Weekly Adalimumab Dosing in Ulcerative Colitis
Weekly Adalimumab Dosing in Ulcerative Colitis
ULTRA 2 (NCT00408629) was a 52-week, Phase 3, randomised, double-blind, placebo-controlled trial that assessed the efficacy and safety of adalimumab in patients with UC. The details have been published previously. Briefly, adult patients with a diagnosis of moderately to severely active UC for ≥3 months and a Mayo score of 6–12 (endoscopy subscore of 2–3) were randomised to receive either double-blind placebo or adalimumab (160/80 mg at weeks 0/2, followed by 40 mg every other week). Patients with prior exposure and response to other anti-TNF antagonists were permitted to enrol in ULTRA 2. UC-related medications were to remain stable during ULTRA 2, except corticosteroids, which could be tapered beginning at or after week 8, at the discretion of the investigator, for patients who demonstrated a satisfactory clinical response.
A rescue option was included, beginning at week 12, whereby patients who met the protocol-defined criteria for inadequate response at week 12 or later could move to open-label adalimumab 40 mg every other week (this intermediate step was required to retain study blinding), with a subsequent escalation to 40 mg weekly for continued inadequate response. Inadequate response was defined as partial Mayo score (Mayo score without endoscopy subscore) ≥ the baseline score on two consecutive visits at least 14 days apart, for patients with a baseline partial Mayo score of 4–7. For patients with a baseline partial Mayo score of 8–9, inadequate response was defined as partial Mayo score ≥7 on two consecutive visits at least 14 days apart.
Patients assessed in this analysis were those randomised to adalimumab in the intent-to-treat population of ULTRA 2 (n = 248). To analyse the effect of escalation from every other week to weekly adalimumab by initial response to induction therapy with adalimumab, patients were stratified by week 8 response per partial Mayo score, defined as a decrease in partial Mayo score ≥2 points and ≥30% from baseline, and a decrease in rectal bleeding score ≥1 point or an absolute rectal bleeding score ≤1. While escape to open-label could occur from week 12 onward, week 8 was chosen as the time point for stratification of patients as responders to induction therapy, as this time point corresponded to the timing of one of the study's co-primary endpoint assessments. In addition, 8 weeks was felt to represent a reasonable amount of time to assess initial response to adalimumab induction dosing, and week 8 responders are likely to be representative of patients to continue maintenance therapy with adalimumab in clinical practice.
Week 52 endpoints were assessed in patients who escalated to open-label weekly dosing, according to week 8 response status. Patients who moved from blinded to open-label every other week therapy and remained on every other week dosing were also analysed separately. The endpoints measured were remission (full Mayo score ≤2, with no individual subscore >1), response per full Mayo score (decrease in full Mayo score ≥3 points and ≥30% from baseline, with a decrease in rectal bleeding score ≥1 point or an absolute rectal bleeding score ≤1), mucosal healing (endoscopy subscore ≤1), and corticosteroid-free remission (full Mayo score ≤2, with no individual subscore >1 and discontinued corticosteroid use before week 52).
The partial Mayo score was assessed at all study visits and was calculated from the worst patient-reported stool frequency and rectal bleeding subscores from the 3 days prior to the study visit. Endoscopy was performed at baseline, weeks 8, 32 and 52. Adverse events were monitored throughout the study and recorded from the first dose up to 70 days after the last adalimumab dose. Serum was collected at baseline, weeks 2, 4, 8, 32 and 52 to determine adalimumab trough concentration.
Response at week 8 (per partial Mayo score) was analysed using nonresponder imputation (NRI), in which patients with a missing partial Mayo score at week 8 were considered to be nonresponders. Patient demographics were compared between week 8 responders and nonresponders using χ test for categorical variables and one-way anova for continuous variables. Wilcoxon test was used for comparisons of baseline CRP and UC duration. Logistic regression was used to determine predictors of escalation to weekly dosing. Baseline variables assessed were age, sex, steroid use, immunomodulator use, Mayo score, CRP, weight, disease duration and prior anti-TNF use. The time to weekly dosing was measured using Kaplan–Meier curves. Patients who did not dose escalate were censored at the date of their last dose in the study. Efficacy endpoints were analysed using as-observed and NRI methods. For the NRI method, patients who discontinued from the study prior to week 52 or those with missing data were considered not to have achieved the endpoint. Adalimumab trough serum concentration at week 8 was compared between week 8 responders and nonresponders in patients who remained on blinded or open-label every other week dosing and in patients who escalated to weekly dosing. The effect of escalation to weekly dosing on adalimumab serum trough concentrations was evaluated by comparing the last serum trough concentration prior to escalation to weekly dosing to the first trough level after escalation to weekly dosing for patients with available data at both time points.
Methods
Study Design and Patients
ULTRA 2 (NCT00408629) was a 52-week, Phase 3, randomised, double-blind, placebo-controlled trial that assessed the efficacy and safety of adalimumab in patients with UC. The details have been published previously. Briefly, adult patients with a diagnosis of moderately to severely active UC for ≥3 months and a Mayo score of 6–12 (endoscopy subscore of 2–3) were randomised to receive either double-blind placebo or adalimumab (160/80 mg at weeks 0/2, followed by 40 mg every other week). Patients with prior exposure and response to other anti-TNF antagonists were permitted to enrol in ULTRA 2. UC-related medications were to remain stable during ULTRA 2, except corticosteroids, which could be tapered beginning at or after week 8, at the discretion of the investigator, for patients who demonstrated a satisfactory clinical response.
A rescue option was included, beginning at week 12, whereby patients who met the protocol-defined criteria for inadequate response at week 12 or later could move to open-label adalimumab 40 mg every other week (this intermediate step was required to retain study blinding), with a subsequent escalation to 40 mg weekly for continued inadequate response. Inadequate response was defined as partial Mayo score (Mayo score without endoscopy subscore) ≥ the baseline score on two consecutive visits at least 14 days apart, for patients with a baseline partial Mayo score of 4–7. For patients with a baseline partial Mayo score of 8–9, inadequate response was defined as partial Mayo score ≥7 on two consecutive visits at least 14 days apart.
Patients assessed in this analysis were those randomised to adalimumab in the intent-to-treat population of ULTRA 2 (n = 248). To analyse the effect of escalation from every other week to weekly adalimumab by initial response to induction therapy with adalimumab, patients were stratified by week 8 response per partial Mayo score, defined as a decrease in partial Mayo score ≥2 points and ≥30% from baseline, and a decrease in rectal bleeding score ≥1 point or an absolute rectal bleeding score ≤1. While escape to open-label could occur from week 12 onward, week 8 was chosen as the time point for stratification of patients as responders to induction therapy, as this time point corresponded to the timing of one of the study's co-primary endpoint assessments. In addition, 8 weeks was felt to represent a reasonable amount of time to assess initial response to adalimumab induction dosing, and week 8 responders are likely to be representative of patients to continue maintenance therapy with adalimumab in clinical practice.
Data Analysis
Week 52 endpoints were assessed in patients who escalated to open-label weekly dosing, according to week 8 response status. Patients who moved from blinded to open-label every other week therapy and remained on every other week dosing were also analysed separately. The endpoints measured were remission (full Mayo score ≤2, with no individual subscore >1), response per full Mayo score (decrease in full Mayo score ≥3 points and ≥30% from baseline, with a decrease in rectal bleeding score ≥1 point or an absolute rectal bleeding score ≤1), mucosal healing (endoscopy subscore ≤1), and corticosteroid-free remission (full Mayo score ≤2, with no individual subscore >1 and discontinued corticosteroid use before week 52).
Clinical Assessment
The partial Mayo score was assessed at all study visits and was calculated from the worst patient-reported stool frequency and rectal bleeding subscores from the 3 days prior to the study visit. Endoscopy was performed at baseline, weeks 8, 32 and 52. Adverse events were monitored throughout the study and recorded from the first dose up to 70 days after the last adalimumab dose. Serum was collected at baseline, weeks 2, 4, 8, 32 and 52 to determine adalimumab trough concentration.
Statistical Analysis
Response at week 8 (per partial Mayo score) was analysed using nonresponder imputation (NRI), in which patients with a missing partial Mayo score at week 8 were considered to be nonresponders. Patient demographics were compared between week 8 responders and nonresponders using χ test for categorical variables and one-way anova for continuous variables. Wilcoxon test was used for comparisons of baseline CRP and UC duration. Logistic regression was used to determine predictors of escalation to weekly dosing. Baseline variables assessed were age, sex, steroid use, immunomodulator use, Mayo score, CRP, weight, disease duration and prior anti-TNF use. The time to weekly dosing was measured using Kaplan–Meier curves. Patients who did not dose escalate were censored at the date of their last dose in the study. Efficacy endpoints were analysed using as-observed and NRI methods. For the NRI method, patients who discontinued from the study prior to week 52 or those with missing data were considered not to have achieved the endpoint. Adalimumab trough serum concentration at week 8 was compared between week 8 responders and nonresponders in patients who remained on blinded or open-label every other week dosing and in patients who escalated to weekly dosing. The effect of escalation to weekly dosing on adalimumab serum trough concentrations was evaluated by comparing the last serum trough concentration prior to escalation to weekly dosing to the first trough level after escalation to weekly dosing for patients with available data at both time points.
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