臨床研究等提出・公開システム

A Multicenter, Randomized, Placebo-controlled, Double-blind, Proof-of-concept Study of Guselkumab in Participants with Systemic Sclerosis

A study of Guselkumab in Participants with Systemic Sclerosis

56

Baseline characteristics included participants in the "full analysis set," that is, all randomized participants who received at least 1 dose (complete or partial) of study intervention. Almost all participants were female and Asian, with a median age of 51.5 years (range: 18-72 years). The median duration of systemic sclerosis (SSc) disease was 4.7 months (range: 2-30 months). Participants had a median Modified Rodnan Skin Score (mRSS) of 12.0, Health Assessment Questionnaire-Disability Index (HAQ-DI) score of 0.2500, Frequency Scale for the Symptoms of Gastroesophageal reflux disease (FSSG) score of 12.0, Physician global assessment (PhGA) score of 5.10, Patient global assessment (PGA) score of 4.40, % predicted forced vital capacity (FVC) of 99.0 and % diffusing capacity of the lung for carbon monoxide (DLCO) (Hemoglobin-corrected) of 99.65. The demographic and other baseline characteristics including disease characteristics of participants were generally comparable between the 2 treatment groups.

A total of 60 participants were screened for the study, out of which 56 were randomized into guselkumab group (29 participants) and placebo (27 participants). A total of 55 participants completed the main study (at Week 52). One participant in guselkumab group terminated main study participation prematurely due to withdrawal by participant. All participants in the placebo group continued study intervention through main study. Participants who completed the main study (Week 0 through 52: i.e., after the Week 48 evaluation, prior to Week 52 evaluation) and who, in the opinion of the investigator, could benefit from continued treatment, participated in the long-term extension (LTE) by signing the informed consent form before or at Week 52. Fifty-one participants (guselkumab/guselkumab group: 25 participants and placebo/guselkumab: 26 participants) received study intervention during the LTE period. In total, 48 (94.1%) participants completed the LTE period, and 3 (5.9%) participants discontinued study participation prematurely.

The safety analysis included all randomized participants who received at least 1 dose (complete or partial) of study intervention. Participants were analyzed based on the intervention they received, regardless of the intervention groups to which they are assigned. Overall, guselkumab was well tolerated through Week 24 and Week 52. Adverse Events (AEs) through Week 24: - Twenty (69.0%) participants in the guselkumab group and 24 (88.9%) participants in the placebo group experienced 1 or more AEs. - Most AEs were considered mild or moderate in severity by the investigator. No severe AEs were observed. - No deaths, serious adverse events (SAEs) or AEs leading to discontinuation of study intervention were reported through Week 24. AEs through Week 52: - Twenty-five (86.2%) participants in the guselkumab group and 26 (96.3%) participants in the placebo experienced 1 or more AEs. - Most AEs were considered mild or moderate in severity by the investigator, except 1 (3.7%) participant in the placebo group had one severe AE (COVID-19) and 1 (3.4%) participant in the guselkumab group had 3 severe AEs (systemic scleroderma, ileus paralytic, and pneumatosis intestinalis). - No deaths were reported through Week 52. - Six SAEs were reported in 1 (3.4%) participant receiving guselkumab (Ileus paralytic, pneumatosis intestinalis, and systemic scleroderma). One SAE (COVID-19) was reported in 1 participant of the placebo group. - One (3.4%) participant receiving guselkumab discontinued study intervention due to a severe AE of systemic scleroderma. AEs during the LTE period: - Forty-eight (94.1%) of the 51 participants had 1 or more AEs during the LTE period. The incidence of AEs was similar in participants who previously received placebo during the main study as for those who previously received guselkumab (25 [96.2%] and 23 [92.0%] participants, respectively). - One (4.0%) participant who previously received guselkumab during the main study had an AE leading to death during the LTE period (myocarditis), which was considered not related to study intervention by the investigator. - No other SAEs were reported during the LTE period. - The AE leading to death also led to discontinuation of study intervention. No other AEs leading to discontinuation of study intervention were reported during the LTE period.

Primary Efficacy Endpoint: The primary efficacy endpoint was Change from Baseline in Modified Rodnan Skin Score (mRSS) at Week 24. Primary efficacy analysis was based on a full analysis set, that included all randomized participants who received at least 1 dose (complete or partial) of study intervention. Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 24 The mRSS is an accepted clinical measure of skin thickness. Investigators assessed the thickening of the skin using the mRSS through simple palpation on 17 different skin sites. Each skin site was rated on a 0 to 3 scale: where 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness and unable to pinch. Individual skin scores in the 17 body areas were summed up and defined as the total mRSS which ranged from 0 (no thickening) to 51 (severe thickening), where higher score indicated more severity of skin thickening/worst outcome. The mRSS improved (decreased) from baseline at Week 24, with a mean change (SD) of -9.2 (3.17) in guselkumab group, and 3.4 (3.76) in the placebo group. Guselkumab treatment showed a significantly greater change from baseline (decrease) in mRSS at Week 24 compared with the placebo group (LS Mean difference [80% CI] = -12.6 [-13.8, -11.4], p<0.001). Secondary Efficacy Endpoint: Secondary endpoints were efficacy, pharmacokinetics (PK) and immunogenicity. Efficacy analysis was based on full analysis set, that included all randomized participants who received at least 1 dose (complete or partial) of study intervention. PK analysis set included all participants who received at least 1 complete administration of guselkumab and had at least 1 observed post dose PK data. Immunogenicity analysis set included all participants who received at least 1 administration of guselkumab and had at least 1 observed post dose immune response data. Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 52 The mRSS decreased at Week 52 from baseline, with a mean change (SD) of -9.1 (5.20) in guselkumab group and 3.0 (4.68) in placebo group. Guselkumab group showed a greater change from baseline (decrease) in mRSS at Week 52 compared with the placebo group (LS Mean difference [80% CI] = -12.0 [-13.3, -10.7]). Percentage of Participants Who Experienced Worsening of Modified Rodnan Skin Score at Week 24 and Week 52 The worsening of mRSS was defined as an increase from baseline greater than or equal to (>=) 5 points and >=20 percent (%) in mRSS. The percentage of participants who experienced worsening of mRSS at Week 24 and Week 52 was lower in the guselkumab group (3.4%; 20.7%) compared with the placebo group (25.9%; 77.8%). Percentage of Participants Who Achieved a Score of 0.6 in American College of Rheumatology Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (ACR CRISS) at Week 24 and Week 52 ACR CRISS is a composite endpoint. Firstly, participants were evaluated on not-improved criterion: new onset of renal crisis, >=15% decline in forced vital capacity [FVC] percent predicted relative to baseline, new onset of pulmonary arterial hypertension, and new onset of left ventricular failure. If yes, these participants were assigned probability score of 0.0. For remaining participants, percentage was based on CRISS domains: mRSS, FVC percent predicted, physician's global assessment, patient's global assessment and Health Assessment Questionnaire Disability-Index (HAQ-DI). The algorithm determines predicted probability of improvement from baseline by incorporating change in mRSS, FVC percent predicted, physician and patient global assessments and HAQ-DI. Outcome was a continuous variable between 0.0 and 1.0 (0 to 100%). Higher score=greater probability of improvement. ACR CRISS score >=0.60 was considered improved, while predicted probability below 0.60 was considered not improved. The percentage of participants achieving an ACR CRISS score of 0.6 at Week 24 and 52 was greater in the guselkumab group (86.2%; 79.3%) than in the placebo group (3.7%; 3.7%), respectively. Change From Baseline in Forced Vital Capacity (FVC) at Week 24 and Week 52 FVC was the total amount of air (in liters) exhaled from the lungs during the lung function test measured by spirometer. LS Mean of change from baseline at Week 24 in FVC were -51.9 in the guselkumab and -4.7 in the placebo groups, whereas at Week 52 were -26.5 in guselkumab and -12.3 in the placebo groups. Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 24 and Week 52 LS Mean change from baseline at Week 24 in % predicted FVC were -0.7 in both the guselkumab and placebo groups; whereas at Week 52 were -0.2 in the guselkumab group and -0.4 in the placebo group. Change From Baseline in the Measured Absolute Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) at Week 24 and Week 52 DLCO is a measurement of the ability of the lungs to transfer gases from the air to the blood. DLCO is measured using the single breath method. LS Mean change from baseline at Week 24 in DLCO were -0.60 in the guselkumab group and -0.51 in the placebo group, whereas at Week 52 were -0.35 in the guselkumab group and -0.56 in the placebo group. Change From Baseline in the Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) at Week 24 and Week 52 LS Mean change from baseline at Week 24 in % predicted DLCO were -4.57 in the guselkumab group and -2.49 in the placebo group, whereas at Week 52 were -1.71 in the guselkumab group and -1.85 in the placebo group. Change From Baseline in Digital Ulcer Counts at Week 24 and Week 52 Digital ulcers were defined as a full thickness (>3 millimeters [mm] in maximal diameter) skin lesion with loss of epithelium including lesions covered by eschar (excluding pitting scars and hyperkeratotic lesions). Healing was defined by re-epithelialization with loss of pain and exudate. The digital ulcer assessments and counting were performed by the investigator designee. LS Mean of change from baseline at Week 24 in digital ulcer counts that were -0.0 in the guselkumab group and 4.8 in the placebo group, whereas at Week 52 were -0.1 in the guselkumab group and 4.1 in the placebo group. Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24 and Week 52 HAQ-DI assessed the degree of difficulty participants experienced in 8 daily living activity domains during past week: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Each activity category consisted of 2-3 items. For each item, the level of difficulty was scored from 0 to 3 (0=no difficulty, 1=some difficulty, 2=much difficulty, 3=unable to do). Total HAQ-DI score was computed as the sum of domain scores divided by the number of domains answered, providing a score from 0 (no difficulty) to 3 (maximum difficulty), where higher score indicated greater disability. LS Mean change from baseline at Week 24 in the HAQ-DI score were -0.0529 in the guselkumab group and 0.3477 in the placebo group, whereas at Week 52 were -0.0572 in guselkumab group and 0.1782 in the placebo group. Serum Concentration of Guselkumab Serum concentration of guselkumab was reported. The lower limit of quantification (LLOQ) for guselkumab was 0.01 micrograms per milliliter (mcg/mL). Following IV administration of guselkumab 400 mg at Weeks 0, 4, and 8, the median serum guselkumab concentration at Week 8 (1-hour postdose) was 164 ug/mL. Steady state guselkumab concentration was reached by the third SC maintenance dose (Week 20). Number of Participants With Anti-Guselkumab Antibody Serum samples were assessed for anti-drug antibodies. The overall incidence of treatment-induced antibodies to guselkumab through Week 24/52 was 0 participants and 6 (20.7%) participants, respectively.

Guselkumab demonstrated clinical efficacy compared with placebo, as evidenced by the change in the mRSS at Week 24 and Week 52. Other secondary efficacy endpoints (ACR CRISS and HAQ-DI) supported the primary endpoint results. Objective of LTE was to evaluate the long-term safety and efficacy of guselkumab. Overall, changes in efficacy parameters were maintained during the LTE period. Data from the study supports positive benefit-risk profile of guselkumab and it was well tolerated in participants with SSc.

July. 09, 2025

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2051200133

Numaguchi Hirotaka

Janssen Pharmaceutical K.K.

3-5-2 Nishi-kanda, Chiyoda-ku, Tokyo

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

Medical Information Center

Janssen Pharmaceutical K.K.

3-5-2 Nishi-kanda, Chiyoda-ku, Tokyo

+81-120-183-275

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

Complete

Feb. 08, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- Diagnosis of systemic sclerosis (SSc) according to American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) 2013 criteria

- Diffuse cutaneous SSc according to the LeRoy criteria that is, skin fibrosis proximal to the elbows and knees in addition to acral fibrosis

- Disease duration of =<36 months (defined as time from first non-Raynaud phenomenon manifestation).

- Greater than or equal to (>=) 10 and less than or equal to (<=) 22 modified Rodnan skin score (mRSS) units at screening and Week 0

- Forced vital capacity (FVC) >= 60 percent (%) of predicted at screening

- Diffusing capacity of the lung for carbon monoxide (DLCO) >= 40% of predicted (hemoglobin-corrected) at screening.

- Participants who meet 1 of the following criteria at screening: increase of >=3 mRSS units, compared with an assessment performed within the previous 2 to 6 months; Involvement of 1 new body area with an increase of >=2 mRSS units compared with an assessment performed within the previous 2 to 6 months; and Involvement of 2 new body areas with increase of >=1 mRSS units compared with the assessment within the previous 2 to 6 months

- History of liver or renal insufficiency (estimated creatinine clearance below 60 milliliter per minute [mL/min]); significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances

- Has any known severe or uncontrolled SSc complications including hemoptysis, pulmonary hemorrhage, renal crisis

- Has an interstitial lung disease requiring oxygen therapy

- Has any rheumatic disease other than SSc such as rheumatoid arthritis (RA), polymyalgia rheumatica (PMR), systemic lupus erythematosus, polymyositis/dermatomyositis that could interfere with assessment of SSc

- Has a current diagnosis or signs or symptoms of severe, progressive, or uncontrolled renal, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances. (or, in the investigator's opinion, any other concomitant medical condition that places the participant at risk by participating in this study)

Both

Scleroderma, Systemic

Group A: Guselkumab Dose 1
Guselkumab Dose 1 will be administered intravenously.

Group A: Guselkumab Dose 2
Guselkumab Dose 2 will be administered subcutaneously.

Group B: Placebo
Placebo will be administered intravenously or subcutaneously.

Change from Baseline in Modified Rodnan Skin Score (mRSS) at Week 24
Baseline and Week 24
The mRSS is a validated physical examination method for estimating skin induration. It correlates with biopsy measures of skin thickness and reflects prognosis and visceral involvement, especially in early disease. It is scored on 0 (normal) to 3 (severe induration) ordinal scales over 17 body areas, with a maximum score of 51 and is used to categorize severity of systemic sclerosis (SSc). Higher the score maximum the severity.

Change From Baseline in mRSS at Week 52

Percentage of Participants with Worsening of mRSS at Week 24 and Week 52

Percentage of Participants Achieving a Score of 0.6 in American College of Rheumatology Combined Response Index in diffuse cutaneous systemic sclerosis (dcSSc) (ACR CRISS) at Week 24 and Week 52
ACR CRISS is composite response index for clinical trials in early dcSSc developed by an international group of experts in SSc. Application of ACR CRISS algorithm in a randomized clinical trial is a 2-step process. Firstly, participants will be evaluated to have met the criterion for not improved. If yes, these participants are assigned a probability score of 0.0. For the remaining participants, calculate the probability based on change in 5 measures: mRSS, percentage (%) of predicted FVC, HAQ-DI, patient's global assessment, and physician's global assessment, where each measure has a probability score between 0 and 1.

Change from Baseline in Forced Vital Capacity (FVC) at Week 24 and Week 52
Pulmonary function test will be assessed by FVC.

Change from Baseline in Percent (%) Predicted Forced Vital Capacity (FVC) at Week 24 and Week 52
Pulmonary function test will be assessed by % predicted FVC.

Change from Baseline in the Measured Absolute Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) at Week 24 and Week 52
Pulmonary function test will be assessed by measuring absolute DLCO.

Change from Baseline in the Derived % Predicted DLCO at Week 24 and Week 52
Pulmonary function test will be assessed by % predicted DLCO.

Change from Baseline in Digital Ulcer Counts at Week 24 and Week 52
Digital ulcers are defined as a full thickness (greater than [>] 3 millimeters [mm] in maximal diameter) skin lesion with loss of epithelium including lesions covered by eschar. Healing is defined by re epithelialization with loss of pain and exudate

Change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24 and Week 52
The HAQ-DI is a 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping and activities of daily living). Responses in each functional area are scored from 0 to 3 (0=no difficulty and 3=inability to perform a task in that area). Overall score is computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.

Percentage of Participants with Treatment-emergent Adverse Event (TEAE)
From baseline up to Week 24, Week 52, Week 76 and Week 104
Treatment-emergent AEs are AEs with onset during the treatment phase or that are a consequence of a preexisting condition that has worsened since baseline.

Percentage of Participants with Serious Adverse Event (SAE)
From baseline up to Week 24, Week 52, Week 76 and Week 104
A SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a suspected transmission of any infectious agent via a medicinal product; is medically important.

Percentage of Participants with Adverse Events of Special Interest (AESI)
From baseline up to Week 24, Week 52, Week 76 and Week 104
Any newly identified malignancy or case of active tuberculosis (TB) or interstitial lung disease (ILD) occurring after the first study intervention administration(s) in participants are considered as AESI.

Serum Concentration of Guselkumab
Serum samples will be analyzed to determine concentrations of guselkumab using a validated, specific, and sensitive method.

Number of Participants with Antibodies of Guselkumab
Number of participants with incidence antibodies of Guselkumab antibody will be assessed.

+81-52-691-7151

Dec. 22, 2020

none