Case Report: Oxytocin and Its Association With Psychotherapy Process and Outcome

The potential of Oxytocin (OT) as a facilitator of psychotherapy has been previously acknowledged, nonetheless, randomized controlled trials thus far have not yielded conclusive results. One approach suggested to clarify empirical inconsistencies is to refine the study hypotheses and data collection process by utilizing an in-depth idiographic exploration of the investigated phenomena. In this case illustration we provide an in-depth analysis comparing two patients hospitalized in a closed psychiatric ward with depression and undergoing psychotherapy twice a week. These two patients were randomly allocated to receive either OT or placebo, twice a day for a period of 4 weeks. Both patients completed longitudinal assessments of process and outcome measures, and therapists' clinical notes were extracted and reviewed. Reliable clinical change was calculated for all outcome and process measures. The results indicated that the patient receiving OT showed significant improvement in interpersonal distress, as well as in anxiety and depression symptoms, while the placebo patient showed no significant change during the study period. Furthermore, while both patients showed no significant changes in the therapeutic alliance ratings, the therapist of the OT patient regularly reported positive changes in alliance in the medical notes, while no such report was observed in the placebo patient. These results suggest that changes produced by OT administration may be more noticeable by the therapist. Implications for future studies aimed at assessing the effect of OT on psychotherapy process and outcome are discussed.

Consistent Efficacy Demonstrated By Avatrombopag in Immune Thrombocytopenia (ITP) Regardless of the Number of Lines of Prior ITP Treatment

Background: Clinical management of ITP depends on both disease severity and risk of bleeding. Treatment typically is considered when platelet counts (PC) fall below 30,000/µL, with a target PC of ≥50,000/µL to mitigate the risk of bleeding. The standard-of-care after failure of 1st line therapy (corticosteroids or intravenous immunoglobulin) has been shifting from splenectomy and rituximab, toward an increased use of thrombopoietin receptor agonists (TPO-RAs), as supported by the recent American Society of Hematology guidelines (Neunert 2019). The TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have well understood efficacy profiles, but ELT has an FDA boxed safety warning for hepatotoxicity, necessitating hepatic function monitoring. Additionally, ELT is an orally administered chelating agent that requires dosing two hours prior to, or four hours after, meals containing polyvalent cations such as calcium or magnesium to mitigate clinically relevant effects on the pharmacokinetic profile (ELT prescribing information). In addition, ROMI, an injection, is typically is administered by a health care practitioner. Avatrombopag (AVA) is an oral TPO-RA for patients with ITP. In clinical trials, AVA rapidly increased platelet counts as early as day 5 and maintained the median PC in the target range (50 to 150×109/L) with chronic dosing. Further, it has an exposure-adjusted safety profile generally comparable to placebo and no boxed safety warning for hepatotoxicity. AVA does not chelate polyvalent cations; therefore it is administered with food, and there are no restrictions regarding meal composition. Aims: To understand how the number of prior ITP treatments impacted the efficacy of avatrombopag in a Phase 3 study. Methods: A 6-month, multicenter, randomized, double-blind, Phase 3 study enrolled 32 AVA and 17 placebo-treated (PBO) patients with ITP. The primary endpoint was the median number of cumulative weeks of platelet count (PC) response (achieving a PC ≥50,000/µL) over the course of the study without rescue medication. Patients receiving any rescue medication during the study were deemed to be non-responders for the remainder of the study. Due to the limited number of study participants, for the post-hoc analyses reported here, the study population was segmented by whether a patient had received <3 or ≥3 prior ITP treatments upon entering the Phase 3 clinical trial. Analyses of efficacy measures were performed in these two sub-populations and are presented for hypothesis generation. Results: Table 1 shows key differences in baseline characteristics between each group, suggesting that those receiving ≥3 prior ITP medications may have had more refractory disease. The median cumulative number of weeks of PC response for the entire population during the study was 12.4 vs. 0.0 for AVA and PBO respectively (p<0.0001), and the mean was 12.0 vs 0.1. For patients receiving <3 prior ITP treatments (n=13), the median and mean cumulative number of weeks of PC response were 13.7 and 12.2 for AVA and 0.0 and 0.0 for PBO; for patients receiving ≥3 prior ITP treatments (n=19), the median and mean were 11.0 and 11.8 weeks respectively for AVA and 0.0 and 0.2 for PBO. The proportion of AVA patients achieving a PC response at least once during the study was 87.5% for the entire population, 84.6% for those receiving <3 and 89.5% for those with ≥3 prior ITP treatments. Only 1 placebo patient ever achieved a response level PC, and that patient had received ≥3 prior ITP treatments. Similar results were noted for achieving a PC response twice or more during the study. A PC response at Day 8 was noted in 65.6% of the AVA patients and 0.0% in PBO (p<0.0001) overall, with 76.9% and 57.9% of AVA patients receiving <3 and ≥3 prior ITP treatments responding at Day 8 respectively. Finally, a durable PC response (achieving a PC ≥50,000/µL for 6 of the final 8 weeks of the study, calculated in an intent-to-treat fashion) was noted in 34.4% of AVA patients and 0.0% for PBO overall (p=0.009), while 38.5% and 31.6% of AVA patients having received <3 or ≥3 prior ITP treatments respectively. Conclusions: In this Phase 3 study, the number of prior ITP treatments a patient had received did not seem to definitively predict PC response to AVA, though on some measures the group receiving <3 fared slightly better. These data suggest that AVA efficacy is relatively consistent, even if a patient has received multiple prior ITP therapies before AVA initiation. Disclosures Vredenburg: Dova Pharmaceuticals: Current Employment. Tian:Dova Pharmaceuticals: Current Employment. Jamieson:Dova Pharmaceuticals: Current Employment. McCrae:Rigel: Consultancy; Dova: Consultancy; Momenta Pharmaceuticals: Consultancy; Novartis: Honoraria.

AB1059 A RANDOMIZED, PLACEBO-CONTROLLED STUDY OF ANAKINRA IN PATIENTS WITH STILL´S DISEASE

Background:Adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (SJIA) are rare autoinflammatory disorders associated with an activated IL-1 pathway, characterized by spiking fever, rash, arthritis, lymphadenopathy, hepatosplenomegaly and serositis. There is a growing understanding that SJIA and AOSD are one disease with different ages of onset, i.e. Still’s disease. The anaSTILLs study (anakinra inStill´sdisease) was designed to further evaluate efficacy and safety of anakinra in patients with Still´s disease across all age groups.Objectives:The primary objective was to demonstrate efficacy of anakinra versus placebo as assessed by ACR30 response with absence of fever at Week 2. Secondary objectives included: early onset of efficacy, sustained efficacy, time to study drug discontinuation, safety, pharmacokinetics, clinical signs and biomarkers.Methods:‘anaSTILLs’ was a randomized, double-blind, placebo-controlled, 12-week study including patients with active and newly diagnosed (6 months) Still´s disease according to adapted ILAR criteria if <16, or Yamaguchi criteria, if ≥16 years of age at disease onset. Patients were randomized to anakinra 2 mg/kg (max 100 mg/day), 4 mg/kg (max 200 mg/day) or placebo.Results:12 patients were randomized and received study drug: 6 anakinra (2 mg/kg n=2, 4 mg/kg n=4) and 6 placebo, the study was terminated early due to slow recruitment. 1 patient on placebo had lymphoma, not Still’s disease, and was excluded; thus in total 11 patients were analyzed for efficacy, 8 were children [median (range) age=4.0 (1-11) years] and 3 were adults [median (range) age=32.0 (25-51) years]. 55% were male and the mean symptom duration was 74.2 days. All patients on anakinra but none on placebo achieved ACR30 response with absence of fever at Week 2 (p-value=0.0022). The efficacy of anakinra was further demonstrated by superiority to placebo in ACR50/70/90 responses with absence of fever at Week 2. All placebo patients discontinued the study within 6 weeks, 2 due to progressive disease, 2 due to lack of efficacy and 1 due to withdrawal by patient. There was a numerically higher proportion with early onset of efficacy (Week 1) in the anakinra group compared to placebo. The ACR30/50/70/90 responses in the anakinra group were sustained throughout the study period. Patients in the anakinra group had a prompt and persistent decrease in CRP and ferritin levels at Week 1, which was not observed in the placebo group. There were no unexpected safety findings. All anakinra patients developed anti-drug antibodies (ADAs) at some timepoint during the study. ADAs were persistent throughout the treatment period, except in one patient. Titers were low to moderate. One placebo patient had low ADA titers at one occasion. No neutralizing antibodies were observed and the ADAs did not appear to impact clinical efficacy or safety.Conclusion:Anakinra is superior to placebo in the treatment of Still’s disease. ADAs occur frequently but do not appear to adversely impact efficacy or safety. These results confirm the benefits of anakinra treatment in patients with active, newly diagnosed Still´s disease across ages.Disclosure of Interests:Laura Schanberg Grant/research support from: Sobi, BMS, Consultant of: Aurinia, UCB, Sanofi, Peter Nigrovic Grant/research support from: Novartis, BMS, Pfizer, Consultant of: Novartis, BMS, Pfizer, Sobi, Miach Orthopedics, Simcere, XBiotech, Quench Bio, Ashley Cooper: None declared, Winn Chatham Grant/research support from: Sobi, Consultant of: Sobi, Shoghik Akoghlanian: None declared, Namrata Singh: None declared, Egla Rabinovich Grant/research support from: AbbVie, UCB Pharma, Janssen Research & Development, Akaluck Thatayatikom: None declared, Alysha Taxter: None declared, Jonathan Hausmann Consultant of: Novartis, Milan Zdravkovic Shareholder of: Sobi, Employee of: Sobi, Sven Ohlman Shareholder of: Sobi, Employee of: Former employee of Sobi, Henrik Andersson Employee of: Sobi, Susanna Cederholm Shareholder of: Sobi, Employee of: Sobi, Margareta Wikén Shareholder of: Sobi, Employee of: Former employee of Sobi, Rayfel Schneider Grant/research support from: Roche, Novartis, Sobi, Pfizer, Consultant of: Sobi, Novartis, Novimmune, Fabrizio De Benedetti Grant/research support from: AbbVie, Pfizer, Novartis, Novimmune, Sobi, Sanofi, Roche, Speakers bureau: AbbVie, Novartis, Roche, Sobi

Quality of life (QoL) and symptom burden in patients (pts) with advanced melanoma during the treatment-free interval (TFI) after discontinuation of nivolumab (NIVO) or NIVO plus ipilimumab (IPI).

9568 Background: The TFI after discontinuation of study therapy has been reported to be longer with NIVO+IPI compared to NIVO or IPI alone, but QoL during the TFI has not been reported in advanced melanoma (MEL) studies. 1-y data from CheckMate (CM) 067 showed maintenance of QoL after treatment (tx) discontinuation with NIVO or NIVO+IPI. Here, we present long-term QoL results from CM 067 during the TFI (period off study tx and free of subsequent therapy), based on an updated 4-y dataset. Methods: In CM 067, 945 pts were randomized 1:1:1 to receive NIVO 3 mg/kg + placebo; NIVO 1 mg/kg + IPI 3 mg/kg × 4, then NIVO 3 mg/kg; or IPI 3 mg/kg × 4 + placebo. Patient-reported outcomes (PRO) were collected using the EORTC QLQ-C30 (5 functional domains, 9 symptoms, global health status) and EQ-5D-3L (utility index, visual analog scale) at baseline, on-tx visits, and follow-up (FU) visits 1 (FU1; 30 d after last dose) and 2 (FU2; 84 d after FU1). EQ-5D-3L was also collected at survival FU visits every 3 mo after FU2 in the first year and every 6 mo thereafter. Within the PRO analysis population, 480 of 764 pts who discontinued protocol tx (for any reason, including drug toxicity; n = 155) had PRO scores, collected prior to initiation of subsequent anticancer therapy, evaluated. Mean changes in PRO scores from last on-tx visit were reported for each FU visit. Results: Across tx arms, PRO scores were maintained from last on-tx visit to FU1 or FU2 for pts who discontinued for any reason. EORTC QLQ-C30 functional and symptom scales remained stable during the TFI. Among pts who discontinued tx due to toxicity, clinically meaningful deterioration in QoL was observed in a few subscales at FU1, but QoL was restored to the same level as the last on-tx visit in all except one subscale by FU2. PRO scores remained stable beyond FU2 for the EQ-5D-3L, regardless of reason for discontinuation. Data interpretation at later FU visits was limited due to smaller sample sizes. Sensitivity analyses for mean change in PRO scores from randomization to FU visits will be presented. Conclusions: QoL was maintained during the TFI, compared to last on-tx visit, in pts with MEL treated with NIVO or NIVO+IPI.

Liquid Formulation of AbobotulinumtoxinA: A 6-Month, Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of a Single Treatment, Ready-to-Use Toxin for Moderate-to-Severe Glabellar Lines

Background Safety and efficacy of botulinum toxin A for glabellar line (GL) treatment are well established. Currently approved formulations require reconstitution before injection. Objectives The authors sought to assess 6-month efficacy, safety, and patient satisfaction of new ready-to-use abobotulinumtoxinA solution for injection (ASI) in patients with moderate-to-severe GL at maximum frown. Methods The authors conducted a phase 3, double-blind, randomized, placebo-controlled trial (NCT02353871). Patients (N = 185) were randomized (2:1) to receive ASI 50 U or placebo. GL severity was evaluated at days 8, 15, 29, 57, 85, 113, 148, and 183 employing a 4-point scale for investigator’s live assessment (ILA) and subject's self-assessment (SSA). Primary endpoint was ILA of GL at maximum frown at day 29, and secondary endpoints were ILA and SSA of GL at maximum frown (all time points), patient satisfaction with GL appearance, time to onset, and duration of action. Results Responder rates were significantly higher for ASI vs placebo (88.3% vs 1.4%; P &lt; 0.0001) at day 29 by ILA and all time points by ILA (P &lt; 0.0001-0.0441) and SSA (P &lt; 0.0001-0.0036). Sixty percent of patients reported onset of treatment response on or before day 3 (P &lt; 0.0001 vs placebo), and in 5% of patients, efficacy by ILA lasted 6 months (day 183; P = 0.0441 vs placebo). Patient satisfaction rates were significantly higher for ASI vs placebo at all visits (P &lt; 0.0001). Safety was comparable with the known abobotulinumtoxinA profile. Conclusions ASI was significantly efficacious for improving moderate or severe GL vs placebo by investigator and patient assessment. ASI was associated with high patient satisfaction, a long duration of action, and comparable safety profile to abobotulinumtoxinA. Level of Evidence: 1

Tofacitinib or adalimumab versus placebo: patient-reported outcomes from OPAL Broaden—a phase III study of active psoriatic arthritis in patients with an inadequate response to conventional synthetic disease-modifying antirheumatic drugs

ObjectivesTofacitinib is an oral Janus kinase inhibitor for treatment of psoriatic arthritis (PsA). We evaluated patient-reported outcomes (PROs) in patients with PsA refractory to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) and tumour necrosis factor inhibitor-naïve in a 12-month, phase III randomised controlled trial (OPAL Broaden [NCT01877668]).MethodsPatients (N=422) received tofacitinib 5 mg or 10 mg twice daily, adalimumab 40 mg subcutaneously every 2 weeks or placebo advancing to tofacitinib 5 mg or 10 mg twice daily at month 3. Least squares mean changes from baseline and percentages of patients reporting improvements ≥minimum clinically important differences (MCID); and scores ≥normative values in: Patient Global Assessment of disease activity (PtGA), Pain, Patient Global Joint and Skin Assessment (PGJS), Short Form-36 Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), EuroQol 5-Dimensions-3-level questionnaire (EQ-5D-3L) and Ankylosing Spondylitis Quality of Life (ASQoL) were determined. Nominal p values were cited without multiple comparison adjustments.ResultsAt month 3, PtGA, Pain, PGJS, FACIT-Fatigue, EQ-5D-3L, ASQoL and SF-36v2 Physical Component Summary (PCS), physical functioning (PF), bodily pain (BP) and vitality domain scores exceeded placebo with both tofacitinib doses (p≤0.05); SF-36v2 social functioning with 5 mg twice daily (p≤0.05). Percentages reporting improvements ≥MCID in PtGA, Pain, PGJS, FACIT-Fatigue, ASQoL and SF-36v2 PCS, PF, BP and general health scores exceeded placebo with both tofacitinib doses (p≤0.05) and were similar with adalimumab.ConclusioncsDMARD-IR patients with active PsA reported statistically and clinically meaningful improvements in PROs with tofacitinib compared with placebo at Month 3.

Initial depression severity and response to antidepressants v. placebo: patient-level data analysis from 34 randomised controlled trials

SummarySeveral often-cited meta-analyses have reported that the efficacy of antidepressant medications depends on the severity of depression. They found that drug–placebo differences increased as a function of initial severity, which was attributed to decreased responsiveness to placebo among patients with severe depression rather than to increased responsiveness to medication. We retested this using patient-level data and also undertaking a meta-analysis of trial-level data from 34 randomised placebo controlled trials (n = 10 737) from the NEWMEDS registry. Although our trial-level data support prevous findings, patient-level data did not show any significant effect of initial depression severity on drug v. placebo difference.

A multicenter, randomized, placebo-controlled trial of endovenous thermal ablation with or without polidocanol endovenous microfoam treatment in patients with great saphenous vein incompetence and visible varicosities

Objectives * Varithena 017 Investigator Group: Michael Vasquez, MD, Venous Institute of Buffalo, Amherst, NY; Antonios Gasparis, MD, Stony Brook University Medical Center, Stony Brook, NY; Kathleen Gibson, MD, Lake Washington Vascular, Bellevue, WA; James Theodore King, MD, Vein Clinics of America, Oakbrook Terrace, IL; Nick Morrison, MD, Morrison Vein Institute, Scottsdale, AZ; Girish Munavalli, MD, Dermatology, Laser & Vein Specialists of the Carolinas, Charlotte, NC; Eulogio J. Sanchez, MD, Batey Cardiovascular Center, Bradenton, FL. Varithena® is a trademark of Provensis Ltd, a BTG International group company. To determine the efficacy and safety of polidocanol endovenous microfoam (PEM 0.5%, 1.0%) and placebo each administered with endovenous thermal ablation. Methods A multicenter, randomized, placebo-controlled, blinded study was conducted in patients with great saphenous vein incompetence and symptomatic and visible superficial venous disease. Co-primary endpoints were physician-assessed and patient-assessed appearance change from Baseline to Week 8. Results A total of 117 patients received treatment (38 placebo, 39 PEM 0.5%, 40 PEM 1%). Physician-rated vein appearance at Week 8 was significantly better with PEM ( p = 0.001 vs. placebo); patient-assessed appearance trended similarly. Polidocanol endovenous microfoam provided improvements in clinically meaningful change in patient-assessed and physician-assessed appearance ( p < 0.05), need for additional treatment ( p < 0.05), saphenofemoral junction reflux elimination, symptoms, and QOL. In PEM recipients, the most frequent adverse event was superficial thrombophlebitis (35.4%) Conclusions Endovenous thermal ablation + PEM significantly improved physician-assessed appearance at Week 8, increased the proportion of patients with a clinically meaningful change in appearance, and reduced need for additional treatment. www.clinicaltrials.gov (NCT01197833)