The primary objective of this study is to assess the efficacy of IgPro20 0.5 g/kg weekly subcutaneous (SC) doses in comparison to placebo in adult subjects with DM, as measured by responder status based on the Total Improvement Score (TIS)…
ID
Source
Brief title
Condition
- Musculoskeletal and connective tissue disorders NEC
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the responder status based on the total Improvement
Score (TIS) assessments at Weeks 17, 21, and 25.
Secondary outcome
Key secondary endpoints of the study are:
* TIS at Week 25
* Change from Baseline in Manual Muscle Testing (MMT-8) at Week 25
* Change from Baseline in Cutaneous Dermatomyositis Disease Area and Severity
Index (CDASI) total activity score at Week 25
* Reduction of oral corticosteroid dose at Week 25
Background summary
Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of acquired
muscle disorders characterized by muscle weakness, elevated creatine kinase
(CK) levels, myopathic electromyographic findings, characteristic
histopathological findings, and in certain cases, an association with
autoantibodies. IIM are best classified into 4 main subtypes: dermatomyositis
(DM), polymyositis (PM), necrotizing myopathy, and inclusion body myositis. The
identification of the correct subtype and the distinction of these diseases
from other disorders which have characteristics that mimic them is fundamental
to treatment, because each subtype has a different prognosis and response to
therapies.
Incidence and prevalence of DM varies greatly across studies. In a nationwide
patient register and rheumatology quality register, the average incidence was
11 per 1,000,000 (13 for women and 9.7 for men) while prevalence rate was 14
per 100,000 (17 for women and 11 for men). Both incidence and prevalence rates
increased with age with a peak in the 70-79 year range.
Diagnosis of DM is achieved by the evaluation of a combination of clinical and
pathological features. Dermatomyositis, with its characteristic skin rash and
relatively greater responsiveness to corticosteroids and other immunomodulators
than the other IIM subgroups, is quite distinguishable and carries significant
morbidity and mortality. If left untreated, muscle weakness leads to ambulation
difficulties (restriction to wheel chair or confinement to bed). Within the
patients with DM, a subgroup of patients with amyopathic / hypomyopathic DM has
been identified. These patients present with characteristic rash but without
obvious muscle weakness or elevations in muscle enzyme. This DM subgroup
represents about 20% of all DM cases. These patients are at increased risk of
breast, lung, and ovarian cancer and may also have systemic involvement such as
interstitial lung disease and cardiac disease.
Primary treatment modalities include corticosteroids, intravenous
immunoglobulin G (IVIG), plasmapheresis, and other immunomodulators (such as
methotrexate, azathioprine, and cyclosporin A). In clinical practice,
corticosteroids are usually the first choice medication in DM; however,
long-term treatment with corticosteroids has significant side effects and is
not well tolerated in patients. One study estimated the 10-year survival rate
of 160 DM / PM patients treated with immunomodulators such as corticosteroids,
methotrexate, and azathioprine to be 62%, highlighting the continued unmet need
in this disease.
The trigger that initiates DM or other IIM subtypes or causes flares is not
clearly understood. However, it is known that environmental factors in
genetically susceptible individuals can trigger myositis with involvement of
several cellular and humoral mechanisms. In DM, inflammatory cells
(predominantly CD4+ cells) and perifascicular atrophy, in addition to immune
attacks targeting capillaries leading to capillary loss and subsequent ischemia
are observed. More recently, the importance of B lymphocytes, macrophages, and
dendritic cells and CD4+ CD25+ T-regulatory cells have been described as having
a different role and weight in DM versus PM (where inflammatory cells
[predominantly CD8+ cells] are noted in the perimysium and in perivascular
areas).
Because of the heterogeneity of IIM as mentioned above, and the possibility of
different clinical outcome among subtypes, this study will enroll only subjects
with DM, including (clinically) amyopathic DM and adults first diagnosed with
DM as juveniles (< 18 years old), to evaluate the safety and efficacy of
IgPro20.
Study objective
The primary objective of this study is to assess the efficacy of IgPro20 0.5
g/kg weekly subcutaneous (SC) doses in comparison to placebo in adult subjects
with DM, as measured by responder status based on the Total Improvement Score
(TIS) assessments at Weeks 17, 21, and 25.
The secondary objectives of the study are:
• To assess the efficacy, with additional clinical outcome measures, of IgPro20
in comparison to placebo
• To assess the safety of IgPro20 in comparison to placebo
• To assess the safety and efficacy of IgPro20 at Week 53
• To assess the safety of IgPro20 after Week 53 to end of study participation
Study design
This is a phase 3, multicenter, randomized, placebocontrolled, double-blind
study of IgPro20 (subcutaneous immunoglobulin G [SCIG]) treatment in adult
subjects with dermatomyositis (DM) with or without muscle weakness.
After screening, subjects will be randomized 1:1 to 1 of 2 treatment sequences:
Sequence A: 0.5 g/kg IgPro20 for 24 weeks (study period 1) followed by 0.5
g/kgIgPro20 for 28 weeks (study period 2)
OR
Sequence B: placebo for 24 weeks (study period 1) followed by 0.5 g/kg IgPro20
for 28 weeks (study period 2).
Subjects with demonstrated treatment benefit at the End of Period 2 (EOP2)
(Total Improvement Score [TIS] >= 20 points at Week 49) will be eligible to
continue long term treatment with IgPro20 for up to 3 years in Study Period 3.
Intervention
Subjects will be randomized 1:1 to 1 of 2 treatment sequences:
Sequence A: 0.5 g/kg IgPro20 for 24 weeks (study period 1) followed by 0.5
g/kgIgPro20 for 28 weeks (study period 2)
OR
Sequence B: placebo for 24 weeks (study period 1) followed by 0.5 g/kg IgPro20
for 28 weeks (study period 2).
Subjects with demonstrated treatment benefit at the End of Period 2 (EOP2)
(Total Improvement Score [TIS] >= 20 points at Week 49) will be eligible to
continue long term treatment with IgPro20 for up to 3 years in Study Period 3.
All IgPro20 will be administered by SC infusions as weekly doses.
The total dose / volume of IgPro20 will be calculated on the basis of the body
weight.
Study burden and risks
Please refer to section 6. 'Possible side effects and discomforts' in the
subject information sheet for an overview of the risks and side effects.
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Age
Inclusion criteria
• Capable of providing written informed consent by signing an informed consent
form and willing and able to adhere to all protocol requirements
• Age >= 18 years
• Diagnosis of at least probable idiopathic inflammatory myopathies per
European League
Against Rheumatism/American College of Rheumatology (EULAR/ACR) Classification
Criteria: minimum aggregate score of 5.5 without and 6.7 with muscle biopsy
(historical muscle biopsy is acceptable) which includes confirmation of DM rash
/ skin manifestation (present or by history [historical skin biopsy is required
for amyopathic DM subjects])
• Disease activity defined by:
• Presence of DM rash / skin manifestation (eg, Gottron's papules / sign,
heliotrope rash, periorbital edema, V sign, Shawl sign) at Screening Visit OR
• One objective disease activity measure within 3 months before Baseline:
o Magnetic resonance imaging showing active inflammation (edema) of a proximal
skeletal muscle - OR -
o Electromyogram showing acute changes such as spontaneous activity not
explained by other disease - OR -
o Muscle biopsy with perivascular or perimysial inflammation - OR -
o CK > 4 x upper limit of normal (ULN)
• Disease severity defined by a minimum value of 2 cm on a 10 cm Physician
Global Disease Activity Visual Analog Scale and:
o MMT-8 <= 142 OR
o CDASI total activity score >= 14
• Subject has failed other DM treatment or is on DM treatment such as
immunosuppressants and/or antimalarials on a stable dose >= 3 months before
Baseline; and/or oral corticosteroids (<= 20 mg/day prednisolone equivalent
and/or topical) on a stable dose >= 1 month before Baseline
Exclusion criteria
• Cancer-associated myositis, defined as the diagnosis of myositis within 2
years of the diagnosis of cancer
• Evidence of malignancies diagnosed within the previous 5 years. Note:
Subjects with a history of carcinoma in situ of the cervix that has been
excised and cured with >= 5 years since excision or subjects with documented
history of treated basal or squamous cell skin cancer may be enrolled into the
study..
• Physician Global Damage Assessment >= 3 on a 5-point Likert scale where a
score of 3 represents severe damage
• Clinically relevant improvement between Screening Visit and Baseline, defined
by >= 2 cm improvement on a 10 cm Physician Global Disease Activity Assessment
Visual Analog Scale
• Known or suspected hypersensitivity or other severe reactions to IgPro20 or
to any of its excipients, or other immunoglobulins (Igs)or severe reactions to
blood products
• Other significant medical conditions that could increase the risk to the
subject, eg:
o History of allogeneic bone marrow / stem cell transplant / solid organ
transplant
o Cardiac insufficiency (New York Heart Association Class III or IV) or
unstable ischemic heart disease
o Chronic kidney disease stage IV or V
o Recent surgery requiring general anesthesia within the previous 4 weeks
before Screening
o Known hyperprolinemia type I or type II
o Documented thrombophilic abnormalities including blood hyperviscosity,
protein C or protein S deficiency, anti-thrombin-III deficiency, plasminogen
deficiency, antiphospholipid antibodies, Factor V Leiden mutation,
dysfibrinogenemia, or prothrombin G20210A mutation
o History of documented thrombotic episode, eg, pulmonary embolism, deep vein
thrombosis, myocardial infarction, or thromboembolic stroke at any time
o More than 3 of the following specified risk factors for thromboembolic events
(documented and current conditions) occurring concurrently: atrial
fibrillation, coronary disease, diabetes mellitus, dyslipidemia, hypertension,
obesity (body mass index >= 30 kg/m2), recent significant trauma and immobility
(wheelchairbound or bedridden)
o Uncontrolled, severe, or rapidly progressive interstitial lung disease which
will prevent the subject from successful participation in the study
o Severe skin disease at planned infusion sites that would make subcutaneous
(SC) infusions infeasible
o Medical conditions whose symptoms and effects could alter protein catabolism
and or Immunoglobulin G (IgG) utilization (eg, protein-losing enteropathies,
nephrotic syndrome, known Immunoglobulin A [IgA] deficiency with antibodies to
Immunoglobulin A)
• Other conditions which would prevent correct assessment or lead to impaired
muscle strength (eg, other neurological disorders including, but not limited
to, Parkinson*s disease or severe musculoskeletal conditions like severe
osteoarthritis or deformities)
• Laboratory exclusions at Screening:
o positive result for any of the following human immunodeficiency virus (HIV),
hepatitis B virus (HBV), hepatitis C virus (HCV)
o Creatinine > 1.5 × ULN or Blood Urea Nitrogen (BUN) > 3 × ULN
• Any of the following therapies:
o Within 1 month before Baseline: intramuscular, intravenous, or
intra-articular corticosteroids including adrenocorticotropic hormone (any
dose), doses > 20 mg/day prednisolone equivalent (any route), or any change to
physiotherapy
o Within 2 months before Baseline: IgG (Note: subject may enroll < 2 months
after stopping IgG therapy if clinical deterioration is experienced after
withdrawal)
o Within 3 months before Baseline: plasma exchange or plasmapheresis
o Within 6 months before Baseline: Cyclophosphamide or alkylating agents
o Within 6 months or 5 half-lives of the drug, whichever is longer, before
Baseline: other biologic therapies including investigational agents
o Within 9 months before Baseline: Rituximab or evidence of persistent B cell
depletion after stopping therapy
• Male subject or female subject of childbearing potential either not using or
not willing to use a medically reliable method of contraception (see protocol
section 7.4.2), not sexually abstinent during the study, or not surgically
sterile before study enrollment
• Pregnant or breastfeeding
• Alcohol, drug, or medication abuse within 1 year of providing informed consent
• Previously received investigational medicinal product (IMP) in this study or
failed screening more than 1 time in this study
• Involved in the planning and/or conduct of the study (applies to CSLB staff,
staff at the study site, and third-party vendors)
• Any issue that, in the opinion of the investigator, would render the subject
unsuitable for participation in the study or unable to comply with study
procedures, eg inability to self-administer IMP or by aid through a caregiver
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003171-35-NL |
| ClinicalTrials.gov | NCT04044690 |
| CCMO | NL69702.018.19 |