Zonisamide Outpatient Study

NCT03376139 | Withdrawn Phase 2 DMC FDA Drug

• 2 other identifiers: AS140026-A4W81XWh-15-2-0077
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of this study is to determine if, compared to placebo, zonisamide (400mg/day) is a safe and efficacious treatment for post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) in Veterans with PTSD and co-occurring AUD.

Conditions

Post Traumatic Stress Disorder; Alcohol Use Disorder

Keywords

Alcohol; Alcoholic; Alcoholism; Alcohol abuse; Alcohol Use Disorder; Alcohol use; Alcohol dependence; Alcohol dependent; PTSD; Post-Traumatic Stress Disorder; Veteran

Outcome Measures

Primary Outcomes (3)

• Change from baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total symptom severity score

  CAPS-5 is a 30-item questionnaire, corresponding to the DSM-5 diagnosis for PTSD. All symptoms are assessed on a five-point scale (0=Absent, 1=Mild/subthreshold, 2=Moderate/threshold, 3=Severe/markedly elevated, 4=Extreme/incapacitating). CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 DSM-5 PTSD symptoms, possible scores ranging from 0-80 with higher values indicating a worse symptom severity.

  Baseline to post-treatment (weeks 0, 3, 5, 7)

• Percent change in fear-potentiated startle (FPS) responses from acquisition on day 1 to recall on day 35.

  Baseline to post-treatment (weeks 1, 5, 7)

• Change from baseline in the percent of heavy drinking days (%HDD)

  Timeline Follow-Back (TLFB) of self-report assessment of heavy drinking days over the course of the five-week study treatment.

  Baseline to post-treatment (weeks 0-7)

Secondary Outcomes (15)

• Severity and numbers of AEs

  Baseline to post-treatment (weeks 0-7)

• Treatment retention

  Baseline to post-treatment (weeks 0-5)

• Medication compliance

  Baseline to post-treatment (weeks 0-5)

• Medication adherence

  Baseline to post-treatment (weeks 0-5)

• Blood pressure

  Baseline to post-treatment (weeks 0-7)

Study Arms (2)

Zonisamide (up to 400 mg/day)

EXPERIMENTAL

Zonisamide capsules titrated to a maximum tolerated dose of 400 mg/day for 35 days +/- 4 days, followed by a 14 day down-titration period.

Drug: Zonisamide

Placebo

PLACEBO COMPARATOR

Encapsulated placebo filler (lactose) for 35 +/- 4 days, followed by a 14 day down-titration period. Placebo will go through a similar perceived titration process to maintain blind.

Drug: Placebo Comparator

Interventions

Zonisamide DRUG

Zonisamide capsules titrated to a maximum tolerated dose of 400 mg/day for 35 days +/- 4 days, followed by a 14 day down-titration period.

Zonisamide (up to 400 mg/day)

Placebo Comparator DRUG

Encapsulated placebo filler (lactose) for 35 +/- 4 days, followed by a 14 day down-titration period. Placebo will go through a similar perceived titration process to maintain blind.

Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Be willing and able to sign and date an informed consent form
• Be a military service member or Veteran
• Male or female, 18-55 years of age
• Meet Diagnostic and Statistical Manual (DSM)-5 criteria for AUD
• Meet the DSM-5 diagnostic criteria for PTSD; PTSD diagnosis and severity will be determined based on CAPS-5 score greater than or equal to 33
• Self-report drinking heavily (5 standard units for males, 4 for females) on at least 30% of the 42 days prior to the screening interview
• Score less than 10 on the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) assessed in the context of a breath alcohol concentration (BAC) less than or equal to 0.02% to demonstrate that they do not need medical detoxification (Sullivan et al. 1989)
• Have blood lab tests assessed at screening with ranges falling within the acceptable limits as noted in the protocol.
• Have normal vitals (heart rate 60-100 bpm, systolic blood pressure 90-140 mmHg and diastolic blood pressure 60-90 mmHg) and a baseline ECG that demonstrates clinically normal sinus rhythm, clinically normal conduction, normal QTc, and no clinically significant arrhythmias. Note that clinical judgement will be used when characterizing bradycardia among some healthy subject populations, for example, conditioned veterans. Thus, some individuals with bradycardia (i.e., heart rate less than 60 bpm) may be enrolled as determined by the admitting physician.
• Have a self-reported medical history and brief physical examination demonstrating no clinically significant contraindications for study participation, in the judgment of the admitting physician
• Psychotropic medication free (with exception of SSRIs/SNRIs) for 7 or more days (or longer, depending on medication half-life) prior to enrollment
• Be willing/able to stop use of any sleep medication for the duration of the study
• Be willing to comply with all study procedures and be available for the duration of the study
• Women must either be unable to conceive (i.e., surgically sterilized, sterile, or post-menopausal) or using double-mode form of contraception (i.e. barrier plus, e.g., birth control pills + intrauterine device, condoms + spermicide, etc.). Women can be receiving hormone replacement treatment (HRT) if the HRT dose has been stable for a period of at least 3 months
• Women must provide negative urine pregnancy tests prior to randomization

You may not qualify if:

• DSM-5 criteria for substance use disorders other than alcohol or nicotine or test positive for prescription or illegal drugs. Regarding marijuana/THC, an individual must test negative at the screening. If an individual's test is positive, they will be given a grace period where they will have the opportunity to return and test negative prior to being enrolled.
• Be pregnant or nursing
• Be taking blood pressure medications, psychotropics (with exception of SSRIs/SNRIs), drugs effecting the CNS, medications contraindicated with ethanol, any sulfonamide, or any other medication that could interact with study medications or alter the effects of alcohol.
• a. Note that participants may currently be seeking treatment (or already receiving a behavioral treatment) for AUD, but may not be taking medications used in the treatment of AUD (acamprosate, disulfiram, oral naltrexone, and extended-release injectable naltrexone, and topiramate)
• Have neurological or psychiatric disorders other than PTSD or AUD (except mild/moderate depression succeeding PTSD). Examples include:
• Current psychosis, bipolar illness or major depression requiring treatment.
• Organic brain disease or dementia assessed clinical interview.
• History of any psychiatric disorder which would require ongoing treatment or which would make study compliance difficult.
• History of suicide attempts within the past year and/or current suicidal ideation/plan
• Have evidence of untreated or unstable medical illness including: cardiovascular, neuroendocrine, autoimmune, renal, hepatic, or active HIV+, AIDS infection.
• Have a history of medically adverse reactions to alcohol (e.g., loss of consciousness, chest pain, or epileptic seizure) or major alcohol-related medical complications requiring hospitalization (i.e. hepatitis or pancreatitis)
• Have contraindication(s) to take the study medications such as renal or hepatic impairment, congenital metabolic disorders, or hypersensitivity/allergies to study drug or similar compounds
• Have current epilepsy or evidence suggestive of seizure disorder
• Have past brain injury/head trauma with current symptoms (e.g. not photophobic, dizziness, etc.) or past report of loss of consciousness (LOC) for greater than 30 minutes and/or have been blast-exposed or had LOC of greater than 1 minute and current post-concussive symptoms
• Self-report more than thirty days abstinence from alcohol during the three months prior to enrollment/consent

Sponsors & Collaborators

• Pharmacotherapies for Alcohol and Substance Use Disorders Alliance: lead
• Congressionally Directed Medical Research Programs: collaborator
• Michael E. DeBakey VA Medical Center: collaborator
• Baylor College of Medicine: collaborator

Study Sites (1)

Michael E. DeBakey Veterans Affairs Medical Center

Houston, Texas, 77030, United States

Location

Related Publications (4)

• Acheson DT, Geyer MA, Baker DG, Nievergelt CM, Yurgil K, Risbrough VB; MRS-II Team. Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty Marines. Psychoneuroendocrinology. 2015 Jan;51:495-505. doi: 10.1016/j.psyneuen.2014.09.030. Epub 2014 Oct 7.

  PMID: 25444643 BACKGROUND

• Acheson DT, Feifel D, Kamenski M, Mckinney R, Risbrough VB. Intranasal oxytocin administration prior to exposure therapy for arachnophobia impedes treatment response. Depress Anxiety. 2015 Jun;32(6):400-7. doi: 10.1002/da.22362. Epub 2015 Mar 31.

  PMID: 25826649 BACKGROUND

• Acheson D, Feifel D, de Wilde S, McKinney R, Lohr J, Risbrough V. The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. Psychopharmacology (Berl). 2013 Sep;229(1):199-208. doi: 10.1007/s00213-013-3099-4. Epub 2013 May 5.

  PMID: 23644911 BACKGROUND

• Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict. 1989 Nov;84(11):1353-7. doi: 10.1111/j.1360-0443.1989.tb00737.x.

  PMID: 2597811 BACKGROUND

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic; Alcoholism; Alcohol Drinking

Interventions

Zonisamide

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Drinking Behavior; Behavior

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will be conducted in a double-masked fashion in that both the participants and the site investigators and staff interacting with participants and assessing study outcomes will be masked to treatment assignment. The only individuals at the site with assess to treatment assignment information will be the research pharmacists.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2017
• First Posted: December 18, 2017
• Study Start: March 1, 2019
• Primary Completion: August 31, 2019
• Study Completion: August 31, 2019
• Last Updated: March 9, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share

Locations

US (1)