Abstract
Objectives: To determine long-term safety and efficacy of sarilumab as monotherapy or with non-methotrexate (MTX) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in Japanese patients with active rheumatoid arthritis (RA).
Methods: In this double-blind, randomized study (NCT02373202), patients received subcutaneous sarilumab 150 mg q2w (S150) or 200 mg q2w (S200) as monotherapy or with non-MTX csDMARDs for 52 weeks. The primary endpoint was safety.
Results: Sixty-one patients received monotherapy (S150, n = 30; S200, n = 31) and 30 received combination therapy (S150 + csDMARDs, n = 15; S200 + csDMARDs, n = 15). Rates of treatment-emergent adverse events (TEAEs) were 83.3%/90.3%/93.3%/86.7% for S150/S200/S150 + csDMARDs/S200 + csDMARDs, respectively. Nasopharyngitis and neutropenia were the most frequently reported TEAEs. One serious infection was reported in each monotherapy group and in the S200 + csDMARDs group. There were no cases of grade 4 neutropenia; no patients with grade 3 neutropenia experienced associated serious infection. Improvements in ACR20/50/70 response rates were generally similar between the two monotherapy groups and between the two combination groups; improvements in physical function (Health Assessment Questionnaire-Disability Index, HAQ-DI) and DAS28-CRP were observed at weeks 24 and 52 (all groups).
Conclusion: The safety profile of sarilumab was consistent with known class effects of interleukin-6 signaling blockade therapeutics. Sarilumab as mono- or combination therapy improved clinical signs/symptoms and physical function in Japanese RA patients.
Introduction
Interleukin (IL)-6 is a key cytokine in the pathogenesis of rheumatoid arthritis (RA) linked to joint inflammation and destruction [Citation1,Citation2]. Inhibition of the IL-6 signaling pathway through blockade of the IL-6 receptor (IL-6R) is being explored as a therapeutic option for patients with RA. Sarilumab is a human immunoglobulin (Ig)G1 monoclonal antibody against the IL-6R [Citation3]. The efficacy and safety of sarilumab in patients with active RA has been investigated in phase 3 global trials: in combination with methotrexate (MTX) in patients with inadequate response to MTX (the MOBILITY study) [Citation4]; as monotherapy versus adalimumab in patients with intolerance or inadequate response to MTX (MONARCH) [Citation5]; and in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with an inadequate response or intolerance to anti-tumor necrosis factor (TNF) therapy (TARGET) [Citation6]. Sarilumab as monotherapy or combination therapy improved signs and symptoms and physical function in patients with RA. Safety profiles were consistent with previous studies [Citation7,Citation8] and anticipated class effects. Known effects of IL-6 signaling blockade include a higher incidence of infections, elevations in alanine aminotransferase (ALT) and total serum cholesterol, and lower neutrophil count [Citation7–10].
In MOBILITY, treatment with sarilumab 200 mg or 150 mg once every 2 weeks (q2w) plus MTX (versus placebo plus MTX) was associated with significantly higher proportions of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, significantly greater improvements from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at week 16, and significantly reduced radiographic progression of structural damage (modified Sharp/van der Heijde score (SHS)) at week 52 [Citation4]. Although the study was not powered to detect differences between the two doses of sarilumab, the 200 mg q2w dose provided better inhibition of radiographic progression than 150 mg q2w (mean SHS change from baseline at week 52, 0.25 and 0.90, respectively, versus 2.78 for placebo plus MTX, p<.0001) [Citation4]. Efficacy results in TARGET for sarilumab 150 mg q2w and 200 mg q2w versus placebo (all plus csDMARDs) were similar to those in MOBILITY; radiographic progression was not assessed [Citation6]. In MONARCH, in patients with inadequate response or intolerance to MTX, sarilumab 200 mg q2w was clinically superior to adalimumab, as assessed by change from baseline in Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) and HAQ-DI, with similar safety profiles, including infection rates, despite a higher incidence of neutropenia in the sarilumab group [Citation5].
In addition to the anti-IL-6R biological DMARD tocilizumab, some csDMARDs have been developed and widely used in Japan [Citation11]. It is therefore important to assess the use of sarilumab in such clinical settings. This manuscript reports results from the Phase 3 HARUKA study, performed to evaluate the long-term safety and efficacy of sarilumab as monotherapy or in combination with non-MTX csDMARDs in Japanese patients with active RA. A second study in Japan evaluated the efficacy and safety of sarilumab plus MTX in patients with RA with inadequate response to MTX (KAKEHASI) [Citation12].
Materials and methods
Study design
The HARUKA trial (NCT02373202) was a multicenter, randomized, double-blind, 52-week study. Patients were randomized (2:2:1:1) to receive subcutaneous (SC) injections of sarilumab in either the monotherapy stratum (sarilumab 150 mg or sarilumab 200 mg q2w) or combination stratum (sarilumab 150 mg or sarilumab 200 mg q2w, plus current background non-MTX csDMARDs).
Randomization was performed centrally via an interactive voice or web response system (IVRS/IWRS), with allocation for both strata stratified by body weight (<55 kg, ≥55 kg). The monotherapy stratum was also stratified based upon whether the patient was an inadequate responder to MTX (MTX-IR). Investigators and site staff were blinded to study treatment and had no access to randomization information (treatment codes) during the study except under circumstances permitted by the protocol (e.g. emergency safety issues). The number of swollen and tender joints was evaluated by a blinded independent assessor with no access to patient data (including previous joint assessments). The investigator, sponsor, and patients were also blinded to post-baseline data for high-sensitivity C-reactive protein (hs-CRP), serum sarilumab, and anti-sarilumab antibody levels. After the last patient’s week 24 visit, the first database lock occurred and statistical analyses were performed. Patients and all individuals who had contact with patients were to remain blinded until the end of study. Post-screening visits took place at baseline and weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 36, 44, and 52, followed by a post-treatment follow-up at week 58.
The study was performed in accordance with applicable laws and guidelines, including the Declaration of Helsinki and the International Council for Harmonisation guidelines for Good Clinical Practice. The protocol and amendments were approved by the institutional/central review boards for all 40 sites that enrolled patients (a further four sites gained approvals but did not enroll any patients). Details of the sites involved in the study including Principal Investigator names, site numbers and the name of the institutional/central review board can be found in . Written informed consent was obtained from all participants (or legally acceptable representative) prior to the conduct of any study-related procedures.
Table 1. Demographics and patient characteristics at baseline (randomized population).
Patient population
Included in the study were Japanese patients (aged ≥20 years) with moderate to severe RA, defined as: RA diagnosis according to ACR/European League Against Rheumatism (EULAR) 2010 criteria with ≥3 months disease duration; ACR Class I–III functional status (1991 revised criteria [Citation13]); at least four of 68 tender joints and four of 66 swollen joints at screening; and hs-CRP ≥4 mg/L or erythrocyte sedimentation rate (ESR) ≥28 mm/h. Patients in the monotherapy stratum were: inappropriate for MTX treatment per investigator judgment; or intolerant to MTX, with or without other DMARDs, per investigator judgment; or MTX-IR. Up to 12 patients who were MTX-IR (with or without other DMARDs) were allowed; these patients had to have received treatment for ≥12 weeks before randomization and have been on a stable dose for ≥6 weeks before screening (current treatment to be discontinued before randomization). Patients in the combination stratum had to have received continuous treatment with non-MTX csDMARDs (as monotherapy or combination) for ≥12 weeks before randomization and have been on a stable dose for ≥6 weeks prior to screening.
The main exclusion criteria were: recent treatment (within 4–12 weeks before screening according to drug used) with glucocorticosteroids, cyclosporine, mycophenolate, azathioprine, cyclophosphamide, TNF antagonists or other RA-directed biologics; new treatment or dose adjustment of nonsteroidal anti-inflammatory drugs (NSAIDs; except for low-dose acetylsalicylic acid for cardiovascular disease) or cyclo-oxygenase-2 inhibitors, or treatment with oral prednisone or equivalent >10 mg/day, within 4 weeks of randomization; active or incompletely treated tuberculosis; history of or current infections; other relevant autoimmune, inflammatory, or malignant disease.
Assessments
The primary endpoint was the long-term safety of sarilumab treatment, either as monotherapy or in combination with non-MTX csDMARDs. Safety assessments included adverse events (AEs; including treatment-emergent AEs (TEAEs), serious TEAEs, AEs of special interest and AEs leading to discontinuation or death), laboratory safety variables, vital signs, physical examination, and electrocardiograms. Safety data were collected at the time of informed consent and each study visit.
Secondary efficacy endpoints were ACR20/50/70 response rates over time (assessed at screening, baseline, then at weeks 2, 4, 8, 12, 24, and 52), change from baseline in ACR components, change from baseline in DAS28 using CRP level (DAS28-CRP), DAS28-CRP remission at weeks 12, 24, and 52, change from baseline in physical functioning (according to HAQ-DI), and HAQ-DI response at weeks 12, 24, and 52 (defined as change from baseline ≤ −0.3 or ≤ −0.22 [Citation14]).
Statistical analysis
The sample size was not based on statistical considerations but was determined to allow documentation of safety in a sufficient number of patients. Approximately, 60 patients for the monotherapy stratum and 30 patients for the combination stratum were to be enrolled. Baseline patient demographics and characteristics and primary and secondary endpoints were summarized using descriptive statistics.
The safety population was the randomized population who received at least one dose or partial dose of study medication (analyzed according to treatment received) or for whom it was unclear whether the study medication was taken (analyzed according to randomized group). The efficacy analysis population was the modified intent-to-treat (mITT) population, including all randomized patients who received at least one dose of study medication. For ACR response, patients with insufficient data, completely missing ACR components after imputation or who prematurely discontinued study treatment were considered non-responders.
Results
Patients
Overall, 91 patients were randomized to receive sarilumab 150 mg q2w monotherapy (n = 30), sarilumab 200 mg q2w monotherapy (n = 31), sarilumab 150 mg q2w + csDMARDs (n = 15), or sarilumab 200 mg q2w + csDMARDs (n = 15), in 40 sites in Japan (). Of the 91 treated patients, 79 (86.8%) completed the 52-week treatment period. The first patient was enrolled in February 2015 and the last patient completed the trial in November 2016.
Figure 1. Patient disposition. csDMARDs: conventional synthetic disease-modifying antirheumatic drugs; MTX: methotrexate; q2w: once every 2 weeks.
Baseline demographics and disease characteristics were generally balanced between treatment groups within the monotherapy and combination strata considering the small sample size, except that a higher mean CRP was observed in the 150 mg combination compared with the 200 mg combination group, and the mean age was higher in the 200 mg combination group compared with the 150 mg combination group (). At baseline, 29 patients (47.5%) in the monotherapy stratum were receiving oral corticosteroids and 52 (85.2%) were receiving NSAIDs. All patients in the combination stratum were receiving non-MTX csDMARDs (detailed in ), 13 (43.3%) were receiving oral corticosteroids, and 19 (63.3%) were receiving NSAIDs. Non-MTX csDMARDs received included bucillamine (a d-penicillamine derivative csDMARD [Citation15]), iguratimod (a csDMARD suppressing production of Igs and inflammatory cytokines, and inhibiting activation of nuclear factor-kappa B [Citation16]), and mizoribine (an inhibitor of inosine monophosphate dehydrogenase in the purine synthesis cycle like mycophenolate mofetil [Citation17]).
The median duration of study treatment was 364 days across all treatment groups; however, the mean duration was 337 compared with 262 days in the 150 mg and 200 mg combination groups, respectively. This difference was due to more patients in the 200 mg combination group not completing the 52-week treatment period; in the 200 mg combination group, six patients discontinued by week 52 (five before week 24), and in the 150 mg combination group, two discontinued by week 52 (one before week 24), mostly due to AEs (). The mean duration of treatment was similar in the monotherapy groups (340 and 352 days for the 150 and 200 mg dose groups, respectively).
Efficacy
Improvements in ACR20, ACR50, and ACR70 response rates were similar between the two monotherapy groups and between the two combination groups, with the exception of the combination group comparison at week 52 where there was a lower proportion of responders in the 200 mg group compared with the 150 mg group for all ACR measures; this was mainly due to the small sample size and the proportion of patients who discontinued from the study (; ). Similar to observations at week 24, all ACR components in patients treated with sarilumab in both strata were generally improved relative to baseline at week 52 ().
Figure 2. ACR response rates over time (ACR20/ACR50/ACR70) and disease activity (DAS28-CRP) over time. Apparent differences in ACR response rates between weeks 24 and 52 in the combination 200 mg group were mainly due to the small sample size and the high proportion of patients who discontinued early from the study. ACR20/50/70: American College of Rheumatology 20%/50%/70% responses; BL: baseline; csDMARDs: conventional synthetic disease-modifying antirheumatic drugs; DAS28-CRP: Disease Activity Score in 28 joints using C-reactive protein; MTX: methotrexate; q2w: once every 2 weeks; RA: rheumatoid arthritis; SE: standard error.
Table 2. Efficacy results (mITT population)Table Footnotea.
Improvements of DAS28-CRP from baseline were observed through the 52-week treatment period in both treatment groups within each strata (). By week 12, over 35% of patients in the monotherapy strata had achieved DAS28-CRP remission (), and the proportions of patients who achieved DAS28-CRP remission at week 24 (>45%) were maintained at week 52. More than half of the patients in the combination groups had achieved DAS28-CRP remission by week 12. The incidence of patients with DAS28-CRP remission at week 52 was generally comparable with week 24. For both definitions of a clinically meaningful HAQ-DI response (≥0.3 and ≥0.22 units of improvement from baseline), HAQ-DI response rates were generally comparable at weeks 24 and 52 in both treatment groups within each strata ().
Safety
A summary of AEs and the most common TEAEs is shown in . The most frequently reported TEAEs by system organ class were infections and infestations for both monotherapy groups and for the 200 mg combination group, and musculoskeletal and connective tissue disorders for the 150 mg combination group. The most frequently reported TEAEs by preferred term were nasopharyngitis (both monotherapy groups and the 200 mg combination group) and neutropenia (150 mg combination group).
Table 3. Summary of treatment-emergent AEs and most common treatment-emergent AEs (safety population)Table Footnotea.
Serious AEs were reported by one, two, zero, and three patients in the 150 mg monotherapy, 200 mg monotherapy, 150 mg combination, and 200 mg combination groups, respectively. Serious infections (requiring hospitalization) were the most frequently reported serious AE, reported by one patient in each of the monotherapy groups; one patient in the 150 mg monotherapy group had herpes zoster oticus and one patient in the 200 mg monotherapy group had bacterial pneumonia. One patient in the 200 mg combination group was hospitalized with concurrent chronic sinusitis and periorbital abscess. No opportunistic infections were reported in either of the combination groups. AEs led to permanent discontinuation of treatment in one patient in the monotherapy stratum (150 mg group, herpes zoster oticus) and seven patients in the combination stratum (two patients [13.3%] in the 150 mg group [hepatic function abnormal and ALT increased] and five patients [33.3%] in the 200 mg combination group [chronic sinusitis, breast cancer female, gastric cancer, thrombocytopenia, and both white blood cell count decreased and stomatitis]). No deaths occurred during the study.
Neutropenia was reported for one patient (3.3%) in the 150 mg monotherapy group and three patients (9.7%) in the 200 mg monotherapy group. In the combination stratum, neutropenia was reported for five patients (33.3%) in the 150 mg group and three patients (20.0%) in the 200 mg group. Most cases of decreases in absolute neutrophil counts (ANCs) were ≥1.0 Giga/L to < the lower limit of normal (LLN; grades 1–2 neutropenia) (occurring in 14 [46.7%] and 17 [54.8%] of patients in the 150 and 200 mg monotherapy groups, respectively, and three [20.0%] and nine [60.0%] of patients in the 150 and 200 mg combination groups, respectively) (). ANC <1.0 Giga/L occurred in six patients in the monotherapy stratum (two [6.7%] in the 150 mg group; four [12.9%] in the 200 mg group) and eight patients in the combination stratum (five [33.3%] in the 150 mg group; three [20.0%] in the 200 mg group). There were no cases of ANC <0.5 Giga/L (grade 4 neutropenia) and no patients with grade 3 neutropenia experienced associated serious infections in either stratum.
Table 4. Laboratory assessments (safety population)Table Footnotea.
Thrombocytopenia was reported for one patient in each group in both strata (leading to discontinuation for one patient in the 200 mg combination group); none were associated with bleeding event; mean platelet counts remained within the normal range.
Hepatic AEs affected eight patients in the monotherapy stratum (two patients [6.7%] in the 150 mg monotherapy group [hepatic function abnormal and ALT increased], six patients [19.4%] in the 200 mg monotherapy group [four hepatic function abnormal, one ALT increased, one hepatic steatosis]; none of whom discontinued) and two patients (13.3%) in the 150 mg combination group (ALT increased and hepatic function abnormal), in both cases leading to treatment discontinuation. Most patients across all groups had ALT and aspartate aminotransferase (AST) values ≤3 × the upper limit of normal (ULN) and there were no ALT values >10 ULN or AST values >5 ULN ().
Elevations in lipids were reported in one patient (3.3%) in the 150 mg monotherapy group, three patients (9.7%) in the 200 mg monotherapy group, and one patient (6.7%) in the 200 mg combination group. No serious lipid elevations or elevations in lipids leading to discontinuation were reported. No major adverse cardiovascular events were reported in either stratum.
Hypersensitivity events were reported for approximately one-quarter of patients in the monotherapy stratum (eight patients [26.7%] in the 150 mg group; seven patients [22.6%] in the 200 mg group) and by two patients (13.3%) in each of the combination groups. Hypersensitivity AEs of rash, eczema, eczema nummular, and injection site rash were reported in the combination stratum; the most frequently reported hypersensitivity AEs in the monotherapy stratum were eczema and dermatitis contact (each reported by three patients across both groups). There were no cases of anaphylaxis.
Five patients (16.7%) in the 150 mg monotherapy group and two patients (6.5%) in the 200 mg monotherapy group developed anti-drug antibodies (ADAs) during the TEAE period; median peak titers were 30.0 in both groups. No patients developed neutralizing antibodies. None of the patients in the combination stratum were ADA positive. There was no evidence of a relationship between ADA formation and hypersensitivity or lack of efficacy.
No malignancies were reported for the monotherapy stratum. Two cases of malignancy (13.3%) were reported in the 200 mg combination group (breast cancer female and gastric cancer).
No cases of diverticulitis, gastrointestinal perforation, or gastrointestinal ulceration were reported.
None of the vital signs or electrocardiograms that met criteria for potentially clinically significant abnormalities were associated with clinically relevant manifestations.
Discussion
This study showed that both 150 mg and 200 mg of sarilumab as monotherapy or in combination with non-MTX csDMARDs had similar safety profiles in Japanese patients with active moderate to severe RA. The AE profile was as expected and as previously reported [Citation4–6]. Patients in both the monotherapy and combination strata showed improvements in clinical signs and symptoms, and physical function.
Infections and infestations were the most common TEAEs by system organ class for both the monotherapy and the 200 mg combination groups; musculoskeletal disorder and connective tissue disorder (followed by infections and infestations) were the most frequent TEAEs by system organ class for the 150 mg combination group. Nasopharyngitis and neutropenia were the most frequently reported TEAEs by preferred term at week 52. There were no cases of grade 4 neutropenia (ANC <0.5 Giga/L) and no patients with grade 3 neutropenia experienced associated serious infection in either stratum, confirming previous findings that neutropenia is not associated with risk of infection following sarilumab treatment [Citation4–6]; notably in MONARCH, infection rates were similar between patients treated with sarilumab versus adalimumab despite a higher incidence of neutropenia with sarilumab [Citation5]. The lack of an association between neutropenia and infection in patients treated with IL-6 inhibitors has also been observed with tocilizumab, where transient neutropenia was suggested to be due to margination of neutrophils [Citation9,Citation18]. Laboratory abnormalities in the current study were also consistent with the anticipated effects of IL-6 inhibition, and no clinically significant vital signs or electrocardiograms were reported.
Efficacy data showed that treatment with sarilumab monotherapy or added to non-MTX csDMARDs provided sustained clinical benefit through 52 weeks for the majority of Japanese patients with active RA who were intolerant, inappropriate, or inadequate-responders to MTX (the monotherapy stratum), or who were inadequate responders to non-MTX csDMARDs (the combination stratum), and were generally consistent with the results achieved at week 24. The exceptions were differences in ACR response rates between weeks 24 and 52 in the 200 mg combination group and between the 150 mg and 200 mg combination groups at week 52; these results were mainly due to the small sample size and the proportion of patients who discontinued from the study.
Based on the results of the large MOBILITY study [Citation4], the KAKEHASI bridging study in Japanese patients [Citation12], and the strategy of recent RA treatment guidelines in aiming for early clinical remission [Citation19], a dose of 200 mg sarilumab q2w is recommended. In the MOBILITY study, both 150 mg and 200 mg q2w doses provided sustained clinical efficacy, with radiographic results after 1 year of follow-up suggesting that the 200 mg q2w dose of sarilumab provided substantially better inhibition of radiographic progression than the 150 mg q2w dose [Citation4]. In the current study and other global studies, there were no major problems with tolerance in the 200 mg q2w groups reported [Citation4–6].
The tolerability and efficacy results for Japanese patients in this study are consistent with the results of the KAKEHASI study in Japanese MTX-IR patients [Citation12] and of global sarilumab studies in non-Japanese populations [Citation4–6], supporting the use of sarilumab in Japan. In the KAKEHASI study, sarilumab plus MTX showed sustained clinical efficacy, and a safety profile consistent with the anticipated effects of an IL-6 inhibitor [Citation10], as previously observed in the MOBILITY study [Citation4]. The positive results achieved with sarilumab without the use of MTX in the current study will be of importance to the Japanese population, where the use of csDMARDs, including MTX, has developed in a unique manner. The safety profiles of sarilumab in combination with non-MTX csDMARDs, which included bucillamine, iguratimod, and mizoribine, and of sarilumab monotherapy, were acceptable.
A limitation of this study was the small sample size (especially in the combination therapy groups); this study was conducted to evaluate the safety and efficacy of sarilumab monotherapy and combination therapy for treatment of RA specifically in Japanese patients.
In conclusion, sarilumab 150 mg q2w or 200 mg q2w, both as monotherapy or in combination with non-MTX csDMARDs, has an acceptable safety profile consistent with IL-6-signaling blockade, and improves the signs and symptoms of RA and physical function in Japanese patients with active RA. The safety and efficacy profiles were consistent with those seen in sarilumab studies in non-Japanese populations.
Conflict of interest
Hideto Kameda has received consulting fees, speaking fees, and/or honoraria from AbbVie G.K.; Asahi Kasei Pharma Corporation; Bristol-Myers Squibb; Chugai Pharmaceutical Co., Ltd.; Eli Lilly Japan K.K.; Janssen Pharmaceutical K.K.; Mitsubishi Tanabe Pharma; Novartis Pharma K.K.; and Sanofi K.K.; and has received research grants from AbbVie G.K.; Asahi Kasei Pharma Corporation; Astellas Pharma Inc.; Bristol-Myers Squibb; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; Mitsubishi Tanabe Pharma; Novartis Pharma K.K. and Sanofi K.K.
Kazuteru Wada, Yoshinori Takahashi, Owen Hagino, and Hubert van Hoogstraten are employees of Sanofi and may hold stock and/or stock options in the company.
Neil M. H. Graham is an employee of Regeneron and may hold stock and/or stock options in the company.
Yoshiya Tanaka has received speaking fees from Daiichi Sankyo, Inc.; Astellas Pharma Inc.; Pfizer Inc; Mitsubishi Tanabe Pharma; Bristol-Myers Squibb; Chugai Pharmaceutical Co., Ltd.; YL Biologics Ltd.; Eli Lilly and Company; Sanofi K.K.; Janssen Pharmaceutical K.K.; UCB Japan Co. Ltd.; and has received research grants from Mitsubishi Tanabe Pharma; Takeda Pharmaceutical Company; Bristol-Myers Squibb; Chugai Pharmaceutical Co., Ltd.; Astellas Pharma Inc.; AbbVie G.K.; MSD K.K.; Daiichi Sankyo, Inc.; Pfizer Inc; Kyowa Kirin, Inc.; Eisai Co., Ltd.; and Ono Pharmaceutical Co., Ltd.
Supplemental Material
Download MS Word (34.9 KB)Acknowledgements
The authors would like to thank the study participants and study investigators. The authors thank Ms Mariko Sumi’s contribution as a biological statistician on this study. Medical writing assistance, under the direction of the authors, was provided by Annette Smith, PhD, of CMC AFFINITY, a division of Complete Medical Communications Ltd, Macclesfield, UK, and Claire Lavin, PhD, on behalf of CMC AFFINITY, funded by Sanofi and Asahi Kasei Pharma Corporation.
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References
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