International multicenter randomized, placebo-controlled phase III clinical trial of β-d-mannuronic acid in rheumatoid arthritis patients

  • Zahra Rezaieyazdi
  • Abid Farooqi
  • Hossein Soleymani-Salehabadi
  • Arman Ahmadzadeh
  • Mona Aslani
  • Saiedeh Omidian
  • Arezoo Sadoughi
  • Zohreh Vahidi
  • Mandana Khodashahi
  • Shazia Zamurrad
  • Seyed Shahabeddin Mortazavi-Jahromi
  • Hossein Fallahzadeh
  • Mostafa Hosseini
  • Zahra Aghazadeh
  • Parvin Ekhtiari
  • Hidenori Matsuo
  • Bernd H. A. Rehm
  • Salvatore Cuzzocrea
  • Antimo D’Aniello
  • Abbas MirshafieyEmail author
Original Article



The oral administration of drug β-d-mannuronic acid (M2000) showed a potent therapeutic effect in phase I/II study in rheumatoid arthritis (RA) patients. Here, our aim is to assess the efficacy and safety of this new drug in RA patients under a multinational, randomized placebo-controlled phase III clinical trial.


Patients (n = 288) with active disease at baseline and inadequate response to conventional drugs were randomly allocated to three groups; (1) receiving mannuronic acid at a dose of two capsules (500 mg) per day orally for 12 weeks, (2) placebo-controlled, and (3) conventional. The primary endpoints were the America College of Rheumatology 20 response (ACR20), 28-joint disease activity score (DAS28) and Modified Health Assessment Questionnaire-Disability Index (M-HAQ-DI). In addition, the participants were followed-up for safety assessment.


In this phase III trial, after 12 weeks of treatment, there was a significant reduction in ACR20 between mannuronic-treated patients compared to placebo and conventional groups. Moreover, there was a similar significant improvement for DAS28 following mannuronic therapy. The statistical analysis showed a significant reduction in the swollen and tender joint count in mannuronic-treated patients compared with the placebo group. On the other side, mannuronic acid showed no-to-very low adverse events in comparison to placebo.


The results of this multinational, phase III clinical trial provided a potent evidence base for the use of β-d-mannuronic acid as a new highly safe and efficient drug in the treatment of RA.


Mannuronic acid M2000 Rheumatoid arthritis DMARDs NSAIDs Clinical III trial 



We should appreciate from the medical personnel and provided facilities by the Ghaem Hospital in Mashhad, Loghman Hakim Hospital, Imam Khomeini Hospital, Imam Hossein Hospital in Tehran, Shahid Sadoughi Hospital in Yazd and Department of Rheumatology at Pakistan Institute of Medical Sciences in Islamabad, Pakistan.

Compliance with ethical standards

Conflicts of interest

The authors declare no conflict of interest.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Rheumatic Diseases Research CenterMashhad University of Medical SciencesMashhadIran
  2. 2.Department of RheumatologyPakistan Institute of Medical SciencesIslamabadPakistan
  3. 3.Department of RheumatologyShahid Sadoughi University of Medical SciencesYazdIran
  4. 4.Department of RheumatologyLoghman Hakim Hospital, Shahid Beheshti University of Medical SciencesTehranIran
  5. 5.Department of Immunology, School of Public HealthTehran University of Medical SciencesTehranIran
  6. 6.Inflammation and Inflammatory Diseases Research Center, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  7. 7.Research Center of Prevention and Epidemiology of Non-Communicable Disease, Departments of Biostatistics and Epidemiology, Faculty of HealthShahid Sadoughi University of Medical SciencesYazdIran
  8. 8.Department of Epidemiology and Biostatistics, School of Public HealthTehran University of Medical SciencesTehranIran
  9. 9.Nagasaki National HospitalNagasakiJapan
  10. 10.Centre for Cell Factories and Biopolymers, Griffith Institute for Drug DiscoveryGriffith UniversityNathanAustralia
  11. 11.Department of Chemical, Biological, Pharmaceutical and Environmental SciencesUniversity of MessinaMessinaItaly
  12. 12.Laboratory of NeurobiologyZoological Station of Naples “Anton Dohrn”NaplesItaly

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