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

NCT01951560 | Completed Phase 1 DMC

• 1 other identifier: VPA-C-002
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

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.

Conditions

Shock,Hemorrhagic

Outcome Measures

Primary Outcomes (1)

• Dose limiting toxicity (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.

  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.

Study Arms (2)

valproic acid (Depacon)

EXPERIMENTAL

Valproic acid by IV infusion over one hour

Drug: Valproic Acid

Isotonic saline solution

PLACEBO COMPARATOR

The placebo administered by IV infusion over 1 hour

Drug: Isotonic saline solution

Interventions

Valproic Acid DRUG

By infusion over 1 hour

Also known as: Depacon

valproic acid (Depacon)

Isotonic saline solution DRUG

By infusion over 1 hour

Isotonic saline solution

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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.
• Negative urine pregnancy test in female volunteers
• Body mass index (BMI) between 18 kg/m2 and 30 kg/m2
• Subjects must be non-smokers
• Negative alcohol screen
• Willing and able to be confined to the clinical research facility as required by the protocol.
• Willing and able to comply with the investigational nature of the study and able to communicate well with investigators.
• Ability to comprehend and willingness to provide written informed consent in accordance with institutional and regulatory guidelines.

You may not qualify if:

• 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).
• Subjects with a-amylase \>130 U/L or lipase \>300 U/L or creatinine \> upper limit of normal (ULN)
• Subjects with \>2times ULN aspartate aminotransferase (AST) or alanine amino transferase (ALT) or \>1.5 times total bilirubin
• 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.
• Subjects with a history of alcohol consumption exceeding 14 drinks/week on average within the 6 months before study entry.
• Subjects whose sitting blood pressure is above 140/90 mmHg on 2 evaluations at least 10 minutes apart at screening.
• Subjects who have donated blood in excess of 500 mL within 60 days prior to the first dose of study medication.
• Subjects with a positive result on drug screen, hepatitis B surface antigen (HBsAg), hepatitis C (HCV), or human immunodeficiency (HIV) tests
• 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.
• Subjects who have been treated with an investigational drug within 30 days.
• Subjects who have previously received or are currently taking valproic acid.
• Subjects who have a history of drug abuse.
• 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).
• Subjects who have had a febrile illness within 5 days prior to the first dose of study medication.
• Subjects with inadequate venous access.

Sponsors & Collaborators

• Dr. Hasan Alam: lead

Study Sites (1)

The University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (1)

• Georgoff PE, Nikolian VC, Bonham T, Pai MP, Tafatia C, Halaweish I, To K, Watcharotone K, Parameswaran A, Luo R, Sun D, Alam HB. Safety and Tolerability of Intravenous Valproic Acid in Healthy Subjects: A Phase I Dose-Escalation Trial. Clin Pharmacokinet. 2018 Feb;57(2):209-219. doi: 10.1007/s40262-017-0553-1.

  PMID: 28497259 DERIVED

MeSH Terms

Conditions

Shock, Hemorrhagic

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Hasan Alam, MD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Hasan Alam, MD, Norman Thompson Professor of Surgery Section Head, General Surgery

Study Record Dates

• First Submitted: September 23, 2013
• First Posted: September 26, 2013
• Study Start: September 1, 2013
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: December 19, 2016

Record last verified: 2016-12

Locations

US (1)