A Study of IMU-838 versus Placebo in Adults with Relapsing Multiple Sclerosis
(ENSURE-2)
Scientific Title of Study
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-2)
India Poland Romania Bosnia and Herzegovina Estonia Peru Russian Federation Serbia Turkey Ukraine United Kingdom United States of America Armenia Germany
Room no-705, 7th Floor,Department of neurology, ,Sri Aurobindo Marg, Ansari Market, Ansari Nagar, New Delhi,Delhi, 110029 South DELHI
8929919736
mantriaiims@gmail.com
Dr Abdul Qavi
Dr Ram Manohar Lohia Institute of Medical Sciences
Room no 102, 1st Floor, Department of Neurology Vibhuti Khand, Gomti Nagar, Lucknow-Uttar Pradesh Lucknow UTTAR PRADESH
7376128123
drqavi2008@gmail.com
Dr Debashis Chowdhury
GB Pant Institute of Post Graduate Medical Education and Research
Room No. 501, 5th Floor Department of Neurology, Academic Block, 2, JL Nehru Marg, New Delhi Central DELHI
9718599306
profdebashishchowdhury@gmail.com
Dr Praveen Gupta
Marengo Asia Hospital (part of north east healthcare Pvt Ltd)
Room no 810, 811, Ground Floor, Marengo Asia International Institute of Neuro and Spine (MAINS),Golf course, extension road, Sushant Lok II, sector 56, Ghata, Gurugram, Haryana 122011 Gurgaon HARYANA
9555481717
dr.praveen.gupta@marengoasia.com
Dr Sureshkumar Radhakrishnan
Polakulath Narayanan Renai Medicity Multi Super Specialty Hospital
Polakulath Narayanan Renai Medicity Multi Super Specialty Hospital, Post Box No. 2250, Palarivattom P.O, Kochi, Kerala, India, PIN Code- 682025 Ernakulam KERALA
914842880288
drsureshkumar15research@gmail.com
Dr Dheeraj Khurana
Post Graduate Institute of Medical Education and Research
Room No 18, Department of Neurology, Block A, Nehru Hospital, Madhya Marg, Sector 12, Chandigarh Chandigarh CHANDIGARH
7087009695
khurana.dheeraj@pgimer.edu.in
Dr Dinesh Kumar
Sri Guru Ram Das Institute of Medical Sciences and Research
The IMP will be administered once daily as oral tablets. On Day 1 of the MP, patients will receive a small bottle and large bottle. The small bottle will contain 7 tablets of 15 mg IMU-838 (or placebo). The patients will take one 15-mg tablet every morning 15 to 60 minutes before breakfast for the first 7 days after randomization (from Day 1 to Day 7). Starting on Day 8, the patients will begin taking the medication from the large bottle (30 mg IMU-838 [or placebo]) once daily in the morning 15 to 60 minutes before breakfast for the remainder of the MP. When patients enter the OLT within the MP, they will also start with a 15-mg tablet of IMU-838 (small bottle) once daily in the morning 15 to 60 minutes before breakfast for 7 days. After 7 days, patients will take one 30-mg tablet (large bottle) of IMU-838 once daily in the morning 15 to 60 minutes before breakfast for the remainder of the MP. When patients enter the EP, they will also start with a 15-mg tablet of IMU-838 (small bottle) once daily in the morning 15 to 60 minutes before breakfast for 7 days. After 7 days, the patients will take one 30-mg tablet (large bottle) of IMU-838 once daily in the morning 15 to 60 minutes before breakfast for the remainder of the EP. STUDY PERIOD The trial duration for each patient may be up to 10 years. The trial consists of a Screening period of up to 2 months, a maximum MP of 72 weeks, a FU-SAF Visit + 4 weeks from Visit 8, FU-DC Visits + 12 weeks and +24 weeks from Visit 8, USVs (as applicable), and an optional open-label IMU-838 treatment during the EP for up to 8 years.
1. Male or female patient (age ≥18 to ≤55 years).
2. Patients with an established diagnosis of MS according to 2017 McDonald Criteria.
3. Patients with RMS comprising of relapsing remitting MS (RRMS) and active secondary progressive MS, both defined according to Lublin criteria 1996 and 2014.
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
4. Active disease as defined by Lublin 2014 evidenced prior to Screening by:
a. At least 2 relapsesa in the last 24 months before randomization, or
b. At least 1 relapsea 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.
a Relapses must have been assessed and documented by a physician in the patient files.
5. EDSS score between 0 and 5.5 (inclusive) at SV1.
6. 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.
c. 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.
ii. oral, injectable, or implantable progestogen-only hormonal contraceptives associated with inhibition of ovulation.
iii. intrauterine device or intrauterine hormone-releasing system.
iv. bilateral tubal occlusion.
v. 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).
vi. 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).
d. Barrier methods of contraception include:
i. condom.
ii. occlusive cap (diaphragm or cervical/vault caps) with spermicidal gel/film/cream/suppository
7. 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. abstain from sexual intercourse with a female partner (acceptable only if it is the patient’s usual form of birth control/lifestyle choice), or
b. 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
5.
d. if they have a pregnant partner, they must use condoms while taking the IMP to avoid exposure of the fetus to the IMP.
8. Willingness and ability to comply with the protocol.
9. Patients are able to read and understand the given information about the study (including their language capabilities) and provide written informed consent given prior to any study-related procedure.
ExclusionCriteria
Details
MS-related exclusion criteria:
1. Patients with non-active secondary progressive MS and primary progressive MS.
2. Any disease other than MS that may better explain the signs and symptoms, including history of complete transverse myelitis.
3. Clinical signs or presence of laboratory findings suggestive for neuromyelitis optica (NMO) spectrum disorders or myelin oligodendrocyte glycoprotein (MOG)-IgG associated
encephalomyelitis.
4. Any MRI finding, which puts in question the MS diagnosis, including but not limited to a longitudinally extensive spinal cord lesion.
5. 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.
6. Any active and uncontrolled coexisting autoimmune disease, other than MS (except for type 1 diabetes mellitus and inflammatory bowel disease).
7. An MS relapse ending within 30 days before SV1 and/or during the Screening Period (until Day 1).
8. Any corticosteroid treatment for relapse given within 30 days before SV2. Therapy exclusion criteria:
9. 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 11. applies).
10. Any previous treatment with:
a. total lymphoid irradiation
b. bone marrow transplantation
c. stem cell transplantation
d. cladribine, alemtuzumab, or belimumab, including their biosimilars
12. Any use of adrenocorticotrophic hormone or occasional use of systemic corticosteroids (oral or intravenous) 30 days before SV2.
13. Any use of the following concomitant medications is prohibited during Screening and
throughout the duration of the study:
a. 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
14. Conditions (including previous organ transplant) requiring treatments negatively affecting the immune system.
15. 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).
16. 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.
17. Positive test for SARS-CoV-2 within 14 days prior to randomization. These Patients can be randomized earlier if they have 2 consecutive tests confirming negative virus
status.
18. Positive Mycobacterium tuberculosis IFNγ release assay (Tbc-IGRA) at SV1.
19. Positive HIV-antigen-antibody (HIV-Ag/Ab) test at SV1.a
20. 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.
21. 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
22. Renal impairment defined as estimated glomerular filtration rate ≤60 mL/min/1.73m.b
23. Known or suspected Gilbert syndrome.
24. Diagnosis or suspected liver function impairment, which may cause fluctuating liver function tests during this study, as assessed by the investigator.
25. 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.
26. History or clinical diagnosis of gout.
27. 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.
28. Clinically relevant, severe pulmonary diseases, uncontrolled hypertension, or poorly controlled diabetes (HbA1c >9.0).
29. History or presence of any major medical or psychiatric illness (eg, severe depression, schizophrenia, psychotic disorder), history of suicide attempt, or current suicidal ideation,
if any of those conditions in the opinion of the investigator could create undue risk to the patient or could affect adherence with the study protocol.
30. Epilepsy or seizures not adequately controlled by treatment.
31. Any other substantial medical condition that in the opinion of the investigator could create undue risk to the patient or could affect adherence with the study protocol.
32. Current or past (within 12 months of informed consent) drug abuse (does not include therapeutic use of tetrahydrocannabinol [THC])
33. Any condition that would prevent the patient from undergoing an MRI scan, including:
a. claustrophobic conditions
b. unable to receive Gd-based MRI-contrast agents due to history of hypersensitivity to Gd-based contrast agents, or severe renal insufficiency
c. presence of metallic implants incompatible with brain MRI
34. Legal incapacity, limited legal capacity, or any other condition that makes the patient unable to provide consent for the study.
35. An employee of an investigator or sponsor or an immediate relative of an investigator or sponsor.
36. Patients institutionalized due to judicial or administrative order.
37. Pregnant or breastfeeding women or with intention to become pregnant during the study
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.
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
Summary Statistics:Hazard ratio for relapse free survival between patients randomized to IMU-838 and placebo.
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, SV2) MRI until Week 24 MRI
Summary Statistics:Mean difference in the volume of new T2 lesions between IMU-838- & placebo-treated patients, on a logarithmic scale
Week 24
Target Sample Size
Total Sample Size="1050" Sample Size from India="100" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
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-02 will evaluate the efficacy, safety, and tolerability of IMU-838 in patients with active RMS.