Phase III Study of MLN0002 (300 mg) in Treatment of Crohn's Disease

Phase III, Multicenter, Randomized, Double-blinded, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Intravenous MLN0002 (300 mg) Infusion in Induction and Maintenance Therapy in Japanese Subjects With Moderate or Severe Crohn's Disease

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02038920

Enrollment

157

Registered

2014-01-17

Start date

2014-01-28

Completion date

2019-05-21

Last updated

2019-12-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Crohn's Disease

Keywords

Drug Therapy

Brief summary

This study is a phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study to examine the efficacy, safety, and pharmacokinetics of vedolizumab (MLN0002) in induction and maintenance therapy in Japanese participants with moderately or severely active Crohn's disease.

Detailed description

This is a phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study to examine the efficacy, safety, and pharmacokinetics of intravenous vedolizumab (300 mg) infusion in induction and maintenance therapy in Japanese participants with moderately or severely active Crohn's disease.

Interventions

DRUGVedolizumab

Vedolizumab IV injection

DRUGVedolizumab placebo

Vedolizumab placebo-matching IV infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

15 Years to 80 Years

Healthy volunteers

Inclusion criteria

1. In the opinion of the investigator, participants were capable of understanding and complying with protocol requirements 2. Participants or, when applicable, participants legally acceptable representative sign and date the informed consent form prior to initiation of any study procedures 3. Participants aged 15 to 80 years (inclusive) at the time of consent 4. A nonsterilized male participant who has a female partner of child-bearing potential has to agree to use adequate contraception during the period from the signing of informed consent to 6 months after the last dose of the study drug 5. A female participant of child-bearing potential (i.e., nonsterilized or whose last regular menses was within previous 2 years) who has a nonsterilized male partner has to agree to use adequate contraception during the period from the signing of informed consent to 6 months after the last dose of the study drug 6. Participants with a diagnosis of small-intestinal, large-intestinal, or small-/large-intestinal Crohn's disease (CD) established based on the Revised Diagnostic Criteria for Crohn's disease issued by Research Group for Intractable Inflammatory Bowel Disease Designated as Specified Disease by the Ministry of Health, Labor and Welfare of Japan (2012) at least 3 months before the start of administration of study drug 7. Participants with baseline CDAI score of 220 to 450(inclusive) and meeting at least one of the followings: * C-reactive protein (CRP) at screening test is above 0.30 mg/dL * Participants with irregular or semicircular ulcers or multiple aphthae (10 or more) observed over an extensive area of the small or large intestine on endoscopy or imaging test within the 4 months before the start of administration of study drugs * Participants with longitudinal ulcers or a cobblestone appearance observed in the small or large intestine on endoscopy or imaging test within 4 months before the start of administration of study drugs 8. In case of the participants who meet any of the following criteria; participants with ≥ 8-year history of extensive or limited colitis, participants aged ≥ 50 years, or participants with a first-degree family history of colon cancer, those whom the complication of colon cancer or dysplasia was ruled out by total colonoscopy at the start of study drug administration (or the results from total colonoscopy performed within 1 year before giving consent are available) 9. Participants meeting the criteria for treatment failure below with at least one of the following agents received within previous 5 year period before giving consent 1. Corticosteroids * Resistance * Dependence * Intolerance 2. Immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) * Refractory * Intolerance 3. Anti-tumor necrosis factor alpha (TNFα) antibodies * Inadequate response * Loss of response * Intolerance

Exclusion criteria

1. Participants with an evidence of or suspected abdominal abscess 2. Participants with a history of subtotal or total colectomy 3. Participants who have had a resection of the small intestine in at least 3 locations or have a diagnosis of short bowel syndrome 4. Participants with ileostomy, colostomy, or internal fistula, or severe intestinal stenosis 5. Participants who have a treatment history with natalizumab, efalizumab or rituximab 6. Participants who started 5-aminosalicylic acid oral drug or probiotics treatment, antimicrobials to treat Crohn's disease, or 30 mg/day or less of oral corticosteroids within 13 days before initiation of study drug administration. If these drugs were used within 14 days before initiation of study drug administration, the dosage must have been changed or their use discontinued within 13 days before the initiation of study drug administration 7. Participants who had received 5-aminosalicylic acid or corticosteroid enemas/suppositories, intravenous corticosteroid injections, or more than 30 mg/day of oral corticosteroids, medications for diarrhea-predominant irritable bowel syndrome, or Chinese herbal medicine for the treatment of Crohn's disease (e.g., Daikenchuto) within 13 days before initiation of study drug administration 8. Participants who had received azathioprine, 6-mercaptopurine, or methotrexate within 27 days before initiation of study drug administration. However, this shall not apply to participants who have received these drugs for 83 or more days before initiation of the study drug administration and continued the steady dose administration of the drugs for 27 or more days before initiation of the study drug administration 9. Participants who had received cyclosporin, tacrolimus, tofacitinib or any study drugs for treatment of ulcerative colitis within 27 days before initiation of the study drug administration 10. Participants who had received adalimumab within 27 days before initiation of study drug administration or any biological drugs other than adalimumab within 55 days before initiation of study drug administration. Topical administration (such as intraocular implantation for treatment of age-related maculopacy) is allowed 11. Participants who had received any live vaccinations within 27 days before initiation of study drug administration 12. Participants who had undergone intestinal resection within 27 days before initiation of study drug administration or those anticipated to require intestinal resection during the study 13. Participants who had received leukocytapheresis or granulocyte apheresis within 27 days before initiation of the study drug administration 14. Participants who had received intravenous hyperalimentation or total enteral nutrition within the 20 days before initiation of the study drug administration or participants who are fasted 15. Participants who had received enteral nutrition at \> 900 kcal/day or started enteral nutrition at \<= 900 kcal/day within the 20 days before initiation of the study drug administration. Participants receiving 900 kcal/day or less of enteral nutrition for at least 21 days before initiation of the study drug administration whom these dosage was changed or the medications were discontinued within 20 days before initiation of the study drug administration 16. Participants who had been infected with Clostridium difficile, cytomegalovirus, or any other intestinal pathogen within 27 days before the first dose of the study drug 17. Participants with evidence of adenomatous colonic polyps that need to be removed at the start of study drug administration 18. Participants with a history or an complication of dysplasia of the small or large intestine 19. Participants who were suspected to have enteritis other than CD 20. Participants who were hepatitis B surface (HBs) antigen-positive or hepatitis C virus (HCV) antibody-positive at the screening. Or participants who are hepatitis B core (HBc) antibodypositive or HBs antibody positive, even though HBs antigen-negative. However, this does not apply to participants who are only HBs antibody-positive due to hepatitis B virus (HBV) vaccination, HBV-DNA-negative, HCV antigen-negative, or HCV-RNA-negative 21. Participants who had an evidence of history of tuberculosis or a suspected history of tuberculosis (including those who have findings suggesting previous tuberculosis on chest imaging procedure at the screening). However, this does not apply to participants who had completed prophylactic isoniazid, or participants who had been receiving prophylactic isoniazid for more than 21 days before the first dose of the study drug (in the latter case, the screening period are allowed to extend up to 28 days to ensure at least 21-day prophylactic isoniazid and then the study treatment is allowed to start) 22. Participants who had positive T-SPOT test or QuantiFERON test at the screening 23. Participants who had a history or complication of identified congenital or acquire immunodeficiency syndrome (eg, not-classifiable immunodeficiency, human immunodeficiency virus \[HIV\] infection or organ transplantation) 24. Participants who had been affected by extraintestinal infection (eg, pneumonia, sepsis, active hepatitis or pyelonephritis) within 27 days before the first dose of the study drug 25. Participants who had a treatment history with MLN0002 26. Female participants who are lactating at the screening, or have positive urine pregnancy test either at the screening or baseline 27. Participants who had serious complications in the heart, lung, liver, kidney, metabolism, gastrointestinal system, urinary system, endocrine system or blood 28. Participants who had a history of a surgery requiring general anesthesia within 27 days before the first dose of the study drug, or with a schedule of a surgery requiring hospitalization during the study period 29. Participants who had a complication or a history of malignancy. However, this does not apply to the following participants: * Participants who had a curative resection of localized skin basal cell carcinoma or have completed curative radiotherapy * Participants who had not experienced recurrence for more than 1 year since completion of a curative resection or curative radiotherapy for skin squamous cell carcinoma * Participants who had not experienced recurrence for more than 3 years since completion of a curative resection or curative radiotherapy for intraepithelial carcinoma of uterine cervix For participants who had a substantially distant history of malignancy (eg, 10 years or longer without recurrence since treatment completion), the investigator and the sponsor had a discussion to decide eligibility on the basis of type of malignancy and treatment applied 30. Participants who had a history or a complication of the central nervous disorder, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease. 31. Participants who had any subjective symptoms in the subjective PML checklist at the screening or baseline 32. Participants who had any of the following laboratory abnormalities at the screening; * Hemoglobin ≤8 g/dL * White blood cells ≤3,000/μL * Lymphocytes ≤500/μL * Platelets ≤100,000/μL or ≥1,200,000/μL * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3×upper limit of normal (ULN) * Alkaline phosphatase (ALP) ≥3×ULN * Creatinine ≥2×ULN 33. Participants who had a history or a complication of alcohol dependence or illicit drug use within one year before the first dose of the study drug 34. Participants who had a history or a complication of psychotic disorder that could obstruct compliance with the study procedures

Design outcomes

Primary

Measure	Time frame	Description
Induction Phase: Percentage of Participants With Crohn's Disease Activity Index (CDAI)-100 Response	Week 10	A response to therapy is considered a decrease from baseline of at least 100 points in the CDAI score at Week 10. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.
Maintenance Phase: Percentage of Participants With Clinical Remission	Week 60	Clinical remission is defined as the CDAI score ≤150. CDAI is scoring system for the assessment of Crohn's disease activity. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.
Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Events (TEAEs)	From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)	An Adverse event (AE) is defined as any untoward medical occurrence in a study participant who received a drug (including a study drug); it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Number of Participants With TEAE Related to Body Weight (Weight Decreased)	From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)	Reported events on this outcome measure were Weight Decreased.
Number of Participants With TEAE Related to Vital Signs	From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)	Vital signs included body temperature (axilla), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm). Reported events on this outcome measure were Pyrexia, Body temperature increased, Hypertension, and Orthostatic hypotension.
Number of Participants With TEAE Related to Electrocardiogram (ECG) [Bundle Branch Block Right]	From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)	Reported events on this outcome measure were Bundle Branch Block Right.
Number of Participants With Markedly Abnormal Values of Laboratory Parameters Values	From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks)	The laboratory values outside the range (Hemoglobin \<=7 g/dL, Lymphocytes \<500 /microL, White Blood Cell (WBC) \<2000 /microL, Platelets \<7.5 10\^4/microL, Neutrophils \<1000 /microL, Alanine Aminotransferase (ALT) (Glutamic Pyruvic Transaminase; GPT) \>3.0 U/L x upper limit of normal (ULN), Aspartate Aminotransferase (AST) (Glutamic Oxaloacetic Transaminase; GOT) \>3.0 U/L x ULN, Total Bilirubin \>2.0 mg/dL x ULN, Amylase \>2.0 (U/L) x ULN are considered markedly abnormal.

Secondary

Measure	Time frame	Description
Number of Participants With Anti-vedolizumab Antibodies (AVA) in Induction Phase	Weeks 0, 10 and 16 weeks after the last dose of study drug in induction phase	—
Number of Participants With Anti-vedolizumab Antibodies (AVA) in Maintenance Phase	Weeks 0, 10, 30, 60 and 16 weeks after the last dose of study drug in maintenance phase	—
Number of Participants With Anti-vedolizumab Antibodies (AVA) in Open Label Cohort	Weeks 0, 10, 30, 62, 94 and 16 weeks after the last dose of study drug in open-label cohort	—
Induction Phase: Percentage of Participants With Clinical Remission	Week 10	Clinical remission is defined as the CDAI score ≤150. CDAI is scoring system for the assessment of Crohn's disease activity. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.
Number of Participants With Neutralizing Anti-vedolizumab Antibodies (AVA) in Maintenance Phase	Weeks 0, 10, 30, 60 and 16 weeks after the last dose of study drug in maintenance phase	—
Number of Participants With Neutralizing Anti-vedolizumab Antibodies (AVA) in Open Label Cohort	Weeks 0, 10, 30, 62, 94 and 16 weeks after the last dose of study drug in open-label cohort	—
Number of Participants With Neutralizing Anti-vedolizumab Antibodies (AVA) in Induction Phase	Weeks 0, 10 and 16 weeks after the last dose of study drug in induction phase	—
Induction Phase: Change From Baseline in C-reactive Protein (CRP) Values	Baseline to Week 10	—
Maintenance Phase: Percentage of Participants With Crohn's Disease Activity Index (CDAI)-100 Response	Week 60	A response to therapy is considered a decrease from baseline of at least 100 points in the CDAI score at Week 10. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.
Maintenance Phase: Percentage of Participants With Durable Clinical Remission	From Week 14 and Week 60	Durable clinical remission is defined as participants with CDAI score ≤ 150 at both Weeks 14 and 60. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.
Maintenance Phase: Percentage of Participants With Corticosteroid-free Clinical Remission	Week 60	Corticosteroid-free clinical remission is defined as participants using oral corticosteroids at baseline (Week 0) who discontinued corticosteroids and were in clinical remission (CDAI score ≤ 150) at Week 60. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.
Serum Vedolizumab Concentration in Induction Phase	Weeks 2, 6, 10 and 14	—
Serum Vedolizumab Concentration in Maintenance Phase	Weeks 2, 6, 10, 14, 22, 30 and 60	—

Countries

Japan

Participant flow

Recruitment details

Participants took part in the study at 77 investigative sites in Japan from 28 Jan 2014 to 21 May 2019.

Pre-assignment details

Participants with moderate to severe Crohn's disease were enrolled. 157 participants enrolled in induction phase, 41 participants entered maintenance phase and 134 participants entered open-label cohort and received placebo or vedolizumab 300 mg. Open-label cohort occurred between Week 10 and 154 through study with maximum of 94 weeks of treatment.

Participants by arm

Arm	Count
Induction Phase: Vedolizumab, 300 mg Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 in the induction phase.	79
Induction Phase: Placebo Vedolizumab placebo-matching IV infusion once at Weeks 0, 2 and 6 in the induction phase.	78
Total	157

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Induction Phase (Week 0 to 14)	Lack of Efficacy	1	1	0	0	0	0
Induction Phase (Week 0 to 14)	Pretreatment Event/Adverse Event	3	11	0	0	0	0
Induction Phase (Week 0 to 14)	Voluntary Withdrawal	2	0	0	0	0	0
Maintenance Phase (Week 14 to 60)	Lack of Efficacy	0	0	2	4	10	0
Maintenance Phase (Week 14 to 60)	Lost to Follow-up	0	0	1	0	0	0
Maintenance Phase (Week 14 to 60)	Pretreatment Event/Adverse Event	0	0	2	4	2	0
Open Label Cohort (Week 10 to 154)	Lack of Efficacy	0	0	0	0	0	23
Open Label Cohort (Week 10 to 154)	Lost to Follow-up	0	0	0	0	0	1
Open Label Cohort (Week 10 to 154)	Pregnancy	0	0	0	0	0	1
Open Label Cohort (Week 10 to 154)	Pretreatment Event/Adverse Event	0	0	0	0	0	43
Open Label Cohort (Week 10 to 154)	Reason Not Specified	0	0	0	0	0	2
Open Label Cohort (Week 10 to 154)	Voluntary Withdrawal	0	0	0	0	0	7

Baseline characteristics

Characteristic	Induction Phase: Vedolizumab, 300 mg	Induction Phase: Placebo	Total
Age, Continuous	33.9 years STANDARD_DEVIATION 12.25	32.6 years STANDARD_DEVIATION 10.93	33.3 years STANDARD_DEVIATION 11.6
Body Mass Index (BMI)	21.15 kg/m^2 STANDARD_DEVIATION 4.942	19.81 kg/m^2 STANDARD_DEVIATION 2.567	20.48 kg/m^2 STANDARD_DEVIATION 3.989
CDAI Score at Week 0	303.9 score on a scale STANDARD_DEVIATION 63.19	295.0 score on a scale STANDARD_DEVIATION 64.81	299.5 score on a scale STANDARD_DEVIATION 63.95
C-Reactive Protein (CRP)	2.234 mg/dL STANDARD_DEVIATION 2.1763	2.848 mg/dL STANDARD_DEVIATION 3.2303	2.539 mg/dL STANDARD_DEVIATION 2.7593
Current Medical Condition Related to Fistula Had Current Medical Condition	7 Participants	12 Participants	19 Participants
Current Medical Condition Related to Fistula Had No Current Medical Condition	72 Participants	66 Participants	138 Participants
Disease Localization Large Intestine Type	11 Participants	19 Participants	30 Participants
Disease Localization Small Intestine Type	13 Participants	9 Participants	22 Participants
Disease Localization Small/large Intestine Type	55 Participants	50 Participants	105 Participants
Duration of Crohn's Disease	7.20 years	8.35 years	7.90 years
Extraintestinal Manifestations (Based on Case Report Form) Had Extraintestinal Manifestations	37 Participants	26 Participants	63 Participants
Extraintestinal Manifestations (Based on Case Report Form) Had No Extraintestinal Manifestations	42 Participants	52 Participants	94 Participants
Extraintestinal Manifestations (Based on CDAI subscore) Had Extraintestinal Manifestations	55 Participants	56 Participants	111 Participants
Extraintestinal Manifestations (Based on CDAI subscore) Had No Extraintestinal Manifestations	24 Participants	22 Participants	46 Participants
Height	166.3 cm STANDARD_DEVIATION 8.73	166.4 cm STANDARD_DEVIATION 7.97	166.4 cm STANDARD_DEVIATION 8.33
History of Prior Surgery for Crohn's Disease (CD) Had No Surgical History	55 Participants	48 Participants	103 Participants
History of Prior Surgery for Crohn's Disease (CD) Had Surgical History	24 Participants	30 Participants	54 Participants
Race and Ethnicity Not Collected	—	—	0 Participants
Region of Enrollment Japan	79 Participants	78 Participants	157 Participants
Sex: Female, Male Female	28 Participants	26 Participants	54 Participants
Sex: Female, Male Male	51 Participants	52 Participants	103 Participants
Smoking Classification Current Smoker	13 Participants	11 Participants	24 Participants
Smoking Classification Ex-smoker	20 Participants	25 Participants	45 Participants
Smoking Classification Never Smoked	46 Participants	42 Participants	88 Participants
Weight	58.53 kg STANDARD_DEVIATION 14.095	55.03 kg STANDARD_DEVIATION 8.928	56.79 kg STANDARD_DEVIATION 11.906

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 79	0 / 78	0 / 12	0 / 12	0 / 17	0 / 134
other Total, other adverse events	17 / 79	19 / 78	9 / 12	7 / 12	12 / 17	113 / 134
serious Total, serious adverse events	8 / 79	10 / 78	2 / 12	4 / 12	2 / 17	70 / 134

Outcome results

Primary

Induction Phase: Percentage of Participants With Crohn's Disease Activity Index (CDAI)-100 Response

A response to therapy is considered a decrease from baseline of at least 100 points in the CDAI score at Week 10. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.

Time frame: Week 10

Population: Full analysis set (FAS) in the induction phase included participants who were randomized and received at least one dose of the study drug in induction phase.

Arm	Measure	Value (NUMBER)
Induction Phase: Vedolizumab, 300 mg	Induction Phase: Percentage of Participants With Crohn's Disease Activity Index (CDAI)-100 Response	26.6 percentage of participants
Induction Phase: Placebo	Induction Phase: Percentage of Participants With Crohn's Disease Activity Index (CDAI)-100 Response	16.7 percentage of participants

p-value: 0.144895% CI: [0.816, 3.958]Cochran-Mantel-Haenszel

Primary

Maintenance Phase: Percentage of Participants With Clinical Remission

Clinical remission is defined as the CDAI score ≤150. CDAI is scoring system for the assessment of Crohn's disease activity. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease.

Time frame: Week 60

Population: FAS in the maintenance phase included participants who were randomized and received at least one dose of the study drug in the maintenance phase. The FAS in the maintenance phase does not include participants who received placebo in the induction phase and were enrolled into the maintenance phase.

Arm	Measure	Value (NUMBER)
Induction Phase: Vedolizumab, 300 mg	Maintenance Phase: Percentage of Participants With Clinical Remission	41.7 percentage of participants
Induction Phase: Placebo	Maintenance Phase: Percentage of Participants With Clinical Remission	16.7 percentage of participants

p-value: 0.177995% CI: [0.532, 23.953]Pearson's Chi-square Test

Primary

Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Events (TEAEs)

An Adverse event (AE) is defined as any untoward medical occurrence in a study participant who received a drug (including a study drug); it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.