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
Overview
- Phase
- Phase 2
- Intervention
- RPH - 104
- Conditions
- Gout Attack
- Sponsor
- R-Pharm
- Enrollment
- 47
- Locations
- 11
- Primary Endpoint
- Change in Pain Intensity in the Assessed Joint 72 Hours After the Initiation of Treatment in Comparison to Baseline
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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;
- •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;
- •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);
- •Development of acute gout attack within 120 hours (5 days) prior to the randomization date;
- •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;
- •Body mass index ≤40 kg/m2;
- •QTcF interval ≤450 msec for male subjects and ≤470 msec for females on ECG at the screening;
- •For women of child-bearing potential: negative result of the serum pregnancy test performed at the screening;
- •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);
Exclusion Criteria
- •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.
- •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.
- •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;
- •The patient received metamizole or metamizole-containing drugs within 12 hours prior to the randomization;
- •The patient received any drug with analgesic activity (including paracetamol) within 6 hours prior to the randomization;
- •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;
- •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;
- •The patient received colchicine within 7 days prior to the randomization;
Arms & Interventions
RPH - 4 mg
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.
Intervention: RPH - 104
RPH - 20 mg
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.
Intervention: RPH - 104
RPH - 40 mg
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.
Intervention: RPH - 104
RPH - 80 mg
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.
Intervention: RPH - 104
RPH - 160 mg
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)
Intervention: RPH - 104
Voltaren® (diclofenac)
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)
Intervention: Voltaren®
Outcomes
Primary Outcomes
Change in Pain Intensity in the Assessed Joint 72 Hours After the Initiation of Treatment in Comparison to Baseline
Time Frame: Baseline and Day 4 (72 hours after the initiation of treatment with the test drug)
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".
Secondary Outcomes
- 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(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)
- Change in the Rate of Tenderness of the Assessed Joint Evaluated After the Initiation of Treatment With the Test Drug(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)
- Proportion of Patients Who Assessed the Response to Therapy With the Test Drug as "Excellent" or "Good"(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(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(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(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(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(up to day 60)
- Changes in the Health Assessment Questionnaire (HAQ) Parameters: Disability Index(Baseline and 15, 29 and 45 days 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(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)
- Changes in the Health Assessment Questionnaire (HAQ) Parameters: Arising(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(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(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(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(Baseline and 15, 29 and 45 days following the initiation of treatment with the test drug)