The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only.

Transcription

1 The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only. Please note that the results reported in any single trial may not reflect the overall potential risks or benefits of a product which are based on an evaluation of an entire research program. Before prescribing any Takeda products, healthcare professionals should consult prescribing information for the product approved in their country.

2 M FINAL CLINICAL STUDY REPORT SYNOPSIS Study Title: A Phase I/II, Randomized, Placebo-Controlled, Double-Blind, Parallel Group, Multicenter Study to Determine the Safety, Pharmacokinetics, and Effectiveness of Multiple Doses of in Patients with Mildly to Moderately Active Ulcerative Colitis Investigators and Study Centers: This study was conducted at 12 study centers in the United States; 3 of these study centers were initiated but enrolled no patients. Investigators at all 12 study centers are identified in section 6. Publication (reference): None Study Period: Initiation Date (first patient enrolled): 05 December 2000 Completion Date (last patient completed): 05 April 2004 Study Phase: 1/2 Study Objectives: The primary objectives of this study were to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of 2 dose levels and 2 doses of (0.5 and 2.0 mg/kg) in patients with active ulcerative colitis who were not receiving corticosteroids or immunosuppressives. A secondary objective of this study was to preliminarily assess the ability of to reduce ulcerative colitis activity in these patients. Methodology: Millennium Study M was a placebo-controlled, randomized, double-blind, parallelgroup, multicenter study involving patients with mildly to moderately active ulcerative colitis who were not receiving corticosteroids or immunosuppressives. Patients were assigned randomly to 1 of 3 treatment groups: placebo, at 0.5 mg/kg or at 2.0 mg/kg. All treatments were administered intravenously on Days 1 and 29. The study consisted of 3 periods: Screening (Days 14 to 1), Treatment (Days 1 to 29), and Observation (Days 30 to 180). At Screening Visit S1 (Day -14 to -7), patients were assessed for eligibility and baseline measurements were obtained. At Visit S2 (Day 1), eligibility was confirmed and eligible patients were treated on this same day as part of Visit 1 (Day 1). 1

3 Methodology: The Treatment period included Visits 1 through 4 (Days 1-29). Patients received study drug at 2 of these visits (Visit 1 [Day 1] and Visit 4 [Day 29]). The Observation period spanned Days and included Visits 5 through 11 at which post-treatment assessments of safety, efficacy, and quality of life were conducted, and PK and PD variables were determined. During the Treatment period (Days 1 to 29) and the post-treatment Observation period (Days 30 to 180), study procedures included monitoring for adverse events (AEs), physical examinations, clinical laboratory tests, anti- antibody assessment, vital signs, Ulcerative Colitis Clinical Score (UCCS), sigmoidoscopy with modified Baron score, Powell Tuck score, and the Inflammatory Bowel Disease Questionnaire (IBDQ). A complete PK and PD profile was to be obtained on all patients. Blood samples were to be obtained for determination of serum levels and for flow cytometry analysis of binding to α4β7 sites on memory T and B cells and lymphocyte subset analysis were to be obtained. After Day 180, visits were to be scheduled at 30-day intervals if attachment to the α4β7 sites on circulating lymphocytes had not returned to baseline. Patients were to be followed offstudy with telephone contact at 6-month intervals for 2 years (at 1, 1.5 and 2 years after first administration of study drug) to collect data regarding disease activity (need for surgery) and safety (infection, malignancy). Number of Patients (Planned and Analyzed): The planned number of patients to be enrolled in the study was 30 patients (6 patients in the placebo group and 12 patients in each of the 2 groups). The study sample size was based on the need to obtain sufficient safety information to allow further testing of multiple doses of in a larger sample of patients and was not based on formal statistical calculations that would assume the need to detect a minimum level of efficacy. A total of 30 patients with ulcerative colitis were enrolled and treated with or placebo in this study. 2

4 Diagnosis and Main Criteria for Inclusion: Non-hospitalized, male or non-pregnant, non-lactating females aged 18 to 80 years with ulcerative colitis of at least 6 months duration were candidates for the study. Specifically, patients with left sided or universal colitis, with the extent of colonic involvement at least 25 cm, were to be enrolled. Patients must have had endoscopic and/or histopathological documentation consistent with ulcerative colitis obtained preferably within 24 months of screening and had to be currently experiencing active disease documented with a UCCS of 5 to 9 with a score of at least 1 on either stool frequency or rectal bleeding and a modified Baron score of 2 or more on endoscopic screening on Day 1. Patients may have received a therapeutic dose of oral 5-aminosalicyclic acid (5-ASA) compounds provided the compound had been administered for at least 4 weeks, the dose was stable for 2 weeks prior to the screening visit, and there was a commitment to remain on the 5-ASA compound at the same dose at least through Day 57 of the study. Patients who received oral corticosteroids within 4 weeks or parenteral steroids within 6 weeks of the screening visit were to be excluded, as were patients who received topical (eg, rectal) corticosteroids or 5-ASA compounds within 1 week. Patients deemed to have had a rebound flare of ulcerative colitis after stopping corticosteroids were not to be entered. Test Product, Dose and Mode of Administration, Batch Number: Two dose levels of were evaluated in this study: 0.5 mg/kg and 2.0 mg/kg. was diluted in 0.9% sodium chloride to a volume of 50 ml and administered by intravenous infusion. Duration of Treatment: Patients received study drug on Day 1 and Day 29. Reference Therapy, Dose and Mode of Administration, Batch Number: Placebo was administered in this study. Placebo consisted of 0.9% sodium chloride that was supplied by the study site s pharmacy. 3

5 CRITERIA FOR EVALUATION Pharmacokinetics: Serum concentrations of were to be measured for all patients and the following PK variables determined: maximum serum concentration for each dosing interval (C max 1-29; C max ); the time at which C max occurred (T max ); clearance (Cl); volume of distribution (V d ); half-life (t 1/2 ); area under the serum concentration versus time curve (AUC and AUC 0- ); and accumulation ratios (C max /C max 1-29 ; AUC /AUC 1-29 ). Pharmacodynamics: The unbound α4β7 sites on circulating lymphocytes following the administration of were to be quantified by flow cytometry for all patients and correlated with serum levels. Efficacy: The primary efficacy analysis was based on the proportion of patients with a remission, defined as a 0 or 1 in the total UCCS score and 0 to 1 in the Modified Baron score with no evidence of rectal bleeding at the Day 43 evaluation. Patients who discontinued treatment prior to the second dose of study drug due to worsening clinical condition or who required additional therapy for the treatment of UC up to Day 43 were to be considered treatment failures in this analysis. In addition, patients who were lost to follow-up with no postbaseline assessments were also to be considered failures in this analysis. Fisher s exact test was used to perform the comparisons among all treatment groups, and pair-wise comparisons between the active groups and the placebo. The following secondary efficacy parameters were evaluated: change in mean UCCS over time, change in modified Baron score over time, change in Powell Tuck score over time, change in IBDQ scores over time and change in serum CRP concentration over time. Categorical data were to be analyzed in a similar fashion to the primary efficacy analysis. Safety: Safety evaluations included the assessment of AEs, electrocardiograms, physical examination findings, vital signs, and clinical laboratory test results, including assessment of a potential HAHA response. Safety data were to be summarized and tabulated. All serious adverse events (SAEs) were reviewed by independent Data Safety Monitoring Boards (DSMBs) on an ongoing basis to determine whether the events were related to study drug administration or were expected events for patients with Crohn s disease or ulcerative colitis. 4

6 Statistical Methods: All patients who received at least 1 dose of study drug were included in safety evaluations. Safety evaluations were to be based on the incidence, severity, and type of AEs, and changes in the patient s physical examination findings, vital signs measurements, and clinical laboratory test results. Efficacy evaluations were to be based on the primary outcome measure and secondary outcome measures (see Efficacy section above). Statistical analyses were to be performed by conducting pairwise comparisons of each dose with placebo. A primary intent-to-treat (ITT) analysis was to be conducted utilizing data from all patients who received at least 1 dose of study drug. An analysis also was to be conducted utilizing data for an efficacy evaluable (per protocol [PP]) analysis population consisting of all patients who received both doses of study drug on Days 1 and 29, and who had no major protocol violations. SUMMARY AND CONCLUSIONS Demographics and Patient Characteristics: A total of 30 patients were enrolled and treated with or placebo in this study: 6 patients received placebo, 12 patients received 0.5 mg/kg, and 12 patients received 2.0 mg/kg groups. Twenty-one (70%) patients completed the study through the Day 180 Followup visit. Of the 9 (30%) patients who discontinued early from the study, 3 (10%) patients withdrew consent, 3 (10%) discontinued due to AEs, and 3 (10%) patients did not complete the study for reasons categorized as Other. Overall, there were no important differences across treatment groups for demographic characteristics. Mean age was slightly higher in the placebo group (48.5 years) than in the 0.5 mg/kg or 2.0 mg/kg groups (40.8 and 43.8 years, respectively). The percentage of male and female patients was 50% and 50% in the placebo group, 42% and 58% in the 0.5 mg/kg group, and 67% and 33% in the 2.0 mg/kg group. In all 3 treatment groups, the majority (75-92%) of patients were White. The 3 treatment groups were similar in terms of baseline disease characteristics with the exception of total UCCS score. The total UCCS score was higher in the treatment groups (mean scores of 6.9 and 7.5 in the 0.5 mg/kg and 2.0 mg/kg groups, respectively) than in the placebo group (mean score of 6.3). This was mainly due to the higher scores for rectal bleeding, a subcomponent of the UCCS, in the groups at baseline. 5

7 Demographics and Baseline Characteristics (cont d): The 3 treatment groups were similar in terms of the number of acute exacerbations in the past 12 months (mean number of acute exacerbations was 1.2, 1.1 and 1.3 in the placebo, 0.5 mg/kg and 2.0 mg/kg groups, respectively). Overall, the most common previous therapies for ulcerative colitis were: systemic corticosteroids (prednisone, cortisone), topical rectal corticosteroids, topical rectal 5-ASA, any 5-ASA containing compound, antibiotics used for IBD (metronidazole/ciprofloxacin), sulfasalzine/dipentum and anti-diarrheal medications. All (100%) patients received at least 1 concomitant medication during the study. The most frequently reported medications were other analgesics and antipyretics and intestinal antiinflammatory agents. Intestinal anti-inflammatory agents were reported for more patients in the treatment groups (75% and 92% in the 0.5 mg/kg and 2.0 mg/kg groups, respectively) than in the placebo group (33%). Efficacy Results: The primary efficacy analysis was based on the proportion of patients with a clinical remission, defined as a 0 or 1 in the total UCCS score and 0 to 1 in the modified Baron score with no evidence of rectal bleeding at the Day 43 evaluation. This study was not powered to address efficacy. Three patients in the groups achieved a clinical remission. No patient in the placebo group achieved a clinical remission at any of the time points assessed. In the 0.5 mg/kg group, clinical remission was achieved in 1 patient, Patient 08005, at both Day 29 and Day 43. In the 2.0 mg/kg group, 2 patients achieved a clinical remission; Patient had a remission at both Day 29 and Day 43, and Patient had a remission at Day 43. None of the differences across treatment groups were statistically significant (p 0.778). Secondary efficacy parameters evaluated were: change in mean UCCS over time; change in modified Baron score over time; change in Powell Tuck score over time; change in IBDQ scores over time; and change in serum CRP concentration over time. Overall, the 2 active treatment groups showed larger decreases in total UCCS after treatment than did the placebo group. Likewise, the 2 active treatment groups showed a slightly greater decrease in modified Baron and Powell Tuck scores after treatment. 6

8 Efficacy Results (cont d): At baseline, the total IBDQ scores were 129.2, 143.1, and points for the placebo, 0.5 mg/kg, and 2.0 mg/kg groups, respectively. At Day 43, total IBDQ scores had increased by 16.7, 34.0, and 42.1 points for the placebo, 0.5 mg/kg, and 2.0 mg/kg groups, respectively. In general, a similar trend was seen for changes from baseline in the IBDQ dimensional scores (bowel symptoms, systemic symptoms, emotional function, and social function). Within each treatment group, mean scores for bowel symptoms, systemic symptoms, emotional function, and social function generally increased over time through Day 113, and larger increases were seen in the active treatment groups. A change from baseline mean total IBDQ score of at least 16 points was considered clinically meaningful. The active treatment groups had a higher proportion of patients who improved by at least 16 points from baseline IBDQ score at each time point assessed. At Day 43, the number of patients who improved by at least 16 points from baseline IBDQ score was 2 (40%), 7 (78%), and 9 (75%) in the placebo, 0.5 mg/kg, and 2.0 mg/kg groups, respectively. Overall, the 2 active treatment groups showed a slightly larger decrease in modified Riley histopathological evaluation after treatment. At baseline (Day 1 predose) mean values for the modified Riley histopathological evaluation were 5.7, 5.5, and 6.2 for the placebo, 0.5 mg/kg and 2.0 mg/kg groups, respectively. Mean changes from baseline at Day 43 were -0.6, -1.1, and -2.4 for the placebo, 0.5 mg/kg, and 2.0 mg/kg groups. Pharmacokinetic and Pharmacodynamic Results: Blood samples for PK and PD analyses were collected from all 30 patients (6, 12, and 12 patients in the placebo, 0.5 and 2.0 mg/kg groups, respectively). Intravenous administration of 0.5 or 2.0 mg/kg provided dose-independent initial saturation of α4β7 and a dose-dependent duration of saturation of α4β7 associated with the persistence of in serum. Clearance of from the serum and the associated recovery of free α4β7 sites on memory T cells was similar after administration of on Days 1 and 29. PK analysis revealed dose-proportional exposure to, with t1/2 values after the first dose that were broadly similar at 0.5 and 2.0 mg/kg (approximately 9 and 12 days, respectively). Serum concentrations of approximately 1 to 10 µg/ml were associated with saturation of α4β7 on approximately 90% of CD4+/CD45RO+ T cells. After administration of 0.5 or 2.0 mg/kg on Days 1 and 29, α4β7 remained completely saturated on memory T cells of HAHA- patients, on average, through Day 57 or 85, respectively. Complete recovery of free α4β7 on T cells was not evident until Day 113 or after Day 180, respectively. elicited anti-idiotypic HAHA titers which interfered with pharmacokinetic and pharmacodynamic determinations and appeared to clear from the serum. 7

9 Safety Results: The percentage of patients who received both planned doses of study drug was 83%, 92%, and 100% in the placebo, 0.5 mg/kg, and 2.0 mg/kg groups, respectively. Five (83%) patients treated with placebo, 10 (83%) patients in the 0.5 mg/kg group, and 9 (75%) patients in the 2.0 mg/kg group experienced at least 1 AE during the study. There was no apparent difference in the overall incidence of AEs between the 3 treatment groups. The most commonly reported AEs overall (reported for 2 patients in any treatment group) were: aggravated ulcerative colitis; nausea; fatigue aggravated; arthralgia; and dermatitis not otherwise specified (NOS). AEs that were reported more frequently in patients who received were: aggravated ulcerative colitis, fatigue aggravated, arthralgia, headache (headache NOS and headache NOS aggravated), and hot flushes (hot flushes NOS and hot flushes aggravated). The majority of AEs were mild or moderate in severity. Two (33%) patients in the placebo group, 2 (17%) patients in the 0.5 mg/kg group and 3 (25%) patients in the 2.0 mg/kg group experienced at least 1 severe AE during the study. Severe aggravated ulcerative colitis was reported in 2 patients, 1 patient in the placebo group and 1 patient in the 2.0 mg/kg group. There were no apparent dose-related trends in the severity of events. Three (50%) patients in the placebo group, 5 (42%) patients in the 0.5 mg/kg group and 5 (42%) patients in 2.0 mg/kg group experienced at least 1 AE that was determined by the investigator to have a possible or probable relationship to study drug. No patient had any AE that was determined to have a definite relationship to study drug. Fatigue aggravated was reported only in patients who received and was considered possibly or probably related in 2 patients in the 0.5 mg/kg group and in 1 patient in the 2.0 mg/kg group. Arthralgia was reported only in patients who received and was considered possibly or probably related in 2 patients in the 0.5 mg/kg group and in 1 patient in the 2.0 mg/kg group. Hot flushes were reported only in patients who received, in 2 patients who received 2.0 mg/kg group, and in 1 case was considered remotely related and in the other probably related. 8

10 Safety Results (cont d): During the study, a total of 6 SAEs were reported in 5 patients, 3 (50%) patients treated with placebo and 2 (8%) patients treated with (1 patient each in the 0.5 mg/kg and 2.0 mg/kg groups). There was no apparent increase in the overall incidence of SAEs across dose level. The most commonly reported SAEs were gastrointestinal (GI) disorders. Aggravated ulcerative colitis was the most commonly reported SAE and was observed in 1 (17%) placebo patient, 1 (8%) patient in the 0.5 mg/kg dose group, and 1 (8%) patient in the 2.0 mg/kg group. Both reports of aggravated ulcerative colitis observed in patients were considered by the investigator to have no relationship to study drug. All other SAEs were single occurrences in the placebo group: small intestinal obstruction NOS, cellulitis, and bursitis. Three patients experienced AEs leading to study discontinuation, 1 patient in the placebo group and 2 patients in the 0.5 mg/kg group. In all cases, the main AE leading to discontinuation was aggravated ulcerative colitis. There were no patient deaths reported during this study. For the 21 patients with available longterm follow-up data, there were no serious infections, lymphomas, colon cancers, or deaths reported in any patient during the follow-up period. Four patients (all of whom received at 2.0 mg/kg) underwent a colectomy within 2 years after the first dose of study drug. Overall, for the hematology, clinical chemistry, and urinalysis parameters assessed, there were no clinically meaningful differences across treatment groups or any apparent trends for mean values over time. No clinically relevant trends were noted with regard to change from baseline in any physical examination, vital signs, or ECG parameters. Despite generally complete, consistent saturation of α4β7 by on target cells, including CD4+/CD45RO+ memory T cells, there was no evidence of depletion of peripheral blood lymphocyte immunophenotypes. A subset of patients who received therapy developed a HAHA response. Fifty-five percent of patients were HAHA + during the treatment period of 57 days. The HAHA rate increased after the cessation of treatment and reached 77% by Day 180. The higher dose of was associated with a lessened HAHA response. There were no AEs that appeared to be associated with HAHA. 9

11 Conclusions: The key conclusions that can be drawn from this study are: was well tolerated. A few AEs, including aggravated ulcerative colitis, fatigue aggravated, arthralgia, headache, and hot flushes, were more common with versus placebo. However, the significance of these findings is not clear given the small sample size. The most commonly reported SAEs were GI disorders, principally aggravated ulcerative colitis. There were no serious infections, lymphomas, colon cancers, or deaths during long term follow-up. A subset of patients who received developed a HAHA response. Approximately half of these patients were HAHA + (titer 5) by Day 57. The HAHA rate increased after the cessation of treatment and reached 77% by Day 180. The higher dose of was associated with a lessened HAHA response. However, given the small number of patients in this study, no definitive conclusions can be drawn concerning the clinical significance of a HAHA titer 5. PD analyses showed a dose-independent initial saturation of α4β7 and a dose-dependent duration of saturation of α4β7 associated with the persistence of in the serum. Clearance of from the serum and the associated recovery of free α4β7 sites on memory T cells was similar after administration of on Days 1 and 29. PK analysis revealed dose-proportional exposure to, with t 1/2 values after the first dose that were broadly similar at 0.5 and 2.0 mg/kg (approximately 9 and 12 days, respectively). Serum concentrations of approximately 1 to 10 µg/ml were associated with saturation of α4β7 on approximately 90% of CD4 + /CD45RO + T cells. Despite generally complete, consistent saturation of α4β7 by on target cells, including CD4 + /CD45RO + memory T cells, there was no evidence of depletion of peripheral blood lymphocyte immunophenotypes. This study was not powered for efficacy. Three patients (and no placebo patients) achieved a clinical remission. provided greater improvement in the total UCCS, Powell Tuck Score, and IBDQ than did placebo. Date of Report: FINAL, 21 December