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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Open-label, Single-dose, Active-controlled Randomized Phase IIa Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of RPH-104 (RPH-104/L04018) Administered at Different Doses to Patients With Acute Gout Attack

Conditions
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Gout Attack

Intervention / Treatment
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* Drug: RPH - 104
* Drug: Voltaren®


Participation Criteria
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Eligibility Criteria
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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: Absolute neutrophil count (ANC) <1.5 x 10^9/L; White blood cell count <4.0 х 10^9/L 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RPH - 4 mg<br>Subjects randomized to receive RPH-104, 4 mg, subcutaneous single-dose injection. In order to administer RPH-104 at the dose of 4 mg, 0.1 mL of RPH-104 solution is injected. | Drug: RPH - 104<br>* solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial<br>|
| Experimental: RPH - 20 mg<br>Subjects randomized to receive RPH-104, 20 mg, subcutaneous single-dose injection. In order to administer RPH-104 at the dose of 20 mg, 0.5 mL of RPH-104 solution is injected. | Drug: RPH - 104<br>* solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial<br>|
| Experimental: RPH - 40 mg<br>Subjects randomized to receive RPH-104, 40 mg, subcutaneous single-dose injection. In order to administer RPH-104 at the dose of 40 mg, 1 mL of RPH-104 solution is injected. | Drug: RPH - 104<br>* solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial<br>|
| Experimental: RPH - 80 mg<br>Subjects randomized to receive RPH-104, 80 mg, subcutaneous single-dose injection. In order to administer RPH-104 at the dose of 80 mg, 2 mL (whole vial) of RPH-104 solution is injected. | Drug: RPH - 104<br>* solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial<br>|
| Experimental: RPH - 160 mg<br>Subjects randomized to receive RPH-104, 160 mg, two subcutaneous injections of 80 mg administered at different injection sites. (1 vial of 2mL solution per each site) | Drug: RPH - 104<br>* solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial<br>|
| Active Comparator: Voltaren® (diclofenac)<br>Subjects randomized to receive Voltaren® (diclofenac) orally with water at the dose 50 mg thrice daily for 3 days (150 mg total daily dose), then 25 mg thrice daily for 9 days (75 mg total daily dose) | Drug: Voltaren®<br>* Enteric-coated tablets, 25 mg and 50 mg<br>* Other names: Diclofenac;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pain Intensity in the Assessed Joint 72 Hours After the Initiation of Treatment in Comparison to Baseline | Change in pain intensity in the assessed joint 72 hours after the initiation of treatment with the test drug measured using the Visual Analogue Scale (VAS) in comparison to baseline. VAS is a hard copy 100 mm scale with the indications: Absence of pain on the left side of the scale (0 mm point) and The most severe pain ever experienced on the right side of the scale (100 mm point)) The better outcome would be Absence of pain, the worse outcome would be The most severe pain ever experienced. | Baseline and Day 4 (72 hours after the initiation of treatment with the test drug) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pain Intensity in the Assessed Joint in 15, 30, 45 Minutes, 1, 1.5, 2, 4, 8, 24, 48, 72 Hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 Following the Initiation of Treatment and Compared to Baseline | Change in pain intensity in the assessed joint in 15, 30, 45 minutes, 1, 1.5, 2, 4, 8, 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug measured using the Visual Analogue Scale (VAS) and compared to baseline. VAS is a hard copy 100 mm scale with the indications: Absence of pain on the left side of the scale (0 mm point) and The most severe pain ever experienced on the right side of the scale (100 mm point)) The better outcome would be Absence of pain, the worse outcome would be The most severe pain ever experienced. | Baseline and 15, 30, 45 minutes, 1, 1.5, 2, 4, 8, 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 after the initiation of treatment | 
| Proportion of Patients Who Assessed the Response to Therapy With the Test Drug as Excellent or Good | Proportion of patients who assessed the response to therapy with the test drug as Excellent or Good in 15, 30, 45 minutes, 1, 1.5, 2, 4, 8, 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug. The patient's response to therapy was assessed in the form of frequency tables by assessment point and therapy group. The rates of the response were specified in the evaluation form as: Excellent, Good, Fair, Weak, Poor (where excellent represents the best possible response to treatment and poor indicates the worst treatment response). | 15, 30, 45 minutes, 1, 1.5, 2, 4, 8, 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 after the initiation of treatment with the test drug | 
| Change in the Rate of Swelling of the Assessed Joint Evaluated After the Initiation of Treatment With the Test Drug | Change in the rate of swelling of the assessed joint evaluated in 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug compared to baseline. The rates of swelling were specified in the evaluation form as: absence = no swelling, mild = palpable swelling, moderate = visible swelling, severe = bulging outside the joint (where severe represented the worst possible degree of swelling and absence was the best outcome). | Baseline and 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug | 
| Change in the Rate of Tenderness of the Assessed Joint Evaluated After the Initiation of Treatment With the Test Drug | Change in the rate of tenderness of the assessed joint evaluated in 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug compared to baseline. Tenderness degrees: absent = no tenderness, mild = tenderness when touched, moderate = pain and flinching, severe = pain, flinching and withdrawal of the limb (where severe represents the worst possible degree of tenderness and absent is the best outcome). | Baseline and 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug | 
| Change in the Rate of Erythema of the Assessed Joint Evaluated After the Initiation of Treatment With the Test Drug | Change in the rate of erythema of the assessed joint evaluated in 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug compared to baseline.The rates of erythema were specified as absence, presence, impossible to evaluate. | Baseline and 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug | 
| Change in the Rate of Movement Restrictions in the Specified Timeframes After Initiation of Treatment | Change in the rate of movement restrictions in the assessed joint evaluated in 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug compared to baseline. For the assessment, the categorical scale consistent with the Form for evaluation (Investigator's Assessment) of the restriction of movements was used. The rates of movement restrictions (amplitude of movements) were specified in the evaluation form as 1 - Normal range, 2 - Slightly limited range,  3 - Moderately limited range ,4 - Severely limited range and 5 - Joint movement is impossible  (where higher score means worse outcome). | Baseline and in 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 following the initiation of treatment with the test drug | 
| Time to Achieve the 50% Decrease in Pain Intensity in the Assessed Joint Relative to the Baseline | Time to achieve the 50% decrease in pain intensity in the assessed joint relative to the baseline VAS level. VAS is a hard copy 100 mm scale with the indications: Absence of pain on the left side of the scale (0 mm point) and The most severe pain ever experienced on the right side of the scale (100 mm point)). The better outcome would be Absence of pain, the worse outcome would be The most severe pain ever experienced. | Baseline and one of the pain intensity measurements in accordance with the schedule: 15, 30, 45 minutes, 1, 1.5, 2, 4, 8, 24, 48, 72 hours, on Days 5, 6, 10, 15, 18, 22, 29 and 45 after the initiation of treatment | 
| Time to Use of the Rescue Medication | Time to use of the rescue medication was calculated as the time in hours from the date/time of administration (first dose) of the investigational product to the date/time of the first use of the rescue medication. | from the date/time of IP administration (first dose) to the date/time of the first use of the rescue medication, up to day 60 | 
| Proportion of Patients Who Received a Rescue Therapy Agent | The proportion of patients who received the rescue medication within 72 hours of starting the investigational product therapy | 72 hours after the initiation of treatment with the test drug | 
| Proportion of Patients Who Received a Rescue Therapy Agent | The proportion of patients who received the rescue medication over the entire treatment period | up to day 60 | 
| Changes in the Health Assessment Questionnaire (HAQ) Parameters: Disability Index | Changes in the Health Assessment Questionnaire (HAQ) parameters in 15, 29 and 45 days following the initiation of treatment with the test drug as compared to baseline. (The result for each of the 8 categories (Dressing and Grooming, Arising, Eating, Walking, Hygiene, Reach, Grip, Activities) of the HAQ questionnaire was calculated as the maximum score of responses (on an ordinal scale from 0 (best) to 3 (worst): without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3)) to questions included in this category. If the patient required outside help or any of the specified aids or devices to perform actions related to a certain category, then this category was assigned 2 points, if the point was not equal to 3, i.e. points 0 and 1 increased to 2. The sum of points for the evaluated categories was calculated and divided by the number of categories, which gives a disability index in the range of 0 to 3.) | Baseline and 15, 29 and 45 days following the initiation of treatment with the test drug | 
| Changes in the Health Assessment Questionnaire (HAQ) Parameters: Arising | Changes in the Health Assessment Questionnaire (HAQ) parameters in 15, 29 and 45 days following the initiation of treatment with the test drug as compared to baseline. The result was calculated as the maximum score of responses (on an ordinal scale from 0 to 3) to questions included in this category. Patients were asked about their ability to complete these tasks in the past week using the following categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 (best) to 3 (worst). If the patient required outside help or any of the specified aids or devices to perform actions related to a certain category, then this category was assigned 2 points, if the point was not equal to 3, i.e. points 0 and 1 increased to 2. | Baseline and 15, 29 and 45 days following the initiation of treatment with the test drug | 
| Changes in the Health Assessment Questionnaire (HAQ) Parameters: Eating | Changes in the Health Assessment Questionnaire (HAQ) parameters in 15, 29 and 45 days following the initiation of treatment with the test drug as compared to baseline. The result was calculated as the maximum score of responses (on an ordinal scale from 0 to 3) to questions included in this category. Patients were asked about their ability to complete these tasks in the past week using the following categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 (best) to 3 (worst). If the patient required outside help or any of the specified aids or devices to perform actions related to a certain category, then this category was assigned 2 points, if the point was not equal to 3, i.e. points 0 and 1 increased to 2. | Baseline and 15, 29 and 45 days following the initiation of treatment with the test drug | 
| Changes in the Health Assessment Questionnaire (HAQ) Parameters: Walking | Changes in the Health Assessment Questionnaire (HAQ) parameters in 15, 29 and 45 days following the initiation of treatment with the test drug as compared to baseline. The result was calculated as the maximum score of responses (on an ordinal scale from 0 to 3) to questions included in this category. Patients were asked about their ability to complete these tasks in the past week using the following categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 (best) to 3 (worst). If the patient required outside help or any of the specified aids or devices to perform actions related to a certain category, then this category was assigned 2 points, if the point was not equal to 3, i.e. points 0 and 1 increased to 2. | Baseline and 15, 29 and 45 days following the initiation of treatment with the test drug | 
| Changes in the Health Assessment Questionnaire (HAQ) Parameters: Hygiene | Changes in the Health Assessment Questionnaire (HAQ) parameters in 15, 29 and 45 days following the initiation of treatment with the test drug as compared to baseline. The result was calculated as the maximum score of responses (on an ordinal scale from 0 to 3) to questions included in this category. Patients were asked about their ability to complete these tasks in the past week using the following categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 (best) to 3 (worst). If the patient required outside help or any of the specified aids or devices to perform actions related to a certain category, then this category was assigned 2 points, if the point was not equal to 3, i.e. points 0 and 1 increased to 2. | Baseline and 15, 29 and 45 days following the initiation of treatment with the test drug | 
| Changes in the Health Assessment Questionnaire (HAQ) Parameters: Grip | Changes in the Health Assessment Questionnaire (HAQ) parameters in 15, 29 and 45 days following the initiation of treatment with the test drug as compared to baseline. The result was calculated as the maximum score of responses (on an ordinal scale from 0 to 3) to questions included in this category. Patients were asked about their ability to complete these tasks in the past week using the following categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 (best) to 3 (worst). If the patient required outside help or any of the specified aids or devices to perform actions related to a certain category, then this category was assigned 2 points, if the point was not equal to 3, i.e. points 0 and 1 increased to 2. | Baseline and 15, 29 and 45 days following the initiation of treatment with the test drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperuricemia, acute arthritis, gouty arthritis, gout