Pooled Safety Results Across Phase 3 Randomized Trials of Intravenous Golimumab in Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis

M. Elaine Husni; Atul Deodhar; Sergio Schwartzman; Soumya D. Chakravarty; Elizabeth C. Hsia; Jocelyn H. Leu; Yiying Zhou; Kim H. Lo; Arthur Kavanaugh

Disclosures

Arthritis Res Ther. 2022;24(73) 

In This Article

Results

Patients

In the combined RA, PsA, and AS trials, 1279 patients were randomized and received ≥ 1 administration of placebo (n = 539) or IV golimumab (n = 740). A total of 1248 patients received ≥ 1 golimumab administration, including those who were randomized to placebo and initiated IV golimumab at pre-specified time points for crossover or early escape (Figure 1). Baseline demographic and disease characteristics have been reported in each study[2,5,7] with selected characteristics shown in Table 1 for reference. Patients with RA had a higher mean age than patients with PsA or AS, and there were fewer men than women in the RA trial and fewer women than men in the AS trial. MTX use varied by trial; at baseline, 75% of patients were receiving MTX and 45% were receiving oral corticosteroids. All patients received MTX in the RA trial by design, while 70% in the PsA trial were receiving MTX at baseline. A minority (18%) of patients in the AS trial were receiving MTX at baseline. Corticosteroid use at baseline was also higher in the RA trial (65.0%) compared with the PsA (27.7%) and AS (26.4%) trials (Table 1).

Detailed patient disposition through the end of the studies has been previously reported.[2–8] In total, 1104 (86%) patients who received ≥ 1 golimumab administration (including 468 placebo ➔ golimumab patients) completed study treatment through week 52/100. In these pooled analyses, the mean duration of follow-up ranged from 16 to 23 weeks for placebo and 47 to 96 weeks for golimumab. The number of IV administrations per patient (mean ± SD) was 3.9 ± 0.8 for placebo and 9.0 ± 3.6 for golimumab. For golimumab-treated patients, the total PY of exposure used to determine the incidence/100 PY was 1077 in the RA trial, 417 in the PsA trial, and 203 in the AS trial for a pooled total PY of 1697.

Adverse Events During the Placebo-controlled Periods of the IV Golimumab Trials

Across the trials, during the placebo-controlled periods, 40.6% of placebo-treated patients and 50.3% of IV golimumab-treated patients experienced ≥ 1 AE, and 2.4% and 3.8% respectively had ≥ 1 serious AE (SAE) (Table 2). Details for each study have been previously reported.[2,5,7] Across the three studies, a greater proportion of golimumab-treated patients discontinued treatment because of an AE (2.3%) compared with placebo (0.7%; Table 2). Infections were the most common type of AE. Through the placebo-controlled periods, infections and serious infections, respectively, occurred in 17.3% and 0.4% of placebo patients and in 23.8% and 0.8% of golimumab-treated patients (Table 2). Adverse events reported in ≥ 3% of patients in any treatment group included upper respiratory tract infection, nasopharyngitis, and increases in serum aminotransferases (Table 2). Most SAEs were singular events, with no clear relationship to the underlying conditions or study treatment across the three trials. Three deaths occurred during the placebo-controlled periods of the trials, all among patients receiving placebo and none in the golimumab groups: in the RA trial, one death due to stroke; in the PsA trial, one each due to acute cardiac failure subsequent to pneumonia and cardiorespiratory insufficiency due to metastasis (esophageal neoplasm).[2,5]

Adverse Events in IV Golimumab-treated Patients Over the Course of Treatment

Through completion of the studies, the numbers/100 PY of AEs, SAEs, and discontinuations due to AEs were numerically greater in the RA trial, followed by the PsA and then AS trials (Table 3). Altogether, discontinuation due to an AE during treatment with IV golimumab occurred at a rate of 5% over the course of all trials.

Six deaths occurred in golimumab-treated patients, and all occurred after the placebo-controlled periods: pneumonia with subsequent presumed myocardial infarction, acute abdominal syndrome (abscess fluid removed during laparotomy was positive for TB), septic shock secondary to a pyogenic lung abscess, dehydration due to Clostridium difficile, and one of unknown cause in the RA trial[2–4] and one due to acute hepatitis of mixed etiology in the PsA trial.[6] No deaths occurred in the AS trial.[7,8]

Adverse Events of Interest

Malignancies occurred in 2 (0.4%) patients receiving placebo (non-small cell lung cancer and esophageal neoplasm in the PsA trial; Table 2). In addition, one case of non-treatment-emergent lung adenocarcinoma occurred in a patient randomized to placebo in the RA trial. Among IV golimumab-treated patients, eight malignancies occurred in seven (0.6%) patients: basal cell carcinoma, breast cancer, cervical carcinoma in situ, and chronic lymphocytic leukemia, and one patient with both Bowen's disease and basal cell carcinoma (all in the RA trial) and gastric cancer and colon cancer (one patient each) in the PsA trial. The incidence of malignancies/100 PY (95% CI) across the three studies was 0.4 (0.2, 0.9) (Table 3). There were no cases of lymphoma.

In total, 49 (3.9%) of all golimumab-treated patients had a serious infection; the incidence/100 PY (95% CI) was 3.4 (2.5, 4.4) across the three trials (4.0 [2.9, 5.4] in the RA trial; 2.6 [1.3, 4.7] in the PsA trial, and 1.5 [0.3, 4.3] in the AS trial; Table 3). Serious infections included pneumonia (n = 11), urinary tract infection (n = 5), sepsis (n = 4), appendicitis (n = 2), empyema (n = 2), and erysipelas (n = 2); other serious infections were singular events and included infected dermal cyst, acute pyelonephritis, periodontitis, and acute hepatitis of mixed etiology.[4,6,8] Among the golimumab-treated patients, six cases of active TB occurred (RA trial, n = 3; PsA trial, n = 2; AS trial, n = 1) (Table 3)), all in patients who screened negative for TB at baseline and lived in countries endemic for TB (Argentina, Lithuania, Malaysia, Mexico, and Ukraine).[4,6,8] No opportunistic infections occurred in the PsA or AS trials. Four opportunistic infections occurred among golimumab-treated patients in the RA trial: cryptococcal pneumonia (n = 1) and localized vertebral candidiasis (n = 1) (both classified as serious and led to discontinuation of golimumab),[4] and two golimumab-treated patients were diagnosed with non-serious esophageal candidiasis infection.

One demyelinating event (non-infectious encephalomyelitis) occurred in a patient receiving golimumab in the PsA trial.[5] Two events of uveitis occurred in patients who were receiving placebo (both in the AS trial). One golimumab-treated patient had de novo uveitis (RA trial); the patient had a concurrent herpes simplex infection of the eye. Two patients reported pregnancy during the trial, both randomized to golimumab: one patient (RA trial) discontinued study treatment with no additional information provided, and the other patient (PsA trial) discontinued study treatment and had an elective termination. There were no cases of drug-induced lupus or aplastic anemia.

Two patients experienced heart failure (both in the PsA trial): one patient in the placebo group developed acute heart failure that had a fatal outcome, and one patient in the golimumab group had a non-serious AE of chronic heart failure (hypertension and ischemic heart disease ongoing at baseline; the patient discontinued study treatment). Two patients experienced deep vein thrombosis: one golimumab-treated patient in the RA trial and one placebo-treated patient in the PsA trial. The incidence (95% CI) of MACE among all golimumab-treated patients was 0.5/100 PY (0.2, 1.0), all occurring in the RA trial (Table 3): two deaths (one due to unknown cause and the aforementioned presumed myocardial infarction secondary to pneumonia), three non-fatal myocardial infarctions, and four non-fatal strokes. The incidence (95% CI) of MACE among patients receiving placebo was 1.4/100 PY (0.3, 4.0): two deaths (the aforementioned stroke [RA trial] and acute cardiac failure subsequent to pneumonia [PsA trial]) and one non-fatal stroke (PsA trial).[2,5]

During the placebo-controlled periods, infusion reactions were seen in 2.8% of all IV golimumab-treated patients (Table 2); the incidence remained low over the course of the trials (3.0/100 PY; Table 3). No infusion reaction was considered serious or severe. One patient in the PsA trial receiving golimumab discontinued study agent due to chest tightness associated with infusion.

Adverse Events in Patients With and Without Concomitant Methotrexate or Oral Corticosteroids

Across the three trials, 965 (placebo, n = 391; golimumab, n = 574) were receiving concomitant MTX at baseline (Table 4). Concomitant MTX treatment was mandatory in the RA trial and optional in the PsA and AS trials. During the placebo-controlled periods of the PsA and AS trials, infections, serious infections, and SAEs occurred in comparable proportions of patients receiving vs. not receiving concomitant MTX (Table 4). Pooling data across the three trials, infections appeared to be more common in patients with vs. without MTX use at baseline during the placebo-controlled periods and through trial completion. However, interpretation of these findings is limited by the requirement for all patients in the RA trial to use concomitant MTX. Through the end of the PsA trial, concomitant MTX treatment was associated with elevations in serum hepatic alanine aminotransferase (ALT) from ≥ 3 to < 5 times the upper limit of normal (ULN); the occurrence of ALT elevations ≥ 5× ULN was similar between patients with and without MTX use (Table 4). No clear relationship was seen between MTX use and aspartate aminotransferase elevation (data not shown).

A total of 573 (placebo, n = 224; golimumab, n = 349) patients were receiving concomitant low-dose oral corticosteroids at baseline (Table 5). Concomitant treatment with oral corticosteroids was associated with an increased rate of SAEs during the placebo-controlled period of the RA trial (Table 5). However, the trend did not continue through the extended course of golimumab treatment in the RA trial, and SAEs were not more common in patients receiving corticosteroid treatment in the PsA and AS trials. Among the pooled golimumab-treated patients, the incidence of serious infections per 100 PY (95% CI) through the end of the studies was similar between patients who received concomitant oral corticosteroids (3.4 [2.2, 4.8]) and those who did not (3.4 [2.2, 4.9]).

Immunogenicity

In total, 1205 patients received ≥ 1 administration of IV golimumab and had appropriate samples for evaluating immunogenicity. Through week 52 of all three trials, 269 (22%) patients were positive for antibodies to golimumab (RA trial, 23%; PsA trial, 22%; AS trial, 20%), including 71 (6%) who were positive for neutralizing antibodies. Infusion reactions occurred in 20 (2.1%) patients who tested negative for antibodies to golimumab and in 11 (4.1%) who tested positive for antibodies to golimumab; the proportions of infusions with an infusion reaction were 0.4% and 0.8%, respectively. In the PsA and AS trials, in which not all patients received MTX, the occurrence of antibodies to golimumab was lower in patients who were receiving MTX at baseline compared with patients who were not (Table 4); a similar trend was observed for neutralizing antibodies (data not shown).

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