A Study to Determine the Safety, Tolerability and Pharmacokinetics of PMZ-2010 (Centhaquin) in Healthy Volunteers

Study Overview
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Brief Summary
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Shock is a condition of reduced tissue perfusion, resulting in the inadequate delivery of oxygen and nutrients that are necessary for cellular function. The current resuscitative agents can extend patient's life to a limited extent. Centhaquin (PMZ-2010) in very low doses reduced blood lactate levels, improved blood pressure, cardiac output, survival and proved to be a highly effective resuscitative agent. The investigators are conducting a phase I clinical study in humans to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of centhaquin citrate in normal healthy volunteers.

Detailed Description
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Shock is a condition of reduced tissue perfusion, resulting in the inadequate delivery of oxygen and nutrients that are necessary for cellular function. Common causes of shock are hypovolemia (excessive blood or fluid loss), sepsis, cardiac failure, dengue and neuroendocrine dysfunction. The current resuscitative measures include administration of crystalloid solutions (e.g., 0.9% saline, Ringer's lactate, or hypertonic saline) or colloid solutions (e.g., hydroxyethyl starch, albumin, or dextrans). These agents can extend patient's life to a limited extent. Centhaquin (PMZ-2010) in very low doses reduced blood lactate levels, improved blood pressure, cardiac output, survival and proved to be a highly effective resuscitative agent. The investigators are conducting a phase I clinical study in humans to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of centhaquin citrate in normal healthy volunteers. Successful completion of phase I studies will lead to efficacy studies in patients with hypovolemic shock.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase I Study to Determine the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of PMZ-2010 (Centhaquin) in Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: PMZ-2010 (Centhaquin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects to be enrolled in this trial must fulfill all of these criteria: Sex: male Age: 18-60 yr old, both inclusive Having a Body Mass Index (BMI) between 18.5-28 kg / m2 (both inclusive) and body weight not less than 45 kg Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; and to comply with the requirements of the entire study Voluntarily given written informed consent to participate in this study Be of normal health as determined by the principal investigator from medical history, physical examination and laboratory investigations, 12-lead ECG and X-ray chest of the subjects performed within 10 days prior to the admission of the study Ability and willingness to abstain from alcohol, methylxanthine-containing beverages or food (coffee, tea, coke, chocolate, power drinks) and grapefruit (juice) from 48 h prior to each admission until study completion Exclusion Criteria: Subjects meeting any of these criteria will not be enrolled in the study: Employees of JCDC or Pharmazz India Private Limited Not willing to use contraceptives (preferably condoms) during sexual activity for the period of 3 months from the date of check-in History of hypersensitivity and / or intolerance to Centhaquin or any other related compounds. History of anaphylaxis to drugs or allergic reactions in general, which the Investigator considers may affect the outcome of the study. Clinically abnormal ECG and Chest X-ray. Physical findings: clinically relevant abnormal physical findings (including body temperature) suggesting underlying pathologies or those which could interfere with the objectives of the study. Subjects with impaired renal function as measured by glomerular filtration rate <90 mL/min/1.73m2 estimated using the modification of diet in renal disease (MDRD) formula [GFR for Male =186 × (Serum Creatinine)-1.154 × Age-0.203 ]12 Laboratory values that are significantly different than the normal reference range and/or are deemed to be of clinical significance by the investigator Presence of reactive disease markers of HIV 1 and II, HBsAg, HCV or VDRL. Positive for alcohol breath test and/or urine drug screen (barbiturates, benzodiazepines, amphetamine, cocaine, opiates, tetra-hydro cannabinol). Any evidence of organ dysfunction or any clinically significant deviation from the normal, in physical or clinical determinations. Diseases: relevant history of renal, hepatic, cardiovascular, respiratory, skin, haematological, endocrine, neurological or gastrointestinal diseases. History of depression, psychosis, schizophrenia or any other severe psychiatric diseases, or epilepsy, or any other illness that may interfere with the aim of the study. History of any significant illness in the 4 weeks preceding the screening Medications: history of intake of any medications including over the counter medications (OTC) and any herbal agents at least 4 weeks period prior to study drug administration. Investigational drug trials: participation in the evaluation of any drug in the 3 months prior to the start of the study (dosing with IMP). Blood donation: Subjects who, through completion of this study, would have donated and/or lost more than 300 mL of blood in the past 12 weeks Note: In case the blood loss is ≤ 200 mL; subject may be dosed 60 days after blood donation or last sample of the previous study Regular smokers who smoke more than 10 cigarettes daily or have difficulty abstaining from smoking for the duration of each study period. History of drug dependence or alcoholics

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose of 0.005 mg/kg of PMZ-2010<br>A single dose of 0.005 mg/kg of PMZ-2010 (n=3) or placebo (n=1) | Drug: PMZ-2010 (Centhaquin)<br>* As per the randomization schedule, injection of PMZ-2010 or placebo (100 ml normal saline) will be administered to each subject under supervision of investigator as an intravenous infusion over one hour. PMZ-2010 will be dissolved in normal saline (100 ml) before administration.<br>* Other names: Placebo (normal saline);|
| Experimental: Single dose of 0.01 mg/kg of PMZ-2010<br>A single dose of 0.01 mg/kg of PMZ-2010 (n=3) or placebo (n=1) | Drug: PMZ-2010 (Centhaquin)<br>* As per the randomization schedule, injection of PMZ-2010 or placebo (100 ml normal saline) will be administered to each subject under supervision of investigator as an intravenous infusion over one hour. PMZ-2010 will be dissolved in normal saline (100 ml) before administration.<br>* Other names: Placebo (normal saline);|
| Experimental: Single dose of 0.05 mg/kg of PMZ-2010<br>A single dose of 0.05 mg/kg of PMZ-2010 (n=3) or placebo (n=1) | Drug: PMZ-2010 (Centhaquin)<br>* As per the randomization schedule, injection of PMZ-2010 or placebo (100 ml normal saline) will be administered to each subject under supervision of investigator as an intravenous infusion over one hour. PMZ-2010 will be dissolved in normal saline (100 ml) before administration.<br>* Other names: Placebo (normal saline);|
| Experimental: Single dose of 0.10 mg/kg of PMZ-2010<br>A single dose of 0.10 mg/kg of PMZ-2010 (n=3) or placebo (n=1) | Drug: PMZ-2010 (Centhaquin)<br>* As per the randomization schedule, injection of PMZ-2010 or placebo (100 ml normal saline) will be administered to each subject under supervision of investigator as an intravenous infusion over one hour. PMZ-2010 will be dissolved in normal saline (100 ml) before administration.<br>* Other names: Placebo (normal saline);|
| Experimental: 3 doses equivalent to MTD of PMZ-2010<br>Three equally divided doses (total dose/day equivalent to MTD) of PMZ-2010 (n=3) or placebo (n=1) for 2 days | Drug: PMZ-2010 (Centhaquin)<br>* As per the randomization schedule, injection of PMZ-2010 or placebo (100 ml normal saline) will be administered to each subject under supervision of investigator as an intravenous infusion over one hour. PMZ-2010 will be dissolved in normal saline (100 ml) before administration.<br>* Other names: Placebo (normal saline);|
| Experimental: 3 doses equivalent to 2*MTD of PMZ-2010<br>Three equally divided doses (total dose/day equivalent to 2*MTD) of PMZ-2010 (n=3) or placebo (n=1) for 2 days | Drug: PMZ-2010 (Centhaquin)<br>* As per the randomization schedule, injection of PMZ-2010 or placebo (100 ml normal saline) will be administered to each subject under supervision of investigator as an intravenous infusion over one hour. PMZ-2010 will be dissolved in normal saline (100 ml) before administration.<br>* Other names: Placebo (normal saline);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Measure blood pressure, heart rate, body temperature, ECG, laboratory parameters and clinical assessment.after single and multiple ascending doses of PMZ-2010. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of pharmacokinetics of PMZ-2010 in plasma | Maximum concentration (Cmax), Time of maximum plasma concentration (Tmax), Area under the concentration-time curve (AUC) from time of dosing to the last quantifiable concentration (AUClast), Terminal elimination half-life (t½), Clearance (CL/F), Apparent volume of distribution during the terminal elimination phase (Vz/F) of PMZ-2010 in plasma after single ascending doses. | 24 hours | 
| Phamacodynamics profile of PMZ-2010 | Change in systolic and diastolic blood pressure, pulse rate, heart rate, QTcF after single ascending dose and multiple ascending doses | 7 days |