| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pain relief following surgery |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy and duration of analgesia following local administration of HTX-011 with saline placebo during the first 72 hours following unilateral open inguinal herniorrhaphy. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the efficacy and duration of analgesia for HTX-011 with bupivacaine HCl without epinephrine during the first 72 hours following surgery in this study population.
- To compare the effect of HTX-011 with saline placebo and bupivacaine HCl without epinephrine on opioid load during the first 72 hours following surgery in this study population.
- To assess the safety and tolerability of HTX-011 in this study population.
- To further establish the pharmacokinetic (PK) parameters of bupivacaine and meloxicam in HTX-011 in this study population. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is able to provide written informed consent, adhere to the study visit schedule, and complete all study assessments.
2. Is male or female, and ≥18 years of age at screening.
3. Is scheduled to undergo a unilateral open inguinal herniorrhaphy with mesh under general anesthesia.
4. Has an American Society of Anesthesiologists Physical Status of I, II, or III.
5. Female subjects are eligible only if all of the following apply:
a. Not pregnant (female subjects of child-bearing potential must have a negative urine pregnancy test at screening and on Day 1 before surgery).
b. Not lactating.
c. Not planning to become pregnant during the study.
d. Is surgically sterile; or is at least 2 years post-menopausal; or is in a monogamous relationship with a partner who is surgically sterile; or is practicing abstinence or agrees to use double-barrier contraception in the event of sexual activity; or is using an insertable, injectable, transdermal, or combination oral contraceptive approved by applicable regulatory authorities for greater than 2 months prior to screening and commits to the use of an acceptable form of birth control for the duration of the study and for 30 days after study drug administration. Note: women in only a same-sex relationship do not need to meet this criterion. |
|
| E.4 | Principal exclusion criteria |
1. Had any prior inguinal hernia repair except as a child (less than 6 years of age).
2. Has a planned concurrent surgical procedure (eg. bilateral herniorrhaphy).
3. Has pre-existing concurrent acute or chronic painful physical/restrictive condition expected to require analgesic treatment in the postoperative period for pain that is not strictly related to herniorrhaphy and which may confound postoperative assessments.
4. Has contraindication or known or suspected history of hypersensitivity or clinically significant idiosyncratic reaction to bupivacaine (or other local anesthetics), meloxicam (or other NSAIDs),oxycodone, morphine, acetaminophen/paracetamol, or fentanyl.
5. Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 6 months.
6. Has taken any NSAIDs (including meloxicam) within least 10 days prior to the scheduled surgery with the exception of subjects on low dose (≤100 mg) daily acetylsalicylic acid for cardioprotection.
7. Has taken long-acting opioids within 3 days prior to scheduled surgery.
8. Has taken any opioids within 24 hours prior to scheduled surgery.
9. Has been administered bupivacaine within 5 days prior to scheduled surgery.
10. Has been administered any local anesthetic within 72 hours prior to scheduled surgery, other than for pretreatment prior to a needle placement, to treat an AE that occurs after signing the ICF, or to decrease venous irritation (eg. caused by propofol, in which case no more than a single administration of lidocaine 1% 20 mg IV may be administered).
11. Has initiated treatment with any of the following medications within 1 month prior to study drug administration or is taking any of these medications to control pain: selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin, or cyclooxygenase-2 (COX-2) inhibitors. (Note: If a subject is taking one of these medications for a reason other than pain control, the subject must be on a stable scheduled dose [ie, not “as needed”] for at least 1 month prior to study drug administration.) Anxiolytics prior to surgery are permitted, if necessary.
12. Has been administered systemic steroids within 5 half-lives or 10 days prior to administration of study drug (whichever is longer). Note that for purposes of this exclusion criterion, inhaled steroids are not considered systemic.
13. Has a medical condition such that, in the opinion of the Investigator, participating in the study would pose a health risk to the subject or confound the postoperative assessments. Conditions may include, but are not limited to, any of the following:
a. History of clinically significant cardiac abnormality such as myocardial infarction within 6 months prior to signing the ICF, New York Heart Association class III or IV, or clinically significant abnormalities of electrocardiogram (ECG) or cardiac function.
b. History of coronary artery bypass graft surgery within 12 months prior to signing the ICF.
c. History of severe liver function impairment as defined by Child-Pugh Class C, having an aspartate aminotransferase >3 × the upper limit of normal (ULN), or having an alanine aminotransferase >3 × ULN.
d. History of severe kidney function impairment as defined by creatinine clearance (Cockcroft-Gault) <30 mL/min, being on dialysis, and/or having a serum creatinine >2 × ULN.
e. History of known or suspected coagulopathy or uncontrolled anticoagulation.
f. Loss of sensation in extremities or significant peripheral neuropathy.
14. As per subject history and/or medical records, has active infection or is currently undergoing treatment for Hepatitis B, Hepatitis C, or HIV.
15. Has uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the Investigator, might interfere with study assessments.
16. Had malignancy in the last year, with exception of nonmetastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.
17. Has known or suspected history of drug abuse, a positive drug screen on the day of surgery, or recent history of alcohol abuse. Note: Subjects with positive drug screen who are taking a prescribed medication that is known to result in positive drug test (eg, amphetamine and dextroamphetamine for attention-deficit/hyperactivity disorder, benzodiazepine for anxiety disorder) may be eligible for participation in the study. Subjects taking medical marijuana are not allowed to participate.
18. Previously participated in an HTX-011 study.
19. Received an investigational product or device in a clinical trial within 30 days or within 5 elimination half-lives (whichever is longer) prior to surgery, or is planning to take part in another clinical trial while participating in this study.
20. Has undergone 3 or more surgeries within 12 months prior to signing the ICF, other than for diagnostic procedures (eg, colonoscopy).
21. Has a BMI >39 kg/m2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean area under the curve (AUC) of the Numeric Rating Scale of pain intensity scores with activity (NRS-A) through 72 hours (AUC0-72) for HTX-011 compared with saline placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy
- Mean AUC0-72 of the NRS-A pain intensity scores for HTX-011 compared with bupivacaine HCl.
- Mean total postoperative opioid consumption (in morphine equivalents) through 72 hours for HTX-011 compared with saline placebo.
- Proportion of subjects who are opioid-free through 72 hours for HTX-011 compared with bupivacaine HCl.
- Mean total postoperative opioid consumption (in morphine equivalents) through 72 hours for HTX 011 compared with bupivacaine HCl.
Safety
- Incidence of TEAEs, SAEs, and ORAEs through Day 28.
- Change from baseline in clinical laboratory results.
- Change from baseline in ECG data.
- Change from baseline in vital signs.
- Wound healing assessment at 72 hours and on Day 10 and Day 28.
Pharmacokinetic
- Calculated maximum plasma concentration (Cmax).
- Calculated time to reach maximum plasma concentration (Tmax). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the date of the last subject’s last assessment (scheduled or unscheduled). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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