A Multi-Center, Randomized, Double-Blinded Phase 3 Study to Evaluate the Efficacy, Safety, and Tolerability of IMU-838 versus Placebo in Adults with Relapsing Multiple Sclerosis (ENSURE 1)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- Immunic AG
- 入组人数
- 1,050
- 试验地点
- 7
- 主要终点
- Objective:Demonstrate the efficacy of IMU-838 versus placebo in adult patients with active RMS in delaying the occurrences of relapses based on time to first relapse.
研究概览
简要总结
Efficacy, safety, and tolerability of the currently approved multiple sclerosis (MS) therapeutics are regarded to be substantially different among the available treatment options. As all these therapeutic agents have to be administered chronically, a high treatment adherence is required, and therefore there is a need to increase the tolerability of the drugs. Among the available disease modifying treatments (DMTs), oral administration is preferred by a considerable proportion of patients with MS.
IMU-838 (vidofludimus calcium) selectively inhibits pyrimidine synthesis in activated cells via inhibition of dihydroorotate dehydrogenase (DHODH), which is a proven effective mechanism to treat MS. Teriflunomide, a currently approved DHODH inhibitor in the United States of America (USA) and European Union (EU) to treat RMS, showed consistent effects across multiple markers of MS burden and activity, including annual relapse rate (ARR) and risk of disability progression in several clinical trials. However, teriflunomide is associated with hepatotoxicity and clinically important adverse events (AEs), such as diarrhea, alopecia and neutropenia, which are thought to be off-target effects related to inhibition of certain kinases and which confounds the use of teriflunomide in patients with RMS. Current data suggest that IMU-838 may show an improved safety and tolerability profile compared with teriflunomide and other oral MS drugs. In addition, because teriflunomide has a long half-life of 19 days in patients with MS, accelerated elimination with cholestyramine or charcoal may be considered when a treatment with teriflunomide must be terminated. The blood half-life of IMU-838 is roughly 30-40 hours, and therefore well-suited for once daily oral administration and a quick washout after treatment discontinuation.
In a Phase 2 trial in relapsing-remitting MS patients, IMU-838 showed a statistically significant inhibition on development of MS lesions in the brain over 24 weeks of double-blinded treatment versus placebo treatment. Based on these data, IMU-838 may represent a novel oral treatment option for patients with active RMS fostering adherence. Clinical trial P3-IMU-838-RMS-01 will evaluate the efficacy, safety, and tolerability of IMU-838 in patients with active RMS.
研究设计
- 研究类型
- Interventional
- 分配方式
- Other
- 盲法
- Participant and Investigator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 55.00 Year(s)（—）
- 性别
- All
入选标准
- •Male or female patient (age ≥18 to ≤55 years).
- •Patients with an established diagnosis of MS according to 2017 McDonald Criteria.
- •Patients with RMS comprising of relapsing remitting MS (RRMS) and active secondary progressive MS, both defined according to Lublin criteria 1996 and 2014.a a Patients are eligible for this trial if their disease modifying treatment has failed due to efficacy, safety, or tolerability issues, if they have contraindications or no access to treatment, or if they refuse the offered MS treatment.
- •Active disease as defined by Lublin 2014 evidenced prior to Screening by: a.
- •At least 2 relapses in the last 24 months before randomization, or b.
- •At least 1 relapse in the last 12 months before randomization, or c.
- •A positive Gd+ MRI scan (brain and/or spine) in the last 12 months prior to randomization.
- •EDSS score between 0 and 5.5 (inclusive) at SV
- •Female patients: a.
- •must be of non-childbearing potential, ie, surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before SV1) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or b.
- •if of childbearing potential, must have a negative pregnancy test at SV1 (blood test) and before the first IMP intake (Day 1 blood or urine test).
- •They must agree not to attempt to become pregnant, must not donate ova, and must use a highly effective contraceptive method (see below) together with a barrier method between study consent and 30 days after the last intake of the IMP.
- •highly effective forms of birth control are those with a failure rate less than 1% per year and include: i.
- •oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraceptives associated with inhibition of ovulation.
- •oral, injectable, or implantable progestogen-only hormonal contraceptives associated with inhibition of ovulation.
- •intrauterine device or intrauterine hormone-releasing system.
- •bilateral tubal occlusion.
- •vasectomized partner (ie, the patient’s male partner underwent effective surgical sterilization before the female patient entered the clinical study and is the sole sexual partner of the female patient during the clinical study).
- •sexual abstinence (acceptable only if it is the patient’s usual form of birth control/lifestyle choice; periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception).
- •Barrier methods of contraception include: i.
- •occlusive cap (diaphragm or cervical/vault caps) with spermicidal gel/film/cream/suppository.
- •Male patients must agree not to father a child or to donate sperm starting at SV1, throughout the clinical study, and for 30 days after the last intake of the IMP.
- •Male patients must also: a.
- •use adequate barrier contraception during treatment with the IMP and until at least 30 days after the last intake of the IMP, and c.
- •if they have a female partner of childbearing potential, the partner should use a highly effective contraceptive method as outlined in inclusion criterion
- •if they have a pregnant partner, they must use condoms while taking the IMP to avoid exposure of the fetus to the IMP.
- •Willingness and ability to comply with the protocol.
- •Patients are able to read and understand the given information about the study (including their language capabilities) and provide written informed consent prior to any study-related procedure.Â.
排除标准
- •MS-related exclusion criteria:
- •Patients with non-active secondary progressive MS and primary progressive MS.
- •Any disease other than MS that may better explain the signs and symptoms, including history of complete transverse myelitis.
- •Clinical signs or presence of laboratory findings suggestive for neuromyelitis optica (NMO) spectrum disorders or myelin oligodendrocyte glycoprotein (MOG)-IgG-associated encephalomyelitis.
- •Any MRI finding, which puts in question the MS diagnosis, including but not limited to a longitudinally extensive spinal cord lesion.
- •History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or adequately treated cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence full remission at the current time.
- •Any active and uncontrolled coexisting autoimmune disease, other than MS (except for type 1 diabetes mellitus and inflammatory bowel disease).
- •An MS relapse ending within 30 days before SV1 and/or during the Screening Period (until Day 1).
- •Any corticosteroid treatment for relapse given within 30 days before SV
- •Therapy exclusion criteria:
- •Use of experimental/investigational drug (with the exception of COVID-19 vaccines approved by emergency use authorization) within 8 weeks or 5 times the respective half-life before the date of informed consent, whichever is longer, and throughout the duration of the study; and/or participation in drug clinical studies within 6 months prior to Screening.
- •(For selected approved marketed products, if used as an investigational drug, exclusion criterion
- •Any previous treatment with: a.
- •total lymphoid irradiation b.
- •bone marrow transplantation c.
- •stem cell transplantation d.
- •cladribine, alemtuzumab, or belimumab, including their biosimilars
- •Any use of adrenocorticotrophic hormone or occasional use of systemic corticosteroids (oral or intravenous) 30 days before SV
- •any medication known to significantly increase urinary elimination of uric acid, in particular lesinurad, as well as uricosuric drugs such as probenecid b.
- •treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, bosutinib, sorafenib, enasidenib, erlotinib, regorafenib, pazopanib, and nilotinib c.
- •any drug significantly restricting water diuresis, in particular vasopressin and vasopressin analogs Immune response exclusion criteria
- •Conditions (including previous organ transplant) requiring treatments negatively affecting the immune system.
- •Clinically significantly low lymphocyte and/or neutrophil count (Common Terminology Criteria for AEs Grade of 2 or higher), ie, lymphocyte count <800/mm³ (0.8 x 109/L) and/or neutrophil count <1500/mm³ (1.5 x 109/L).
- •History of chronic systemic infections within 6 months before the date of informed consent, including but not limited to tuberculosis and human immunodeficiency virus (HIV).
- •HIV infection that is undetectable within the prior 6 months is not an exclusion criterion.
- •Positive test for SARS-CoV-2 within 14 days prior to randomization.
- •Positive Mycobacterium tuberculosis IFNγ release assay (Tbc-IGRA) at SV
- •Positive HIV-antigen-antibody (HIV-Ag/Ab) test at SV1.a
- •Any live vaccinations within 30 days before the date of informed consent or during the study except for any virus-based SARS-CoV-2 or influenza vaccine.
- •Please note that mRNA-based vaccinations are allowed at any time.
- •Other medical history and concomitant disease exclusion criteria:
- •Presence of the following laboratory values at SV1 a.
- •platelet count <100,000/mm³ (<100 x 109/L) b.
- •serum creatinine >1.5 x ULN c.
- •total bilirubin, ALT, or GGT >1.5 x ULN d.
- •serum uric acid levels at SV1 >1.2 x ULN e.
- •indirect (unconjugated) bilirubin >1.2 x ULN
- •Renal impairment defined as estimated glomerular filtration rate ≤60 mL/min/1.73m.b
- •Known or suspected Gilbert syndrome.
- •Diagnosis or suspected liver function impairment, which may cause fluctuating liver function tests during this study, as assessed by the investigator.
- •Known history of nephrolithiasis or underlying condition with a strong association of nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia.
- •As an exception, included can be only patients with history of a singular period of nephrolithiasis currently recovered (symptom free within at least 3 years prior to screening visit), while stones were not composed of uric acid or oxalate.
- •History or presence of serious or acute heart disease such as uncontrolled cardiac dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled congestive heart failure (New York Heart Association [NYHA] class 3 or 4).
- •Note: NYHA class 3: Cardiac disease resulting in marked limitation of physical activity.
- •Patients are comfortable at rest.
- •Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
- •NYHA class 4: Cardiac disease resulting in inability to carry on any physical activity without discomfort.
- •Symptoms of heart failure or anginal syndrome may be present even at rest.
- •If any physical activity is undertaken, discomfort is increased.
- •Clinically relevant, severe pulmonary diseases, uncontrolled hypertension, or poorly controlled diabetes (HbA1c >9.0).
- 另有 8 项未显示
结局指标
主要结局
Objective:Demonstrate the efficacy of IMU-838 versus placebo in adult patients with active RMS in delaying the occurrences of relapses based on time to first relapse.
时间窗: 72 Weeks
Endpoint:Time to first confirmed relapse, as determined by the INEC, relapse occurred after the start of treatment administration & before the end of the main period (EOMP) censored at a maximum of 72 weeks, Visit 8/EOMP
时间窗: 72 Weeks
Summary Statistics:Hazard ratio for relapse free survival between patients randomized to IMU-838 and placebo.
时间窗: 72 Weeks
次要结局
- Objective:To evaluate the effect of IMU-838 versus placebo on volume of new T2-lesions(Variable/Endpoint:Changes in total volume of new T2-lesions from baseline (BL) magnetic resonance imaging (MRI) until Week 24 MRI)