E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic Lupus Erythematosus |
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E.1.1.1 | Medical condition in easily understood language |
Systemic lupus erythematosus (SLE) is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042945 |
E.1.2 | Term | Systemic lupus erythematosus |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the efficacy of a 200-mcg dose every 4 weeks for 48 weeks of IPP-201101 compared with placebo in patients with active systemic lupus erythematosus (SLE) as assessed by the SLE responder index (SRI) at week 52. |
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E.2.2 | Secondary objectives of the trial |
•the SRI response at each visit during the study
•the reduction of the SLEDAI-2K total score by at least 4 points at each visit during the treatment period
•the effect of IPP-201101 on disease activity
•the effect of IPP-201101 on the status of disease
Assessed at each visit during the treatment period, the following:
•the reduction of the SLEDAI-2K total score by at least 5 points
•the reduction of the SLEDAI-2K total score by at least 6 points
•the SRI-5 response
•the SRI-6 response
•the effect of IPP-201101 on arthritis, as assessed by the 28-joint count examination for pain and tenderness
•the effect of IPP-201101 on the incidence of disease flares
•the effect of IPP-201101 on the occurrence of SLE–induced organ damage at visits at weeks 24 and 52 or final assessment
•the effect of IPP-201101 on health-related quality of life,
•the effect of IPP-201101 on steroid dose over time throughout the study |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Criteria for Inclusion: Patients are included in the study if all of the following criteria are met:
(a)The patient is a man or woman between 18 and 70 years of age with an established diagnosis of SLE as defined by ACR Classification Revised Criteria. The diagnosis is fulfilled provided that at least 4 criteria are met.
(b)The patient has a positive test result for ANA at screening (titer must be at least 1:80 [by human epithelial cell tumor line (HEp-2) ANA assay]) and/or a positive test result for anti-dsDNA Ab at screening (value must be 30 IU/mL or more by enzyme-linked immunosorbent assay [ELISA]).
(c)Written informed consent is obtained.
(d)Female and males receiving IPP-201101 and their female partners must use a highly effective contraceptive during treatment and for 30 days after discontinuation of study drug treatment.
Women must be surgically sterile, 2 years postmenopausal, or, if of childbearing potential, use a highly effective method of contraception. Men and their partner must have highly effective accepted method of contraception, Single barrier/Double barrier and spermicides are not acceptable methods of contraception.
Highly effective methods of contraception include, true abstinence, intrauterine device (IUD), or hormonal contraception associated with inhibition of ovulation (oral, transdermal, implanted, and injected), intrauterine hormone-releasing system (IUS), bilateral tubal
occlusion, vasectomised partner.
True abstinence is defined when this is in line with the preferred and usual lifestyle of the subject.” [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception].
(e)The patient has a SLEDAI-2K clinical score of at least 6 points during screening. A SLEDAI-2K clinical score is the calculated score without inclusion of the points that may be contributed by having a positive titer for anti-dsDNA Ab or decreased serum complement levels.
(f)The patient does not have an “A” score on the BILAG-2004 scale.
If the patient is using oral corticosteroids, the weekly cumulative dose must not exceed 80 mg of prednisone equivalent; the weekly dose must be stable over the 4 weeks preceding the 1st dose of study drug.
(g)If the patient is using antimalarials, methotrexate, leflunomide, mycophenolate mofetil (MMF), or azathioprine, the start date must be at least 3 months prior to the 1st dose of study drug, and the daily dose must be stable over the 4 weeks preceding the 1st dose of study drug.
(h)If the patient is not currently using corticosteroids, antimalarials, methotrexate, MMF, or azathioprine, the last dose (in case of previous use) must be at least 4 weeks prior to the 1st dose of study drug. For leflunomide, the stop date must be at least 8 weeks before the 1st dose of study drug unless an adequate cholestryamine washout has been performed. If cholestyramine washout is performed, the last use of leflunomide must be at least 4 weeks before the 1st dose of study drug.
(i)The patient must be willing and able to comply with study restrictions, to remain at the study center for the required duration during each study visit, and to return to the study center for the final assessment as specified in this protocol.
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E.4 | Principal exclusion criteria |
Criteria for Exclusion: Patients are excluded from participating in this study if 1 or more of the following criteria are met:
(a)The patient has been treated with intramuscular or intravenous (iv) pulse steroids (ie, 250 to 1000 mg iv total daily dose of methylprednisolone) within 4 weeks of the 1st dose of study drug. The use of intra-articular steroids may be allowed after consultation with the medical expert.
(b)The patient has received tacrolimus, cyclosporin A, or iv immunoglobulins (IVIG) within 3 months of the 1st dose of study drug.
(c)The patient has received cyclophosphamide within 6 months prior to the 1st dose of study drug.
(d)The patient has been treated for SLE with agents such as fusion proteins, therapeutic proteins, or monoclonal antibodies or antibody fragments, within 6 months of the 1st dose of study drug.
(e)The patient has received B-cell depleting agents such as rituximab or belimumab or epratuzumab within one year of the 1st dose and has not yet normalized the B-cell count (ie, CD20+ B-cell count is less than normal range and the absolute lymphocyte count [ALC] is less than normal range).
(f)The patient has New York Heart Association (NYHA) Class III or IV congestive heart failure.
(g)The patient has an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m2 (via Modification of Diet in Renal Disease [MDRD] equation).
(h)The patient has an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value greater than 2 times the upper limit of the normal range (ULN) or a total bilirubin level greater than 1.5 times ULN.
(i)The patient has a planned immunization with a live or live attenuated vaccine within 3 months prior to administration of the 1st dose of study drug and for 3 months after administration of the last dose of study drug.
(j)The patient has any clinically significant abnormalities on ECG that are not related to SLE, as determined by the investigator. Patients with stable ECG changes without evidence of active cardiovascular disease may participate at the discretion of the investigator and medical monitor.
(k)The patient has an ongoing active systemic infection requiring treatment or a history of severe infection, such as hepatitis or pneumonia, in the 3 months prior to administration of the 1st dose of study drug. Less severe infections in the 3 months prior to administration of the 1st dose of study drug are permitted at the discretion of the investigator and medical monitor.
(l)The patient has any concomitant medical condition unrelated to SLE that may interfere with his or her safety or with evaluation of the study drug, as determined by the investigator.
(m)The patient has a history of a medical condition other than SLE that has required treatment with oral corticosteroids in excess of 80 mg of prednisone equivalent/week within 3 months of the 1st dose of study drug.
(n)The patient has a positive test result for hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCV Ab).
(o)The patient has a known positive history of antibodies to human immunodeficiency virus (HIV) or HIV disease or other immunosuppressive state (eg, agammaglobulinemia, etc).
(p)The patient has a history of alcohol or substance dependence or abuse (with the exception of nicotine),according to the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, Fourth Edition, Text Revision (DSM-IV-TR), within 3 months of the screening visit or has current substance abuse.
(q)The patient has a history of severe allergic reactions to or hypersensitivity to any component of the study drug or placebo.
(r)The patient has undergone or is undergoing treatment with another investigational drug for the treatment of lupus within 6 months prior to the 1st dose of study drug or has received any other investigational drug for any other condition within 4 weeks prior to the 1st dose of study drug.
(s)The patient has previously participated in a ImmuPharma- or ImmuPharma-sponsored clinical study with IPP-201101.
(t)The patient is a pregnant or lactating woman. (Any women becoming pregnant during the study will be withdrawn from the study.)
(u)The patient is unlikely to comply with the study protocol or is unsuitable for any other reason, as judged by the investigator or medical monitor.
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E.5 End points |
E.5.1 | Primary end point(s) |
Assessed by the SLE responder index (SRI) at week 52. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• the SRI response at each visit during the study
• the reduction in the SLEDAI-2K total score by at least 4 points at each visit during the treatment period
• the effect of IPP-201101 on disease activity, as assessed by the BILAG-2004 disease activity index, at each visit during the treatment period
• the effect of IPP-201101 on the status of disease (PhGA scale) at each visit during the treatment period
• the reduction of the SLEDAI-2K total score by at least 5 points at each visit during the treatment period
• the reduction of the SLEDAI-2K total score by at least 6 points at each visit during the treatment period
• the SRI-5 response at each visit during the treatment period
• the SRI-6 response at each visit during the treatment period
• the effect of IPP-201101 on arthritis, as assessed by the 28-joint count examination for pain and tenderness at
each visit during the treatment period
• the effect of IPP-201101 on the incidence of disease flares (ie, Safety of Estrogens in Lupus Erythematosus:
National Assessment [SELENA] Flare Index [SFI] and SLEDAI-2K score of greater than 15) at each visit
during the treatment period
• the effect of IPP-201101 on the occurrence of SLE–induced organ damage (eg, Systemic Lupus International Collaborative Clinics/American College of Rheumatology [SLICC/ACR] Damage Index (SDI) and adverse event inquiry) at visits at weeks 24 and 52 (or final assessment)
• the effect of IPP-201101 on health-related quality of life, as assessed by completion of the Medical Outcome Survey Short Form 36 (SF-36) at visits at weeks 12, 24, 36, and 52 (or final assessment)
• the effect of IPP-201101 on steroid dose over time throughout the study The exploratory efficacy objectives of the study are to determine the following:
• the effect of IPP-201101 on the following biologic markers of disease activity at each visit during the
treatment period:
anti–double-stranded deoxyribonucleic acid antibody (anti-dsDNA Ab) complement components (C3 and C4)
• the effect of IPP-201101 on the following biologic markers of disease activity at visits at weeks 4, 12, 24, 36,
and 52 (or final assessment):
— antinuclear antibody (ANA)
— anti-uridine rich 70 kilodalton small nuclear ribonucleoprotein particle Ab (anti–U1-70K snRNP Ab)
— anti-Smith antibody (anti-Sm Ab)
— C-reactive protein (CRP)
— immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin E (IgE), immunoglobulin A
(Ig A)
• the effect of IPP-201101 on fatigue using the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue scale at visits at weeks 12, 24, 36, and 52 (or final assessment)
• in vitro intracellular and secreted cytokine response
The safety and tolerability of IPP-201101 will be evaluated by the following:
• occurrence of adverse events throughout the study
• clinical laboratory (serum chemistry, hematology, and urinalysis) test results at each visit during the treatment period
• vital signs (systolic and diastolic blood pressures, pulse, temperature, and body weight) measurements at each visit during the treatment period
• 12-lead electrocardiogram (ECG) findings at week 52 (or final assessment)
• physical examination findings, including physical examination symptom directed findings, at specified time points at each visit during the treatment period
• evaluation for suicidality at each visit during the treatment period using the Columbia-Suicide Severity Rating Scale (C-SSRS)
• concomitant medication usage throughout the study
The immunogenicity of IPP-201101 will be assessed by the following:
• any presence of anti–IPP-201101 antibodies (anti–IPP-201101 Ab) at visits at weeks 2, 4, 12, 20, 28, 36, 44, and 52 (or final assessment) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
weeks 12, 24, 36, and 52 (or final assessment) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |