A Study of Guselkumab in Participants With Systemic Sclerosis

• Guselkumab Dose 1 (Drug): Guselkumab Dose 1 will be administered intravenously.
• Guselkumab Dose 2 (Drug): Guselkumab Dose 2 will be administered subcutaneously.
• Placebo (Drug): Placebo will be administered intravenously or subcutaneously.

Primary outcomes

• Main Study: Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 24 [Baseline and Week 24]: Change from baseline in mRSS at Week 24 was reported. The mRSS is an accepted clinical measure of skin thickness. The investigator assessed the thickening of the skin using the mRSS through simple palpation on 17 different skin sites in the fingers, hands, forearms, arms, feet, legs, and thighs (bilaterally) and face, chest, and abdomen (singly). 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 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.

Secondary outcomes

• Main Study: Change From Baseline in Modified Rodnan Skin Score at Week 52 [Baseline and Week 52]: Change from baseline in mRSS at Week 52 was reported. The mRSS is an accepted clinical measure of skin thickness. The investigator assessed the thickening of the skin using the mRSS through simple palpation on 17 different skin sites in the fingers, hands, forearms, arms, feet, legs, and thighs (bilaterally) and face, chest, and abdomen (singly). 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 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.
• Main Study: Percentage of Participants Who Experienced Worsening of Modified Rodnan Skin Score at Week 24 and Week 52 [Week 24 and Week 52]: The percentage of participants who experienced worsening of mRSS at Week 24 and Week 52 was reported. The worsening of mRSS was defined as an increase from baseline greater than or equal to (>=) 5 points and >=20 percent (%) in mRSS. The mRSS is an accepted clinical measure of skin thickness. The investigator assessed the thickening of the skin using the mRSS through simple palpation on 17 different skin sites in the fingers, hands, forearms, arms, feet, legs, and thighs (bilaterally) and face, chest, and abdomen (singly). 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 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.
• Main Study: 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 [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). 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.
• Main Study: Change From Baseline in Forced Vital Capacity (FVC) at Week 24 and Week 52 [Baseline, 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 which assessed the change in lung function related to the disease status of an underlying interstitial lung disease.
• Main Study: Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 24 and Week 52 [Baseline, Week 24 and Week 52]: Change from baseline in the percent predicted FVC at Week 24 and Week 52 was reported. FVC was the total amount of air (in liters) exhaled from the lungs during the lung function test measured by spirometer which assessed the change in lung function related to the disease status of an underlying interstitial lung disease.
• Main Study: Change From Baseline in the Measured Absolute Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) at Week 24 and Week 52 [Baseline, 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. Participants breathe in (inhale) air containing a very small, harmless amount of a tracer gas, such as carbon monoxide. Participants hold their breath for 10 seconds, then rapidly blow it out (exhale). The exhaled gas was tested to determine amount of the tracer gas absorbed during the breath.
• Main Study: Change From Baseline in the Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) at Week 24 and Week 52 [Baseline, Week 24 and Week 52]: Change from baseline in the percent predicted DLCO at Week 24 and Week 52 was reported. 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. Participants breathe in (inhale) air containing a very small, harmless amount of a tracer gas, such as carbon monoxide. Participants hold their breath for 10 seconds, then rapidly blow it out (exhale). The exhaled gas was tested to determine amount of the tracer gas absorbed during the breath.
• Main Study: Change From Baseline in Digital Ulcer Counts at Week 24 and Week 52 [Baseline, 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.
• Main Study: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24 and Week 52 [Baseline, 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, 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.
• Main Study: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Through Week 24 and Week 52 [From Baseline (Week 0) up to Week 24 and Week 52]: An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs were defined as AEs that occur at or after the initial administration of study intervention. All TEAEs including serious and non-serious events are reported in this outcome measure.
• Long-term Extension (LTE) Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From Week 52 up to Week 112]: An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs were defined as AEs that occurred at or after the initial administration of study intervention. All TEAEs including serious and non-serious events are reported in this outcome measure.
• Main Study: Number of Participants With Treatment-Emergent Serious Adverse Events (TESAEs) Through Week 24 and Week 52 [From Baseline (Week 0) up to Week 24 and Week 52]: An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/ incapacity, or resulted in congenital anomaly/birth defect. TEAEs were defined as AEs that occur at or after the initial administration of study intervention.
• Long-term Extension (LTE) Period: Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) [From Week 52 up to Week 112]: An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/ incapacity, or resulted in congenital anomaly/birth defect. TEAEs were defined as AEs that occur at or after the initial administration of study intervention.
• Main Study: Number of Participants With Adverse Events of Special Interest (AESI) Through Week 24 and Week 52 [From Baseline (Week 0) up to Week 24 and Week 52]: AESI were defined as any newly identified malignancy or case of active tuberculosis (TB) or interstitial lung disease (ILD) occurring after the first study intervention administration in study participants and was reported by the investigator to the sponsor or designee within 24 hours after being made aware of the event. AESIs for this study included drug-induced liver injuries, active TB, ILD, hypersensitivity reaction, opportunistic infection and adverse cardiovascular events.
• Long-term Extension (LTE) Period: Number of Participants With Adverse Events of Special Interest (AESI) [From Week 52 up to Week 112]: AESI were defined as any newly identified malignancy or case of active tuberculosis (TB) or interstitial lung disease (ILD) occurring after the first study intervention administration in study participants and was reported by the investigator to the sponsor or designee within 24 hours after being made aware of the event. AESIs for this study included drug-induced liver injuries, active TB, ILD, hypersensitivity reaction, opportunistic infection and adverse cardiovascular events.
• Main Study: Serum Concentration of Guselkumab [Pre-dose at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Post- dose at Weeks 0, 4, 8]: Serum concentration of guselkumab was reported. The lower limit of quantification (LLOQ) for guselkumab was 0.01 micrograms per milliliter (mcg/mL).
• Long-term Extension (LTE) Study: Serum Concentrations of Guselkumab [Pre-dose (at Weeks 56, 60, 64, 76, 88, 96) and Week 104]: Serum concentration of guselkumab was reported. The LLOQ for guselkumab was 0.01 mcg/mL.
• Main Study: Number of Participants With Anti-Guselkumab Antibody [From Baseline (Week 0) up to Week 52]: Number of participants with anti-guselkumab antibody were reported. Serum samples were assessed for anti-drug antibodies.
• Long-term Extension (LTE) Study: Number of Participants With Anti-guselkumab Antibody [From Week 52 up to Week 104]: Number of participants with anti-guselkumab antibody were reported. Serum samples were assessed for anti-drug antibodies.

Sex: All, ages: 18 Years to 75 Years

Inclusion criteria:

* 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

Exclusion Criteria:

* 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)

Participant flow

Outcome results

• Main Study: Change From Baseline in Modified Rodnan Skin Score (mRSS) at Week 24 (Primary), Least squares mean, Score on a scale: Main Study: Group A: Guselkumab -9.5 +/- 0.74; Main Study: Group B: Placebo 3.1 +/- 0.77 (p < 0.001)
• Main Study: Change From Baseline in Modified Rodnan Skin Score at Week 52 (Secondary), Least squares mean, Score on a scale: Main Study: Group A: Guselkumab -9.3 +/- 0.89; Main Study: Group B: Placebo 2.7 +/- 0.93
• Main Study: Percentage of Participants Who Experienced Worsening of Modified Rodnan Skin Score at Week 24 and Week 52 (Secondary), Number, Percentage of participants: Main Study: Group A: Guselkumab 3.4; Main Study: Group B: Placebo 25.9
• Main Study: 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 (Secondary), Number, Percentage of participants: Main Study: Group A: Guselkumab 86.2; Main Study: Group B: Placebo 3.7
• Main Study: Change From Baseline in Forced Vital Capacity (FVC) at Week 24 and Week 52 (Secondary), Least squares mean, Liters: Main Study: Group A: Guselkumab -51.9 +/- 33.91; Main Study: Group B: Placebo -4.7 +/- 35.78
• Main Study: Change From Baseline in Percent Predicted Forced Vital Capacity (FVC) at Week 24 and Week 52 (Secondary), Least squares mean, Percent predicted FVC: Main Study: Group A: Guselkumab -0.7 +/- 1.21; Main Study: Group B: Placebo -0.7 +/- 1.26
• Main Study: Change From Baseline in the Measured Absolute Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) at Week 24 and Week 52 (Secondary), Least squares mean, Milliliter/minute/millimeter mercury: Main Study: Group A: Guselkumab -0.60 +/- 0.257; Main Study: Group B: Placebo -0.51 +/- 0.265
• Main Study: Change From Baseline in the Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) at Week 24 and Week 52 (Secondary), Least squares mean, Percent predicted DLCO: Main Study: Group A: Guselkumab -4.57 +/- 1.338; Main Study: Group B: Placebo -2.49 +/- 1.347
• Main Study: Change From Baseline in Digital Ulcer Counts at Week 24 and Week 52 (Secondary), Least squares mean, Ulcers: Main Study: Group A: Guselkumab -0.0 +/- 0.47; Main Study: Group B: Placebo 4.8 +/- 0.48
• Main Study: Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24 and Week 52 (Secondary), Least squares mean, Score on a scale: Main Study: Group A: Guselkumab -0.0529 +/- 0.09062; Main Study: Group B: Placebo 0.3477 +/- 0.09439
• Main Study: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Through Week 24 and Week 52 (Secondary), Count of participants, Participants: Main Study: Group A: Guselkumab 20; Main Study: Group B: Placebo 24
• Long-term Extension (LTE) Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Secondary), Count of participants, Participants: LTE Period: Group A: Guselkumab Then Guselkumab 23; LTE Period: Group B: Placebo Then Guselkumab 25
• Main Study: Number of Participants With Treatment-Emergent Serious Adverse Events (TESAEs) Through Week 24 and Week 52 (Secondary), Count of participants, Participants: Main Study: Group A: Guselkumab 0; Main Study: Group B: Placebo 0
• Long-term Extension (LTE) Period: Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) (Secondary), Count of participants, Participants: LTE Period: Group A: Guselkumab Then Guselkumab 1; LTE Period: Group B: Placebo Then Guselkumab 0
• Main Study: Number of Participants With Adverse Events of Special Interest (AESI) Through Week 24 and Week 52 (Secondary), Count of participants, Participants: Main Study: Group A: Guselkumab 0; Main Study: Group B: Placebo 0
• Long-term Extension (LTE) Period: Number of Participants With Adverse Events of Special Interest (AESI) (Secondary), Count of participants, Participants: LTE Period: Group A: Guselkumab Then Guselkumab 0; LTE Period: Group B: Placebo Then Guselkumab 0
• Main Study: Serum Concentration of Guselkumab (Secondary), Mean, mcg/mL: Main Study: Group A: Guselkumab NA +/- NA
• Long-term Extension (LTE) Study: Serum Concentrations of Guselkumab (Secondary), Mean, mcg/mL: LTE Period: Group A: Guselkumab Then Guselkumab 12.167 +/- 5.4753; LTE Period: Group B: Placebo Then Guselkumab 19.285 +/- 8.3377
• Main Study: Number of Participants With Anti-Guselkumab Antibody (Secondary), Count of participants, Participants: Main Study: Group A: Guselkumab 6
• Long-term Extension (LTE) Study: Number of Participants With Anti-guselkumab Antibody (Secondary), Count of participants, Participants: LTE Period: Group A: Guselkumab Then Guselkumab 6; LTE Period: Group B: Placebo Then Guselkumab 0

Adverse events

Time frame: All-cause mortality: Main Study: From screening (Week [-6]) up to Week 60 and LTE Period: From Week 52 up to Week 112 ; SAEs and Non-serious AEs: Main Study: From baseline (Week 0) up to Week 60; LTE Period: From Week 52 up to Week 112

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2022-11-15)
• Statistical Analysis Plan (PDF, 2023-06-07)

• Janssen Pharmaceutical K.K., Japan Clinical Trial, Study director, Janssen Pharmaceutical K.K.