Placebo In Maintenance Therapy Research Articles

EFFICACY, SAFETY AND IMMUNOGENICITY OF SUBCUTANEOUS INFLIXIMAB (CT-P13 SC) MONOTHERAPY VERSUS COMBINATION THERAPY WITH IMMUNOSUPPRESSANTS – POST HOC ANALYSIS OF LIBERTY-CD AND LIBERTY-UC STUDY

Abstract INTRODUCTION CT-P13 subcutaneous (SC) infliximab formulation demonstrated superiority over placebo in maintenance therapy in Crohn's disease (CD) and Ulcerative Colitis (UC) patients in two parallel 54 weeks studies (LIBERTY-CD and LIBERTY-UC). We performed a post-hoc subgroup analysis comparing patients treated with CT-P13 SC with and without combination immunosuppressants (IS) at baseline in CD and UC. AIMS & METHODS Patients with moderately to severely active CD and UC who responded at W10 to CT-P13 intravenous infliximab 5mg/kg (Weeks 0, 2 and 6) were randomized (2:1) to receive CT-P13 SC 120 mg (CT-P13 SC) or placebo every 2 weeks until W54 as maintenance therapy. IS (azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) were allowed if patients maintained stable doses at least 8 weeks prior to W0, and stable doses were maintained up to W54. RESULTS 231 CD and 294 UC patients were randomized to receive CT-P13 SC maintenance therapy. Among them, 71 (30.7%) and 65 (22.1%) patients received CT-P13 SC with IS in CD and UC, respectively (In CD; 63, 4 and 4 patients of AZA, 6-MP, MTX, respectively, In UC; 63, 2 and 0 patients of AZA, 6-MP, MTX, respectively). There were no meaningful differences in efficacy outcomes at Week 54 by CT-P13 concentration tertiles at Week 54 between monotherapy and combination therapy groups in both studies (Table 1). In combined analysis of CD and UC patients, no statistically significant differences were seen in safety profile between monotherapy and combination therapy groups in the maintenance period except for infection rate (Table 2). In combined analysis of CD and UC patients, rate of anti-drug antibody [ADA] positive conversion up to W54 was statistically lower in combination therapy group (70.2% monotherapy vs 47.8% combination therapy [p<0.0001]). CONCLUSION No meaningful differences in efficacy outcomes at W54 were observed between monotherapy and combination therapy of CT-P13 SC in CD and UC patients. Concomitant IS use was associated with less ADA formation, whereas more infections are seen for combination therapy during maintenance period in CD and UC patients. The overall safety profile during maintenance period was otherwise comparable between monotherapy and combination therapy in CD and UC patients. This post-hoc analysis suggests limited benefit of concomitant IS with CT-P13 SC but a higher infection risk. Notably, patients were not randomized according to IS use nor were the studies ‘powered’ to demonstrate differences. Proportion of patients achieving efficacy outcomes at W54 by tertile of Serum concentrations of Infliximab (ng/mL) at W54 (Pharmacokinetic population) Safety results in maintenance period (Safety population)

P957 Subcutaneous infliximab (CT-P13 SC) for ulcerative colitis: 2-year extension results of the LIBERTY-UC study

Abstract Background Superiority of CT-P13 subcutaneous (SC) infliximab formulation over placebo in maintenance therapy was demonstrated in both ulcerative colitis1 and Crohn’s disease2. LIBERTY-UC study was continued up to Week 102 as an extension phase treatment. We now present the efficacy and safety results up to Week 102 of CT-P13 SC 120 mg group in the LIBERTY-UC study (NCT04205643). Methods Patients who completed the maintenance phase up to Week 54 and, in the opinion of the investigator, would benefit from continued treatment continued the open-label extension phase from Week 56 to Week 102. During extension phase, all patients received CT-P13 SC regardless of previous treatment group randomised at the start of maintenance phase. The patients who had received the adjusted dose of CT-P13 SC 240 mg during the maintenance phase continued receiving CT-P13 240 mg in the extension phase. Patients with dose adjustment to CT-P13 SC 240 mg prior to Week 54 were considered as not to achieve each endpoint. At Week 54 and 102, clinical remission, clinical response, endoscopic-histologic mucosal improvement and corticosteroid-free remission were assessed by among patients who entered and treated in extension phase (Figure 1A), and who entered and treated in extension phase and had valid efficacy results at the visit of interest (Figure 1B). Safety was evaluated throughout the extension phase. Results A total of 237 patients in CT-P13 SC 120 mg group entered into extension phase. Among them, 208 (87%) patients completed extension phase. Proportion of patients who achieved clinical remission, clinical response, endoscopic-histologic mucosal improvement and corticosteroid-free remission at Week 54 and Week 102 among patients who entered and treated in extension phase (i.e., patients who had missing or invalid data were considered as not to achieve each endpoint) are presented in Figure 1A. Among patients who entered and treated in extension phase based on the no imputation for missing or invalid data, each endpoints are generally well maintained or slightly higher in Week 102 compared to Week 54 (Figure 1B). During extension phase, no new safety signals were observed compared to maintenance phase1 (table 1). Conclusion The efficacy of CT-P13 SC 120 mg in UC patients was generally sustained through extension phase. No new safety concerns were found during the extension phase as well. These results indicate that long term use of CT-P13 SC can maintain clinical benefit as well as safety with the convenience of SC administration for patient with moderately to severely active UC. [1] Sands et al., Journal of Crohn's and Colitis, 2023.17(Supplement_1), i623-i624. [2] Colombel et al., Journal of Crohn's and Colitis, 2023.17.Supplement_1: i161-i162

P492 Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for ulcerative colitis: A Phase 3, randomized, placebo-controlled study: Results of the LIBERTY-UC study

Abstract Background CT-P13 subcutaneous (SC) infliximab formulation was developed to provide patients with a convenient option for treatment. Previous studies have shown efficacy and safety of CT-P13 SC comparable to CT-P13 intravenous (IV) in inflammatory bowel disease (IBD)1 and rheumatoid arthritis2. This study aimed to demonstrate superiority of CT-P13 SC over placebo in maintenance therapy after induction therapy of CT-P13 IV in patients with ulcerative colitis (UC). Methods Patients with moderately to severely active UC (modified Mayo score 5 to 9 with endoscopic subscore of ≥ 2 points) were enrolled LIBERTY-UC (NCT04205643) and treated with open label CT-P13 IV 5 mg/kg at Weeks 0, 2 and 6 as induction therapy. At Week 10, patients who had a clinical response, defined as decrease in modified Mayo score from baseline of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point, were randomised in a 2:1 ratio to receive either CT-P13 SC 120 mg (CT-P13 SC) or placebo SC arms every 2 weeks up to Week 54. The primary endpoint was clinical remission at Week 54. The key secondary endpoints of clinical response, endoscopic-histologic mucosal improvement, and corticosteroid-free remission were assessed at Week 54. Safety was evaluated up to Week 54. Results A total of 548 patients were enrolled. Among them, 438 patients (79.9%) responded to CT-P13 IV induction dosing and were randomised (294 in CT-P13 SC arm and 144 in placebo arm, respectively) at Week 10. The rate of clinical remission at Week 54 was significantly greater in CT P13 SC (43.2%) compared to placebo (20.8%) (P<0.0001). Clinical response, endoscopic-histologic mucosal improvement and corticosteroid-free remission also showed statistically greater improvement with CT-P13 SC treatment group, compared to placebo treatment group (Table 1). The safety profile during maintenance phase was generally comparable between CT-P13 SC and placebo arms (table 2). No deaths were reported. Conclusion CT-P13 SC was more effective than placebo for clinical remission, clinical response, endoscopic histologic mucosal improvement, and corticosteroid-free remission at Week 54 in patients with moderately to severely active UC. No new safety concerns were identified. These results demonstrate that the CT-P13 SC provides both a robust clinical benefit and the convenience of SC administration to patient with moderately to severely active UC. 1 Schreiber et al., 2021. Gastroenterology 2021;160:2340–23 2 Westhovens et al., 2020. Rheumatology 2020;00:1

Multicentre randomized phase II trial of olaparib as maintenance therapy in platinum-sensitive advanced endometrial carcinoma: The GINECO-UTOLA study.

TPS6109 Background: Advanced endometrial cancer (EC) patients relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). Data from the TGCA suggest opportunities to targeting DNA repair in women with EC. Particularly type 4 (High copy number or serous like, with frequent TP53 mutations) and type 2 (microsatellite instability hypermutated) EC can be associated with defects in double strand break DNA repair by homologous recombination (HR) and could potentially be targeted by olaparib. We propose a placebo-controlled, multicenter, two-arm, phase II trial comparing olaparib versus placebo in maintenance therapy after chemotherapy in patients with advanced/metastatic EC. Methods: The primary objective of this trial is to evaluate the efficacy of maintenance olaparib in comparison to placebo after platinum based chemotherapy, defined by PFS according to Recist. Key eligibility criteria include: advanced/metastatic histologically confirmed EC (excepted carcino-sarcoma, small cells& neuroendocrine); prior surgery, adjuvant chemotherapy, radiation and hormonal therapy are permitted; objective or stable response after first-line chemotherapy is mandatory. 147 patients are randomized (2:1) after chemotherapy to receive Olaparib 300mg twice daily or placebo in maintenance after at least 4 cycles of platinum based chemotherapy. Olaparib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Stratification is on IHC P53 and MMR status. Primary hypothesis is a 66.7% relative increase in the median PFS rate in the olaparib arm (from 4.5 to 7.5 months), corresponding to a 0.60 Hazard Ratio. Secondary endpoints include PFS according to P53, MMR and NGS HRD status, PFS2, disease specific survival, time to subsequent therapy, overall survival, objective response, disease control rate, patient reported outcomes (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24, EORTC-FA, EQ5D) and safety. Trial is recruiting in France (in February n= 40 randomization). Conclusion: this will be the first study that evaluate the efficacy of olaparib in maintenace after chemotherapy in advanced/metastastic EC, stratified on molecular profil. Clinical trial information: NCT03745950.

Efficacy, safety and tolerability of aripiprazole in bipolar disorder: An updated systematic review and meta-analysis of randomized controlled trials

Numerous studies have investigated aripiprazole as a treatment for bipolar disorder (BD). therefore we conducted this comprehensive meta-analysis to investigate the efficacy and safety profile of aripiprazole in treating BD. Two authors conducted systematic searches of PubMed and ScienceDirect from inception until May 14th, 2017. Randomized controlled trials (RCTs) of people with BD who received aripiprazole were included. A total of 20 RCTs met the eligibility criteria, including two which investigated the efficacy of aripiprazole versus haloperidol (aripiprazole=340; haloperidol=337), three which compared aripiprazole versus lithium (aripiprazole=208; lithium=212), and 15 with multiple comparisons of aripiprazole versus a placebo (aripiprazole=1923; placebo=1499). Compared to a placebo, aripiprazole improved acute mania (Hedges' g: −0.299, p=0.001) and psychosis (Hedges' g: −0.296, p<0.001) in the acute mania state, but did not improve depressive symptoms (Hedges' g: −0.127, p=0.054) in the acute depressive state. Aripiprazole was associated with lower relapse rates in bipolar mania when used in combination versus a placebo in maintenance therapy (odds ratio: 0.522, p<0.029). Aripiprazole was also associated with higher levels of high density lipoprotein, lower dropout rates, but no difference in extrapyramidal symptoms in the maintenance phase versus a placebo or in comparison with other medications (haloperidol or lithium). Our results suggest that aripiprazole is effective and safe in treating bipolar mania. Further trials are necessary to evaluate the efficacy and tolerability versus other medications.

Abstract A035: Pharmacokinetics and pharmacodynamics of the immunotherapeutic TLR-9 agonist MGN1703 – conclusions by comparison of data from clinical trials with healthy volunteers and cancer patients

Abstract Background: The synthetic DNA-based immunomodulator MGN1703 is a member of the new dSLIM® family of TLR-9 agonists, comprising covalently closed dumbbell-like DNA molecules which consist entirely of natural DNA with two single-stranded CG-containing loops separated by a double-stranded stem. MGN1703 exerts its function by activating the innate and both arms of the adaptive immune system. MGN1703 has already shown a good safety profile and benefit for patients compared to placebo in maintenance therapy of metastatic colorectal carcinoma (mCRC) after fist-line induction therapy in a phase 2 clinical trial (MGN1703-C02, IMPACT). Methods: Following preclinical studies in mice and monkeys, a human clinical program was performed, including a phase 1 trial (MGN1703-C01), on a variety of solid tumors, and the double-blinded, placebo-controlled phase 2 IMPACT trial with mCRC patients. Additionally, a single dose crossover, placebo-controlled phase 1 cardiac safety trial, MGN1703-C04, was conducted to assess cardiac and general safety, pharmacokinetics (PK) and pharmacodynamics (PD) in healthy volunteers (HV). Fourteen HV were randomized and 13 subjects completed the study receiving a subcutaneous dose of 60 mg MGN1703 during one treatment period and a single dose of placebo during the other. Results: After single dose administration of MGN1703 standard PK parameters were determined in the MGN1703-C04 trial: mean Tmax (14h), AUC0-t (5000 ng•hr/mL) and shape of the curve of MGN1703 concentration in serum. These were similar to single dose data obtained from cancer patients, where a mean Tmax of 10h and a mean AUC0-t of 5340 ng•hr/mL have been observed. Notably, multiple doses resulted in similar levels in serum of cancer patients, without accumulation of MGN1703. PD was mainly evaluated by analyzing levels of the chemokine IP-10 in serum of the HV as an equivalent of innate immune activation. Elevated IP-10 levels in the serum of HV were shown peaking at 24-48 hours after dosing with MGN1703. This is clearly in line with expected time frame of immune activation subsequent to MGN1703 appearance in the serum of the HV. Timing and levels of IP-10 elevation are in keeping with data from the peripheral blood of cancer patients, where in addition to IP-10 also the subsequent activation of innate immune cells – especially the up-regulation of CD169 on monocytes – as a consequence of MGN1703 administration was observed. Conclusions: The data show obvious similarities between healthy volunteers and cancer patients with respect to PK and PD and also confirm the appearance of the appropriate immunomodulatory signature downstream of MGN1703 appearance. This supports the twice weekly application scheme of current immunotherapy studies with MGN1703, e.g. the ongoing phase 3 IMPALA trial in mCRC patients. Further data will allow for evaluation of a possible association with clinical parameters in cancer patients. Citation Format: Manuel Schmidt, Kerstin Kapp, Detlef Oswald, Matthias Schroff, Burghardt Wittig, Alfredo Zurlo. Pharmacokinetics and pharmacodynamics of the immunotherapeutic TLR-9 agonist MGN1703 – conclusions by comparison of data from clinical trials with healthy volunteers and cancer patients. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A035.

ITOC2 – 035. The immunotherapeutic TLR-9 agonist MGN1703 – Pharmacokinetic and pharmacodynamic data from healthy volunteers and cancer patients

<h3>Background</h3> MGN1703 is a synthetic DNA-based TLR-9 agonist which has shown a good safety profile and a benefit compared to placebo in maintenance therapy of patients with metastatic colorectal carcinoma. <h3>Methods</h3> In addition to the phase 1 and 2 trials with cancer patients a single dose crossover placebo-controlled phase 1 trial, MGN1703-C04, was performed to assess safety, pharmacokinetics (PK) and pharmacodynamics in healthy volunteers (HV). <h3>Results</h3> Standard PK parameters like mean Tmax (14h), AUC0-t (5001ngh/mL) and shape of the curve in the MGN1703-C04 trial were similar to single dose data obtained from cancer patients, with mean Tmax of 10h and AUC0-t of 5336ngh/mL. Notably, multiple doses resulted in similar levels without accumulation of MGN1703. In MGN1703-C04 elevated IP-10 levels were detected in the serum of HV peaking at 24–48h after dosing with MGN1703. The elevation of IP-10 is in keeping with data from cancer patients, which additionally showed activation of innate immune cells after dosing with MGN1703, e.g. up-regulation of CD169 on blood monocytes. <h3>Conclusions</h3> The data show similarities between HV and cancer patients with respect to PK and – following-up downstream – the immunomodulatory profile, supporting the twice weekly application scheme of ongoing cancer studies. Further data will allow evaluation of possible association with clinical parameters.

Manipulation of the Microbiota for Treatment of IBS and IBD—Challenges and Controversies

There is compelling rationale for manipulating the microbiota to treat inflammatory bowel diseases (IBDs). Although studies of animal models of intestinal inflammation produced promising results, trials in humans have been disappointing. In contrast to IBD, the role of the microbiota in the development of irritable bowel syndrome (IBS) only recently has been considered, but early stage results have been encouraging. As pharmaceutical companies develop fewer truly novel agents for treatment of these disorders, consumers seek safer, long-term strategies to deal with chronic symptoms. We assess the rationale for modulating the microbiota for treatment of IBD and IBS, and discuss whether current concepts are simplistic and overstated or simply under-researched. Are claims exaggerated and expectations unrealistic? Difficulties with microbiota terminology and technologies, as well as differences among patients and the heterogeneity of these diseases, pose additional challenges in developing microbiota-based therapies for IBD and IBS.

Randomized, placebo-controlled, double-blind trial of Boswellia serrata in maintaining remission of Crohnʼs disease

Complementary therapies are frequently used by patients with inflammatory bowel disease (IBD). The aim of this study was to evaluate the efficacy and safety of long-term therapy with a new Boswellia serrata extract (Boswelan, PS0201Bo) in maintaining remission in patients with Crohn's disease (CD). In 22 German centers a double-blind, placebo-controlled, randomized, parallel study was performed. In all, 108 outpatients with CD in clinical remission were included. Patients were randomized to Boswelan (3×2 capsules/day; 400 mg each) or placebo for 52 weeks. The primary endpoint was the proportion of patients in whom remission was maintained throughout the 52 weeks. Secondary endpoints were time to relapse, changes of Crohn's Disease Activity Index (CDAI), and IBD Questionnaire (IBDQ) scores. The trial was prematurely terminated due to insufficient discrimination of drug and placebo with regard to the primary efficacy endpoint. A total of 82 patients were randomized to Boswelan (n=42) or placebo (n=40). Sixty-six patients could be analyzed for efficacy. 59.9% of the actively treated patients and 55.3% of the placebo group stayed in remission (P=0.85). The mean time to diagnosis of relapse was 171 days for the active group and 185 days for the placebo group (P=0.69). With respect to CDAI, IBDQ, and laboratory measurements of inflammation, no advantages in favor of active treatment were detected. Regarding safety concerns, no disadvantages of taking the drug compared to placebo were observed. The trial confirmed good tolerability of a new Boswellia serrata extract, Boswelan, in long-term treatment of CD. However, superiority versus placebo in maintenance therapy of remission could not be demonstrated.

Meta‐analysis: the effect and adverse events of Lactobacilli versus placebo in maintenance therapy for Crohn disease

Lactobacilli are used in an attempt to maintain remission for Crohn disease. The aim of this study was to evaluate the efficacy and adverse events of Lactobacilli compared with placebo in maintenance therapy for Crohn disease. We searched MEDLINE, EMBASE, the Cochrane Controlled Trials Register, OVID and BIOSIS. All randomized trials comparing Lactobacilli with placebo in maintenance therapy for Crohn disease were included. Six randomized controlled trials with a total of 359 participants met the inclusion criteria. From the meta-analyses, the relative risk (RR) of clinical relapse rate was 1.15 (95% confidence interval (CI) 0.90-1.48) comparing Lactobacilli with placebo and RR of endoscopic relapse rate was 1.31 (95%CI 0.57-3.00). Subgroup analyses showed RR for clinical relapse rates of Lactobacilli versus placebo was 0.99 (95%CI 0.76-1.29) in adults, 1.85 (95%CI 1.00-3.41) in children, 1.68 (95%CI 1.07-2.64) in Lactobacillus rhamnosus strain GG and 0.91 (95%CI 0.68-1.23) in Lactobacillus johnsonii respectively. The pooled RR of adverse events was 0.83 (95%CI 0.61-1.12). Our meta-analysis suggests that compared with placebo, administration of L. rhamnosus strain GG as maintenance therapy may increase the relapse rates of Crohn disease. L. johnsonii is inefficacious in reducing the incidence of relapse.

Comment on Guideline Watch: Practice Guideline for the Treatment of Patients with Bipolar Disorder, 2nd Edition

In the year since publication of the Watch, the results of several clinically important studies have been published. The efficacy of aripiprazole (1) and divalproex extended release (2) in the acute treatment of mania were each demonstrated compared to placebo. Olanzapine and risperidone monotherapy were equivalent in the acute treatment of mania (3). The efficacy of quetiapine in the acute treatment of bipolar depression was confirmed in a second study (4), and the drug has received FDA approval for the treatment of bipolar depression. The olanzapine/fluoxetine combination was found to be superior in efficacy compared to lamotrigine, but had considerably more side effects (5). Both aripiprazole (6) and olanzapine (7) were found to be superior to placebo in maintenance therapy. Several studies have supported the use of cognitive behavioral therapy or systematic psychoeducation to prolong remission (8–10).

Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.

The newer 5-ASA preparations were intended to avoid the adverse effects of SASP while maintaining its therapeutic benefits. The efficacy and safety of 5-ASA preparations have been evaluated in numerous clinical trials that have often lacked sufficient statistical power to arrive at definitive conclusions. Previously, it was found that newer 5-ASA drugs were more effective than placebo but no more effective than SASP in inducing remission in ulcerative colitis. This updated review includes more recent studies and evaluates the effectiveness, dose-responsiveness, and safety of 5-ASA preparations in terms of more precise outcome measures. To assess the efficacy, dose-responsiveness and safety of the newer release formulations of 5-aminosalicylic acid (5-ASA) compared to placebo or sulfasalazine (SASP) in the maintenance of remission in ulcerative colitis. A computer-assisted literature search for relevant studies (1981-2002) was performed using MEDLINE, BIOS, the Cochrane Controlled Trials Register, the Cochrane IBD Group Specialized Trials Register, and the Science Citation Index, followed by a manual search of reference lists from previously retrieved articles, review articles, symposia proceedings, and abstracts from major gastrointestinal conferences. Studies were accepted for analysis if they were prospective, randomized, double-blinded, and placebo- or SASP-controlled clinical trials of parallel design with treatment duration of at least six months. Based on an intention to treat principle, the primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes were the number of patients experiencing adverse events, the number of patients withdrawn due to adverse events, and exclusions or withdrawals after entry into the study (not due to relapse). All data were analyzed using the Peto odds ratio and corresponding 95% confidence intervals (CI). The Peto odds ratio for the failure to maintain clinical or endoscopic remission (withdrawals and relapses) for 5-ASA versus placebo was 0.47 (95% CI, 0.36 to 0.62) with an NNT of 6. These values were also calculated for the trials in which SASP and 5-ASA were compared, revealing an odds ratio of 1.29 (95% CI, 1.05 to 1.57), with a negative NNT value (-19), suggesting a higher degree of therapeutic effectiveness for SASP. SASP and 5-ASA had similar adverse event profiles, with odds ratios of 1.16(0.62 to 2.16), and 1.31(0.86 to 1.99), respectively. The NNH values were determined to be 171 and 78 respectively. The newer 5-ASA preparations were superior to placebo in maintenance therapy. However, the newer preparations had a statistically significant therapeutic inferiority relative to SASP. This review updates the existing review of oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (Issue 3, 2002).