Optimal Regimens of Sulfamethoxazole-Trimethoprim for Chemoprophylaxis of Pneumocystis Pneumonia in Patients with Systemic Rheumatic Diseases: 52-Week Follow-up of a Non-Blinded, Randomized Controlled Trial

Masayoshi Harigai^1,2, Masako Utsunomiya^2,3,4, Hiroaki Dobashi⁵, Toshio Odani^6,7, Kazuyoshi Saito^8,9, Naoto Yokogawa¹⁰, Kenji Nagasaka^11,12, Kenchi Takenaka^3,11, Makoto Soejima^11,13, Takahiko Sugihara¹⁴, Hiroyuki Hagiyama¹⁵, Shinya Hirata¹⁶, Kazuo Matsui^17,18, Yoshinori Nonomura¹⁹, Masahiro Kondo²⁰, Fumihito Suzuki^13,21, Makoto Tomita²², Mari Kihara²³, Waka Yokoyama³, Fumio Hirano²⁴, Hayato Yamazaki³, Ryoko Sakai^2,25, Toshihiro Nanki^2,26, Ryuji Koike^2,3, Hitoshi Kohsaka³ and Nobuyuki Miyasaka³, ¹Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, ²Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan, ³Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan, ⁴Department of Rheumatology, Musashino Red Cross Hospital, Tokyo, Japan, ⁵Internal Medicine Division of Hematology, Rheumatology, and Respiratory Medicine, Kagawa University, Kagawa, Japan, ⁶Third Department of Internal Medicine, Obihiro-Kosei General Hospital, Hokkaido, Japan, ⁷Molecular Physiology and Therapeutics Branch/Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research (NIDCR)/ National Institutes of Health (NIH), Bethesda, MD, ⁸Tobata General Hospital, Fukuoka, Japan, ⁹The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan, ¹⁰Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan, ¹¹Department of Rheumatology, Ome Municipal General Hospital, Tokyo, Japan, ¹²Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences,, Tokyo Medical and Dental University, Tokyo, Japan, ¹³Department of Rheumatology, Soka Municipal Hospital, Saitama, Japan, ¹⁴Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan, ¹⁵Department of Rheumatology, Yokohama City Minato Red Cross Hospital, Kanagawa, Japan, ¹⁶Department of Hematology, Rheumatology, and Infectious Disease, Kumamoto University, Kumamoto, Japan, ¹⁷Department of Rheumatology, Kameda Medical Center, Chiba, Japan, ¹⁸Department of Internal Medicine, Takikawa Municipal Hospital, Hokkaido, Japan, ¹⁹Department of Rheumatology, Tokyo Kyosai Hospital, Tokyo, Japan, ²⁰Department of Rheumatology, Faculty of Medicine, Shimane University, Shimane, Japan, ²¹Department of Rheumatology, JA Toride Medical Center, Ibaraki, Japan, ²²Clinical Research Center, Tokyo Medical and Dental University, Tokyo, Japan, ²³Department of Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan, ²⁴Departments of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan, ²⁵Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan, ²⁶Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: drug safety, prevention, randomized trials and rheumatic disease

Session Information

Date: Sunday, November 5, 2017

Title: Epidemiology and Public Health I: Lung, Bone, and Infection Outcomes

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Sulfamethoxazole-trimethoprim (SMX/TMP) is a standard drug for the prophylaxis of Pneumocystis pneumonia (PCP), but is sometimes discontinued due to adverse events (AEs). We have previously reported the results of this non-blinded, randomized, non-inferiority trial up to week 24 to explore an effective SMX/TMP regimen for PCP with a low drug discontinuation (d/c) rate. We here report the results at week 52.

Methods: Adult patients with systemic rheumatic diseases who started prednisolone >0.6 mg/kg/day were randomized into three groups and treated up to week 24: a single-strength group (SS, SMX/TMP of 400/80 mg daily), half-strength group (HS, 200/40 mg daily), and escalation group (ES, started with 40/8 mg daily, raising incrementally to 200/40 mg daily). After week 24, attending physicians determined the use of SMX/TMP including doses, intervals, and treatment duration. The observation period was up to week 52 irrespective of the use of SMX/TMP. The primary endpoint was non-incidence rates (non-IR) of PCP at week 24. Secondary endpoints were PCP non-incidence rate at week 52, treatment d/c rate, and AEs. We estimated the non-incidence rates of PCP using the exact confidence interval as a post-hoc analysis and analyzed treatment d/c rates using the Kaplan-Meier method and log-rank test.

Results: Of 183 patients randomly allocated at a 1:1:1 ratio into the three groups, 58 patients in SS, 59 in HS, and 55 in ES started SMX/TMP and were analyzed. Of the 172 patients who started SMX/TMP, 32, 46, and 38 at week 24, and 29, 43, and 34 at week 52 were receiving SMX/TMP as allocated. No cases of PCP were reported up to week 52. Estimated non-IR of PCP in patients who received daily SMX/TMP of 200/40 mg, either starting at this dose or increasing incrementally, was 96.8–100%. From week 0 to 52, the overall d/c rate was significantly lower in HS compared to that in SS (22.7% vs 47.2%, p = 0.004) (Figure). The d/c rates due to AEs were significantly lower in HS (19.1%, p = 0.007) and ES (20.3%, p = 0.007) compared to that in SS (41.8%). The IR of AEs requiring dose reduction of SMX/TMP (p = 0.007) and AEs of special interest (p = 0.001) at week 52 were different among the three groups with significantly higher IR in SS compared to HS and ES. Almost all AEs requiring dose reduction of SMX/TMP and AEs of special interest were reported by week 24.

Conclusion: The combined group of HS and ES had an excellent estimated non-IR of PCP at week 52 and both were superior in safety to SS. From the perspective of feasibility and drug d/c rates, the daily half-strength regimen is suggested to be optimal for prophylaxis of PCP in patients with systemic rheumatic diseases.

Disclosure: M. Harigai, Eisai Ltd, Takeda Ltd, Teijin, 2,Eli Lilly and Company, BMS, Chugai, Janssen, 5; M. Utsunomiya, None; H. Dobashi, None; T. Odani, None; K. Saito, None; N. Yokogawa, None; K. Nagasaka, Chugai Pharmaceutical Co., Ltd., 5; K. Takenaka, None; M. Soejima, None; T. Sugihara, Takeda Pharmaceutical Co. Ltd., Mitsubishi-Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Ayumi Pharmaceutical Co., Ltd., UCB Japan Co. Ltd, Astellas Pharma Inc., Janssen Pharmaceutical K.K., Pfizer Japan Inc., and Bristol Myers Squibb K.K, 5; H. Hagiyama, None; S. Hirata, None; K. Matsui, None; Y. Nonomura, None; M. Kondo, None; F. Suzuki, None; M. Tomita, None; M. Kihara, None; W. Yokoyama, None; F. Hirano, Chugai Pharmaceutical Co., Ltd.; Ono Pharmaceuticals; Mitsubishi Tanabe Pharma Co.; UCB Japan; CSL Behring; Towa Pharmaceutical Co., Ltd.; Abbvie Japan Co., Ltd.; Japan Blood Products Organization; Ayumi Pharmaceutical Co.; and Nippon Kayaku Co., Ltd, 3,Astellas Pharma Inc, 5; H. Yamazaki, None; R. Sakai, None; T. Nanki, Eisai, Eli Lilly, Bristol-Myers, Ono, Novartis, 2,UCB, Eisai, Chugai, 5,Mitsubishi-Tanabe, Eisai, Astellas, Janssen, AbbVie, Pfizer, UCB, Ayumi, 8; R. Koike, None; H. Kohsaka, CHUGAI PHARMACEUTICAL CO.,LTD., 2,GSK, 5,CHUGAI PHARMACEUTICAL CO.,LTD., 8; N. Miyasaka, None.

To cite this abstract in AMA style:

Harigai M, Utsunomiya M, Dobashi H, Odani T, Saito K, Yokogawa N, Nagasaka K, Takenaka K, Soejima M, Sugihara T, Hagiyama H, Hirata S, Matsui K, Nonomura Y, Kondo M, Suzuki F, Tomita M, Kihara M, Yokoyama W, Hirano F, Yamazaki H, Sakai R, Nanki T, Koike R, Kohsaka H, Miyasaka N. Optimal Regimens of Sulfamethoxazole-Trimethoprim for Chemoprophylaxis of Pneumocystis Pneumonia in Patients with Systemic Rheumatic Diseases: 52-Week Follow-up of a Non-Blinded, Randomized Controlled Trial [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/optimal-regimens-of-sulfamethoxazole-trimethoprim-for-chemoprophylaxis-of-pneumocystis-pneumonia-in-patients-with-systemic-rheumatic-diseases-52-week-follow-up-of-a-non-blinded-randomized-controlled/. Accessed .

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