands of 82 volunteers, and samples of bacteria were collected on days 1 and 5, immediately after drying and 6 hours later after antiseptic application. Student’s t test and ANOVA were applied in a statistical study. The NaOCl with H2O2 composition demonstrated noninferiority to both sodium hypochlorite only and alcohol products and superiority to these antiseptics on day 5 (P<0.05 at a significance level of 5% for each comparative trial in this day) at equivalence margin of 20%. The effectiveness of the NaOCl plus H2O2 composition as an antiseptic was explained by the formation of singlet oxygen in the system. Together, these data suggest that NaOCl and H2O2 may be an effective hand antisepsis that avoids the drawbacks seen with alcohol solutions.

Differences in Psychological Characteristics Between People With Knee Osteoarthritis From Japan and Australia

BackgroundThe aim of this study was to investigate differences in psychological characteristics between people with knee osteoarthritis (OA) from Japan and Australia.Methods A total of 62 adults from Japan and 168 adults from Australia aged over 50 years with knee pain were included. Japanese data were collected from patients with knee OA diagnosed by medical doctors. Australian data were baseline data from a randomized controlled trial. Psychological characteristics evaluated were depressive symptoms (depression subscale of the 21-item short-form of Depression Anxiety Stress Scale), fear of movement (Brief Fear of Movement Scale for Osteoarthritis), and pain catastrophizing (Pain Catastrophizing Scale). Psychological characteristics were compared between the Japanese and Australian cohorts by calculating 95% confidence intervals (CIs) for difference of the mean. To test for equivalence of the average values of characteristics, the equivalence margin was set at 0.5 standard deviations (SD) of the mean, where these SDs were based on the Australian data. When the 95%CI for the difference of the mean value lay entirely within the range of equivalence margin (i.e. between -0.5 and 0.5 times the Australian SD), the outcome was considered equivalent.ResultsThere were no significant differences between the groups from Japan and Australia for depressive symptoms (mean ± SD; Japan 4.9±5.4, Australia 4.2±4.7) and fear of movement (11.7±3.8, 12.5±3.2, respectively). Mean (95%CI) between group differences were 0.75 (-0.79 to 2.28) for depressive symptoms and -0.77 (-1.77 to 0.22) for fear of movement. Based on the equivalence test, 95%CIs of mean difference between groups for depressive symptoms was within the range of equivalence margin (±2.35). However, the lower limit of the 95% CI of difference in mean for fear of movement (-1.77) was just outside the lower equivalence margin (-1.60). People from Japan with knee OA showed significantly higher pain catastrophizing (20.7±11.0) than those from Australia (14.8±9.6).ConclusionsPeople from Japan with knee OA showed higher pain catastrophizing than people from Australia. The level of depressive symptoms and fear of movement appeared to be equivalent between people from the two countries.

Efficacy and safety of bimatoprost 0.01% formulated in tight junction modulation technology compared to marketed benzalkonium chloride preserved bimatoprost 0.01% ophthalmic solution in healthy beagle dogs

Background: This study was undertaken to compare the efficacy and safety of the new technology tight junction modulation (TJM) bimatoprost 0.01% (TJM-bimatoprost), containing polyhexamethylene biguanide hydrochloride as a preservative, and marketed bimatoprost 0.01% (BKC-bimatoprost) in healthy beagle dogs.Methods: This was a cross-over study and all animals in the study were assigned to one of two treatment arms to receive either TJM-bimatoprost (n=6) or BKC-bimatoprost (n=6) ophthalmic solution. Dosing for period 1 was started on day 3 (8 am everyday) and it continued till day 12. Assessments were carried out every day at 8 am, 9 am, 2 pm and 8 pm throughout the study period till day 17.Results: For the pooled analysis (n=12 in each group) of period 1 and 2, there was a significant decrease (p<0.001) in mean intra-ocular (IOP) 1 hour post administration as compared to the baseline and this trend continued all throughout the study in both treatment arms. Twenty fours after last dose, on day 12, IOP measurements were 14.20±1.59 mmHg and 13.89±1.5 mmHg in the TJM-bimatoprost and the BKC-bimatoprost group respectively. The analysis of the primary end point revealed that 95% confidence interval for the between group differences in mean IOP values were well within the pre-defined equivalence margin of ±1.5 mmHg. In terms of safety, there was no difference in mean pupillary diameter in the TJM-bimatoprost and BKC-bimatoprost group.Conclusions: The results of this study enhance our understanding of the proprietary TJM technology by establishing efficacy and safety of TJM-bimatoprost in animal models.

AB1255 AGREEMENT BETWEEN PATIENT-REPORTED OUTCOME MEASURES COLLECTED VIA A SMARTPHONE APPLICATION VS A TOUCHSCREEN SOLUTION IN AN OUTPATIENT CLINIC AMONG PATIENTS WITH INFLAMMATORY ARTHRITIS: A RANDOMISED, WITHIN-PARTICIPANT TRIAL

Background:Patient-reported outcome measures (PROMs) are essential to understand the patient’s perception of arthritis activity. In Demark, PROMs are registered on a touchscreen in the outpatient clinic. However, some patients find it inconvenient due to e.g. waiting in queue, lack of privacy, uncomfortable seating position, reduced upper limb strength and dexterity with seeing the touchscreen due to deformity of the cervical spine. The widespread use of smartphones makes it possible for patients to register PROMs via an application (app) on their own device.Objectives:The primary aim is to evaluate the agreement (i.e. similarity) between the two devices assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI) status among patients with inflammatory arthritis.Methods:The study was a randomised, crossover, agreement trial (NCT03486613) conducted at Aalborg University Hospital, Denmark. Participants were recruited through an invitation on the touchscreen in the outpatient clinic. Patients with an established diagnosis (≥ 12 months) of rheumatoid arthritis (RA), psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) and experience with the PROM questionnaires (≥ 3 previous registrations) were enrolled and randomised in ratio 1:1 (stratified by diagnosis) to PROM registration through the DANBIO app and the touchscreen in random order. Figure 1A and 1B shows the two devices.The sample size calculation was based on a prespecified equivalence margin of ±0.11 HAQ-DI points (i.e. ≤ half of the minimal important difference of 0.22 points) yielding a power of 99.2% for 60 enrolled patients. There was a wash-out period of 1-2 days between the two device registrations to minimise the potential carryover effect.A paired t-test was used to calculate the mean HAQ-DI score for the two devices and the difference in HAQ-DI score with a 95% confidence interval (CI). A Bland-Altman plot was used to assess limits of agreement (LoA).Results:60 patients (20 with RA, 20 with PsA and 20 with axSpA) were randomised of whom 51.7% were male. Mean age was 53.7 years (range 22-77) and mean disease duration was 12.5 years (range 1.0-34.8).Mean HAQ-DI was 0.608 (95%CI 0.437;0.779) for the DANBIO app and 0.614 (95%CI 0.446;0.783) for the touchscreen (Table 1). Agreement between scores obtained with the two devices is illustrated with Bland-Altman plots in figure 2A and 2B. The paired mean difference of HAQ-DI between the two devices was -0.006 (95%CI -0.0424; 0.030); thus the 95% confidence interval for the mean difference was within the prespecified equivalence margin of ±0.11 HAQ-DI points.Table 1.HAQ-DI scores, difference and LoA for the two devices.App, mean (SD)Touchscreen, mean (SD)Difference, mean (95%CI)LoAMissing valuesHAQ-DI (0-3)0.608 (0.656)0.614 (0.646)-0.006 (-0.042;0.030)-0.277;0.2641Conclusion:The current study showed no statistical or clinically important difference in HAQ-DI measurement captured by a smartphone app or outpatient touchscreen. Therefore, we feel confident that the two devices perform similarly enough to be used interchangeably in patients with inflammatory arthritis.Disclosure of Interests:Line Uhrenholt Speakers bureau: Abbvie, Eli Lilly and Novartis (not related to the submitted work), Robin Christensen: None declared, Lene Dreyer: None declared, Annette Mortensen Speakers bureau: MSD and Eli Lilly (not related to the submitted work)., Ellen-Margrethe Hauge Speakers bureau: Fees for speaking/consulting: MSD, AbbVie, UCB and Sobi; research funding to Aarhus University Hospital: Roche and Novartis (not related to the submitted work)., Niels Steen Krogh: None declared, Mikkel Kramme Abildtoft: None declared, Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Salome Kristensen: None declared

0681 Comparison Of Upper Airway Stimulation Outcomes Between Regions And Bmi Groups From The Adhere Registry

Introduction As factors influencing Upper Airway Stimulation (UAS) effectiveness in obstructive sleep apnea (OSA) patients are of interest, we compared changes in apnea hypopnea index (AHI) and Epworth Sleepiness Scale (ESS) based on region and baseline body mass index (BMI). Methods Patients (15≥AHI≤65) of the ADHERE registry with AHI at one-year were grouped by region (Europe (EU) vs United States (US)), and BMI (≤32kg/m2 vs 32-35kg/m2). T-tests and equivalence testing (if the former non-significant) was performed using two-one-sided t-tests. Equivalence margin for AHI was set between -5 and 5 and -2 and 2 for ESS. Results By December 2019, 553 of 1600 patients completed 1-year follow-up. Average age was 60±11, 75% male, BMI 29±4 kg/m2, ESS=11±6. Median AHI decreased from 33 to 10, median ESS decreased from 11 to 6. Response defined by 50% AHI reduction and &lt;20 was 70%. Both regions had similar improvements in median AHI (EU: 33 to 10, US: 34 to 10, p &lt; 0.001 vs baseline), median ESS (EU: 12 to 7; US: 11 to 6, p&lt;0.001 vs baseline), and treatment response (EU: 71%, US: 68%). The mean AHI and ESS difference between regions met the equivalence margin. (AHI: mean difference: 0.34, CI:-1.78, 2.46, ESS: mean difference: 0.57, CI:-0.04, 1.19). Mean change in AHI at 1-year was equivalent in BMI groups (≤32 kg/m2 vs 32-35 kg/m2 respectively) median difference: -19.6 vs. -18.8; mean difference: -0.48, (CI:-3.95, 2.97) However, treatment response ratio was different; 73% vs. 60%, p=0.02, i.e. higher BMI patients were less likely to achieve AHI &lt; 20. ESS scores were equivalent; median: 6 vs. 7; mean difference: -0.33, CI: [-1.16, 0.47]. Conclusion UAS influence on OSA severity defined by AHI and sleepiness was similar irrespective of region and BMI category, however, treatment response defined by 50% AHI reduction and &lt;20 was greater in those with lower BMI. Support The statistical support was provided by Inspire Medical System.