A Phase 1 Study to Evaluate Pregabalin and Acetaminophen in Healthy Volunteers

Study Overview
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Brief Summary
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This is a Phase 1, randomized, double-blind, placebo-controlled, single and multiple ascending dose study to determine a maximum tolerated dose of IV PGB and to evaluate the safety, tolerability, and PK of an admixture of IV PGB and a fixed dose of 1300 mg IV APAP in healthy adult volunteers.

Detailed Description
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This is a Phase 1, randomized, double-blind, placebo-controlled, single and multiple ascending dose study to determine a maximum tolerated dose (MTD) of IV PGB and to evaluate the safety, tolerability, and PK of an admixture of IV PGB and a fixed dose of 1300 mg IV APAP in healthy adult volunteers. Up to 60 subjects will be enrolled into one (1) of six (6) sequential cohorts (n=10 per cohort [8 APAP + PGB and 2 placebo]). The dose for the first cohort will be 1300 mg APAP and 100 mg PGB. For subsequent cohorts, the dose of APAP will remain constant at 1300 mg while the dose of PGB will be varied (will start with 100 mg TID and then based on tolerability will be either increased or decreased by 25 mg) based on Safety Monitoring Committee decision. The placebo will be the saline solution.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Intravenous Pregabalin and Acetaminophen (Ofirmev®) in Healthy Volunteers

Conditions
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Postoperative Pain

Intervention / Treatment
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* Drug: Pregabalin 100mg
* Drug: Acetaminophen 1300mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 18 to 55 years, inclusive at time of Screening Body mass index (BMI) between 18.5 and 28.0 kg/m2 inclusive, with a minimum weight of 50 kg and a maximum of 100 kg Healthy as determined by pre-study medical history, physical examination, vital signs, complete neurological examination, and 12-lead ECG confirming normal sinus rhythm Negative tests for Hepatitis B surface antigen (HbsAg), hepatitis C virus antibody (anti-HCV), human immunodeficiency virus (HIV)-1 and HIV-2 antibody at Screening Routine clinical laboratory tests should be within normal limits at Screening and Admission (Day -1) or abnormalities deemed not clinically significant by the Investigator; for liver function tests, AST and ALT values should not be greater than 1.5 times the upper limit of normal range Negative screen for drugs of abuse or exhibit detectable alcohol levels by breathalyzer at the time of Screening or Admission Non-smokers or ex-smokers (must have ceased smoking ≥3 months prior Screening visit) Female subjects: Must be of non-childbearing potential by surgical sterilization or postmenopausal OR Must not be pregnant, breast feeding, or planning to become pregnant AND must be practicing both a highly effective method of birth control from Screening until at least 90 days after the last dose of study drug. Women of childbearing potential must have a negative pregnancy test result at Screening and upon admission to the Clinical Trial Unit. Exclusion Criteria: Has a clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine, connective tissue diseases or disorders Has a history of severe drug allergy, or severe hypersensitivity or severe food allergy, including anaphylaxis or known allergy or sensitivity to any component of PGB or APAP Has a history of alcoholism or drug abuse Has acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) at the time of Screening or Admission Consumption of drugs with enzyme-inducing properties, within 3 weeks prior to the initial dose of study drug and throughout the treatment phase Has used any prescription medicines, over the counter medicines, or herbal supplements, within 7 days of dosing Has used any investigational product or participated in any clinical trial within 30 days prior to Screening Has donated or received any blood or blood products within the 3 months prior to Screening; Not able to comply with the requirements of this study, including assessments, duration of admission of the study and expected follow up visits Is unwilling or unable to give written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1300 mg Acetaminophen and 100 mg IV Pregabalin<br>The dose for the first cohort will be 1300 mg APAP and 100 mg PGB. For subsequent cohorts, the dose of APAP will remain constant at 1300 mg while the dose of PGB will be varied (will start with 100 mg TID and then based on tolerability will be either increased or decreased by 25 mg based on Safety Monitoring Committee decision). | Drug: Pregabalin 100mg<br>* Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma aminobutyric acid with anticonvulsant, anxiolytic and sleep-modulating properties.<br>* Other names: PGB;Drug: Acetaminophen 1300mg<br>* Acetaminophen is a non-salicylate antipyretic and non-opioid analgesic agent.<br>* Other names: Ofirmev;|
| No Intervention: Placebo<br>Saline solution | |
| Experimental: 1300 mg Acetaminophen and 100 mg +/- 25 IV Pregabalin<br>Decisions to escalate or decrease the dose for Cohorts 2 through 6 will be dependent upon blinded review of emerging safety and tolerability data by the Safety Monitoring Committee (SMC). However, PK data is not part of the SMC review, but may be reviewed by a SMC designee at a later time. | Drug: Pregabalin 100mg<br>* Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma aminobutyric acid with anticonvulsant, anxiolytic and sleep-modulating properties.<br>* Other names: PGB;Drug: Acetaminophen 1300mg<br>* Acetaminophen is a non-salicylate antipyretic and non-opioid analgesic agent.<br>* Other names: Ofirmev;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Related Adverse Events | The incidence and severity of treatment-emergent adverse events | 7 days | 
| Treatment related Drowsiness and Dizziness | The incidence and severity of somnolence and dizziness | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma PK endpoints for APAP and PGB, SAD Phase, Cmax | Maximum observed concentration | 7 days | 
| Plasma PK endpoints for APAP and PGB, SAD Phase, Tmax | Time to maximum observed drug concentration (Tmax) | 7 days | 
| Plasma PK endpoints for APAP and PGB, SAD Phase, t1/2 | Apparent elimination half-life | 7 days | 
| Plasma PK endpoints for APAP and PGB, SAD Phase, AUC0-last | Area under the drug concentration-time curve from time zero to the last measurable concentration | 7 days | 
| Plasma PK endpoints for APAP and PGB, SAD Phase, AUC0-inf | AUC from time zero to infinity | 7 days | 
| Plasma PK endpoints for APAP and PGB, SAD Phase, λz | Apparent terminal elimination rate constant | 7 days | 
| Plasma PK endpoints for APAP and PGB, SAD Phase, CL | Apparent clearance | 7 days | 
| Plasma PK endpoints for APAP and PGB, SAD Phase, Vz | Apparent terminal volume of distribution | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, AUCτ | Area under the plasma concentration-time curve during a dosage interval | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, Tmax,ss | Time to Cmax at SS | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, Cmax,ss | Maximum concentration at SS | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, Cmin,ss | Minimum concentration at ss | 7 dyas | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, Cav,ss | Average plasma concentration at SS | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, Vz, ss | Apparent volume of distribution at SS | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, CLss | Apparent total clearance at SS | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, λz,ss | Apparent first order terminal elimination rate constant at steady state | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, R | Accumulation index | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state, LF | Linearity factor | 7 days | 
| Plasma PK endpoints for APAP and PGB, multiple doses at steady state | Fluctuation ratio | 7 days |