Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Evaluation of RPH-104 Administered at Different Doses to Patients With Acute Gout Attack

The primary goal of the study was to evaluate the parameters of efficacy, pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of RPH-104 in adult patients with acute gout attack.

The study consisted of two periods:

Period 1. In Study Period 1, eligible patients were enrolled in a group of 22 patients and randomized to receive either RPH-104 4 mg or Voltaren® (diclofenac) in the 15:7 ratio (15 RPH-104: 7 Voltaren® (diclofenac)). In order to prevent damage to the gastric and duodenal mucosa caused by Voltaren® (diclofenac), all patients receiving Voltaren® (diclofenac) had to simultaneously take Ortanol® (omeprazole) 20 mg, orally (1 capsule) daily before breakfast throughout the course of Voltaren® (diclofenac) treatment

Period 2. Upon completion of the enrollment of 22 patients, Study Period 2 started. In Period 2, newly enrolled patients were randomly assigned to one of 5 treatment groups: RPH-104 20 mg, 40 mg, 80 mg and 160 mg and active control (Voltaren® (diclofenac)). It was planned to include 14 patients in the RPH-104 groups in Period 2, and 7 patients in the Voltaren® (diclofenac) group.

The enrollment of patients in Period 1 and Period 2 was sequential. There was no pause between the enrollment of patients in Period 1 and Period 2. The study design included screening (24 hours), 11 visits to the study site, and a phone call at the end of the 60-day follow-up period.

Total number of patients which were planned to be enrolled for the study: 85 (15 patients in the group of treatment with RPH-104 4 mg and 14 patients in the each of the other treatment groups). Due to the low patient recruitment rate in the study and the negative impact of the COVID-19 pandemic on the recruitment, at the decision of the sponsor, an interim analysis of the data of 47 patients included in the study as of November 2020 was carried out in order to assess the feasibility of continuing recruitment and further conducting the study.

Patients who did not tolerate pain were allowed to receive a rescue medication, triamcinolone acetonide 40 mg intramuscularly, to intensify therapy 2 hours after the test product was administered. If the attack recurred after the use of the rescue medication, treatment was carried out in accordance with the standard practice of the hospital.

The primary efficacy endpoints were evaluated 72 hours after the end of administration of the test drug. The secondary efficacy endpoints were evaluated for 45 days of the treatment period and follow-up. The safety parameters were evaluated for 60 days of the treatment period and follow-up. Total duration of the study for a volunteer was not more than 70 days.

Eligibility Criteria:
Inclusion Criteria:

* 1. The subject has given his / her informed consent to participate in this study; the Informed Consent Form has been signed both by the patient and the Investigator;
* 2. Established diagnosis of gout according to Gout Classification Criteria established by the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) in 2015;
* 3. Pain in at least one joint at the screening and immediately prior to initiation of therapy with the study drugs, with intensity 50 mm to 100 mm according to the Visual Analogue Scale (VAS);
* 4. Development of acute gout attack within 120 hours (5 days) prior to the randomization date;
* 5. History of 1 or more acute gout attacks prior to the Screening Visit;
* 6.The patients receiving uric acid-lowering drugs should continue receiving these drugs at a constant dose for at least 4 weeks prior to enrolment to the study and throughout the entire study period; the patients not receiving uric acid-lowering drugs may start receiving this treatment after the end of the study;
* 7. Body mass index ≤40 kg/m2;
* 8. QTcF interval ≤450 msec for male subjects and ≤470 msec for females on ECG at the screening;
* 9. For women of child-bearing potential: negative result of the serum pregnancy test performed at the screening;
* 10. The consent of a woman of child-bearing potential, as well as of a man who has female partners of child-bearing potential, to abstain from sexual intercourses or to use effective birth control methods throughout the entire study period and for 60 days after RPH-104 administration (if the patient received RPH-104);
* 11. The patient is able to fulfil the requirements of the Study Protocol as judged by the Investigator

Exclusion Criteria:

* 1. The patient received therapy with ibuprofen in a dose of up to 400 mg inclusive within 4 hours or \>400 mg within 8 hours prior to randomization.
* 2. The patient received therapy with diclofenac in a dose of up to 50 mg inclusive within 8 hours or \>50 mg within 24 hours prior to randomization.
* 3. The patient received any other non-steroidal anti-inflammatory drug (NSAID) within 24 hours prior to the randomization;
* 4.The patient received opioids within 48 hours prior to the randomization;
* 5. The patient received metamizole or metamizole-containing drugs within 12 hours prior to the randomization;
* 6. The patient received any drug with analgesic activity (including paracetamol) within 6 hours prior to the randomization;
* 7. The patient received a long-acting NSAID (half-life ≥24 hours) within 5 half-life periods or 1 month prior to the randomization whichever is longer;
* 8. The patient received extended-release naproxen, meloxicam, nabumetone, celecoxib, etoricoxib or indomethacin within 5 days prior to the randomization;
* 9 . The patient received corticosteroids (including their intra-articular administration and inhalations) within 4 weeks prior to the randomization;
* 10. The patient received colchicine within 7 days prior to the randomization;
* 11. Intolerance or contraindications for NSAID use;
* 12. Contraindications for the use of Ortanol® capsules 20 mg;
* 13. Chronic heart failure functional class II-IV (classification of NYHA);
* 14. A history of or current clinically significant ventricular arrhythmias or clinically significant atrial tachyarrhythmias;
* 15. Unstable angina or stable exercise-induced angina of functional class III or IV;
* 16. Secondary gout, chemotherapy-induced gout, lead- or transplantation-induced gout;
* 17. Rheumatoid arthritis, confirmed or suspected infectious septic arthritis or any other type of acute inflammatory arthritis;
* 18. Clinically significant renal impairment determined based on creatinine clearance (estimated using the Cockcroft-Gault equation) \<60 mL/min, or patients on hemodialysis;
* 19. Blood coagulation disorders; history of gastrointestinal bleedings or perforation;
* 20. Pregnant or breast-feeding women;
* 21. Elective surgery or major surgical intervention (minor surgical procedures, such as catheter placement or bone marrow biopsy, are not exclusion criteria) within 14 days before the first dose of the investigational medicinal product;
* 22. Current or suspected HIV-infection, HBsAg, Hepatitis C Virus antibodies (HCVAb), other acute or chronic bacterial, fungal or viral infections at the moment of subject's enrolment to the study;
* 23. Presence of any risk factors for tuberculosis based on the results of assessment using Tuberculosis Risk Assessment Questionnaire at the screening or confirmed tuberculosis or any other infectious disease of the lungs or bronchi based on findings of the chest X-ray exam in two views performed within 3 months prior to the screening visit, or the need for using therapy with tuberculosis medications, such as isoniazid in the course of the study;
* 24. Neutropenia, leukopenia, or thrombocytopenia determined based on the following laboratory parameters assessed during the screening:

  1. Absolute neutrophil count (ANC) \<1.5 x 10\^9/L;
  2. White blood cell count \<4.0 х 10\^9/L
  3. Platelet count \<150 х 10\^9/L;
* 25. Immunization with live vaccines within 3 months prior to the subject's enrolment to the study or planned vaccination within 60 days after the expected date of the first dose of the test drug;
* 26. History of allergic reactions to biologicals, Voltaren® (diclofenac) or Ortanol® (omeprazole);
* 27. Contraindications for subcutaneous, intramuscular, intravenous or intra-articular injections;
* 28. History of malignancy (except for patients with localized in situ basal cell carcinoma of the skin or in situ cervical cancer, who can be enrolled to the study immediately after the therapy for this disease), unless it is in remission for ≥5 years, as well as patients who are being examined for cancer or patients with suspected malignancy;
* 29. A condition or disease, which, in the Investigator's opinion, could put the patient's safety at risk or affect the test drug safety assessment;
* 30. Any other conditions and diseases, such as uncontrolled diabetes mellitus, uncontrolled hypertension, congestive heart failure, exacerbation of peptic ulcer disease, clinically significant liver diseases, kidney diseases, uncontrolled thyroid dysfunction, unhealed wounds, ulcers or bone fractures, psychiatric disorders, uncontrolled epilepsy, drug dependence, which could prevent the patient from complying with this Study Protocol.
* 31. The patient received biologicals or investigational medicinal products within 5 half-life periods of these drugs or 3 month prior to the randomization whichever is longer;
* 32. Blood donation or blood loss of ≥400 mL within 8 weeks prior to the randomization.
* 33. The patient was already randomized in this clinical study.