Maintenance Trial Research Articles

Health-Related Quality of Life in Polish Patients with Multiple Myeloma Treated in the Phase 3 ATLAS Trial of Post-Transplant Maintenance with Carfilzomib, Lenalidomide, Dexamethasone or Lenalidomide Alone

Introduction Results of the unplanned interim analysis of the ATLAS trial (Dytfeld, Lancet Oncology 2023) suggest a progression-free survival benefit of carfilzomib, lenalidomide, and dexamethasone (KRd) post-transplant maintenance over single-agent lenalidomide (R). Use of triplet combination, with frequent hospital visits and repeated intravenous infusions raises questions about its long-term tolerability and the impact on health-related quality of life (HRQoL) compared with relatively convenient and well-tolerated single-agent oral lenalidomide. Here, we present a descriptive, longitudinal assessment of HRQoL in Polish patients with multiple myeloma treated in the ATLAS trial. Methods ATLAS is an ongoing phase 3 trial that randomized 180 patients with newly-diagnosed multiple myeloma after ASCT to receive maintenance therapy with KRd or R. In the KRd arm, patients with standard-risk cytogenetics who achieved MRD-negativity after cycle 6 de-escalated therapy to receive R alone after cycle 8. HRQoL assessment was not required by the study protocol, however, the FACT/GOG-Ntx questionnaires were collected according to local protocols for post-transplant data collection at 7 Polish sites at screening (approximately 3 months post-transplant) and after cycles (C) 6, 12, 18, 24, 30, and 36. Therefore, the modified intention-to-treat (mITT) population in this analysis consisted of 134 patients enrolled in these sites. The domains evaluated by the FACT/GOG-Ntx questionnaire include physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and neurotoxicity (Ntx). The outcomes are summarized in FACT/GOG-Ntx Trial Outcome Index (TOI, combining PWB, FWB, and Ntx), FACT-G Total Score (PWB, SWB, EWB, and FWB), and FACT/GOG-Ntx Total Score (all five domains). Based on previous reports, the minimally important difference (MID) was defined as a change of at least 10% of the instrument range (Tremblay, BMC Cancer 2021). Student's t-test was used for comparisons between normally distributed variables and Wilcoxon rank-sum test for not normally distributed. Rates of patients experiencing MID were compared using chi-square test. Results HRQoL questionnaires were available for 123 out of 134 patients (92%). The numbers of completed questionnaires at screening, C6, C12, C18, C24, C30, C36 were 115 (86% of randomized patients / 86% of expected patients), 111 (83%/86%), 102 (76%/85%), 93 (69%/85%), 82 (61%/86%), 74 (55%/87%), and 56 (42%/80%), respectively. Throughout the analyzed timepoints, the mean PWB, SWB, EWB, FWB, NTx scores (Figure 1), FACT/GOG-NTx TOI, FACT-G Total Score, and FACT/GOG-Ntx Total Score (Figure 2) did not differ between the two study arms. A similar pattern was observed in the changes in individual patient scores compared to baseline. During the treatment course, the rates of patients experiencing a decrease in HRQoL scores, reaching the MID threshold in at least one evaluation, were consistent in both groups - 19 out of 59 (32%) patients treated with KRd and 20 out of 52 (38%) patients in the R arm (p=0.49) in the FACT/GOG-NTx TOI, 23/59 (39%) in the KRd arm and 21/52 (40%) in the R arm in the FACT-G Total Score (p=0.88), and 24/59 (41%) in the KRd arm and 19/52 (37%) in the R arm in the FACT/GOG-Ntx Total Score (p=0.65). Similarly, there were no differences in the respective results in terms of patients experiencing an increase in HRQoL scores, reaching the MID threshold in at least one evaluation - 8 out of 59 (14%) patients treated with KRd and 11 out of 52 (21%) patients in the R arm (p=0.28) in the FACT/GOG-NTx TOI, 10/59 (17%) in the KRd arm and 13/52 (25%) in the R arm in the FACT-G Total Score (p=0.29), and 8/59 (14%) in the KRd arm and 6/52 (12%) in the R arm in the FACT/GOG-Ntx Total Score (p=0.75). Conclusions The results of this analysis do not imply a negative impact of post-transplant maintenance with carfilzomib, lenalidomide, and dexamethasone compared to single-agent lenalidomide on the HRQoL.

Planned Interim Safety Analysis of the Phase 3 Randomized Trial of Selinexor and Lenalidomide Versus Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Patients with Newly Diagnosed Multiple Myeloma (ALLG MM23; Sealand)

Introduction: Upregulation of Exportin 1(XPO1), a molecule that mediates nuclear export of tumor suppressor proteins, is associated with poor prognosis and resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors in myeloma (MM). Selinexor (S) is an oral selective XPO1 inhibitor, that is approved in combination with bortezomib and dexamethasone to treat adult patients with MM who have received at least one prior therapy. We hypothesize that low dose S when combined with low dose lenalidomide (R) will be synergistic and will improve progression free survival (PFS) compared to R maintenance post autologous stem cell transplant (ASCT) in patients (pts) with transplant eligible (TE) newly diagnosed (NDMM). We report here the results of the planned futility analysis, after at least 30 patients had completed a minimum of 6 months follow-up in the phase III randomized SeaLAND (ALLG MM23) study (ANZCTR12620000291987). Method: Eligible pts were TE NDMM who have had 3 to 6 cycles of induction containing bortezomib (V), dexamethasone ± R. Registration occurred pre-ASCT; screening and randomization occurred from day 75 to 115 post-ASCT. Twenty pts in the lead in safety phase were given low-dose S [40mg (increased to 60mg from C2 if well tolerated) po D1,8,15,22] with R (15mg D1 to 21; 10mg in C1 to 3) in a 28-day cycle. Upon review by the independent safety committee in May 2023, after the first twenty pts had completed 2 cycles of SR, a starting dose of S of 40mg/week was deemed generally safe with no escalation recommended. Subsequent patients were randomized 1:1 to either SR (S capped at 40mg/week) or R. Primary objective was to determine 3-year-PFS; secondary objectives included safety/tolerability and additional efficacy measurements. Results: As of 30 May 2023, 117 pts (70% male) received maintenance (69 pts SR; 48pts R). 103 patients (61 SR and 42 R) had clean data at a cut-off date and were included in this analysis. Median (med) age was 60 (range 34-75). 27.4% of patients had high risk cytogenetics; ISS stage 1,2,3 occurred in 31.5%, 47% and 26.5%, respectively. Med follow-up for the overall group was 11.9 (0.3-28) months, with a med 10 (1-27) cycles [10 (1-27) SR; 9.5 (2-21) R] and 86.1% of patients continued treatment (83.1% SR; 90.7% R). All patients (n=103) had ≥ 1 treatment-emergent adverse event (TEAE); 64% grade (Gr) 3-4 (84% SR, 36% R); SAE occurred in 21% (28% SR, 12% R). Hematologic Gr 3-4 TEAEs were anemia (1.6% SR; 4.8% R), neutropenia (60.7 SR; 28.6% R) and thrombocytopenia (24.6% SR; 0% R). Gastrointestinal TEAE occurred in 50.4% of all patients (67.5% SR, 26.2% R). Diarrhea, nausea and vomiting in the SR (Gd 3-4)/R (Gd 3-4) group occurred in 26.3% (3.3%)/23.8% (2.4%), 57.1% (9.8%)/7.1% (0%), and 8.2% (1.6%)/0% (0%), respectively. The incidence of gastrointestinal TEAE in the SR group decreased from C3 onwards. Infections occurred in 41% of all patients (49% SR, 29% R); Gd 3-4 infections in 9 % (15% SR, 0% R). COVID-19 infections occurred in 16% (13% SR; 19% R), and all but one was Gd 1-2. 1 patient died (SR arm) due to progressive disease. In the SR group, the med RDI (relative dose intensity) of S was 66.7% (20.8-150%), and in the R group; the med RDI of R was 100% (33.3-100%). Most patients in the SR arm (n=61) tolerated S dose between 80mg (20mg per week) to 160mg (40mg per week), which remained consistent with time (figure 1). Conclusion: A dose of S 40mg weekly was generally tolerable when combined with R 10-15mg days 1-21 in a 28-day cycle, as maintenance therapy post ASCT. The safety profile was consistent with each of S and R individually. Recruitment in the ALLG MM23 (SeaLAND) study is ongoing and updated safety and treatment data will be presented at the meeting. Acknowledgement: Patients, their families, and participating ALLG members and member sites. ALLG acknowledges the support of Karyopharm for funding and Selinexor supply.

Tagraxofusp Maintenance Post-Hematopoietic Stem Cell Transplantation Provides Long-Term Survival and Manageable Safety for a Patient with Blastic Plasmacytoid Dendritic Cell Neoplasm

Introduction:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive hematologic malignancy that commonly involves four major compartments: cutaneous, bone marrow/blood, lymph nodes, and central nervous system (CNS). Tagraxofusp (TAG) is a first-in-class therapy directed to CD123, a target expressed in BPDCN, and is the only drug approved to treat BPDCN in the US and EU. TAG has demonstrated high rates of durable response and bridge to allogeneic hematopoietic cell transplantation (allo-HCT)(Pemmaraju N et al NEJM 2019). Historically, patients that undergo allogeneic allo-HCT have been reported to have long-term remissions, particularly if transplanted while in complete response; however, ~50% of patients will relapse post-allo-HCT, and strategies are needed to minimize this risk. No clinical studies to date have been conducted to assess the rate of post-HCT relapse in patients who receive TAG maintenance therapy after allo-HCT. This case study reports on a patient who was successfully treated with TAG therapy after allo-HCT in a phase 2 trial (NCT04317781). Methods and Results: A 68-year-old woman with BPDCN underwent allo-HCT and was enrolled in a TAG post-allo-HCT maintenance trial at the MD Anderson Cancer Center in 2021. Therapy prior to allo-HCT included hydroxyurea and TAG + venetoclax + mini-HyperCVAD for 5 cycles. The patient was in morphologic complete remission with low positivity by flow cytometry (positive for minimal residual disease [MRD]) at the time of allo-HCT. After allo-HCT and prior to TAG maintenance therapy, the patient had persistent cytogenic abnormalities on a bone marrow next-generation sequencing (NGS) panel. The patient received TAG 9 mcg/kg for 3 days on a 28-day cycle after allo-HCT. The patient received TAG in the post-allo-HCT setting for a total of 16 cycles. At mid-treatment (post Cycle 6, prior to Cycle 7) with TAG, the disease was in complete remission, and the bone marrow NGS panel was negative for mutations (MRD negative). The patient did not experience any high-grade toxicity or capillary leak syndrome (CLS); the only toxicity observed was weight gain (Grade 0 per CTCAE), TAG was stopped for that cycle, and the event resolved. After Cycle 16, the patient withdrew consent due to the burden of traveling from another state. Bone marrow NGS testing was repeated prior to discontinuing study treatment, and the panel remained negative for MRD, with disease still in complete remission. Conclusions: This case report demonstrates a patient experiencing a clinically meaningful benefit with TAG maintenance therapy after allo-HCT. Both prolonged survival and manageable safety, in this case, highlight the feasibility of long-term TAG maintenance post-allo-HCT to control BPDCN.

A Phase IB/II Study of Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia (ALL) and B-Cell Non-Hodgkin Lymphoma (NHL) As Post-Allogeneic Blood or Marrow Transplant (alloBMT) Remission Maintenance

Background: AlloBMT can be curative as consolidation for high risk B ALL and NHL. However, transplant-related toxicity and disease relapse limit survival. Post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis limits GVHD and facilitates alternative allograft sources. Following PTCy, cellular immune reconstitution is favorable for strategies to augment anti-tumor immunity. Blinatumomab (blina) is effective in the treatment of CD19+ ALL and NHL. Blina leads to T cell activation that may enhance post-transplant tumor-specific T cell responses, leading to a more potent graft-versus-tumor effect. A study of 21 B ALL pts demonstrated the feasibility of post-transplant blina but did not improve survival when pts universally remained on immunosuppression for at least 1 cycle of treatment (Gaballa. Blood. 2022). We present results of a phase Ib/II trial to assess the tolerability and preliminary efficacy of blina as post-alloBMT remission maintenance in B-cell ALL and NHL in pts off immunosuppression. Methods: Pts ≥1 month-old with high risk CD19+ B ALL or ≥18 years-old with NHL who underwent alloBMT with PTCy were eligible. Pts had to be 60-180 days post-transplant with count recovery and in remission. Pts had to be off immunosuppression for ≥4 weeks prior to treatment, and without a history of grade ≥3 acute GVHD or severe chronic GVHD. Pts could receive 2 cycles of blina if they had evidence of disease (including MRD) at their pre- and/or post-transplant evaluations but otherwise received 1 cycle. Blina was given as a continuous infusion at 9 mcg/day on C1D1-7 and 28 mcg/day on C1D8-28 and C2D1-28. Results: The study closed to accrual on January 31, 2023 following enrollment of 42 pts (26 male/16 female) with a median age of 54 (Range 30-73). Among enrolled pts, 19 had Ph-negative B ALL and 23 had B-cell NHL. All pts underwent reduced-intensity conditioning alloBMT using a regimen of fludarabine, cyclophosphamide, and total body irradiation. Median prior lines of therapy were 2 (range 1-6). Additional transplant details are presented in Table 1. All B ALL pts were in an MRD-negative CR by flow cytometry at a sensitivity of 0.01% at alloBMT. All pts received a single cycle of therapy. Pts started blina a median of 137 days post-transplant (range, 90-182). Four pts failed to complete a full cycle due to G4 transaminitis (1), G4 neutropenia (1), relapse (1), and patient preference in the setting of tremors (1). Grade 3 or 4 adverse events felt to be at least possibly related to the study drug included G3 neutropenia (7%), G4 neutropenia (19%), anemia (5%), G3 ALT (5%), G4 AST (2%), G3 AST (2%), and neurotoxicity (7%). Two pts (5%) developed chronic GVHD following blina requiring the resumption of immunosuppression. At a median follow-up of 40 months post-alloBMT, the 3-year relapse-free survival is 73% (95% CI 54-85%) due to a 24% (95% CI 12-39%) incidence of relapse and a 4% (95% CI 0-17%) incidence of non-relapse mortality, as shown in Figure 2. All 3 (100%) relapsed B ALL pts and 2/6 (33%) relapsed B NHL pts presented with CNS involvement. Four pts with CNS relapse (80%) had CNS involvement prior to alloBMT. Among 2 pts who died without relapse, 1 was unrelated to alloBMT, while the other died of therapy-related myeloid neoplasm. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented. Conclusions: Post-alloBMT maintenance therapy with blina is feasible with minimal toxicity in pts off immunosuppression. Initial survival outcomes are promising with the majority of relapses involving the CNS. A randomized trial of maintenance with blina after alloBMT with PTCy is needed to confirm efficacy in this high-risk population.

Targeted Treatment of Schizophrenia Symptoms as They Manifest, or Continuous Treatment to Reduce the Risk of Psychosis Recurrence.

Current pharmacological treatment of schizophrenia employs drugs that interfere with dopamine neurotransmission, aiming to suppress acute exacerbation of psychosis and maintenance treatment to reduce the risk of psychosis recurrence. According to this treatment scheme, available psychotropic drugs intended to treat negative symptoms, cognitive impairment, or anxiety are administered as add-ons to treatment with antipsychotics. However, an alternative treatment scheme proposes a targeted or intermittent treatment approach, by which antipsychotic drugs are administered upon psychosis exacerbation and discontinued upon remission or stabilization, while negative symptoms, cognitive impairment, or anxiety are treated with specific psychotropics as monotherapy. Along these lines, antipsychotics are renewed only in the event of recurrence of psychotic symptoms. This 50-year-old debate between targeted and continuous treatment schemes arises from disagreements about interpreting scientific evidence and discordant views regarding benefit/risk assessment. Among the debate's questions are: (1) what is the percentage of individuals who can maintain stability without antipsychotic maintenance treatment, and what is the percentage of those who exacerbate despite antipsychotic treatment? (2) how to interpret results of placebo-controlled 9- to 18-month-long maintenance trials in a life-long chronic disorder, and how to interpret results of the targeted trials, some of which are open label or not randomized; (3) how to weigh the decreased risk for psychotic recurrence vs the almost certainty of adverse effects on patient's quality of life. Patients' profiles, preferences, and circumstances of the care provision should be considered as the targeted vs continuous treatment options are considered.

Modified-Release Phosphatidylcholine (LT-02) for Ulcerative Colitis: Two Double-Blind, Randomized, Placebo-Controlled Trials

The aim of this study was to evaluate the efficacy of LT-02, a novel modified-release phosphatidylcholine (PC) formulation, for induction and maintenance of remission in patients with mild to moderate ulcerative colitis (UC) and inadequate response to mesalamine. LT-02 was evaluated in a multicenter double-blind, randomized, placebo-controlled study comprising a 12-week induction trial (PCG-2), followed by a 48-week maintenance trial (PCG-4). In PCG-2, patients were randomized 1:1:1 to treatment with 0.8 g LT-02 4 times daily (QID), 1.6 g LT-02 twice daily (BID), or placebo, respectively. All patients continued to take a standard dose of oral mesalamine (≥2.4 g/day). The primary end point in PCG-2 was deep remission. Patients achieving remission at week 12 were randomly assigned 2:1:1 to 1.6 g LT-02 BID, placebo, or 500 mg mesalamine (3 times daily), respectively, in PCG-4; the primary end point was remission at 48 weeks. PCG-2 was terminated early for futility after a prespecified interim analysis; 466 patients (of 762 planned) were randomized. There was no statistically significant difference in deep remission at week 12 (placebo, 13.5%; LT-02 BID, 14.2%; LT-02 QID, 9.7%). In PCG-4, 150 patients (of approximately 400 planned) were randomized. There was no statistically significant difference in remission rates at week 48 (LT-02 BID, 49.3%; mesalamine, 50.0%; placebo, 43.2%). LT-02 was safe. Despite prior evidence of beneficial effects of PC in phase 2 trials, our induction study withLT-02 in patients with mild to moderate UC was terminated prematurely for futility. Signals of efficacy in maintenance therapy require confirmation in an adequately powered maintenance trial. LT-02 was safe and well-tolerated. gov: NCT02280629, NCT02142725.

Efficacy and safety of upadacitinib maintenance therapy for moderately to severely active ulcerative colitis in patients responding to 8 week induction therapy (U-ACHIEVE Maintenance): overall results from the randomised, placebo-controlled, double-blind, phase 3 maintenance study

Upadacitinib is an oral, selective, and reversible JAK inhibitor with demonstrated efficacy in patients with moderately to severely active ulcerative colitis in a phase 2b induction trial, two phase 3 induction trials (U-ACHIEVE Induction and U-ACCOMPLISH), and a primary analysis of the first 451 patients entering a subsequent maintenance trial (U-ACHIEVE Maintenance). Here, we present overall results from the entire U-ACHIEVE Maintenance population. In this randomised, placebo-controlled, double-blind, phase 3 maintenance study done across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 251 clinical centres in 44 countries, patients aged 16-75 years with moderately to severely active ulcerative colitis (adapted Mayo score 5-9, centrally assessed endoscopic subscore of 2 or 3) for 90 days or more were randomly assigned (2:1) to double-blind upadacitinib 45 mg once daily or placebo induction therapy in the phase 2b induction trial or two phase 3 induction trials. Patients with a clinical response per adapted Mayo score after 8 weeks were randomly reassigned (1:1:1) using web-based interactive response technology to 52 week double-blind maintenance therapy with placebo, upadacitinib 15 mg, or upadacitinib 30 mg once daily. Efficacy was analysed at week 52 in the intention-to-treat population, which included all patients randomly reassigned who received at least one dose of study drug. The primary endpoint was clinical remission per adapted Mayo score. Safety through week 52 was assessed with exposure-adjusted event rates (EAERs; events per 100 patient-years) in upadacitinib 45 mg once daily 8-week induction responders who were enrolled per protocol for 44-week or 52-week maintenance therapy (ie, the intention-to-treat population plus patients who received up to 44 weeks' maintenance therapy under earlier protocol amendments) and received at least one dose of study drug. The study is registered with ClinicalTrials.gov, NCT02819635 and is complete. Between Sept 3, 2016, and Jan 14, 2021 987 patients received the upadacitinib 45 mg once daily induction therapy in the phase 2b trial, U-ACHIEVE Induction, or U-ACCOMPLISH. 681 patients with a clinical response to the induction therapy (319 from U-ACHIEVE Induction, 341 from U-ACCOMPLISH, and 21 from the phase 2b induction trial) received placebo (n=223), upadacitinib 15 mg once daily (n=225), or upadacitinib 30 mg once daily (n=233) in U-ACHIEVE Maintenance and were included in this analysis. A greater proportion of patients achieved the primary endpoint with upadacitinib 15 mg (40·4%) and 30 mg once daily (53·6%) versus placebo (10·8%; both p<0·0001 vs placebo). For safety, 746 patients were analysed, representing 552·9 patient-years of exposure; the most common grade 3-4 treatment-emergent adverse events were worsening of ulcerative colitis in nine (4%) patients with placebo, and COVID-19 pneumonia and cryptococcal pneumonia in two (1%) patients each with upadacitinib 30 mg once daily. Higher EAERs of the following treatment-emergent events of special interest were observed with upadacitinib versus placebo: herpes zoster (6·0 events per 100 patient-years with upadacitinib 15 mg once daily and 7·3 events per 100 patient-years with upadacitinib 30 mg once daily vs none per 100 patient-years with placebo [12 and 16 vs no events, respectively), hepatic disorders (17·0 and 9·2 vs 5·9 events per 100 patient-years [34 and 20 vs eight events, respectively), creatine phosphokinase elevation (8·0 and 10·1 vs 3·7 events per 100 patient-years [16 and 22 vs five events], respectively), and neutropenia (5·5 and 8·7 vs 5·2 events per 100 patient-years [11 and 19 vs seven events], respectively). One (<1% of patients) adjudicated major adverse cardiovascular event occurred with placebo and one (<1% of patients) with upadacitinib 30 mg once daily (EAERs 0·7 and 0·5 events per 100 patient-years, respectively). Two (1% of patients) venous thromboembolic events occurred with upadacitinib 15 mg once daily and two (1% of patients) with upadacitinib 30 mg once daily (EAERs 1·0 and 0·9 events per 100 patient-years, respectively). All adjudicated major adverse cardiovascular events and venous thromboembolic events with upadacitinib occurred in patients with relevant known risk factors. Consistent with the primary analysis done among a smaller population, both maintenance doses of upadacitinib showed a positive benefit-risk profile in patients with moderately to severely active ulcerative colitis. Upadacitinib represents an effective treatment option for this population, for whom a large unmet need persists. AbbVie.

Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression

BackgroundAntidepressants are used to treat acute depression in patients with bipolar I disorder, but their effect as maintenance treatment after the remission of depression has not been well studied.MethodsWe conducted a multisite, double-blind, randomized, placebo-controlled trial of maintenance of treatment with adjunctive escitalopram or bupropion XL as compared with discontinuation of antidepressant therapy in patients with bipolar I disorder who had recently had remission of a depressive episode. Patients were randomly assigned in a 1:1 ratio to continue treatment with antidepressants for 52 weeks after remission or to switch to placebo at 8 weeks. The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide. Key secondary outcomes included the time to an episode of mania or hypomania or depression.ResultsOf 209 patients with bipolar I disorder who participated in an open-label treatment phase, 150 who had remission of depression were enrolled in the double-blind phase in addition to 27 patients who were enrolled directly. A total of 90 patients were assigned to continue treatment with the prescribed antidepressant for 52 weeks (52-week group) and 87 were assigned to switch to placebo at 8 weeks (8-week group). The trial was stopped before full recruitment was reached owing to slow recruitment and funding limitations. At 52 weeks, 28 of the patients in the 52-week group (31%) and 40 in the 8-week group (46%) had a primary-outcome event. The hazard ratio for time to any mood episode in the 52-week group relative to the 8-week group was 0.68 (95% confidence interval [CI], 0.43 to 1.10; P=0.12 by log-rank test). A total of 11 patients in the 52-week group (12%) as compared with 5 patients in the 8-week group (6%) had mania or hypomania (hazard ratio, 2.28; 95% CI, 0.86 to 6.08), and 15 patients (17%) as compared with 35 patients (40%) had recurrence of depression (hazard ratio, 0.43; 95% CI, 0.25 to 0.75). The incidence of adverse events was similar in the two groups.ConclusionsIn a trial involving patients with bipolar I disorder and a recently remitted depressive episode, adjunctive treatment with escitalopram or bupropion XL that continued for 52 weeks did not show a significant benefit as compared with treatment for 8 weeks in preventing relapse of any mood episode. The trial was stopped early owing to slow recruitment and funding limitations. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00958633.)

Correlation of mucosal healing endpoints with long-term clinical and patient-reported outcomes in ulcerative colitis.

We evaluated the clinical relevance of achieving histologic endoscopic mucosal improvement (HEMI) and the more stringent target of histologic endoscopic mucosal remission (HEMR) in the phase 3 maintenance trial of upadacitinib for moderately to severely active ulcerative colitis. Clinical and patient-reported outcomes were assessed in patients with clinical response after 8- or 16-week upadacitinib induction who received 52-week upadacitinib maintenance treatment. Cross-sectional and predictive analyses evaluated the relationship between HEMR or HEMI at Week 8/16 and Week 52, respectively, and outcomes at Week 52. Adjusted odds ratios (aOR) were derived from logistic regressions for patients achieving HEMR or HEMI without HEMR versus those not achieving HEMI. Cross-sectional analyses showed that patients with HEMR had greater odds of achieving all clinical and patient-reported outcomes at Week 52 than those not achieving HEMI. In predictive analyses, patients with HEMR at Week 8/16 had significantly greater odds of achieving clinical remission (aOR = 3.6, p = 0.001) and endoscopic remission (aOR = 3.9, p < 0.001) at Week 52 than patients not achieving HEMI and HEMR. For patients achieving HEMI without HEMR, these odds were lower: clinical remission (aOR = 3.2, p < 0.001) and endoscopic remission (aOR = 2.4, p = 0.010). The odds of achieving clinically meaningful improvements in most patient-reported outcomes were directionally similar between HEMI and HEMR, but not statistically different to patients not achieving HEMI. No hospitalizations or surgeries were observed in patients with HEMR at Week 52. Achievement of HEMR or HEMI is clinically relevant with HEMR being associated with greater likelihood of improvement in long-term clinical and patient-reported outcomes. https://www. gov NCT02819635.

Exploratory analysis of reflective, reactive, and homeostatic eating behaviour traits on weight change during the 18-month NoHoW weight maintenance trial

Behaviour change interventions for weight management have found varied effect sizes and frequent weight re-gain after weight loss. There is interest in exploring whether differences in eating behaviour can be used to develop tailored weight management programs. This secondary analysis of an 18-month weight maintenance randomised controlled trial (RCT) aimed to investigate the association between individual variability in weight maintenance success and change in eating behaviour traits (EBT). Data was analysed from the NoHoW trial (Scott et al., 2019), which was designed to measure processes of change after weight loss of ≥5% body weight in the previous year. The sample included 1627 participants (mean age = 44.0 years, SD = 11.9, mean body mass index (BMI) = 29.7 kg/m2, SD = 5.4, gender = 68.7% women/31.3% men). Measurements of weight (kg) and 7 EBTs belonging to domains of reflective, reactive, or homeostatic eating were taken at 4 time points up to 18-months. Increases in measures of ‘reactive eating’ (binge eating, p < .001), decreases in ‘reflective eating’ (restraint, p < .001) and changes in ‘homeostatic eating’ (unlimited permission to eat, p < .001 and reliance on hunger and satiety cues, p < .05) were significantly and independently associated with concomitant weight change. Differences in EBT change were observed between participants who lost, maintained, or re-gained weight for all EBTs (p < .001) except for one subscale of intuitive eating (eating for physical reasons, p = .715). Participants who lost weight (n = 322) exhibited lower levels of reactive eating and higher levels of reflective eating than participants who re-gained weight (n = 668). EBT domains can identify individuals who need greater support to progress in weight management interventions. Increasing reflective eating and reducing reactive eating may enhance weight management success.

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis

BackgroundMirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial.MethodsWe conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed.ResultsA total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer.ConclusionsMirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.)

Efficacy and Safety of IL-12/23 and IL-23 Inhibitors for Crohn's Disease: Systematic Review and Meta-Analysis.

Targeting interleukin-23 (IL-23) is an important therapeutic strategy for Crohn's disease (CD). This systematic review and meta-analysis assessed the efficacy and safety of selective IL-23p19 and IL-12/23p40 inhibitors in patients with moderate-to-severe CD. MEDLINE, Embase, and the Cochrane library (CENTRAL) were searched from inception to May 24, 2023, for randomized, placebo- or active comparator-controlled induction and/or maintenance trials of selective IL-23p19 and IL-12/23p40 inhibitors in pediatric and adult patients with CD. The primary outcome was the proportion of patients in clinical remission. Secondary outcomes were clinical response, endoscopic remission, endoscopic response, and safety. Data were pooled using a random-effects model. Risk of bias and certainty of evidence were assessed using the Cochrane risk of bias tool and the GRADE criteria, respectively. Eighteen trials (n = 5561) were included. Most studies were rated as low risk of bias. Targeting IL-23 was significantly superior to placebo for inducing clinical (risk ratio [RR] = 1.87, 95% confidence interval [CI] 1.58-2.21) and endoscopic (RR = 3.20, 95%CI 2.17-4.70) remission and maintaining clinical remission (RR = 1.39, 95%CI 1.10-1.77) (GRADE high certainty evidence for all outcomes). Subgroup analysis showed that targeting IL-23 was superior to placebo for inducing clinical remission in biologic-naïve (RR = 2.20, 95%CI 1.46-3.32, I2 = 0%, p = 0.39) and biologic-experienced patients (RR = 1.82, 95%CI 1.27-2.60, I2 = 56.5%, p = 0.01). Targeting IL-23 was associated with a decreased risk of serious adverse events in induction (RR = 0.55, 95%CI 0.44-0.73) and maintenance (RR = 0.72, 95%CI 0.53-0.98) trials compared to placebo (high certainty evidence). Targeting IL-23 is effective and safe for inducing and maintaining clinical and endoscopic remission in patients with moderate-to-severe CD.

Prevalence of Homologous Recombination Deficiency in First-Line PARP Inhibitor Maintenance Clinical Trials and Further Implication of Personalized Treatment in Ovarian Cancer.

Among ovarian cancer patients with BRCA mutation or homologous recombination deficiency (HRD), the efficacy of Poly-ADP-ribose polymerase (PARP) inhibitors such as olaparib, niraparib, veliparib, and rucaparib has been proven in a number of clinical trials. BRCA mutation and HRD are currently indicated for PARP inhibitor maintenance treatment in ovarian cancer. HRD diagnostic tests examine various components, resulting in different HRD status definitions and, as a result, different treatment decisions. A number of HRD diagnostic tests exist, but test results provided by different companies may differ as they use different methods and different cutoffs. HRD prevalence difference was shown between PARP inhibitor maintenance trials. It is important to select an appropriate method that can present accurate HRD phenotypes to predict sensitivity to PARP inhibitors so that patients who are most likely to benefit from treatment are selected. Additionally, in the subset data of the PARP inhibitor maintenance trials, there was a difference in HRD prevalence by race as higher HRD prevalence in Japanese and Chinese ovarian cancer patients was shown. Further large-scale investigations on racial differences in HRD prevalence are needed and this may contribute to changes in determining the treatment plan and personalized treatment in ovarian cancer patients.

Measuring time toxicity of systemic therapies for advanced esophageal and gastric cancers.

e13660 Background: Immunotherapy checkpoint inhibitors have demonstrated clinical benefit in esophago-gastric cancers. Little is known regarding time spent on treatment and adverse events that patients experienced to receive their care, or time toxicity, with regards to advances in immunotherapy. Methods: Fifteen phase 3 trials of anti-PD1 and anti-PDL1 inhibitors used for esophageal and gastric cancers were selected from clinicaltrials.gov if they were published by February 2021. The published methods and protocol were reviewed to estimate the number of ‘hospital days’ based on required procedures associated with screening and treatment related care and proportion of serious and severe adverse events that served as a surrogate for time toxicity. Once hospital days were estimated for all randomized groups, they were analyzed according to immunotherapy arms, which included chemo-immunotherapy and immunotherapy-only arms, and non-immunotherapy arms, which included chemotherapy only and observation arms. Results: From the 15 trials included, there were 32 randomized groups, as 2 trials had 3 randomized groups. Six trials eventually led to FDA approval. Six were for immune checkpoint inhibitors in first line setting, and 8 were in subsequent line setting, and 1 were in adjuvant or maintenance trials. Only pembrolizumab, nivolumab, and avelumab were represented. The median estimated hospital days was 38 days (range 7-52), or 1.3 months, over one year. There was no difference comparing immunotherapy vs. immunotherapy-free arms (p = 0.5), but there was difference comparing chemotherapy vs. chemotherapy-free arms (p &lt; .05). The median survival in the group of patients who received combination chemo-immunotherapy was 13.9 months, with time toxicity of 1.4 months. The survival and time toxicity of the chemotherapy, immunotherapy and placebo arms were 9.1 and 1.3 months, 10 and 0.9 months, and 7.5 and 0.3 months, respectively. Conclusions: While there is substantial number of days committed to cancer therapies among patients with esophageal or gastric cancer, we noticed a trend of more time toxicity in patients who received chemo-immunotherapy, vs patients who received immunotherapy alone. Given the modest improvement in survival gleaned from these trials, the magnitude of survival benefit should be weighed against the time toxicity incurred in patients.

Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease

BackgroundUpadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn’s disease.MethodsIn two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn’s disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn’s Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn’s Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]).ResultsA total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib.ConclusionsUpadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn’s disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.)

Endoscopic and Histological Placebo Rates in Crohn's Disease Clinical Trials: A Systematic Review and Meta-analysis.

Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo endoscopic and histological response rates in Crohn's disease (CD) clinical trials. MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to April 2022 to identify placebo-controlled studies of pharmacological interventions for CD. Endoscopic response, remission, and mucosal healing rates for participants assigned to placebo in induction and maintenance studies were pooled using a random-effects model. Point estimates and associated 95% confidence intervals (CIs) were calculated. In total, 16 studies (11 induction, 3 maintenance, 2 induction and maintenance) that randomized 1646 participants to placebo were eligible. For induction trials, the pooled placebo endoscopic response, endoscopic remission, and mucosal healing rates in participants assigned to placebo were 13% (95% CI, 10-16; I2 = 14.1%; P = .14), 6% (95% CI, 3-11; I2 = 74.7%; P < .001), and 6% (95% CI, 4-9; I2 = 26.9%; P = .29), respectively. The pooled endoscopic remission rate in patients who were bio-naïve was 10% (95% CI, 4-23) compared with only 4% (95% CI, 3-7) in bio-experienced patients. For maintenance trials, the pooled endoscopic response, remission, and mucosal healing rates were 7% (95% CI, 1-31; I2 = 78.2%; P = .004), 11% (95% CI, 4-27; I2 = 70.8%; P = .06), and 7% (95% CI, 3-15; I2 = 29.7; P = .23), respectively. Only 3 trials assessed histological outcomes. Endoscopic placebo rates vary according to trial phase and prior biologic exposure. These contemporary data will serve to inform CD trial design, sample size calculation, and end point selection for future trials.

Antidepressants and quality of life in patients with major depressive disorder - Systematic review and meta-analysis of double-blind, placebo-controlled RCTs.

Quality of Life (QoL) is an important outcome in mental disorders. We investigated whether antidepressant pharmacotherapy improved QoL vs. placebo among patients with MDD. Systematic literature search in CENTRAL, Medline, PubMed Central, and PsycINFO of double-blind, placebo-controlled RCTs. Screening, inclusion, extraction, and risk of bias assessment were conducted independently by two reviewers. We calculated summary standardized mean differences (SMD) with 95%-CIs. We followed Cochrane Collaboration's Handbook of Systematic Reviews and Meta-Analyses and PRISMA guidelines (protocol registration at OSF). We selected 46 RCTs out of 1807 titles and abstracts screened, including 16.171 patients, 9131 on antidepressants and 7040 on placebo, a mean age of 50.9 years, with 64.8% women. Antidepressant drug treatment resulted in a SMD in QoL of 0.22 ([95%-CI: 0.18; 0.26] I2 39%) vs. placebo. SMDs differed by indication: 0.38 ([0.29; 0.46] I2 0%) in maintenance studies, 0.21 ([0.17; 0.25] I2 11%) in acute treatment studies, and 0.11 ([-0.05; 0.26], I2 51%) in studies focussing on patients with a physical condition and major depression. There was no indication of subtstantial small study effects, but 36 RCTs had a high or uncertain risk of bias, particularly maintenance trials. QoL and antidepressive effect sizes were associated (Spearman's rho 0.73, p< 0.001). Antidepressants' effects on QoL are small in primary MDD, and doubtful in secondary major depression and maintenance trials. The strong correlation of QoL and antidepressive effects indicates that the current practice of measuring QoL may not provide sufficient additional insights into the well-being of patients.

Effect of Age and Body Weight on the Maintenance Requirement of Lean and Obese Zucker Rats

The effect of age (34–215 days) and body weight (80–627 g) on the maintenance requirements of lean (n = 4) and obese (n = 4) Zucker rats was determined in 5 maintenance trials. The rats were fed a semipurified, 20% protein diet. The metabolizable energy intake (MEI) required for maintenance of body weight (BW) was determined in weekly intake-metabolism trials. Maintenance requirements [kilocalories MEI/(day·kilogram BW)] were lower (P < 0.01) for obese rats than for lean rats, and they decreased with age for both body types, respectively (Y = 206.23 - 0.3524 X; r = -0.547 and Y = 252.61 -0.4818 X; r = -0.649). Maintenance requirements (kilocalories MEI/day) of obese rats were lower (P < 0.01) than lean rats, respectively, when expressed in terms of grams body weight (Y = 7.03 + 0.1333 X; r = 0.994 and Y = 9.04 + 0.1441 X; r = 0.994), metabolic body size (kilogram0.75) (Y = -4.52 + 132.33 X; r = 0.989 and Y = 0.05 + 130.52 X; r = 0.992) or least squares, type-specific exponent [Y = 119.03 (kilogram0.77); r = 0.975 and Y = 120.87 (kilogram0.71); r = 0.986]. The results indicate that obese Zucker rats have lower maintenance requirements than their lean littermates and that maintenance requirements are as closely related to body weight as to metabolic body size or type-specific exponent for each body type.maintenance requirement Zucker rat voluntary activity metabolic body size

A186 ASSOCIATION OF ULCERATIVE COLITIS BOWEL URGENCY IMPROVEMENT WITH CLINICAL RESPONSE AND REMISSION

A186 ASSOCIATION OF ULCERATIVE COLITIS BOWEL URGENCY IMPROVEMENT WITH CLINICAL RESPONSE AND REMISSION

Systematic review: The effectiveness of 6-thioguanine nucleotide-based dose optimisation of thiopurines in the treatment of inflammatory bowel disease

Introduction: Clinical guidelines highlight the potential utility of metabolite-based thiopurine dose optimisation strategies in inflammatory bowel disease (IBD). The aim of this review was to summarise the evidence of effectiveness and safety of a 6-thioguanine nucleotide (6-TGN) metabolite-based dosing strategy for maintenance of remission using azathioprine or mercaptopurine in Crohn's disease and ulcerative colitis. Methods: We searched the Cochrane central register of controlled trials, EMBASE, clinicaltrials.gov, the WHO international clinical trials registry platform, and relevant grey literature, up to 1 December 2021. Inclusion criteria were: all randomised (active comparator) controlled trials of azathioprine or mercaptopurine used for the purposes of maintenance of remission in Crohn's disease or ulcerative colitis where the dose in the intervention arm was optimised based on 6-TGN metabolite assay results. Studies of any duration were eligible for inclusion, and no age restrictions were applied. Results: No studies met the eligibility criteria for this review. Four randomised controlled studies (two of which are currently underway) were identified that assessed the effectiveness of metabolite-based dose optimisation for thiopurine therapy, but were not eligible either because they did not differentiate between induction and maintenance therapy or because of a lack of an appropriate active comparator. Conclusions: There is no RCT-based evidence for dose optimisation using a 6-TGN metabolite-based dosing strategy for maintenance of remission in Crohn's disease or ulcerative colitis. Where evidence is available from combination induction and maintenance trials, it suggests that such a strategy is no better than weight-based dosing. Cochrane protocol registration: CD014795