A Phase 2 Study of Cladribine Add-on to Interferon-beta (IFN-beta) Therapy in Multiple Sclerosis (MS) Subjects With Active Disease (ONWARD) (ONWARD)
2020年10月8日 更新者：EMD Serono Research & Development Institute, Inc.
A Phase II, Multicenter, Randomized, Double Blind, Placebo Controlled, Safety, Tolerability and Efficacy Study of Add-on Cladribine Tablet Therapy With Interferon-beta (IFN-β) Treatment in Multiple Sclerosis Subjects With Active Disease
The goal of this study was to evaluate the safety, tolerability and effectiveness of oral cladribine when taken in combination with Interferon-beta (IFN-beta) therapy for the treatment of multiple sclerosis (MS).
This study randomized around 200 participants from approximately 50 sites located world-wide, who have experienced at least one relapse while taking IFN-beta therapy within 48 weeks prior to Screening, irrespective of disability progression. Secondary progressive multiple sclerosis (SPMS) participants, who were still experiencing relapses, and participants who have received disease modifying drugs (DMDs), other than IFN-beta therapy, during their MS treatment history, but were currently on IFN-beta therapy and have experienced active MS symptoms (at least 1 relapse) during the 48 weeks prior to Screening, were enrolled.
Participants were randomized in a 2:1 fashion to receive up to 4 cycles of oral cladribine or matching placebo in combination with IFN-beta therapy. Participants who completed the double-blind portion of the study were invited to participate in an open-label extension phase of matching study design.
調査の概要
研究の種類
介入
入学 (実際)
172
段階
- フェーズ2
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究場所
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Alabama
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Cullman、Alabama、アメリカ
- Research Site
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Arizona
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Phoenix、Arizona、アメリカ
- Research Site
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Scottsdale、Arizona、アメリカ
- Research Site
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California
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Los Angeles、California、アメリカ
- Research Site
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Colorado
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Boulder、Colorado、アメリカ
- Research Site
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Fort Collins、Colorado、アメリカ
- Research Site
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Florida
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Tampa、Florida、アメリカ
- Research Site
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Georgia
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Atlanta、Georgia、アメリカ
- Research Site
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Illinois
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Peoria、Illinois、アメリカ
- Research Site
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Massachusetts
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Boston、Massachusetts、アメリカ
- Research Site
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Missouri
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Saint Louis、Missouri、アメリカ
- Research Site
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New Jersey
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Newark、New Jersey、アメリカ
- Research Site
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New Mexico
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Albuquerque、New Mexico、アメリカ
- Research Site
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North Carolina
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Charlotte、North Carolina、アメリカ
- Research Site
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Winston-Salem、North Carolina、アメリカ
- Research Site
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Pennsylvania
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Bethlehem、Pennsylvania、アメリカ
- Research Site
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Philadelphia、Pennsylvania、アメリカ
- Research Site
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Tennessee
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Nashville、Tennessee、アメリカ
- Research Site
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Texas
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Houston、Texas、アメリカ
- Research Site
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Round Rock、Texas、アメリカ
- Research Site
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Vermont
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Burlington、Vermont、アメリカ
- Research Site
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Fidenza、イタリア
- Research Site
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Milan、イタリア
- Research Site
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Napoli、イタリア
- Research Site
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Rome、イタリア
- Research Site
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Alicante、スペイン
- Research Site
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Barcelona、スペイン
- Research Site
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Bilbao、スペイン
- Research Site
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Madrid、スペイン
- Research Site
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Malaga、スペイン
- Research Site
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Santiago、スペイン
- Research Site
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Seville、スペイン
- Research Site
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Arkhangelsk、ロシア連邦
- Research Site
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Kazan、ロシア連邦
- Research Site
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Moscow、ロシア連邦
- Research Site
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Novosibirsk、ロシア連邦
- Research Site
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Samara、ロシア連邦
- Research Site
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Smolensk、ロシア連邦
- Research Site
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St. Petersburg、ロシア連邦
- Research Site
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参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
18年～65年 (大人、高齢者)
健康ボランティアの受け入れ
いいえ
受講資格のある性別
全て
説明
Inclusion Criteria:
- Be male or female, 18 to 65 years of age (inclusive)
- Weigh between 40 to 120 kilogram (kg), (inclusive)
- Have definite MS, as confirmed by the revised McDonald criteria 2005, and have relapsing forms of MS, such as relapsing-remitting multiple sclerosis (RRMS) or SPMS with superimposed relapses
- Have experienced at least one relapse within 48 weeks prior to Screening, while receiving IFN-beta treatments (Rebif® 44mcg three times a week, subcutaneously; Avonex®30 mcg every week, intramuscular; or Betaseron® 250 mcg every other day, subcutaneously)
- Have a minimum time on IFN-beta therapy of 48-consecutive weeks prior to Screening. Participants who switched from one IFN-beta therapy to another in the 48 weeks preceding Screening may be entered into the study if they have been on a stable regimen of their current IFN-beta therapy for a minimum of 3 months prior to Screening
- Be clinically stable (other than MS relapse) during the 28 days preceding Screening
The following hematological parameters must be normal (as defined below, inclusively) within 28 days of first dosing of blinded study medication at study day 1 (SD 1)
- Hemoglobin=11.6 to 16.2 gram per deciliter (g/dL)
- Leukocytes (total white blood cells [WBC])=4.1 to 12.3*10^3 per microliter (/UL)
- Absolute lymphocytes count (ALC)= 1.02 to 3.36*10^3/UL
- Absolute neutrophil count (ANC)=2.03 to 8.36*10^3/UL
- Platelet count=140 to 450*10^3/UL
- Have no medical history or evidence of latent tuberculosis infection (LTBI) or active tubercular disease (TB), as evidenced by TB skin test or chest X-ray
- Have an expanded disability status scale (EDSS) from 1.0-5.5, inclusive
- Have no prior exposure to immunosuppressive or cytotoxic agents (with the exception of steroids for MS flare management, or intravenous immunoglobulin-G [IVIG] after allowed wash-out periods
If female, must:
- be neither pregnant nor breast-feeding, nor attempting to conceive, and
- use a highly effective method of contraception throughout the entire duration of the study and for 6 months (6 menstrual cycles) following completion of the last dose of study medication. A highly effective method of contraception is defined as one which result in a low failure rate (that is, less than 1 percent per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or a vasectomized partner. For the purpose of this trial, women of childbearing potential are defined as: All female participants after puberty unless they are post-menopausal for at least 2 years, or are surgically sterile
- If male, must be willing to use contraception to avoid pregnancies throughout the entire duration of the study and for 90 days following the last dose of study medication
- Be willing and able to comply with study procedures for the duration of the study
- Have not met any of the exclusion criteria outlined below; and
- Have voluntarily provided written informed consent, including, for United states of America (USA), participant authorization under Health Insurance Portability and Accountability Act (HIPAA), prior to any study-related procedure that is not part of normal medical care, and with the understanding that the participant may withdraw consent at any time without prejudice to future medical care
- Other protocol defined inclusion criteria may apply
Exclusion Criteria:
- Has primary progressive multiple sclerosis (PPMS) or SPMS without relapses forms
- Has prior or current malignancy other than medically documented complete excision of basal cell skin cancer no less than 5 years prior to Screening
- Has a history of chronic or clinically significant hematological abnormalities
- Prior use of cladribine, fingolimod, teriflunimide, laquinimod, mitoxantrone, campath-1h, cyclophosphamide, azathioprine, methotrexate, daclizumab, natalizumab, lymphoid irradiation, bone marrow transplantation or myelosuppressive/cytotoxic therapy
- Use of cytokine or anti-cytokine therapy or plasmapheresis within 3 months prior to SD 1
- Treatment with IVIG within 30 days of Screening
- Treatment with oral or parenteral corticosteroids 30 days of Screening
- Treatment with adrenocorticotropic hormone within 28 days prior to SD 1
- Use of any investigational drug (other than Rebif® New Formulation [RNF], Avonex® or Betaferon®) or experimental procedure within 6 months prior to SD 1
- Has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 times the upper limit of the normal values
- Suffers from major medical illness such as cardiac, endocrinologic, hepatic, immunologic (other than MS), metabolic, renal, pulmonary, gastrointestinal, dermatologic, or other major disease that would preclude the administration of oral cladribine
- Suffers from major psychiatric illness (including history of, or current, severe depressive disorders and/or suicidal ideation) that in the opinion of the investigator creates undue risk to the participant or could affect compliance with the study protocol
- Has history of active or chronic infectious disease or any disease which compromises immune function (for example, human immunodeficiency virus [HIV]+, human T-lymphotropic virus [HTLV-1], Lyme disease, LTBI or TB)
- Has an allergy or hypersensitivity to gadolinium, to cladribine or any of its excipients, or IFN-beta or any of its excipient(s)
- Has any renal condition that would preclude the administration of gadolinium (for example, acute or chronic severe renal insufficiency [glomerular filtration rate less than 30 milliliter per minute {mL/min} per 1.73 square meter {m^2}])
- Has a positive stool hemoccult test at Screening
- Has a history of seizures not adequately controlled by treatment
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：トリプル
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：Cladribine 3.5 mg/kg, IFN-beta (DB period)
Participants received cladribine tablets orally as cumulative dose of 0.875 mg/kg over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 resulting in total cladribine dose of 3.5 milligram per kilogram (mg/kg) along with interferon (IFN)-beta therapy (Rebif® new formulation [RNF] 44 mcg three times a week, subcutaneously; Avonex® 30 microgram (mcg) every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the Double blind period (DBP) of 96 weeks.
|
Participants were administered with cladribine tablets orally as cumulative dose.
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
他の名前：
|
|
プラセボコンパレーター：Placebo, IFN-beta (DB period)
Participants received matching placebo tablets orally over a course of 4-5 consecutive days at Week 1, 5, 48, and 52 along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during the DB period of 96 weeks.
|
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
他の名前：
Participants were administered with placebo orally.
|
|
実験的：Cladribine 3.5 mg/kg, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the open label (OL) extension (Ext.)
period.
In OL Ext.
period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
|
Participants were administered with cladribine tablets orally as cumulative dose.
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
他の名前：
|
|
プラセボコンパレーター：Placebo, IFN-beta, Cladribine 3.5 mg/kg (OL Ext)
Participants who received placebo initially and completed DB period entered in the OL Ext.
period.
In OL Ext.
period, participant who met the eligibility criteria received OL oral cladribine 3.5 mg/kg over maximum of 48 weeks along with IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
|
Participants were administered with cladribine tablets orally as cumulative dose.
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
他の名前：
Participants were administered with placebo orally.
|
|
実験的：Cladribine 3.5 mg/kg, IFN-beta (Safety follow up)
Participants who received cladribine 3.5 mg/kg initially and completed DB period entered in the OL ext.
safety follow up period.
In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
|
Participants were administered with cladribine tablets orally as cumulative dose.
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
他の名前：
|
|
プラセボコンパレーター：Placebo, IFN-beta (Safety follow up)
Participants who received placebo initially and completed DB period entered in the OL ext.
safety follow up period.
In this period, participants who did not meet eligibility criteria received only IFN-beta therapy (RNF 44 mcg three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) up to 48 weeks.
|
Participants received IFN-beta therapy (Rebif® new formulation [RNF] 44 microgram [mcg] three times a week, subcutaneously; Avonex® 30 mcg every week, intramuscularly; or Betaseron® 250 mcg every other day, subcutaneously) during both DB period of 96 weeks and OL extension period of 48 weeks.
他の名前：
Participants were administered with placebo orally.
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Double Blind Period: Percentage of Participants With Grade 3 or 4 (Common Terminology Criteria for Adverse Events [CTCAE] v 4.0) Hematological or Liver Toxicity
時間枠：Baseline up to Week 96
|
Percentage of participants with Grade 3 or 4 CTCAE v 4.0 toxicity on the following hematology and liver function parameters were reported: lymphocytes, cluster of differentiation 4 (CD4) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin.
According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.
|
Baseline up to Week 96
|
|
Double Blind Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC)
時間枠：Baseline up to Week 96
|
An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug.
A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important.
An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration.TEAEs were entered in infections and infestations SOC as per medical dictionary for regulatory activities (MedDRA) version 11.0
|
Baseline up to Week 96
|
|
Double Blind Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
時間枠：Baseline up to Week 96
|
An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.
SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.
An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration.
TEAEs included both Serious TEAEs and non-serious TEAEs.
|
Baseline up to Week 96
|
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Double Blind Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity
時間枠：Baseline up to Week 96
|
Time to first Grade 3 or 4 hematological toxicity or liver toxicity (lymphocytes, cluster of differentiation 4 (CD4) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin) were estimated using the Kaplan-Meier method.
According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.
10th and 20th percentiles estimated from Kaplan-Meier survival curve.
Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles.
The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study.
Accordingly, lower percentiles are presented according to the number of events observed.
|
Baseline up to Week 96
|
|
Double Blind Period: Time to Recovery From Grade 3 or 4 Hematological Toxicity
時間枠：Baseline up to Week 96
|
Time to recovery from grade 3 or 4 hematological were reported: lymphocytes, platelets, neutrophils, white blood cells and hemoglobin.
According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.
Recovery" as "Recovery from a Grade 3 or 4 toxicity is defined as a return to a Grade 0 or 1.
|
Baseline up to Week 96
|
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Double Blind Period: Mean Changes in Lymphocytes, White Blood Cells (WBC), Neutrophils and Platelets Values From Baseline to Week 96
時間枠：Baseline, Week 96
|
Mean changes in lymphocytes, WBC, neutrophils and platelets from baseline to week 96 were reported.
|
Baseline, Week 96
|
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Double Blind Period: Maximum Corrected QT Interval (QTc)
時間枠：Baseline up to Week 96
|
Criteria for potential clinical concern in ECG parameters: Maximum corrected QT interval (QTc) in range of 450 to less than 480 millisecond (msec).
|
Baseline up to Week 96
|
|
Double Blind Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure
時間枠：Baseline, Week 96
|
Mean change from baseline in vital signs- systolic and diastolic blood pressure was reported.
|
Baseline, Week 96
|
|
Double Blind Period: Mean Change From Baseline in Vital Signs- Pulse Rate
時間枠：Baseline, Week 96
|
Mean change from baseline in vital signs- Pulse Rate was reported.
|
Baseline, Week 96
|
|
Double Blind Period: Mean Change From Baseline in Vital Signs- Weight
時間枠：Baseline, Week 96
|
Mean change from baseline in vital signs- weight was reported.
|
Baseline, Week 96
|
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Double Blind Period: Mean Change From Baseline in Vital Signs- Temperature
時間枠：Baseline, Week 96
|
Mean change from baseline in vital signs- temperature was reported.
|
Baseline, Week 96
|
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Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate
時間枠：Baseline, Week 96
|
Mean change from baseline in ECG parameters- Heart Rate was reported.
|
Baseline, Week 96
|
|
Double Blind Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval
時間枠：Baseline, Week 96
|
Mean change from baseline in ECG parameters- PR, RR, QRS and OT interval was reported.
|
Baseline, Week 96
|
|
Double Blind Period: Mean Changes From Baseline in Hemoglobin Level to Week 96
時間枠：Baseline, Week 96
|
Mean changes in hemoglobin level from baseline to week 96 was reported.
|
Baseline, Week 96
|
|
Double Blind Period: Mean Changes From Baseline in CD4+ Count, CD8+ Count, and CD19+ to Week 96
時間枠：Baseline, Week 96
|
Mean changes CD4+ Count, CD8+ Count, and CD19+ from baseline to Week 96 were reported.
|
Baseline, Week 96
|
|
Double Blind Period: Mean Changes From Baseline in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) to Week 96
時間枠：Baseline, Week 96
|
Mean changes in ALT and AST from baseline to week 96 were reported.
|
Baseline, Week 96
|
|
Open Label Extension Period: Maximum Corrected QT Interval (Qtc)
時間枠：Baseline up to Week 96
|
Criteria for potential clinical concern in ECG parameters: Maximum corrected QT interval (QTc) in range of 450 to less than 480 millisecond (msec).
|
Baseline up to Week 96
|
|
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Systolic and Diastolic Blood Pressure
時間枠：Baseline, Week 72
|
Mean change from baseline in vital signs- systolic and diastolic blood pressure was reported.
|
Baseline, Week 72
|
|
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Pulse Rate
時間枠：Baseline, Week 72
|
Mean change from baseline in vital signs- Pulse Rate was reported.
|
Baseline, Week 72
|
|
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Weight
時間枠：Baseline, Week 72
|
Mean change from baseline in vital signs- weight was reported.
|
Baseline, Week 72
|
|
Open Label Extension Period: Mean Change From Baseline in Vital Signs- Temperature
時間枠：Baseline, Week 72
|
Mean change from baseline in vital signs- temperature was reported.
|
Baseline, Week 72
|
|
Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- Heart Rate
時間枠：Baseline, Week 72
|
Mean change from baseline in ECG parameters- Heart Rate was reported.
|
Baseline, Week 72
|
|
Open Label Extension Period: Mean Change From Baseline in Electrocardiogram (ECG) Parameters- PR, RR, QRS and OT Interval
時間枠：Baseline, Week 72
|
Mean change from baseline in ECG parameters- PR, RR, QRS and OT interval was reported.
|
Baseline, Week 72
|
|
OLE and Safety Follow-up Period: Percentage of Participants With Grade 3 or 4 (Common Terminology Criteria for Adverse Events [CTCAE] v 4.0) Hematological or Liver Toxicity
時間枠：Baseline (OLEP) up to Week 96
|
Percentage of participants with Grade 3 or 4 CTCAE v 4.0 toxicity on the following hematology and liver function parameters were reported: lymphocytes, cluster of differentiation 4 (CD4) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin.
According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.
|
Baseline (OLEP) up to Week 96
|
|
OLE and Safety Follow-up Period: Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) in Infections and Infestations System Organ Class (SOC)
時間枠：Baseline (OLEP) up to Week 96
|
An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug.
A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important.
An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration.TEAEs were entered in infections and infestations SOC as per medical dictionary for regulatory activities (MedDRA) version 11.0
|
Baseline (OLEP) up to Week 96
|
|
OLE and Safety Follow-up Period: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
時間枠：Baseline (OLEP) up to Week 96
|
An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.
SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.
An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration.
TEAEs included both Serious TEAEs and non-serious TEAEs.
|
Baseline (OLEP) up to Week 96
|
|
Open Label Extension Period: Time to First Grade 3 or 4 Hematological Toxicity or Liver Toxicity
時間枠：Baseline up to Week 96
|
Time to first Grade 3 or 4 hematological toxicity or liver toxicity (lymphocytes, cluster of differentiation 4 (CD4+) cell, neutrophils, white blood cells, hemoglobin, Alanine transaminase (ALT), Aspartate transaminase (AST), Platelets and Bilirubin) were estimated using the Kaplan-Meier method.
According to CTCAE v 4.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.
10th and 20th percentiles estimated from Kaplan-Meier survival curve.
Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles.
The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study.
Accordingly, lower percentiles are presented according to the number of events observed.
|
Baseline up to Week 96
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Double Blind Period: Number of Combined Unique Active (CUA) Lesions, Active Time Constant 2 (T2) Lesions, and Time Constant 1 (T1) Gadolinium Enhanced (Gd+) Lesions Per Participant Per Scan
時間枠：Week 96
|
Number of CUA lesions, active T2 lesions, and T1 Gd+ lesions were measured by using magnetic resonance imaging (MRI) scans.
|
Week 96
|
|
Double Blind Period: Mean Number of T1 Hypointense Lesions Per Participant Per Scan at Week 96
時間枠：Week 96
|
Mean number of T1 hypointense lesions per participant per scan at 96 weeks were reported.
T1 hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.
|
Week 96
|
|
Double Blind Period: Percentage of Participants With no Active T2 Lesions at Week 96
時間枠：Week 96
|
Percentage of participants with no active T2 lesions at week 96 were reported.
Active T2 lesions were measured by using magnetic resonance imaging (MRI) scans.
|
Week 96
|
|
Double Blind Period: Percentage of Participants With no Active T1 Gd-Enhanced Lesions at Week 96
時間枠：Week 96
|
Percentage of participants with no active T1 Gd-enhanced lesions at week 96 were reported.
Active T1 Gd-Enhanced lesions were measured by using magnetic resonance imaging (MRI) scans.
|
Week 96
|
|
Double Blind Period: Mean Change in T2 Lesion Volume From Baseline to Week 96
時間枠：Baseline, Week 96
|
Mean change in T2 lesion volume From baseline to Week 96 were reported.
T2 lesions were measured by using magnetic resonance imaging (MRI) scans.
|
Baseline, Week 96
|
|
Double Blind Period: Percent Change in Normalized Brain Volume From Baseline to Week 96
時間枠：Baseline, Week 96
|
Brain volume was measured using magnetic resonance imaging (MRI) scans of the brain.
Percent change in normalized brain volume from baseline to week 96 was reported.
|
Baseline, Week 96
|
|
Double Blind Period: Mean Change in T1 Hypointense Lesion Volume From Baseline to Week 96
時間枠：Baseline, Week 96
|
Mean change in T1 hypointense lesion volume from baseline to week 96 was reported.
T1 Hypointense lesions were measured by using magnetic resonance imaging (MRI) scans.
|
Baseline, Week 96
|
|
Double Blind Period: Annualized Qualifying Relapse Rate
時間枠：Baseline up to Week 96
|
A qualifying relapse was defined as a 2-grade increase in at least one, or a 1-grade increase in at least two, Kurtzke Functional Systems excluding bowel/bladder or cognition changes, in the absence of fever lasting more than or equal to 24 hours, and preceded by more than or equal to 30 days of clinical stability or improvement.
The annualized relapse rate for each treatment group was the mean of the annualized relapse rates for all the participants in the group, calculated as the total number of confirmed relapses divided by the total number of days on study multiplied by 365.25.
|
Baseline up to Week 96
|
|
Double Blind Period: Percentage of Participants Qualifying Relapse-free
時間枠：Baseline up to Week 96
|
A qualifying relapse was defined as a 2-grade increase in 1 or more Kurtzke Functional Systems (KFS) or a 1-grade increase in 2 or more KFS, excluding changes in bowel/bladder or cognition, in the absence of fever, lasting for >= 24 hours, and preceded by at least 30 days of clinical stability or improvement.
Percentage of participants qualifying relapse-free were reported.
|
Baseline up to Week 96
|
|
Double Blind Period and OLE Period: Time to 3-Month Sustained Expanded Disability Status Scale (EDSS) Progression
時間枠：Baseline up to Week 96
|
EDSS progression is based on a standardized neurological exam and focuses on symptoms that commonly occur in Multiple Sclerosis (MS).
Overall scores ranges from 0.0 (normal) to 10.0 (death due to MS).
A sustained progression on EDSS score was defined as an EDSS progression confirmed into two consecutive assessment.
Time to sustained disability progression was analyzed using a Cox proportional hazards model.
10th and 20th percentiles estimated from Kaplan-Meier survival curve.
Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles.
The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study.
Accordingly, lower percentiles are presented according to the number of events observed.
|
Baseline up to Week 96
|
|
Double Blind Period and OLE Period: Time to First Qualifying Relapse
時間枠：Baseline up to Week 96
|
A qualifying relapse was defined as a 2-grade increase in at least one, or a 1-grade increase in at least two, Kurtzke Functional Systems excluding bowel/bladder or cognition changes, in the absence of fever lasting more than or equal to 24 hours, and preceded by more than or equal to 30 days of clinical stability or improvement.
Time to first qualifying relapse were analyzed using a Cox proportional hazards model.
10th and 20th percentiles estimated from Kaplan-Meier survival curve.
Due to the small number of events, estimates from Kaplan-Meier survival curves could only be derived for lower percentiles.
The median (50th percentile) could not be estimated if less than 50% of the participants had an event during the time of the study.
Accordingly, lower percentiles are presented according to the number of events observed.
|
Baseline up to Week 96
|
|
Double Blind Period: Mean Change in New T1 Gd+ Lesions From Baseline to Week 96
時間枠：Baseline, Week 96
|
Mean change in new T1 Gd+ lesions from baseline to week 96 was reported.
|
Baseline, Week 96
|
協力者と研究者
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出版物と役立つリンク
研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。
一般刊行物
- Giovannoni G, Galazka A, Schick R, Leist T, Comi G, Montalban X, Damian D, Dangond F, Cook S. Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety. Drug Saf. 2020 Jul;43(7):635-643. doi: 10.1007/s40264-020-00948-x.
- Montalban X, Leist TP, Cohen BA, Moses H, Campbell J, Hicking C, Dangond F. Cladribine tablets added to IFN-beta in active relapsing MS: The ONWARD study. Neurol Neuroimmunol Neuroinflamm. 2018 Jul 11;5(5):e477. doi: 10.1212/NXI.0000000000000477. eCollection 2018 Sep.
研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始 (実際)
2006年11月30日
一次修了 (実際)
2011年9月30日
研究の完了 (実際)
2012年3月31日
試験登録日
最初に提出
2007年2月15日
QC基準を満たした最初の提出物
2007年2月16日
最初の投稿 (見積もり)
2007年2月19日
学習記録の更新
投稿された最後の更新 (実際)
2020年10月12日
QC基準を満たした最後の更新が送信されました
2020年10月8日
最終確認日
2020年10月1日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- 26593
- 2006-003366-33 (EudraCT番号)
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。