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| ID | Type | Description | Link |
|---|---|---|---|
| U01DA048517 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Beth Israel Deaconess Medical Center | OTHER |
| University of Pennsylvania | OTHER |
| National Institute on Drug Abuse (NIDA) | NIH |
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A dose-escalation study to determine the optimum dose of Clavulanic Acid (CLAV) for effects on craving and efficacy.
This is a randomized, double-blind, placebo-controlled, parallel group inpatient study of clavulanic acid for 10 days in adults (18-65) seeking treatment for cocaine use disorder. For those subjects who can tolerate 500 mg/day for 3 days (or matched placebo), there will be a forced dose escalation to 750 mg/day for 3 days. Subjects who can tolerate 750 mg/day for three days will have a forced dose escalation to 1000 mg/day for 4 days until the study ends.
Thus, there are 3 Periods for each participant:
Period 1: 500 mg CLAV per day for days 1-3; Period 2: 750 mg per day for days 4-6; Period 3: 1000 mg/day for days 7-10.
Subjective, cognitive, and adverse effect assessments, blood pressure and pulse will be performed daily. Structural MRI, resting state MRI (rs-fMRI), functional MRI (fMRI) and Magnetic Resonance Spectroscopy (MRS) scans will be done at baseline and on Days 3, 6 and 10 of the study. At the time of each scan, safety of the subject to complete the scan will be re-assessed. fMRI was not done at baseline.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Clavulanic Acid | Experimental | Participants will receive 10 days of CLAV-- Period 1: 500 mg/day for days 1-3; Period 2: 750 mg/day for days 4-6; Period 3: 1000 mg/day for days 7-10. |
|
| Placebo | Placebo Comparator | Participants will receive 10 days of placebo and will have a "dose" escalation at the same time as the experimental group. They will be given additional placebo pills to match the number given to the experimental group (i.e. 2 PBO capsules/day for days 1-3, 3 PBO capsules/day days 4-6 and 4 PBO capsules/day for days 7-10). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clavulanic Acid | Drug | Drug will be given in 250mg capsules. |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV) | Brain glutamate concentration in the ACC (based on Magnetic Resonance Spectroscopy (MRS)) will be correlated with cocaine craving (measured by Cocaine Craving Questionnaire (CCQ)) in subjects receiving escalating doses of CLAV for 10 days. Measurement will be made at baseline and Day 10 of CLAV (1000 mg/day) in subjects with cocaine use disorder. | ACC glutamate and CCQ will be measured and correlated on Day 10 of treatment with CLAV compared with baseline. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Resting State Network Connectivity From Baseline | Craving-associated neurocircuitry (frontal-striatal-thalamic connectivity) will be examined with resting state functional Magnetic Resonance Imaging (rs-fMRI) and Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving.. The rs-fMRI activity and CCQ were assessed in the 9 participants at baseline and at the end of each of 3 periods. rs-fMRI activity and CCQ were correlated using the Spearman Correlation Coefficient calculation. A negative correlation coefficient indicates an inverse relationship between the assessments; higher rs-fMRI activity correlates with lower craving. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Temple University Episcopal Hospital | Philadelphia | Pennsylvania | 19125 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26543027 | Background | Kim J, John J, Langford D, Walker E, Ward S, Rawls SM. Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice. Amino Acids. 2016 Mar;48(3):689-696. doi: 10.1007/s00726-015-2117-8. Epub 2015 Nov 5. | |
| 38601830 | Derived | Callans LS, Philogene-Khalid H, Jagannathan K, Cunningham R, Yu D, Lu X, Walters MI, Morrison MF. Clavulanic Acid Decreases Cocaine Cue Reactivity in Addiction-Related Brain Areas, a Randomized fMRI Pilot Study. Psychopharmacol Bull. 2024 Apr 4;54(2):8-14. doi: 10.64719/pb.4485. |
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Recruitment materials included newspapers, facebook, and word of mouth. Participants were recruited from the local community between 9/2020 and 11/2021.
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| ID | Title | Description |
|---|---|---|
| FG000 | Clavulanic Acid | 10 Participants will receive CLAV for 10 days over 3 Periods with no CLAV for Day 11. Period 1 CLAV 500 mg/day for 3 days dose Period 2- CLAV 750 mg/day for 3 days. Period 3 CLAV 1000mg for 4 days Clavulanic Acid Only Product: Drug will be given in 250mg capsules. |
| FG001 | Placebo | 3 participants will receive placebo and serve as a control group. They will be blinded to their condition and will have a "dose" escalation at the same time as the experimental group, and be given additional placebo pills to match the number given to the experimental group. Placebo: Placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CLAV 500mg/Day for Days 1-3 |
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| CLAV 750mg/Day for Days 4-6 |
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| CLAV 1000m/d for Days 7-10 |
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| ID | Title | Description |
|---|---|---|
| BG000 | Clavulanic Acid | 10 participants randomized to the CLAV group Clavulanic Acid will be given in 250mg capsules according to the 3 Periods |
| BG001 | Placebo | 3 participants will receive placebo (PBO) and serve as a control group. They will have a "dose" escalation at the same time as the experimental group, and be given additional placebo pills to match the number given to the experimental group. Placebo: Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV) | Brain glutamate concentration in the ACC (based on Magnetic Resonance Spectroscopy (MRS)) will be correlated with cocaine craving (measured by Cocaine Craving Questionnaire (CCQ)) in subjects receiving escalating doses of CLAV for 10 days. Measurement will be made at baseline and Day 10 of CLAV (1000 mg/day) in subjects with cocaine use disorder. | Glutamate (Glu) level (MR-Spectroscopy) in the ACC (9 scans at baseline and 9 scans at Day 10, adjusted for baseline) are correlated with CCQ results (9 baseline questionnaires and 9 day 10 questionnaires). Spearman Correlation Coefficients were calculated. Higher concentrations of ACC glutamate on day 10 correlated with decreased cocaine craving. | Posted | Number | Spearman Correlation Coefficient | ACC glutamate and CCQ will be measured and correlated on Day 10 of treatment with CLAV compared with baseline. | MRS Scans and CCQ | MRS Scans and CCQ |
|
24 days
9 subjects in the CLAV group and 3 subjects in the PBO group will be assessed throughout the study for Adverse Events (AE).
Subjects in the CLAV group are treated in 3 periods: CLAV 500 mg for 3 days, 750mg for the next 3 days and then 1000mg for the last 4 days to complete the 10 days of the study. AEs were reported by period/dose though the same person may have had several AE or the same AE at different doses.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Clavulanic Acid Treatment Period 1-500mg/Day | 10 Participants will be treated with CLAV (500mg/day for 3 days) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mary Morrison, MD, MS | Temple University | 215=707=4037 | mary.morrison@temple.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 15, 2021 | Jan 20, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 1, 2021 | Jan 20, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D019970 | Cocaine-Related Disorders |
| ID | Term |
|---|---|
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D019818 | Clavulanic Acid |
| C109691 | microcrystalline cellulose |
| ID | Term |
|---|---|
| D002969 | Clavulanic Acids |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D009930 |
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Randomized, double-blind, placebo-controlled, parallel group inpatient study
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| Placebo |
| Other |
Placebo |
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| Assessment was done at the end of Period 1, 2 and 3 detailed above. Data from the end of Period 3 (Day 10, 1000mg CLAV) are reported. |
| Craving | Craving will be evaluated by Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving. The results are the CCQ scores on day 10 minus the baseline scores before starting study drug. | CCQ-45 questionnaires were completed daily during the study. Data from day 10 adjusted for baseline score are reported. |
| Change in Brain Glutamine From Baseline | Change in brain glutamine (Gln) concentration in the ACC at Day 10 compared to baseline as assessed by MRS in the ACC. | Brain glutamine will be analyzed at baseline (Day 1 prior to CLAV or PBO dose) and at Day 10 day (having completed Periods 1, 2 and 3 (CLAV 500mg/day for 3 days, 750 mg/day for 3 days and 1000 mg/day for 4 days). |
| Number of Participants With Treatment-related Adverse Events (AEs) | Adverse events (AES) will be defined as any clinically significant changes in vital signs, clinically significant change in Electrocardiogram (EKG) from baseline measurement, clinically significant changes in laboratory bloodwork (Complete blood count, comprehensive metabolic panel, urinalysis), or any self reported side effects compared with baseline. AEs will be collected throughout the study and reviewed by a physician. An evaluation of AE severity (mild, moderate, severe) will be evaluated by a physician based on participant self-report. AEs per subject will be listed by organ system, and the number of AEs within the subject population will be totaled. | 1-24 days (during and up to 2 weeks after study dosing period) |
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| NOT COMPLETED |
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| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Handedness | Count of Participants | Participants |
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| Education | Count of Participants | Participants |
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| OG000 |
| Clavulanic Acid Day 10 |
9 participants who completed Periods 1, 2 and 3 were assessed for brain Glutamate levels in the ACC using MRS at the end of Period 3 (Day 10.)This measure was correlated with CCQ on day 10 adjusted for the baseline. |
| OG001 | Clavulanic Acid Baseline | Same 9 subjects underwent CCQ and MRS on Day 1 prior to receiving CLAV 500 mg. |
|
|
|
| Secondary | Changes in Resting State Network Connectivity From Baseline | Craving-associated neurocircuitry (frontal-striatal-thalamic connectivity) will be examined with resting state functional Magnetic Resonance Imaging (rs-fMRI) and Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving.. The rs-fMRI activity and CCQ were assessed in the 9 participants at baseline and at the end of each of 3 periods. rs-fMRI activity and CCQ were correlated using the Spearman Correlation Coefficient calculation. A negative correlation coefficient indicates an inverse relationship between the assessments; higher rs-fMRI activity correlates with lower craving. | 9 participants completed Period 1 (3 days of CLAV 500mg) Period 2 (3 days of CLAV 750mg) and then Period 3 (4 days of CLAV 1000mg). The rs-fMRI activity in the executive control network and CCQ were correlated using the Spearman Correlation calculation at the end of this course of study drug (Day 10) and are reported. | Posted | Number | Spearman Correlation Coefficient | Assessment was done at the end of Period 1, 2 and 3 detailed above. Data from the end of Period 3 (Day 10, 1000mg CLAV) are reported. |
|
|
|
|
| Secondary | Craving | Craving will be evaluated by Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving. The results are the CCQ scores on day 10 minus the baseline scores before starting study drug. | Posted | Mean | Standard Deviation | difference in score on a scale | CCQ-45 questionnaires were completed daily during the study. Data from day 10 adjusted for baseline score are reported. |
|
|
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| Secondary | Change in Brain Glutamine From Baseline | Change in brain glutamine (Gln) concentration in the ACC at Day 10 compared to baseline as assessed by MRS in the ACC. | Posted | Mean | Standard Deviation | mmol/kg | Brain glutamine will be analyzed at baseline (Day 1 prior to CLAV or PBO dose) and at Day 10 day (having completed Periods 1, 2 and 3 (CLAV 500mg/day for 3 days, 750 mg/day for 3 days and 1000 mg/day for 4 days). |
|
|
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| Secondary | Number of Participants With Treatment-related Adverse Events (AEs) | Adverse events (AES) will be defined as any clinically significant changes in vital signs, clinically significant change in Electrocardiogram (EKG) from baseline measurement, clinically significant changes in laboratory bloodwork (Complete blood count, comprehensive metabolic panel, urinalysis), or any self reported side effects compared with baseline. AEs will be collected throughout the study and reviewed by a physician. An evaluation of AE severity (mild, moderate, severe) will be evaluated by a physician based on participant self-report. AEs per subject will be listed by organ system, and the number of AEs within the subject population will be totaled. | see adverse events report; Blood Pressure, heart rate, EKG were not statistically different between the two groups. | Posted | Count of Participants | Participants | 1-24 days (during and up to 2 weeks after study dosing period) |
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| 0 |
| 10 |
| 0 |
| 10 |
| 6 |
| 10 |
| EG001 | CLavulanic Acid Treatment Period 2-750mg.Day | 9 Participants who completed Period 1 treated with CLAV (750mg/day for 3 days) | 0 | 9 | 0 | 9 | 5 | 9 |
| EG002 | Clavulanic Acid Treatment Period 3--1000mg/Day | 9 Participants who completed Period 1 treated with CLAV (1000mg/day for 3 days) | 0 | 9 | 0 | 9 | 2 | 9 |
| EG003 | Placebo | 3 participants received matched placebo. They will be given additional placebo capsules to match the number given to the CLAV group. | 0 | 3 | 0 | 3 | 1 | 3 |
| flatulence | Gastrointestinal disorders | Systematic Assessment |
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| loose stool | Gastrointestinal disorders | Systematic Assessment |
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| stomach pain | Gastrointestinal disorders | Systematic Assessment |
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| Heartburn | Gastrointestinal disorders | Systematic Assessment |
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| Elevated Liver Function Tests | Hepatobiliary disorders | Systematic Assessment | Drug induced hepatitis, asymptomatic, resolved in 2 weeks, discontinued from study |
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| High blood pressure | Vascular disorders | Systematic Assessment |
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| Itching | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Swollen feet | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Headache | Nervous system disorders | Systematic Assessment |
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| Lightheaded | Nervous system disorders | Systematic Assessment |
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| Joint pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Priapism | Reproductive system and breast disorders | Systematic Assessment |
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| Organic Chemicals |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |