A Randomized Study Investigating Oral Desmetramadol Dose Proportionality and Food Effect In Normal Human Subjects

A Phase 1 Randomized Single Oral Dose Cross-Over Study Investigating Desmetramadol Dose Proportionality And Food Effect In Normal Human Subjects

The purpose of the study is to investigate in healthy human subjects how much desmetramadol (Omnitram) gets in the blood after different oral doses are taken with or without food.

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Drug: Desmetramadol

Detailed Description

An open-label, randomized, balanced, single-dose, four-treatment, four-period, four-sequence (using a Williams' square design) cross-over study with each dose separated by >3 days. There are 4 sequences (Sequence 1, Sequence 2, Sequence 3, and Sequence 4), and 4 Periods (Period I, Period II, Period III, and Period IV). Sequence 1 order is 30 mg dose with food (Period I); 30 mg dose fasted (Period II), 10 mg dose fasted (Period III), and 20 mg dose fasted (Period IV). Sequence 2 order is 10 mg dose fasted (Period I); 30 mg dose with food (Period II), 20 mg dose fasted (Period III), and 30 mg dose fasted (Period IV). Sequence 3 order is 20 mg dose fasted (Period I); 10 mg dose fasted (Period II), 30 mg dose fasted (Period III), and 30 mg dose with food (Period IV). Sequence 4 order is 30 mg dose fasted (Period I); 20 mg dose fasted (Period II), 30 mg dose with food (Period III), and 10 mg dose fasted (Period IV).

To account for potential dropouts, up to 32 eligible subjects will be randomized to obtain a target sample of 24 subjects with PK responses at each of the four treatment periods (based on our completed phase 1 study in 43 subjects, dropouts are unlikely (~5%); see Section 1.2.2). Before each oral dose, subjects will be fasted overnight for at least 10 hours. Treatment sequences will include the following four unblinded single-dose oral treatments: 1) desmetramadol 1 x 10 mg tablet; 2) desmetramadol 2 x 10 mg tablets; 3) desmetramadol 3 x 10 mg tablets; and 4) desmetramadol 3 x 10 mg tablets following a high-fat, high-calorie breakfast served approximately 30 minutes before dosing and entirely consumed within 20 minutes. All subjects will fast for an additional four hours after desmetramadol administration. The fed treatment should be administered the desmetramadol dose approximately 30 minutes after the start of the meal. Desmetramadol will be administered with approximately 240 ml of water. No water is allowed one hour before and one hour after each desmetramadol administration.

This will be an inpatient study. Subjects will be admitted to the clinical pharmacology unit on Study Day -1, and administered a single oral dose treatment on Study Day 1, Study Day 4, Study Day 7 and Study Day 10. After completing study procedures on Day 11 the subject will be discharged from the facility.

Blood specimens for plasma preparation and PK analysis will be collected at the following times: pre-dose (0 h), and post-dose 0.5, 1.0, 1.5, 2.0, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, and 32 h.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Nebraska
    • Lincoln, Nebraska, United States, 68502
      • Celerion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Healthy males and females with vital signs as follows at screening: systolic blood pressure > 90 mm Hg and < 140 mm Hg; diastolic blood pressure > 40 mm Hg and < 90 mm Hg; pulse 40 to 99 beats per minute; respiratory rate 12 to 24 breathes per minute.
2. Age 19 to 55 years.
3. Able and willing to give informed consent
4. Able to comply with all study procedures.

5. If female, must not be of childbearing potential or must agree to use one or more of the following forms of contraception from screening, throughout the study and for 30 days following study drug administration: hormonal (e.g., oral, transdermal, intravaginal, implant or injection for 3 months); double barrier (e.g., condom or diaphragm with spermicide); intrauterine device (IUD) or system (IUS) (for 3 months); vasectomized partner (6 months minimum); or abstinence.

   Screening laboratory results must be within normal range per clinical research unit: serum sodium, potassium, calcium, BUN, creatinine, ALT, AST, total bilirubin, alkaline phosphatase, glucose (random), albumin, total protein, WBC and differential, hemoglobin, and platelets. In addition PT and PTT must be < 1.2 ULN.

6. Electrocardiogram (ECG) without clinically significant abnormalities.

   Urinalysis demonstrating < +1 glucose, and +1 protein.

7. If female, must have a negative pregnancy test at screening
8. Negative urine test for substances of abuse, including opiates, per clinical pharmacology unit standards at screening and clinic check-in.
9. Negative serology tests for HIV, hepatitis B surface antigen, and hepatitis C virus antibody.
10. Weight > 50 Kg and a body mass index (BMI) of 18.0 to 32.0 kg/m (inclusive).
11. Non-smoker of tobacco for a minimum of the past 3 months, and negative urine continine test.

Exclusion Criteria:

1. Oral temperature > 38°C or current illness.
2. History of seizures, epilepsy, or recognized increase risk of seizure (e.g., head trauma, metabolic disorders, alcohol or drug withdrawal).
3. History of cirrhosis or laboratory evidence of liver disease.
4. Having undergone gall bladder removal.
5. Use of alcohol within 24 hours of day -1 until the end of the study; and grapefruit, grapefruit-related citrus fruits (e.g., Seville oranges, pomelos), or grapefruit juice or grapefruit-related juices within 7 days of study drug administration and until the end of the study.
6. History of previous anaphylaxis, severe allergic reaction to tramadol, codeine, or other opioid drugs.
7. Any other unstable acute or chronic disease that could interfere with the evaluation of the safety of the study drug as determined by the principal Investigator in dialogue with the Sponsor Medical Monitor.
8. Females must not be currently pregnant or breast feeding.
9. Unlikely to comply with the study protocol.
10. Known or suspected alcohol or drug abuse within the past 6 months.
11. Received another investigational agent within 4 weeks of Day -1, or within five half-lives of Day -1, whichever is longer; or receiving any other investigational agent during this study.
12. Any concurrent disease or condition that in the opinion of the investigator impairs the subject's ability to complete the trial. Psychological, familial, sociological, geographical or medical conditions which, in the Investigator's opinion, could compromise compliance with the objectives and procedures of this protocol, or obscure interpretation of the trial data.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Desmetramadol 10 mg, fasted; While fasting a single oral dose of 10 mg desmetramadol under.	Drug: Desmetramadol; Analgesic; Other Names: Omnitram
Experimental: Desmetramadol 20 mg, fasted; While fasting a single oral dose of 20 mg desmetramadol.	Drug: Desmetramadol; Analgesic; Other Names: Omnitram
Experimental: Desmetramadol 30 mg , fasted; While fasting a single oral dose of 30 mg desmetramadol.	Drug: Desmetramadol; Analgesic; Other Names: Omnitram
Experimental: Desmetramadol 30 mg , fed; After feeding a single oral dose of 30 mg desmetramadol.	Drug: Desmetramadol; Analgesic; Other Names: Omnitram

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(-/+)-M1, AUC(0-32) and AUC(Inf)	The AUC(0-32) and AUC(inf) of (-/+)-M1 after each treatment (i.e., 10, 20 and 30 mg desmetramadol fasted, and 30 mg desmetramadol fed)	Pre-dose (0 h), and post-dose 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 ,3.5, 4, 6, 8, 12, 16, 24, and 32 h.
(-/+)-M1, Cmax	The Cmax of (-/+)-M1 after each treatment (i.e., 10, 20 and 30 mg desmetramadol fasted, and 30 mg desmetramadol fed)	Pre-dose (0 h), and post-dose 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 ,3.5, 4, 6, 8, 12, 16, 24, and 32 h.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment.	Adverse events will include: 1) reports by participants; 2) observations by investigators; and 3) abnormal laboratory safety test results.	Participant report adverse events throughout study enrolment; investigators observe adverse events during all 11 days of inpatient treatment; laboratory safety labs are obtained on Day 11 (the final study day).

Collaborators and Investigators

• Sponsor: Syntrix Biosystems, Inc.
• Collaborators: National Institute on Drug Abuse (NIDA); Celerion
• Investigators: Principal Investigator: Robert Schwab, MD, Celerion

Publications and helpful links

General Publications

• Zebala JA, Searle SL, Webster LR, Johnson MS, Schuler AD, Maeda DY, Kahn SJ. Desmetramadol Has the Safety and Analgesic Profile of Tramadol Without Its Metabolic Liabilities: Consecutive Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Trials. J Pain. 2019 Oct;20(10):1218-1235. doi: 10.1016/j.jpain.2019.04.005. Epub 2019 Apr 18.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2021
• Primary Completion (Actual): January 18, 2021
• Study Completion (Actual): January 18, 2021

Study Registration Dates

• First Submitted: December 21, 2020
• First Submitted That Met QC Criteria: December 23, 2020
• First Posted (Actual): December 24, 2020

Study Record Updates

• Last Update Posted (Actual): April 4, 2023
• Last Update Submitted That Met QC Criteria: March 11, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Food effect
• Other Study ID Numbers: Omni-Pain-103; R44DA046316 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No