Effect of Metamizole (Dipyrone) on Renal Function in Salt-depleted Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
The planned study is a single-center, randomized, open-label parallel group study in 16 healthy male subjects. Study subjects will be randomly allocated either to the metamizole group (1) or to the naproxen group (2). All participants will start with a low sodium diet (approximately 50 mmol Na+ per day) 7 days before the first drug intake and maintain the diet until the end of the study (14 days in total). Salt-depletion is an accepted model to enhance production of vasodilatory prostaglandins and to increase renal sensitivity to prostaglandin inhibition. On the first day of treatment (Day 1), a single dose of metamizole or naproxen will be administered to investigate the effects after a single dose and to collect single dose pharmacokinetic profiles. Starting on Day 2, all participants will receive therapeutic doses, i.e. 1000 mg metamizole 'ter in die' (TID, three times a day) or 500 mg naproxen 'bis in die' (BID, twice a day) for one week and on Day 7 pharmacokinetics and pharmacodynamics effects will be assessed under near steady-state conditions. The primary objective is the characterization of the renal effects of metamizole by determination of the glomerular filtration rate (GFR) using the inulin clearance. Secondary objectives are the characterization of the urinary excretion of prostaglandin E2 (PGE2) and the prostaglandin I2 (PGI2) metabolite 6-keto-prostaglandin F1 (PGF1)alpha as well as the urinary excretion of sodium and potassium. Overall, clinical experience suggests better renal tolerability of metamizole possibly due to less potent COX-inhibition compared to classical nonsteroidal antiinflammatory drugs (NSAIDs). If this could be confirmed, metamizole would be a valuable alternative for treatment of painful conditions in patients with impaired renal function. Therefore, the aim of this study is to examine the effects of metamizole on renal function in comparison with the non-specific COX-inhibitor naproxen.

Official Title
-----------------
Effect of Metamizole on Renal Function in Salt-depleted Healthy Subjects Single-center, Randomized, Open, Controlled Parallel-group Study to Investigate the Effects of Oral Metamizole or Naproxen on Renal Function in Healthy Male Salt-depleted Subjects

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: metamizole
* Drug: Naproxen


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male subjects aged between 18 and 45 years (inclusive) at screening BMI between 18 and 28 kg/m2 (inclusive) and body weight at least 50 kg at screening. systolic blood pressure (SBP): 100-140 mmHg, diastolic blood pressure (DBP): 60-90 mmHg and heart rate (HR): 45-90 bpm (inclusive), measured on the leading arm*, in the supine position at screening. No clinically significant findings on the physical examination at screening. 12-lead ECG without clinically relevant abnormalities at screening. Signed informed consent prior to any study-mandated procedure. Hematology and clinical chemistry results not deviating from the normal range to a clinically relevant extent at screening. Ability to communicate well with the investigator and to understand and comply with the requirements of the study. leading arm right = writing with right hand Exclusion Criteria: Smoking > 5 cigarettes per day. History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening. Loss of ≥ 250 ml of blood within 3 months prior to screening. Treatment with an investigational drug within 30 days prior to screening. Previous treatment with any prescribed or over-the-counter (OTC) medication (including herbal medicines such as St John's Wort) within 2 weeks prior to the intended start of the study. Legal incapacity or limited legal capacity at screening. Positive results from urine drug screen at screening. History or clinical evidence of any disease (e.g. GIT-disease: Morbus Crohn, Colitis Ulcerosa, anamnestic gastrointestinal bleeding) and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs, or which might increase the risk for toxicity. Known hypersensitivity to Aspirin or other NSAIDs or any excipients of the drug formulations. Known food allergy, which make the adherence to the diet impossible Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metamizole<br>Metamizole 1000mg TID Day 1 till Day 7 | Drug: metamizole<br>* metamizol tablets (500mg): 1000mg TID during 7 days<br>* Other names: dipyrone;|
| Active Comparator: Naproxen<br>Naproxen 500 mg BID Day 1 till Day 7 | Drug: Naproxen<br>* Naproxen tablets (500mg): 500 mg BID during 7 days<br>* Other names: Naproxen sodium;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glomerular filtration rate (GFR) |  | up to 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of the urinary excretion of the prostaglandin E2 (PGE2) and of the prostacyclin (PGI2) metabolite 6-keto-PGF1alpha |  | Day 1 and Day 7 | 
| Measurement of urine levels of sodium, potassium and creatinine and the urinary output |  | Day 1 and Day 7 | 
| Plasma pharmacokinetic (PK) parameters of each drug will be derived either directly from observed data or by analysis of the concentration-time profiles | The maximum plasma concentration (Cmax) and time to reach Cmax (tmax) The terminal elimination rate constant with the respective half-life (t½) The area under the plasma concentration-time curve from zero to different time points (AUC0-24, AUC0-∞) | Day 1 and Day 7 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Effect, metamizole, salt-depleted, subjects