Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1

Experience with continuous levodopa enteral infusion (Duodopa®)in patients with advanced Parkinson's disease in a secondary level hospital

Introduction: Continuous levodopa delivery by enteral infusion (Duodopa®) is an alternative to deep brain stimulation and subcutaneous apomorphine to control motor fluctuations and dyskinesias in advanced Parkinson's disease (PD). We report our experience with Duodopa® therapy in 11 patients with advanced PD. Methods: We retrospectively assessed clinical and quality of life changes in all patients with PD with severe motor fluctuations and dyskinesias who started continuous daily levodopa duodenal infusion through percutaneous endoscopic gastrostomy from September 2006 (Duodopa® was approved for advanced PD treatment in Spain at that date) until April 2010 at the A. Marcide Hospital of Spain. Results: Nine patients received Duodopa® [62.7±10.6 (44–74) years, 63.6% male)]. Pre- Duodopa® clinical characteristics of patients were: disease duration 14.5±8.9 (3–34) years, oral levodopa dose 918.2±277.7 (450–1300) mg/day, and Hoehn and Yahr staging 3.7±0.5 (3–4). Nine patients are still receiving Duodopa®. Patients improved motor fluctuations (72.7% significant improvement), dyskinesia (55.5% significant improvement), daily off-time (90.9%) and daily duration dyskinesia (66.6%) after total infusion time of 170.5 months (3–31). The improvement in Parkinson's Disease Quality of Life Questionnaire-39 (PDQ-39) and Schwab&England Capacity for Daily Living Scale were 38.5±19.8 and 24±12.5 respectively (P<0.05). Equivalent daily dose of levodopa (April 2010) was 1683.4±295.8 (1234–2216) mg/day. Conclusions: Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease Resumen: Introducción: La infusión continua de levodopa intraduodenal (Duodopa®) constituye una alternativa a la infusión subcutánea de apomorfina y a la cirugía en pacientes con enfermedad de Parkinson (EP) avanzada. Describimos nuestra experiencia con Duodopa® en pacientes con EP avanzada. Métodos: Realizamos un estudio epidemiológico, observacional, no intervencionista, poblacional, descriptivo, y retrospectivo, en el que se incluyen todos aquellos pacientes con EP avanzada tratados con Duodopa® por parte de la Sección de Neurología del Hospital A. Marcide de Ferrol hasta abril de 2010. Resultados: Once de un total de 12 pacientes seleccionados fueron tratados con Duodopa® [63,6% varones; edad media 62,7 ± 10,6 (44–74) años]. En el momento de ser seleccionados para recibir Duodopa® presentaban: tiempo medio de evolución de enfermedad de 14,5 ± 8,9 (3–34) años, dosis media de levodopa oral de 918,2 ± 277,7 (450–1300) mg/ día, y un estadio de Hoehn y Yahr de 3,7 ± 0,5 (3–4). Nueve pacientes mantienen el tratamiento con Duodopa®. Hubo mejoría en las fluctuaciones motoras (72,7% gran mejoría) y discinesias (55,5% gran mejoría) con reducción del tiempo off/día (90,9%) y tiempo con discinesias/día (66,6%) después de un tiempo total de seguimiento con Duodopa® de 170,5 (3–31) meses. La mejoría en las escalas PDQ-39 y Schwab&England fue de 38,5 ± 19,8 y 24 ± 12,5 puntos respectivamente (p < 0,05). La dosis media equivalente oral de levodopa (abril 2010) fue de 1683,4 ± 295,8 (1234–2216) mg/día. Conclusiones: Duodopa® pudiera ser un tratamiento efectivo, seguro, y bien tolerado alternativo a la cirugía y apomorfina subcutánea en pacientes con EP avanzada adecuadamente seleccionados. Keywords: Dyskinesias, Duodopa, Parkinson's disease, Motor fluctuations, Continuous enteral infusion, Levodopa, Palabras clave: Discinesias, Duodopa, Enfermedad de Parkinson, Fluctuaciones motoras, Infusión continua enteral, Levodop

Experiencia con la infusión continua de levodopa intraduodenal (Duodopa®) en pacientes con enfermedad de Parkinson avanzada en un hospital de segundo nivel asistencial

Resumen: Introducción: La infusión continua de levodopa intraduodenal (Duodopa®) constituye una alternativa a la infusión subcutánea de apomorfina y a la cirugía en pacientes con enfermedad de Parkinson (EP) avanzada. Describimos nuestra experiencia con Duodopa® en pacientes con EP avanzada. Métodos: Realizamos un estudio epidemiológico, observacional, no intervencionista, poblacional, descriptivo, y retrospectivo, en el que se incluyen todos aquellos pacientes con EP avanzada tratados con Duodopa® por parte de la Sección de Neurología del Hospital A. Marcide de Ferrol hasta abril de 2010. Resultados: Once de un total de 12 pacientes seleccionados fueron tratados con Duodopa® [63,6% varones; edad media 62,7 ± 10,6 (44-74) años]. En el momento de ser seleccionados para recibir Duodopa® presentaban: tiempo medio de evolución de enfermedad de 14,5 ± 8,9 (3-34) años, dosis media de levodopa oral de 918,2 ± 277,7 (450-1300) mg/día, y un estadio de Hoehn y Yahr de 3,7 ± 0,5 (3-4). Nueve pacientes mantienen el tratamiento con Duodopa®. Hubo mejoría en las fluctuaciones motoras (72,7% gran mejoría) y discinesias (55,5% gran mejoría) con reducción del tiempo off/día (90,9%) y tiempo con discinesias/día (66,6%) después de un tiempo total de seguimiento con Duodopa® de 170,5 (3-31) meses. La mejoría en las escalas PDQ-39 y Schwab&England fue de 38,5 ± 19,8 y 24 ± 12,5 puntos respectivamente (p < 0,05). La dosis media equivalente oral de levodopa (abril 2010) fue de 1683,4 ± 295,8 (1234-2216) mg/día. Conclusiones: Duodopa® pudiera ser un tratamiento efectivo, seguro, y bien tolerado alternativo a la cirugía y apomorfina subcutánea en pacientes con EP avanzada adecuadamente seleccionados. Abstract: Introduction: Continuous levodopa delivery by enteral infusion (Duodopa®) is an alternative to deep brain stimulation and subcutaneous apomorphine to control motor fluctuations and dyskinesias in advanced Parkinson's disease (PD). We report our experience with Duodopa® therapy in 11 patients with advanced PD. Methods: We retrospectively assessed clinical and quality of life changes in all patients with PD with severe motor fluctuations and dyskinesias who started continuous daily levodopa duodenal infusion through percutaneous endoscopic gastrostomy from September 2006 (Duodopa® was approved for advanced PD treatment in Spain at that date) until April 2010 at the A. Marcide Hospital of Spain. Results: Nine patients received Duodopa® [62.7 ± 10.6 (44-74) years, 63.6% male)]. Pre-Duodopa® clinical characteristics of patients were: disease duration 14.5 ± 8.9 (3-34) years, oral levodopa dose 918.2 ± 277.7 (450-1300) mg/day, and Hoehn and Yahr staging 3.7 ± 0.5 (3-4). Nine patients are still receiving Duodopa®. Patients improved motor fluctuations (72.7% significant improvement), dyskinesia (55.5% significant improvement), daily off-time (90.9%) and daily duration dyskinesia (66.6%) after total infusion time of 170.5 months (3-31). The improvement in Parkinson's Disease Quality of Life Questionnaire-39 (PDQ-39) and Schwab&England Capacity for Daily Living Scale were 38.5 ± 19.8 and 24 ± 12.5 respectively (P < 0.05). Equivalent daily dose of levodopa (April 2010) was 1683.4 ± 295.8 (1234-2216) mg/day. Conclusions: Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease. Palabras clave: Discinesias, Duodopa, Enfermedad de Parkinson, Fluctuaciones motoras, Infusión continua enteral, Levodopa, Keywords: Dyskinesias, Duodopa, Parkinson's disease, Motor fluctuations, Continuous enteral infusion, Levodop

Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial

Background: Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods: HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov, NCT02100696. Findings: HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation: HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding: F Hoffmann-La Roche

Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study

Background: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. Methods: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18–80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. Findings: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference –0·9% [95% CI –8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. Interpretation: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. Funding: F Hoffmann-La Roche