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A Study to Evaluate the Safety and Tolerability of Valproic Acid in Healthy Volunteers (Part 1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01951560
Recruitment Status : Completed
First Posted : September 26, 2013
Last Update Posted : December 19, 2016
Sponsor:
Information provided by (Responsible Party):
Dr. Hasan Alam, University of Michigan

Brief Summary:

The purpose of the first part of this study is to determine the safety and tolerability of ascending doses of valproic acid (also known as Depacon) administered as intravenous infusion (IV) in doses ranging from 15 mg/kg to 250 mg/kg in healthy subjects.

The second part of the study will also be to determine the safety and tolerability of single ascending doses of valproic acid administered as IV in trauma subjects with hemorrhagic shock.


Condition or disease Intervention/treatment Phase
Shock,Hemorrhagic Drug: Valproic Acid Drug: Isotonic saline solution Phase 1

Detailed Description:

Part 1 of the study will be a single center study intended to assess the safety and tolerability of valproic acid dosages at 15 mg/kg, 30 mg/kg, 60 mg/kg, 90 mg/kg, 120 mg/kg, 150 mg/kg 180 mg/kg, 210 mg/kg and 250 mg/kg. Up to 72 healthy subjects (9 dose groups of 8 subjects) will receive single doses of valproic acid or placebo via a 60-min IV infusion in a ratio of 3:1 active drug: placebo.

Part 2 of the study will be a multicenter, double blind, placebo-controlled study in trauma patients with hemorrhagic shock who are able to give consent or severe trauma patients with hemorrhagic shock in whom a legally authorized representative can give consent. Up to 12 patients (2 dose groups of 6 patients) will receive single doses of valproic acid or placebo via a 60-min IV infusion in a ratio of 2:1 active drug : placebo. The dose levels in Part 2 will be the two highest doses that are demonstrated to have acceptable safety profile based on the review of safety data from Part 1.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 59 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 1, Single Ascending Dose, Double Blind, Placebo Controlled Study to Evaluate the Safety and Tolerability of Valproic Acid in Healthy Volunteers (Part 1) or Trauma Patients(Part 2)
Study Start Date : September 2013
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Shock

Arm Intervention/treatment
Experimental: valproic acid (Depacon)
Valproic acid by IV infusion over one hour
Drug: Valproic Acid
By infusion over 1 hour
Other Name: Depacon

Placebo Comparator: Isotonic saline solution
The placebo administered by IV infusion over 1 hour
Drug: Isotonic saline solution
By infusion over 1 hour




Primary Outcome Measures :
  1. Dose limiting toxicity (DLT) [ Time Frame: Subjects will be monitored for 4 days after the one hour infusion. Dose escalation may occur if less than 2 subjects in any cohort of 8 experience DLT. ]
    Dose limiting toxicity (DLT) will be defined as drug-related grade 2 (moderate) or higher toxicity (excluding fever, chills, nausea or other possible infusion-related effects). The maximum tolerated dose (MTD) will be declared at the dose below which 2 or more subjects experience DLT.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male or female volunteers between the ages of 18 and 65 years, inclusive, in good health based on medical history, physical examination, ECG, and routine laboratory tests (blood chemistry, hematology, urinalysis, and drug screen).
  2. Female subjects must be surgically sterilized or postmenopausal. Criteria for menopause are surgical menopause (hysterectomy, oophorectomy) or age > 45 years with absence of menses for greater than 12 months or a serum follicle stimulating hormone (FSH) elevation > 25m IU/mL.(mIU/mL is the unit used to measure human chorionic gonadotropin (hCG) in pregnancy test). Tubal ligation with menses within the past 12 months is not considered to be surgical sterilization.
  3. Negative urine pregnancy test in female volunteers
  4. Body mass index (BMI) between 18 kg/m2 and 30 kg/m2
  5. Subjects must be non-smokers
  6. Negative alcohol screen
  7. Willing and able to be confined to the clinical research facility as required by the protocol.
  8. Willing and able to comply with the investigational nature of the study and able to communicate well with investigators.
  9. Ability to comprehend and willingness to provide written informed consent in accordance with institutional and regulatory guidelines.

Exclusion Criteria:

  1. Subjects with evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies; however, subjects with untreated, asymptomatic, seasonal allergies may be enrolled).
  2. Subjects with a-amylase >130 U/L or lipase >300 U/L or creatinine > upper limit of normal (ULN)
  3. Subjects with >2times ULN aspartate aminotransferase (AST) or alanine amino transferase (ALT) or >1.5 times total bilirubin
  4. Subjects whose screening ECG demonstrates at least one of the following: heart rate > 100 bpm for more than 30 minutes, (the combination of three of the graphical deflections seen on a typical ECG is called the(QRS)) > 120 msec, corrected QT interval (QTc) > 440 msec if male or 450 msec if female, prevalence rate (PR) > 220 msec or any rhythm other than sinus rhythm, sinus bradycardia (HR <40 bpm), or sinus arrhythmia.
  5. Subjects with a history of alcohol consumption exceeding 14 drinks/week on average within the 6 months before study entry.
  6. Subjects whose sitting blood pressure is above 140/90 mmHg on 2 evaluations at least 10 minutes apart at screening.
  7. Subjects who have donated blood in excess of 500 mL within 60 days prior to the first dose of study medication.
  8. Subjects with a positive result on drug screen, hepatitis B surface antigen (HBsAg), hepatitis C (HCV), or human immunodeficiency (HIV) tests
  9. Subjects who have used prescription or non-prescription drugs, vitamins, herbal supplements or dietary supplements within 14 days prior to the first dose of study medication. Subjects who have used acetaminophen at doses of < 2 grams/day will be eligible for study entry.
  10. Subjects who have been treated with an investigational drug within 30 days.
  11. Subjects who have previously received or are currently taking valproic acid.
  12. Subjects who have a history of drug abuse.
  13. Subjects who are not willing to abstain from consuming products containing caffeine (including chocolate), methyl xanthine, or alcohol from Day -1 through the end of the pharmacokinetics (PK) study (day 4 for part 1 subjects).
  14. Subjects who have had a febrile illness within 5 days prior to the first dose of study medication.
  15. Subjects with inadequate venous access.
  16. Subjects vaccinated within 30 days prior to the first dose of study medication. -

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01951560


Locations
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United States, Michigan
The University of Michigan
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
Dr. Hasan Alam
Investigators
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Principal Investigator: Hasan Alam, MD University of Michigan
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Dr. Hasan Alam, Hasan Alam, MD, Norman Thompson Professor of Surgery Section Head, General Surgery, University of Michigan
ClinicalTrials.gov Identifier: NCT01951560    
Other Study ID Numbers: VPA-C-002
First Posted: September 26, 2013    Key Record Dates
Last Update Posted: December 19, 2016
Last Verified: December 2016
Additional relevant MeSH terms:
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Shock, Hemorrhagic
Hemorrhage
Pathologic Processes
Shock
Valproic Acid
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs