Alcohol Use DisorderPhase 4NCT02582905
Clinical Medication Development for Bipolar Disorder and Alcohol Use Disorders
A Phase 4 study testing Citicoline and Pregnenolone in people with Alcohol Use Disorder and Bipolar Disorder, run by Sherwood Brown, MD, PhD at 3 sites in United States.
Trial summary
Preclinical and clinical data as well as mechanistic justification have been presented suggesting citicoline and pregnenolone are each promising treatments for alcohol use in BPD. Both appear to have favorable side effect profiles and no known drug-drug interactions. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Alcohol Use Disorder, Bipolar Disorder, Schizoaffective Disorder Bipolar Type
- What is being tested?
- Citicoline and Pregnenolone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 96 participants
- Where
- 3 sitesUnited States
- Study dates
- May 2016to May 2023
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Outpatient men and women age 18-70 years old with bipolar I or II disorder or schizoaffective disorder (bipolar type)
- English or Spanish speaking
- Current diagnosis of alcohol use disorder with at least moderate severity (DSM-5 terminology)
- Alcohol use of at least an average of 28 drinks a week if male or an average of 21 drinks per week if female and an average of 3 drinking days a week in the 28 days prior to intake
- Current mood stabilizer therapy (defined as lithium, lamotrigine, carbamazepine, oxcarbazepine or an atypical antipsychotic) with stable dose for ≥ 28 days prior to randomization or valproate/divalproex at a stable dose for ≥ 90 days (longer period due to data suggesting valproate may decrease alcohol use in BPD)
- Diagnosis of substance use disorder other than alcohol, caffeine or nicotine is allowed if 1) alcohol is the self-identified substance of choice and 2) severity of other substance use disorder is ≤ moderate
Who cannot join
- Mood disorders other than bipolar I or II disorders or schizoaffective disorder bipolar type (e.g. bipolar NOS, cyclothymic disorders, schizophrenia, schizoaffective disorder depressive type, or unipolar depression based on the SCID); other disorders (e.g. anxiety, will be allowed)
- Baseline HRSD17 or YMRS scores ≥ 35 to exclude those with very severe mood symptoms at baseline
- Evidence of clinically significant alcohol withdrawal symptoms defined as a CIWA-Ar score of ≥ 10
- Current (last 28 days) treatment with naltrexone, acamprosate, disulfiram, or topiramate as these may also decrease alcohol use
- Oral contraceptives and hormone replacement therapy. This exclusion is due to a possible interaction with pregnenolone.
- Women with hormone sensitive conditions such as breast cancer, uterine cancer, ovarian cancer, endometriosis, uterine fibroids. These persons are excluded because pregnenolone is converted to estrogens.
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- Vulnerable populations (e.g. pregnant, nursing, cognitively impaired, incarcerated)
- High risk for suicide defined as > 1 attempt in past 12 months that required medical attention, any attempt in the past 3 months or current suicidal ideation with plan and intent such that outpatient care is precluded
- Intensive outpatient treatment (defined as ≥3 visits each week) for substance abuse (AA, NA meetings, or less intensive counseling at baseline will be allowed)
- Severe/unstable condition (e.g. cirrhosis, poorly controlled hypertension) or laboratory/physical exam findings consistent with serious illness (e.g. abnormal electrolytes) or AST or ALT >3 times normal
Trial locations and contacts
3 sites in 1 country.
United States3 sites
UT Southwestern Medical Center
Dallas, Texas, 75390
The University of Texas Rio Grande Valley
Edinburg, Texas, 78539
University of Miami
Miami, Florida, 33136
About this study
Preclinical and clinical data as well as mechanistic justification have been presented suggesting citicoline and pregnenolone are each promising treatments for alcohol use in BPD. Both appear to have favorable side effect profiles and no known drug-drug interactions. Thus, they have the potential to be safely used in a dual diagnosis population already taking other medications. A 12-week, randomized, double-blind, parallel-group, placebo-controlled adaptive design study of citicoline and pregnenolone is proposed in 199 persons with alcohol use disorder and bipolar I or II disorder or schizoaffective disorder (bipolar type). The primary aim will be to assess change in alcohol use. Biomarkers of alcohol use, alcohol craving, mood and cognition will also be assessed. Relationships between neurosteroid and choline levels and the outcome measures will be explored.
Read the detailed description
A 12-week, randomized, double-blind, parallel-group, placebo-controlled adaptive, Drop The Loser (DTL) design clinical trial of citicoline and pregnenolone will be conducted in 199 outpatients with bipolar I or II disorder or schizoaffective disorder (bipolar type) and current alcohol use disorder. Potential participants will be identified and an appointment will be arranged. At this appointment, informed consent will be obtained, and assessment procedures, including a review of inclusion and exclusion criteria, will be performed.
A structured clinical interview for Diagnostic Statistical Manual (DSM-5), Structured Clinical Interview for Disorders (SCID) will be performed to establish the diagnoses of bipolar I or II disorder and alcohol use disorder. Recent alcohol use (and, if present, other substance use) will be assessed using the Timeline Followback (TLFB) method. Drinking severity and withdrawal symptoms will be assessed through a variety of measures (e.g., Clinical Institute Withdrawal Assessment of Alcohol Use-Revised (CIWA-Ar), Penn Alcohol Craving Scale (PACS), Short Index of Problems (SIP)). Length of problem alcohol use will be assessed by asking "When did alcohol first start causing you problems?" Blood will be drawn for laboratory analyses including a complete blood count (CBC) and Comprehensive Metabolic Panel (includes a liver panel with AST, ALT as well as lipids and electrolytes), and GGT and carbohydrate-deficient transferrin (CDT) will be added at baseline (week 0) and weeks 6 and 12. Cognition, including the domains of memory, decision making, impulsivity, attention, and executive functioning will also be assessed at baseline and week 12 using the World Health Organization/University of California at Los Angeles Auditory-Verbal Learning Test (WHO-UCLA AVLT), Trail Making Test (TMT), and the Golden Stroop Color Word Test. Women of childbearing potential will receive a urine pregnancy test at baseline, week 6, and week 12 and will be counseled about effective contraceptive methods. A psychiatrist (PI or Co-I) will assess participants at baseline and weekly follow-up visits and will participate in the informed consent process. The active medication or placebo capsules will be initiated at baseline and increased weekly in weeks 1, 2 and 3 to achieve the target doses for citicoline (2000 mg/day) or pregnenolone (500 mg/day). Side effects will be managed in a blinded fashion. Safety and side effects will be assessed with the Systematic Assessment for Treatment Emergent Events (SAFTEE). At weekly visits, mood and suicidality will be assessed through various measures (e.g. Hamilton Rating Scale for Depression (HRSD17), Columbia Suicide Severity Rating Scale (CSSRS) and assessment of alcohol use will again be evaluated. All participants will receive Medical Monitoring (MM) as a psychosocial platform. After study completion, participants will be provided standard psychiatric care until outside referral is arranged.
- Being tested
- Placebo, Citicoline, Pregnenolone
- Keywords
- Alcohol Use Disorder, Bipolar Disorder, Mood, Alcohol craving, Pregnenolone, Citicoline
- Medical subject headings
- Alcoholism, Bipolar Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
Also called Sugar pill
Inactive ingredient matching the active comparators in appearance.
CiticolineDietary supplement
Also called CDP-Choline, cytidine diphosphate-choline
Citicoline is an over-the-counter nutritional supplement that is used for neuroprotective effects. It is a naturally occurring neurochemical in the human body.
PregnenoloneDrug
Also called pregn-5-en-3β-ol-20-one
Pregnenolone is a naturally occurring neurosteroid that is synthesized from cholesterol in the adrenal glands and also in the brain. Pregnenolone produces other neuroactive steroids.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Matching placebo given beginning at 1 capsule twice daily (BID) increasing to 2 capsules BID at week 1, 3 capsules BID at week 2, and 4 capsules BID at weeks 3-12. Receives: Drug: Placebo |
| Citicoline | Experimental | Citicoline will be given beginning at 250 mg BID with an increase to 500 mg BID at week 1, 750 mg BID at week 2, and 1000 mg BID at weeks 3-12. Receives: Dietary Supplement: Citicoline |
| Pregnenolone | Experimental | Pregnenolone will be given beginning at 50 mg BID with an increase to 100 mg BID at week 1, 150 mg BID at week 2, and 250 mg BID at weeks 3-12. Receives: Drug: Pregnenolone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Baseline-to-Exit Change in Drinks Per Drinking Day (TLFB)
The Timeline Follow Back (TLFB) - Alcohol is a clinician-completed assessment calendar that allows for an estimate of an individual's daily drinking habits over time (i.e., "prior 30 days" at baseline and "since last visit" during the study). Drinks per drinking day is calculated as the average number of standard drinks consumed, per each day indicated as a day during which alcohol was consumed, adjusted for the period of time being assessed (e.g., 30 days at baseline). Baseline-to-Exit Change in Drinks per Drinking Day (TLFB) was calculated as Drinks/Drinking Day (Exit) - Drinks/Drinking Day (Baseline), with negative scores indicating a decrease in the number of drinks per drinking day. The TLFB (Timeline Followback) is a method of assessment of alcohol consumption and is not a scale with minimum and maximum values.
Measured: 12 weeks
Secondary outcomes (1)
Examine the Use of an Adaptive Design in a Clinical Trial for Alcohol Use Disorder.
A two-phase adaptive drop-the-loser (DTL) design was incorporated. A planned interim analysis was to be conducted after 50% of participants (n = 99) had been enrolled (phase 1), in which both treatments were to be compared to placebo. Predetermined decision rules were to be applied for dropping a treatment failing to show clinically meaningful efficacy over placebo: (1) The trial will be stopped if neither active treatment appears to be effective (Cohen's d < 0.25) and (2) The trial will continue to phase 2 (re-randomization) if there is evidence that at least one treatment is more effective than placebo. If both treatments were more effective, the trial was to continue with three arms.
Measured: Study Month 30
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Oct 2015 (estimated)
- Study startMay 2016
- Primary completionMay 2023
- Study completionMay 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Alcohol Use DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 96 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sherwood Brown, MD, PhD
- Sponsor type
- University, hospital or other
- Collaborators
- University of Miami, University of Texas Rio Grande Valley
- Responsible party
- Sponsor-investigator, Sherwood Brown, MD, PhD, University of Texas Southwestern Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02582905
- Sponsor's protocol ID
- 072014-005
- Status last verified
- Oct 2024
- First submitted
- 20 Oct 2015
- Last updated
- 9 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Clinical Medication Development for Bipolar Disorder and Alcohol Use Disorders
- ClinicalTrials.gov ID
- NCT02582905
- Acronym / sponsor ID
- 072014-005
- Keywords
- Alcohol Use Disorder, Bipolar Disorder, Mood, Alcohol craving, Pregnenolone, Citicoline
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 96 participants (actual)
- Lead sponsor
- Sherwood Brown, MD, PhDUniversity, hospital or other
- Collaborators
- University of Miami, University of Texas Rio Grande Valley
- Study start
- May 2016 (actual)
- Primary completion
- May 2023 (actual)
- Study completion
- May 2023 (actual)
- First posted
- 21 Oct 2015 (estimated)
- Results
- Posted 9 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Preclinical and clinical data as well as mechanistic justification have been presented suggesting citicoline and pregnenolone are each promising treatments for alcohol use in BPD. Both appear to have favorable side effect profiles and no known drug-drug interactions. Thus, they have the potential to be safely used in a dual diagnosis population already taking other medications. A 12-week, randomized, double-blind, parallel-group, placebo-controlled adaptive design study of citicoline and pregnenolone is proposed in 199 persons with alcohol use disorder and bipolar I or II disorder or schizoaffective disorder (bipolar type). The primary aim will be to assess change in alcohol use. Biomarkers of alcohol use, alcohol craving, mood and cognition will also be assessed. Relationships between neurosteroid and choline levels and the outcome measures will be explored.
Detailed description
A 12-week, randomized, double-blind, parallel-group, placebo-controlled adaptive, Drop The Loser (DTL) design clinical trial of citicoline and pregnenolone will be conducted in 199 outpatients with bipolar I or II disorder or schizoaffective disorder (bipolar type) and current alcohol use disorder. Potential participants will be identified and an appointment will be arranged. At this appointment, informed consent will be obtained, and assessment procedures, including a review of inclusion and exclusion criteria, will be performed.
A structured clinical interview for Diagnostic Statistical Manual (DSM-5), Structured Clinical Interview for Disorders (SCID) will be performed to establish the diagnoses of bipolar I or II disorder and alcohol use disorder. Recent alcohol use (and, if present, other substance use) will be assessed using the Timeline Followback (TLFB) method. Drinking severity and withdrawal symptoms will be assessed through a variety of measures (e.g., Clinical Institute Withdrawal Assessment of Alcohol Use-Revised (CIWA-Ar), Penn Alcohol Craving Scale (PACS), Short Index of Problems (SIP)). Length of problem alcohol use will be assessed by asking "When did alcohol first start causing you problems?" Blood will be drawn for laboratory analyses including a complete blood count (CBC) and Comprehensive Metabolic Panel (includes a liver panel with AST, ALT as well as lipids and electrolytes), and GGT and carbohydrate-deficient transferrin (CDT) will be added at baseline (week 0) and weeks 6 and 12. Cognition, including the domains of memory, decision making, impulsivity, attention, and executive functioning will also be assessed at baseline and week 12 using the World Health Organization/University of California at Los Angeles Auditory-Verbal Learning Test (WHO-UCLA AVLT), Trail Making Test (TMT), and the Golden Stroop Color Word Test. Women of childbearing potential will receive a urine pregnancy test at baseline, week 6, and week 12 and will be counseled about effective contraceptive methods. A psychiatrist (PI or Co-I) will assess participants at baseline and weekly follow-up visits and will participate in the informed consent process. The active medication or placebo capsules will be initiated at baseline and increased weekly in weeks 1, 2 and 3 to achieve the target doses for citicoline (2000 mg/day) or pregnenolone (500 mg/day). Side effects will be managed in a blinded fashion. Safety and side effects will be assessed with the Systematic Assessment for Treatment Emergent Events (SAFTEE). At weekly visits, mood and suicidality will be assessed through various measures (e.g. Hamilton Rating Scale for Depression (HRSD17), Columbia Suicide Severity Rating Scale (CSSRS) and assessment of alcohol use will again be evaluated. All participants will receive Medical Monitoring (MM) as a psychosocial platform. After study completion, participants will be provided standard psychiatric care until outside referral is arranged.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboMatching placebo given beginning at 1 capsule twice daily (BID) increasing to 2 capsules BID at week 1, 3 capsules BID at week 2, and 4 capsules BID at weeks 3-12. |
| Citicoline | Experimental | Dietary Supplement: CiticolineCiticoline will be given beginning at 250 mg BID with an increase to 500 mg BID at week 1, 750 mg BID at week 2, and 1000 mg BID at weeks 3-12. |
| Pregnenolone | Experimental | Drug: PregnenolonePregnenolone will be given beginning at 50 mg BID with an increase to 100 mg BID at week 1, 150 mg BID at week 2, and 250 mg BID at weeks 3-12. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Outpatient men and women age 18-70 years old with bipolar I or II disorder or schizoaffective disorder (bipolar type)
- English or Spanish speaking
- Current diagnosis of alcohol use disorder with at least moderate severity (DSM-5 terminology)
- Alcohol use of at least an average of 28 drinks a week if male or an average of 21 drinks per week if female and an average of 3 drinking days a week in the 28 days prior to intake
- Current mood stabilizer therapy (defined as lithium, lamotrigine, carbamazepine, oxcarbazepine or an atypical antipsychotic) with stable dose for ≥ 28 days prior to randomization or valproate/divalproex at a stable dose for ≥ 90 days (longer period due to data suggesting valproate may decrease alcohol use in BPD)
Key exclusion criteria (10 listed)
- Mood disorders other than bipolar I or II disorders or schizoaffective disorder bipolar type (e.g. bipolar NOS, cyclothymic disorders, schizophrenia, schizoaffective disorder depressive type, or unipolar depression based on the SCID); other disorders (e.g. anxiety, will be allowed)
- Baseline HRSD17 or YMRS scores ≥ 35 to exclude those with very severe mood symptoms at baseline
- Evidence of clinically significant alcohol withdrawal symptoms defined as a CIWA-Ar score of ≥ 10
- Current (last 28 days) treatment with naltrexone, acamprosate, disulfiram, or topiramate as these may also decrease alcohol use
- Oral contraceptives and hormone replacement therapy. This exclusion is due to a possible interaction with pregnenolone.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlaceboAlso: Sugar pillInactive ingredient matching the active comparators in appearance. | Drug | Placebo |
| CiticolineAlso: CDP-Choline, cytidine diphosphate-cholineCiticoline is an over-the-counter nutritional supplement that is used for neuroprotective effects. It is a naturally occurring neurochemical in the human body. | Dietary supplement | Citicoline |
| PregnenoloneAlso: pregn-5-en-3β-ol-20-onePregnenolone is a naturally occurring neurosteroid that is synthesized from cholesterol in the adrenal glands and also in the brain. Pregnenolone produces other neuroactive steroids. | Drug | Pregnenolone |
Primary outcome
Baseline-to-Exit Change in Drinks Per Drinking Day (TLFB)
Time frame: 12 weeks
The Timeline Follow Back (TLFB) - Alcohol is a clinician-completed assessment calendar that allows for an estimate of an individual's daily drinking habits over time (i.e., "prior 30 days" at baseline and "since last visit" during the study). Drinks per drinking day is calculated as the average number of standard drinks consumed, per each day indicated as a day during which alcohol was consumed, adjusted for the period of time being assessed (e.g., 30 days at baseline). Baseline-to-Exit Change in Drinks per Drinking Day (TLFB) was calculated as Drinks/Drinking Day (Exit) - Drinks/Drinking Day (Baseline), with negative scores indicating a decrease in the number of drinks per drinking day. The TLFB (Timeline Followback) is a method of assessment of alcohol consumption and is not a scale with minimum and maximum values.
1 secondary outcome
Examine the Use of an Adaptive Design in a Clinical Trial for Alcohol Use Disorder.
Time frame: Study Month 30
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Citicoline and Pregnenolone in people with Alcohol Use Disorder and Bipolar Disorder, run by Sherwood Brown, MD, PhD at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Baseline-to-Exit Change in Drinks Per Drinking Day (TLFB) (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Oct 2024.