A Blinded, Placebo-Controlled Study of the Safety and Pharmacokinetics of Single Doses of Intravenous Deferiprone in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
Single center, randomized, double-blind, placebo-controlled, adaptive sequential ascending-dose study for the evaluation of the safety, tolerability, and pharmacokinetics of single doses of deferiprone administered by intravenous infusion to healthy males and females. A bioavailability comparison will be included.

Official Title
-----------------
A Single Center, Phase I, Double-blind, Placebo-controlled Evaluation of the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of Deferiprone Administered by Intravenous Infusion to Healthy Male and Female Volunteers

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: Deferiprone
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria: Healthy adult males or females, at least 18 years old but not older than 50 years. Body weight at least 60kg. Body Mass Index (BMI) ≥ 18.50 and ≤ 30.00 kg/m2 Medically healthy with clinically insignificant screening results (e.g., laboratory profiles, medical history, ECG, vital signs, physical examination. Non or ex-smoker (someone who has completely stopped smoking 6 months before study start) For females, negative result on a serum pregnancy test. Main Exclusion Criteria: Absolute neutrophil count (ANC) <1.5x10^9/L. History or presence of hypersensitivity to deferiprone or any related products. History or presence of gastrointestinal, liver or kidney disease, or any other conditions known to interfere with the absorption, distribution, metabolism or excretion of drugs. Presence of significant cardiovascular, pulmonary, hematologic, neurologic, psychiatric, endocrine, immunologic or dermatologic disease. Any history of tuberculosis (TB) or prophylaxis for TB. Suicidal tendency, history of seizures, head trauma with coma or craniotomy/trepanation, state of confusion or relevant psychiatric disease. Inadequate venous access in either arm. Presence of out-of-range cardiac interval or clinically significant ECG abnormalities (PR <110 msec or > 220 msec, QRS <60 msec or >119 msec, QTcB > 450 msec for males and >460 msec for females). Use of acetaminophen, acetylsalicylic acid (ASA), or non-steroidal anti-inflammatory drugs (NSAIDs) in the previous 7 days before study start. Use of any enzyme-modifying drugs, including strong inhibitors of P450 (CYP) enzymes such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, and HIV antivirals OR strong inducers of CYP enzymes such as: barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin, and St. John's wart within 28 days prior to study start. Maintenance therapy with any drug, or significant history of drug dependency or alcohol abuse. Had a clinically significant illness during the 28 days prior to study start. Receipt of an investigational product in another clinical trial within 28 days prior prior to study start. Enrolment in a previous cohort of this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

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

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

Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Single dose of 500mg deferiprone or placebo administered via intravenous infusion. First 2 subjects to enroll: 1 will be randomized to receive deferiprone and the other to receive placebo. Next 14 subjects enrolled: 13 will be randomized to receive deferiprone and 1 to receive placebo. | Drug: Deferiprone<br>* Deferiprone for infusion, 10mg/mL for intravenous infusion. Oral dose of deferiprone: 80mg/mL oral solution. (Cohort 2)<br>* Other names: L1;Drug: Placebo<br>* Placebo: normal saline solution.<br>* Other names: Saline solution.;|
| Experimental: Cohort 2<br>Single dose of 1000mg deferiprone or placebo administered via intravenous infusion and oral solution. Randomization will be done for all 16 subjects at the same time: 14 will be randomized to receive deferiprone and 2 to receive placebo. Subjects enrolled to cohort 2 will receive an oral dose of deferiprone. | Drug: Deferiprone<br>* Deferiprone for infusion, 10mg/mL for intravenous infusion. Oral dose of deferiprone: 80mg/mL oral solution. (Cohort 2)<br>* Other names: L1;Drug: Placebo<br>* Placebo: normal saline solution.<br>* Other names: Saline solution.;|
| Experimental: Cohort 3<br>Single dose of 1500mg deferiprone or placebo administered via intravenous infusion. Randomization will be done for all 16 subjects at the same time, 14 will be randomized to receive deferiprone and 2 to receive placebo. | Drug: Deferiprone<br>* Deferiprone for infusion, 10mg/mL for intravenous infusion. Oral dose of deferiprone: 80mg/mL oral solution. (Cohort 2)<br>* Other names: L1;Drug: Placebo<br>* Placebo: normal saline solution.<br>* Other names: Saline solution.;|
| Experimental: Cohort 4<br>Single dose of 2000mg deferiprone or placebo administered via intravenous infusion. First 2 subjects to enroll: 1 will be randomized to receive deferiprone and the other to receive placebo. Next 14 subjects enrolled: 13 will be randomized to receive deferiprone and 1 to receive placebo. | Drug: Deferiprone<br>* Deferiprone for infusion, 10mg/mL for intravenous infusion. Oral dose of deferiprone: 80mg/mL oral solution. (Cohort 2)<br>* Other names: L1;Drug: Placebo<br>* Placebo: normal saline solution.<br>* Other names: Saline solution.;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Measured Serum Concentration (Cmax) for Serum Deferiprone and Deferiprone 3-O-glucuronide | Cmax was assessed over a 14-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in healthy volunteers who received single intravenous doses of 500 mg, 1000 mg, 1500 mg, and 2000 mg of intravenous deferiprone. Blood samples were obtained pre-dose and at 0.17, 0.33, 0.50, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, and 14 hours post-dose. | 14-hour interval | 
| Time to Maximum Observed Serum Concentration (Tmax) for Serum Deferiprone and Deferiprone 3-O-glucuronide | Tmax was assessed over a 14-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in healthy volunteers who received single intravenous doses of 500 mg, 1000 mg, 1500 mg, and 2000 mg of intravenous deferiprone. Blood samples were obtained pre-dose and at 0.17, 0.33, 0.50, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, and 14 hours post-dose. The results of the Tmax parameter are reported as the median and range (other parameters are reported as mean and standard deviation). | 14-hour interval | 
| Area Under the Curve From Zero to Infinity (AUC0-∞) for Serum Deferiprone and Deferiprone 3-O-glucuronide | AUC0-∞ was assessed over a 14-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in healthy volunteers who received single intravenous doses of 500 mg, 1000 mg, 1500 mg, and 2000 mg of intravenous deferiprone. Blood samples were obtained pre-dose and at 0.17, 0.33, 0.50, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, and 14 hours post-dose. | 14-hour interval | 
| The Terminal Elimination Half-life (T1/2el) for Serum Deferiprone and Deferiprone 3-O-glucuronide | T1/2el was assessed over a 14-hour interval for analyses of deferiprone and its 3-O-glucuronide metabolite in healthy volunteers who received single intravenous doses of 500 mg, 1000 mg, 1500 mg, and 2000 mg of intravenous deferiprone. Blood samples were obtained pre-dose and at 0.17, 0.33, 0.50, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, and 14 hours post-dose. | 14-hour interval | 
| Safety and Tolerability of Single Ascending Doses of Deferiprone When Administered by Intravenous Infusion in Healthy Volunteers. | The number of participants who experienced adverse events (including any changes of clinical significance in physical examinations, vital signs, 12-lead ECG, and clinical laboratory tests) following a single dose of intravenous deferiprone. | From start of intravenous dosing until Day 5 post-dose for all subjects; and from time of oral dose until 24 hours post-dose for subjects who additionally received oral deferiprone | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Cmax for Serum Deferiprone and Deferiprone 3-O-glucuronide Between Deferiprone for Infusion and Oral Deferiprone | Cmax was assessed over a 14-hour interval for deferiprone in healthy volunteers who received a single intravenous dose of 1000 mg and then one week later received a single oral dose of 1000 mg deferiprone oral solution. In both cases, blood samples were obtained pre-dose and at 0.17, 0.33, 0.50, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, and 14 hours post-dose. | 14-hour interval | 
| Absolute Bioavailability of Deferiprone | The pharmacokinetic profile was assessed over a 14-hour interval for deferiprone in healthy volunteers who received a single intravenous dose of 1000 mg and then one week later received a single oral dose of 1000 mg deferiprone oral solution. In both cases, blood samples were obtained pre-dose and at 0.17, 0.33, 0.50, 0.75, 1, 1.33, 1.67, 2, 2.5, 3, 4, 6, 9, 12, and 14 hours post-dose. | 14-hour interval | 
| Safety and Tolerability of a Single 1000 mg Oral Dose of Deferiprone | The number of participants who experienced adverse events (including any changes of clinical significance in physical examinations, vital signs, 12-lead ECG, and clinical laboratory tests) following a single dose of oral deferiprone. Note: All subjects in the 1000 mg cohort received active product, including the 2 who had received placebo for the intravenous infusion. | From dosing until 24 hours post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
DFP, Healthy, Deferiprone, L1