EFFICACY OBJECTIVESThe primary efficacy objective for this study is as follows:* To evaluate the efficacy of TCZ compared with placebo on skin sclerosis, as measured by mRSS at Week 48The secondary efficacy objectives for this study are as follows…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Connective tissue disorders (excl congenital)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy Outcome Measures
The primary efficacy outcome measure for this study is as follows:
* Change in mRSS from baseline to Week 48
The secondary efficacy outcome measures for this study are as follows:
* Proportions of patients with *20%, * 40%, and * 60% improvement in mRSS at
Week 48 compared with baseline
* Change in FVC from baseline to Week 48
* Change in HAQ-DI from baseline to Week 48
* Change in Patient's Global Assessment from baseline to Week 48
* Change in Physician's Global Assessment from baseline to Week 48
* Time to treatment failure, defined as the time from randomization to the time
of one of the following events (whichever occurs first) during the 48-week
double-blind treatment period: death, decline in percent-predicted FVC > 10%
relative to baseline, > 20% increase in mRSS and an increase in mRSS of * 5
points occurrence of a predefined SSc-related complication as adjudicated by
the Clinical Adjudication Committee
Secondary outcome
Safety Outcome Measures
The safety outcome measures for this study are as follows:
* Frequency of deaths
* Nature, frequency, and severity of adverse events
* Incidence of specific laboratory abnormalities
* Change from baseline in digital ulcer count 3.4.3 Immunogenicity Outcome
Measures
The immunogenicity outcome measures for this study are as follows:
* Incidence of anti-TCZ antibodies during the study relative to the prevalence
of anti-TCZ antibodies at baseline
* Correlation between anti-TCZ*antibody status and efficacy, safety, or PK
outcome measures
Pharmacodynamic Outcome Measure
The PD outcome measure for this study is as follows:
* Predose ESR and serum IL-6, sIL-6R, and CRP levels at baseline and at
subsequent timepoints after initiation of study drug
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:
* Predose serum TCZ concentration at baseline and at specified timepoints
thereafter
* Correlation between PK parameters for TCZ and efficacy, safety, or
immunogenicity outcome measures
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:
* Proportions of patients who achieve a response, as determined by the
investigator using CRISS, at Week 48
* Change in the VAS component of the SHAQ from baseline to Week 24 and baseline
to Week 48
* Change in WPAI-GH score from baseline to Week 24 and baseline to Week 48
* Change in EQ-5D-3L score from baseline to Week 24 and baseline to Week 48
* Change in total score and subscores of Saint George*s Respiratory
Questionnaire from baseline to Week 48
* Change in FACIT-Fatigue score from baseline to Week 48.
* Change in HRCT fibrosis score from baseline (based on HRCT scan performed
within 3 months prior to screening) to Week 48
* Change in DLCO from baseline to Week 48
* Proportion of patients with * 15% decline in observed DLCO at Week 48
* Proportion of patients with * 15% decline in percentage of predicted DLCO at
Week 48
* Change in FVC from baseline to Week 24
* Proportion of patients with * 10% decline in observed FVC at Week 24 and at
Week 48
* Proportion of patients with * 10% decline in percentage of predicted FVC at
Week 24 and at Week 48
* Change in mRSS from baseline to Week 24 and Week 96
* Change in observed and percentage of predicted FVC from baseline to Week 96
* Correlation between non-inherited biomarkers (serum levels of CCL18, sVCAM-1,
COMP, and autotaxin; plasma levels of CXCL4; and whole blood gene signatures
associated with plasmablasts and IFN) and efficacy, safety, PK, or
immunogenicity outcome measures
Background summary
SSc is a rare and devastating disease with no approved treatment options. To
date, no therapy has been shown to modify overall disease progression in SSc.
The data from Study WA27788, a double-blind, placebo-controlled study,
demonstrated a clinically meaningful effect of TCZ on mRSS and FVC, as well as
improvements in HAQ-DI, Physician's Global Assessment, and Patient's Global
Assessment at Week 48. This
Phase III study is designed to confirm clinically and statistically the
findings from Study WA27788. Overall, no new or unexpected safety signals were
observed in Study WA27788. The benefit*risk profile for TCZ in SSc is
considered to be positive on the basis of clinically meaningful, albeit not
statistically significant, effects of TCZ on skin sclerosis and pulmonary
function, the concordance of positive clinical and
patient-reported outcomes (PROs), as well as the absence of safety findings
that would be prohibitive of further development.
Study objective
EFFICACY OBJECTIVES
The primary efficacy objective for this study is as follows:
* To evaluate the efficacy of TCZ compared with placebo on skin sclerosis, as
measured by mRSS at Week 48
The secondary efficacy objectives for this study are as follows:
* To evaluate the efficacy of TCZ compared with placebo on pulmonary function,
as measured by FVC at Week 48
* To evaluate the efficacy of TCZ compared with placebo on PROs, as measured by
the HAQ-DI and Patient's Global Assessment at Week 48
* To evaluate the efficacy of TCZ compared with placebo, as measured by the
Physician's Global Assessment at Week 48
* To evaluate the efficacy of TCZ compared with placebo by assessment of time
to treatment failure (death, worsening of mRSS and/or FVC [see Section
4.4.1.1], or clinically significant SSc complication) up to Week 48
SAFETY OBJECTIVES
The safety objectives for this study are as follows:
* To evaluate the safety of TCZ compared with placebo, focusing on the nature,
frequency, and severity of serious and non-serious adverse events, the
frequency of SSc-related complications, and effects on vital signs, physical
findings, and clinical laboratory results
* To evaluate the safety of TCZ compared with placebo by assessing the number
of digital ulcers
* To assess the long-term safety of TCZ
IMMUNOGENICITY OBJECTIVES
The immunogenicity objectives for this study are as follows:
* To characterize the immunogenic potential of TCZ by measuring anti-TCZ
antibodies
* To assess the potential relationship between development of anti-TCZ
antibodies and efficacy, safety, or pharmacokinetic (PK) outcome measures
PHARMACODYNAMIC OBJECTIVE
The pharmacodynamic (PD) objective for this study is as follows:
* To compare changes in levels of PD biomarkers following treatment with TCZ
versus placebo
PHARMACOKINETIC OBJECTIVES
The PK objectives for this study are as follows:
* To characterize the pharmacokinetics of TCZ
* To evaluate potential relationships between PK parameters for TCZ and
efficacy, safety, or immunogenicity outcome measures
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:
* To evaluate the efficacy of TCZ compared with placebo on skin sclerosis, as
measured by mRSS at Week 24
* To evaluate the efficacy of TCZ versus placebo measured by the proportion of
responders as defined by the Combined Response Index for Systemic Sclerosis
(CRISS) at Week 48
* To evaluate the efficacy of TCZ compared with placebo, as measured by the
visual analog scale (VAS) component of the Scleroderma Health Assessment
Questionnaire (SHAQ) at Weeks 24 and 48
* To evaluate the efficacy of TCZ compared with placebo, as measured by the
Work Productivity and Activity Impairment*General Health (WPAI-GH)
questionnaire at Weeks 24 and 48
* To evaluate the efficacy of TCZ compared with placebo, as measured by the
EuroQol 5-Dimension Questionnaire with three levels of severity (EQ-5D-3L) at
Weeks 24 and 48
* To evaluate the efficacy of TCZ compared with placebo, as measured by Saint
George*s Respiratory Questionnaire at Week 48
* To evaluate the effect of TCZ compared with placebo on fatigue as measured by
Functional Assessment of Chronic Illness Therapy*Fatigue (FACIT-Fatigue) score
at Week 48.
* To evaluate the efficacy of TCZ compared with placebo on the basis of change
in pulmonary fibrosis, as determined using high-resolution computed tomography
(HRCT) scans at Week 48
* To evaluate the efficacy of TCZ compared with placebo, as measured by
diffusion capacity of the lung for carbon monoxide (DLCO) at Week 48 and FVC at
Week 24
* To evaluate the maintenance of efficacy of TCZ, as measured by mRSS and FVC
at Week 96
* To assess whether non-inherited biomarkers are predictive of response to TCZ
(i.e., predictive biomarkers), susceptibility to developing adverse events, or
progression to a more severe disease state (i.e., prognostic biomarkers), can
provide evidence of TCZ activity, or can increase the knowledge and
understanding of disease biology
Study design
This Phase III, multicenter, randomized, double-blind, placebo-controlled,
two-arm, parallel-group study is designed to assess the efficacy and safety of
TCZ in patients with SSc. The study consists of two periods: a 48-week,
double-blind, placebo-controlled period, followed by a 48-week open-label
treatment period. Patients will be randomized in a 1:1 ratio to receive SC
injections of 162 mg of TCZ QW or placebo QW for 48 weeks
during the double-blind treatment period. During the open-label treatment
period, all patients will receive SC injections of 162 mg of TCZ QW for up to
48 weeks. Patients receive their first dose of open-label treatment at Week 48.
Intervention
Patients will be randomized in a 1:1 ratio to receive SC injections of 162 mg
of TCZ QW or placebo QW for 48 weeks
during the double-blind treatment period. During the open-label treatment
period, all patients will receive SC injections of 162 mg of TCZ QW for up to
48 weeks. Patients receive their first dose of open-label treatment at Week 48.
Study burden and risks
See question E4 and E9.
Beneluxlaan 2a
Woerden 3446GR
NL
Beneluxlaan 2a
Woerden 3446GR
NL
Listed location countries
Age
Inclusion criteria
- Age ><= 18 years at baseline (Day 1)
- Diagnosis of SSc, as defined using the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) criteria (2013)
- SSc disease duration of <<=60 months (defined as time from the first non-Raynaud phenomenon manifestation)
- mRSS of ><=10 and <<=35 units at screening
- Active disease that meets at least one of the following criteria at screening: Disease duration of <<=18 months defined as time from the first non-Raynaud phenomenon manifestation; Increase in mRSS of ><=3 units compared with the most recent assessment performed within the previous 6 months; Involvement of one new body area and an increase in mRSS of ><=2 units compared with the most recent assessment performed within the previous 6 months; Involvement of two new body areas within the previous 6 months; Presence of at least one tendon friction rub
- Presence of at least one of the following at screening: C reactive protein (CRP) ><=0.6 milligrams (mg) per deciliter (dL) (><=6 mg/Liter [L]); erythrocyte sedimentation rate (ESR) ><=28 millimeter per hour (mm/hr); Platelet count ><=330 x 10^9/L (330,000/microliter)
- Uninvolved or mildly thickened skin at one of the following possible injection site locations: Front, middle region of the thigh; Abdomen, except for the 2-inch area directly around the navel; Outer area of the upper arm (if a patient caregiver is giving the injection)
- For women who are not postmenopausal (><=12 months of non*therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of <1% per year during the treatment period and for up to 3 months after the last dose of study drug
- For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm during the treatment period and for at least 8 weeks after the last dose of study drug
Exclusion criteria
- Pregnant or lactating, or intending to become pregnant during the study
- Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 12 months following randomization
- Skin thickening (scleroderma) limited to the face or areas distal to the elbows or knees at screening
- Rheumatic autoimmune disease other than SSc, including but not limited to rheumatoid arthritis (RA) (diagnosed using ACR/EULAR criteria), systemic lupus erythematosus, mixed connective tissue disorder, polymyositis, dermatomyositis, eosinophilic fasciitis, primary Sjögren's syndrome, and eosinophilic myalgia syndrome, as determined by the investigator
- History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
- Evidence of moderately severe concurrent nervous system, renal, endocrine, or gastrointestinal (GI) disease not related to SSc, as determined by the investigator
- Pulmonary disease with FVC <=55% of predicted (best of three measurements) or diffusion capacity of the lung for carbon monoxide [DLCO] (hemoglobin corrected) <=45% of predicted (best of three measurements)
- Class II or higher pulmonary arterial hypertension (PAH), as defined by the World Health Organization
- Evidence of other moderately severe pulmonary disease (e.g., asthma, emphysema), as determined by the investigator
- Cardiovascular disease with significant arrhythmia, congestive heart failure (New York Heart Association Class II-IV), unstable angina, uncontrolled hypertension, cor pulmonale, or symptomatic pericardial effusion
- History of myocardial infarction in the last 6 months prior to screening
- Current liver disease, as determined by the investigator
- History of diverticulitis or chronic ulcerative lower GI disease, such as Crohn disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations
- Known active current or significant history of recurrent bacterial, viral, fungal, mycobacterial, or other infections, including but not limited to atypical mycobacterial disease, hepatitis B or C, herpes zoster, infected digital ulcers, and osteomyelitis
- Any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks prior to screening or oral antibiotics within 2 weeks prior to screening
- Significant history of recurrent tuberculosis (TB), active TB requiring treatment within the previous 3 years, or untreated latent TB
- Patients should be screened for latent TB, and, if positive, will be eligible for the study after treatment per local standard practices
- History of or currently active primary or secondary immunodeficiency
- Evidence of malignant disease, or malignancies diagnosed within the previous 5 years (with the exception of local basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured)
- Neuropathies or other conditions that might interfere with pain evaluation, as determined by the investigator
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 | EUCTR2015-000424-28-NL |
| ClinicalTrials.gov | NCT02453256 |
| CCMO | NL54269.056.15 |