Submitted by: Jamie Anne Y. Lee 2017-05-18 00:00:00 Last Updated by: Quintiles 2019-01-14 15:58:36 Export to PDF

A Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Study To Evaluate the Safety and Efficacy of M2951 in Subjects with Systemic Lupus Erythematosus (SLE)

PHRR170519-001546

MS200527-0018

2016-CT0390

A Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Study To Evaluate the Safety and Efficacy of M2951 in Subjects with Systemic Lupus Erythematosus (SLE)

This is a Phase II, multicenter, international, randomized, double-blind, placebo-controlled (DBPC) parallel-arm trial, designed to determine the efficacy, dose response, and safety of M2951 in subjects with Systemic Lupus Erythematosus (SLE), and to consider a dose to take forward into Phase III development.
Systemic lupus erythematosus (SLE), also known simply as lupus, is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. ymptoms vary between people and may be mild to severe. Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. Often there are periods of illness, called flares, and periods of remission when there are few symptoms
Approximately 432 subjects are planned to be randomized in a ratio of 1:1:1:1 to receive one of three doses of M2951 (doses 25 mg once daily, 75 mg once daily, or 50 mg twice daily) or placebo, taken orally for 52 weeks. This trial will be conducted at approximately 165 sites across 20 countries.
Duration:
Total duration of subject participation is approximately 420 days (60 weeks), which includes:
Screening: 28 days (up to four weeks)
Treatment: 364 days (52 weeks)
Safety Follow Up: 28 days (four weeks)
Trial Objectives
Primary
1. To evaluate the efficacy and dose response of M2951 compared to placebo in reducing disease activity, in adult subjects with active, autoantibody-positive systemic lupus erythematosus (SLE) who are receiving standard of care (SoC) therapy, based on SLE Responder Index (SRI)-4 response at Week 52 in all subjects, or on SRI-6 response at Week 52 in the High Disease Activity (HDA) subgroup, defined as SLE Disease Activity Index 2000 (SLEDAI-2K) ≥ 10
2. To evaluate the safety of M2951 in subjects with SLE on SoC therapy
Secondary
1. To evaluate the efficacy and dose response of M2951 compared to placebo in delaying time to first severe flare during the Treatment Period, in subjects with SLE on SoC therapy, where a severe flare is defined as at least one British Isles Lupus Assessment Group (BILAG 2004) A in any organ system due to items that are new or worse, compared to the BILAG evaluation at the previous visit.
2. To evaluate the efficacy and dose response of M2951 compared to placebo in reducing disease activity, based on the SRI-4 response at Week 52, in the serologically active subgroup, which is defined as subjects with positive anti-double-stranded deoxyribonucleic acid (anti-dsDNA) and/or low complement levels.

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2017-12-14 15 2019-03-14 0000-00-00

Ongoing

Institution Classification Region LTO #
Merck KGaA Private Business Germany Not Applicable
Institution Classification Region LTO #
Quintiles Philippines, Inc. Private Business NCR CDRR-NCR-CRO-2
Institution Amount Region
Merck KGaA N/A Germany
Name E-Mail Phone Number Postal Address
Elena Lam QMNL.HealthRegistrymailbox@quintiles.com +6328585600 41F Unionbank Plaza Bldg., Meralco Ave., cor. Onyx Road, Ortigas Center, Pasig City, 1605 Philippines
Name E-Mail Phone Number Postal Address
Anand C. Patel, MD MS Anand.C.Patel@emdserono.com +1 978 944 9693 EMD Serono Research & Development Institute 45A Middlesex Turnpike, Billerica, MA, 01821, USA
Name Expertise Affiliation
Harold Michael P. Gomez, MD Rheumatology Angeles University Foundation Medical Center
Juan Javier T. Lichauco, MD Rheumatology St. Luke's Medical Center - Quezon City
Caroline G. Arroyo, MD Rheumatology Iloilo Doctors' Hospital
Edgar Ramiterre, MD Rheumatology Southern Philippines Medical Center
Allan E. Lanzon, MD Rheumatology Mary Mediatrix Medical Center
Llewellyn T. Hao, MD Rheumatology Davao Doctors Hospital
Evelyn Salido, MD Rheumatology De La Salle Health Sciences Institute
Project Location Institutional Ethics Review Board
Angeles University Foundation Medical Center Angeles University Foundation Medical Center Institutional Ethics Review Committee
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Committee
Iloilo Doctors' Hospital Ethics Review Committee Iloilo Doctor's Hospital
Southern Philippines Medical Center SPMC Hospital Research Committee
Mary Mediatrix Medical Center Mary Mediatrix Medical Center Institutional Ethics Review Board
Davao Doctors Hospital Davao Doctors Hospital Ethics Review Committee
De La Salle Health Sciences Institute De La Salle Health Sciences Institute Independent Ethics Committee

Systemic Lupus Erythematosus (SLE)

Primary Endpoints of Efficacy and Safety
The co-primary efficacy endpoints are SRI response at Week 52: SRI-4 in all subjects and SRI-6 in a HDA subgroup. The SRI-4 response, a measure of reduced SLE disease activity, is defined by meeting all of the following conditions compared to Baseline:
1. ≥ 4 point reduction in SLEDAI-2K total score.
2. No significant worsening in PGA score (< 0.3 increase assuming the PGA score is on a 0-3 scale).
3. No new BILAG A organ domain scores and ≤ 1 new BILAG B organ domain score compared to Day 1 using BILAG 2004.
4. No discontinuation of investigational product or protocol-prohibited medication/treatment The SRI-6 response is defined similarly to SRI-4, based on a ≥ 6 point reduction in SLEDAI-2K total score. For SRI response, Baseline is defined as Day 1 predose.

In this study, safety endpoints are considered to be primary endpoints. The safety endpoints are:
1. Nature, severity, and incidence of AEs, SAEs, vital signs, ECGs, absolute values and change from Baseline in serum total Ig levels (IgG, IgA, IgM) and total B cell counts, and clinical laboratory parameters.

The key secondary endpoints are:
1. Time to first severe flare, where a severe flare is defined as at least one BILAG A score in any organ system due to items that are new or worse, compared to the BILAG evaluation at the previous visit, during the Treatment Period
2. SRI-4 response at Week 52, in the serologically active subgroup, which is defined as subjects with positive anti-dsDNA and/or low complement levels.

Other Secondary endpoints are:
1. SRI-6 response at Week 52, in the serologically active subgroup, which is defined as subjects with positive anti-dsDNA and/or low complement levels.
2. SRI-4 Response at Week 52 with a Sustained Reduction of Oral  Corticosteroids (OCS) Dose to 7.5 milligrams prednisone equivalent per day or less (≤ 7.5 mg/day) and less than or equal to (≤) Day 1 dose during Week 41 Through Week 52, in all subjects.
3. SRI-6 Response at Week 52 with a Sustained Reduction of OCS Dose to 7.5 milligrams prednisone equivalent per day or less (≤ 7.5 mg/day) and less than or equal to (≤) Day 1 dose during Week 41 Through Week 52, in the HDA subgroup, defined as SLEDAI-2K ≥ 10 at Screening.
4. SRI-4 Response at Week 52 with a Sustained Reduction of OCS Dose to 7.5 milligrams prednisone equivalent per day or less (≤ 7.5 mg/day) and less than or equal to (≤) Day 1 dose during Week 41 Through Week 52, in the serologically active subgroup, which is defined as subjects with positive anti-dsDNA and/or low complement levels.
5. Time to first flare, flare-free status at Week 52, and annualized flare rate, during the Treatment Period, will be analyzed separately, each assessed with flare defined as:
 o BILAG A Severe flare
 o BILAG A or 2B Moderate to Severe flare
 o SFI Severe flare
6. Disease activity over time, during the Treatment Period, as measured by:
 o Change from Baseline in Low disease activity, defined by SLEDAI-2K ≤ 2, at Week 52
 o Change from Baseline in Low disease activity, defined by clinical SLEDAI-2K
(SLEDAI-2K excluding anti-dsDNA and low complement parameters) ≤ 2, at Week 52
 o Change from Baseline in SLEDAI-2K score at each study visit
 o Change Baseline in CLASI-A at each study visit
 o BICLA response at each study visit
7. Absolute values of and change from Baseline in complement proteins C3 and C4 levels (overall and among subjects below lower limit of normal [LLN] at Baseline), and normalization status (among subjects below LLN at Baseline)
8. Absolute values of and change from Baseline in anti-dsDNA antibodies (overall and among subjects with positive anti-dsDNA antibodies at Baseline)
9. Absolute counts of and change from Baseline counts of T cells, B cells, NK cells, T cell subsets, and B cell subsets
10. Absolute values of and change from Baseline in serum IgG subclass levels
11. Absolute values of and change from Baseline in serum and plasma protein levels, including but not limited to autoantibodies and inflammatory cytokines (e.g., BLyS levels); change from Baseline and comparison and correlation with indices of disease severity, clinical response (e.g., SRI response), or other clinical parameters (e.g., flare rate) with respect to Baseline values, may be assessed
12. mRNA expression analysis to identify changes with respect to treatment, clinical responses, time, and any other potentially relevant factors (e.g., stratification)
13. Absolute values of and change from Baseline in B cell activation in a subset of subjects (approximately 20 evaluable subjects) may be assessed
14. Absolute values of and change from Baseline in BTK pathway activation (phosphoproteomics) in a subset of subjects (approximately 20 evaluable subjects) may be assessed
15. Absolute values of and change from Baseline in HRU, including but not limited to doctor/home/emergency visits, hospitalizations, paid assistance, and missed work
16. Absolute value of and change from Baseline in CLASI-D
17. Absolute value of and change from Baseline in SLICC/ACR damage index

Completed

  • Argentina
  • Bulgaria
  • Chile
  • Colombia
  • Germany
  • Italy
  • Malaysia
  • Mexico
  • Peru
  • Philippines
  • Poland
  • Romania
  • Russia
  • South Africa
  • South Korea
  • Taiwan
  • United States

Clinical Trial

20161215095918

2017-03-13

Date Amendment Classification Reason
2017-06-23 Amendments related to the protocol
2018-01-12 Amendments related to the protocol
2018-04-30 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-10-15 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-10-15 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-10-15 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-10-15 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-10-15 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-10-15 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-10-15 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-06-21 Amendments related to the protocol
2018-10-15 Amendments related to the protocol
2018-12-28 Amendments related to the protocol

Inclusion Criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
1. Signed written informed consent before any study-related procedure is undertaken that is not part of the standard subject management and able to comply with requirements of protocol.
2. Male or female subjects, 18 to 75 years of age.
3. Diagnosis of SLE with either the SLICC criteria for SLE, or at least four of the 11 ACR classification criteria for SLE of at least six months duration prior to Screening.
4. SLEDAI-2K total score ≥ 6 (including SLEDAI-2K clinical score ≥4) at Screening Visit.
5. Positive for anti-double stranded deoxyribonucleic acid (DNA) and/or anti-nuclear antibody (ANA ≥ 1:80) at the time of Screening.
6. A male participant must agree to use and to have their female partners use a highly effective form of contraception (i.e., methods with a failure rate of less than 1% per year) as detailed in inclusion criterion 7 of this protocol one day before first dose of study treatment (as appropriate), during the Treatment Period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this Period.
7. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: [age-related amenorrhea ≥ 12 consecutive months and increased follicle-stimulating hormone (FSH) > 40 mIU/mL] or who have undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to confirm postmenopausal status, an FSH will be drawn at Screening.
8. A history of vaccination against Streptococcus pneumoniae with PPSV23 or Pneumovax® (with repeat administration as necessary to be up to date as per local guidelines) and influenza virus (as seasonally required); or vaccination against these pathogens during Screening. Subjects receiving one or more of these vaccinations during Screening must have at least two weeks between the vaccination(s) and the date of randomization.

Exclusion Criteria
Subjects are not eligible for this study if they fulfill any of the following exclusion criteria:
1. Active, clinically significant, interstitial lung disease or pulmonary arterial hypertension.
2. Proteinuria > 4 g/day (spot urine protein to creatinine ratio [UPCR] > 4 mg/mg), and/or estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 as calculated by the 4-component Modification of Diet in Renal Disease (MDRD) equation by the central laboratory):
a. The four-component Modification of Diet in Renal Disease equation (Levey 2006): eGFR = 175 x (serum creatinine in mg/dL) –1.154 x (age in years) –0.203 x 0.742 (if female) x 1.212 (if race is black)
3. Evidence of recent, acutely worsened renal function (e.g., reduction in eGFR by ≥ 30 mL/min to < 60 mL/min/1.73 m2; or a syndrome of Rapidly Progressive Glomerulonephritis, as defined by a 50% decline in glomerular filtration rate in three months; in the six months prior to Screening).
4. Active central nervous system SLE deemed to be severe or progressive including any history of transverse myelitis, a history of recent uncontrolled seizures or change in seizure therapy in the three months prior to the Screening Visit, and/or associated with significant cognitive impairment leading to inability to provide informed consent and/or comply with
the protocol.
5. Within two weeks prior to Screening or during Screening: use of oral
corticosteroids ≥ 30 mg daily prednisone equivalent, use of injectable corticosteroids, or change in dose of corticosteroids.
6. Within two months prior to Screening or during Screening: initiation of or change in dose of antimalarial, methotrexate, mycophenolate (mofetil [MMF] or sodium [MPS]), or azathioprine.
7. Calcineurin inhibitors (cyclosporine, tacrolimus) and cyclophosphamide must be washed out three months prior to Screening and are prohibited during the study.
8. A stable dose of leflunomide is not exclusionary; however, subjects having discontinued leflunomide must have washed out for three months prior to Screening.
9. Within three months prior to Screening or during Screening, use of abatacept, antitumor necrosis factor alpha agents, intravenous Ig, plasmapheresis, or other disease modifying, immunosuppressive or immunomodulatory therapies not otherwise specified in protocol.
10. Within six months prior to Screening or during Screening: use alkylating agents other than cyclophosphamide (e.g., chlorambucil).
11. Within six months prior to Screening or during Screening: use of belimumab or any anti-B Lymphocyte Stimulator (BLyS) therapy.
12. Within one year prior to Screening Visit use of B cell depleting therapy such as anti-CD20 agents (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab, ocaratuzumab, veltuzumab).
13. Within two weeks prior to Screening, initiation or change in dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or nonsteroidal anti-inflammatory drugs (NSAIDs), or use of NSAIDs above maximum prescribed dose per local label.
14. On anticoagulation (e.g., vitamin K antagonists) or antiplatelet therapy (e.g., clopidogrel)
other than daily aspirin for cardioprotection.
15. On fish oil (unless discontinued prior to first dose).
16. Within one month prior to Screening, vaccination with live or live-attenuated virus vaccine.
17. Known hypersensitivity to any study treatment, component, or placebo.
18. Active clinically significant viral, bacterial or fungal infection, or any episode of infection requiring hospitalization or treatment with parenteral anti-infectives within four weeks prior to Screening, or completion of oral anti-infectives within two weeks before or during Screening, or a history of recurrent infections (i.e., three or more of the same type of infection in a 12 month rolling period). Vaginal candidiasis, onychomycosis and genital or
oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not be exclusionary.
19. History of or positive human immunodeficiency virus (HIV), hepatitis C antibody and/or polymerase chain reaction, hepatitis B surface antigen (+), and/or hepatitis B core total and/or IgM antibody (+) at Screening.
20. History of or current diagnosis of active tuberculosis (TB), untreated latent TB infection (LTBI), or undergoing current treatment for LTBI, determined by a TB skin test with purified protein derivative as evidenced by induration ≥ 5 mm or a positive Quantiferon, or positive or borderline T-SPOT (Elispot) test, either at Screening or documented with results within three months prior to the Screening Visit. Subjects who have previously completed appropriate and documented LTBI treatment or who are undergoing current treatment for LTBI will not be required to be tested. Subjects with current household contacts with active TB will also be excluded. Subjects with indeterminate or positive
Quantiferon or T-SPOT test results: indeterminate tests may be repeated once, and will be considered positive if retest results are positive or indeterminate.
21. History of shingles within 12 months prior to Screening unless vaccinated following onset.
22. History of splenectomy at any time or any major surgery within two months prior to Screening. Major elective surgeries such as abdominal, thoracic or joint replacement surgeries should not be planned to occur in the Study Period.
23. Clinically significant cardiovascular events (e.g., acute myocardial infarction, unstable angina or peripheral vascular disease symptoms, hospitalization for congestive heart failure, cardiac surgery, ischemic or hemorrhagic stroke, or transient ischemic attack) within six months before the Screening Visit or during Screening, or current active angina or untreated hypertension at the Screening Visit.
24. Active cardiac arrhythmia or other ECG abnormality that could constitute a clinical risk (including but not limited to): long QT syndrome, Wolff- Parkinson-White syndrome, or an untreated malignant ventricular arrhythmia (e.g., ventricular fibrillation or tachycardia) at the Screening Visit or Day 1.
25. Presence of uncontrolled or New York Heart Association (NYHA) Class 3 or 4 congestive heart failure.
a. NYHA Class 3: Cardiac disease resulting in marked limitation of physical activity. Subjects are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
b. NYHA Class 4: Cardiac disease resulting in inability to carry on any physical
activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.
26. Antiphospholipid antibody syndrome associated with a thromboembolic event in the 12 months prior to or during Screening. Anticoagulation or anti-platelet therapy is exclusionary, with the exception of daily aspirin for cardioprotection (see criterion 14).
27. Any condition, including any uncontrolled disease state other than SLE, that in the Investigator’s opinion or Sponsor/designee opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct or evaluation.
28. History or current autoimmune diagnosis other than SLE, including demyelinating diseases (e.g., multiple sclerosis, optic neuritis), or any other condition requiring systemic corticosteroid therapy (such as asthma or inflammatory bowel disease) with the exception of concomitant Sjögren’s or secondary Sjögren’s syndrome. The combination of RA and SLE is sometimes referred to as “rupus”.
29. History of cancer other than non-melanoma skin cancer or in situ cervical cancer, unless considered cured > five years.
30. Breastfeeding/lactating or pregnant women.
31. Alanine or aspartate aminotransferase, amylase or lipase > 2X above upper limit of normal (ULN) of laboratory reference range, total bilirubin > 1.5X ULN, thyroid stimulating hormone [TSH] < 0.01 or ≥ 7.1 mIU/L per central laboratory results) or any other clinically significant laboratory abnormality.
32. Participation in any investigational drug study within three months or five half-lives of the investigational drug, whichever is longer, prior to Screening.
33. Total B cell count < 50% of the lower limit of normal at the Screening Visit in subjects who previously received B cell depleting therapy such as with anti-CD20 agents (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab, ocaratuzumab, veltuzumab).
34. Significant cytopenia, such as neutrophil count < 1,500/mm3, or platelet count < 75,000/mm3.
35. Serum IgG below 6 g/L at the Screening Visit.
36. Subjects currently receiving (or unable to stop using prior to receiving the first dose of IMP) medications or herbal supplements known to be potent inhibitors of cytochrome (CYP)3A (must stop at least one week prior), potent inducers of CYP3A (must stop at leas+D80t three weeks prior), or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least one day prior).
37. Active infective process or any other clinically significant abnormality on chest X-ray (CXR). Chest X-ray must have been taken within three months prior to the Screening Visit, or during the Screening Period.
38. History or current alcohol, substance, or drug abuse:
a. Excessive alcohol use is defined as alcohol and/or substance abuse or dependence
(as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th
edition, Text revision) in the past year or a history of alcohol or substance abuse,
as determined by the Investigator.
39. Subjects who have evidence of serious suicide risk including any history of suicidal behavior in the last three months and/or any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in the month prior to Screening, or significant suicide risk, as determined by the Investigator, including any history of active suicidal ideation with intent to act in the last three months or any history of suicidal behavior in the subject’s lifetime.
40. Legal incapacity or limited legal capacity.

Interventional

M2951

Drug

M2951
Drug: M2951-25 mg once daily will be administered for 52 weeks
Drug: M2951-75 mg once daily will be administered for 52 weeks
Drug: M2951- 50 mg twice daily will be administered for 52 week
Drug: Placebo - Placebo matched to M2951 will be administered for 52 weeks

Randomized

Double Blind

Unspecified

Parallel

- To evaluate the efficacy and dose response of M2951 compared to placebo in reducing disease activity in adult subjects with active, autoantibody-positive SLE who are receiving SoC therapy based on SRI-4 response at Week 52 in all subjects, or on SRI-6 response at Week 52 in the HDA subgroup, defined as SLEDAI-2K ≥ 10.
- To evaluate the safety of M2951 in subjects with SLE on SoC therapy.

Phase II

28

24

Early completion of global study recruitment.

14 Dec 2017

Utilization Utilization Info
No records found.

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