A Multicenter, Randomized, Placebo-Controlled Phase 2 Study to Evaluate the Clinical Efficacy, Safety, and Tolerability of ARX-F01 Sublingual Sufentanil in Patients Undergoing Elective Unilateral Total Knee Replacement

Study Overview
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Brief Summary
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The purpose of this study is to evaluate three different dosage strengths of sublingual ARX-F01 (Sufentanil NanoTab) versus a sublingual Placebo NanoTab for the treatment of post-operative pain in subjects following total knee replacement surgery. We hypothesize that subjects receiving placebo will have poor pain relief and will drop out of the study sooner and more often than the ARX-F01-treated subjects.

Official Title
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A Multicenter, Randomized, Placebo-Controlled Phase 2 Study to Evaluate the Clinical Efficacy, Safety, and Tolerability of ARX-F01 Sublingual Sufentanil in Patients Undergoing Elective Unilateral Total Knee Replacement

Conditions
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Post Operative Pain

Intervention / Treatment
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* Drug: Sufentanil NanoTab
* Drug: Placebo NanoTab
* Drug: Sufentanil NanoTab
* Drug: Sufentanil NanoTab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients between 45 to 80 years of age. Patient is scheduled for an elective, unilateral, unicondylar, bi- or tri-compartmental, cemented or uncemented knee replacement under general or spinal anesthesia that does not include use of an intrathecal opioid. Patient must be classified as American Society of Anesthesiologists (ASA) class I - III. Patient must have Body Mass Index [BMI = weight (kg)/height (m2)] between 18 and 39, inclusively. Female patients of childbearing potential must be using an effective method of birth control from the screening visit through the end of study. Acceptable methods of birth control include oral or transdermal contraceptives, condom, spermicidal foam, intrauterine device (IUD), progestin implant or injection, abstinence, vaginal ring, or sterilization of partner. The reason for non-childbearing potential, such as bilateral tubal ligation, bilateral oophorectomy, hysterectomy, or postmenopausal for ≥1 year, must be specified in the patient's case report form (CRF). The patient must be willing and able to understand the study procedures and the use of pain scales, and to communicate meaningfully with the study personnel. The patient must provide written informed consent and sign the Informed Consent approved by the Institutional Review Board (IRB). Exclusion Criteria: Patient has previously undergone a knee replacement of the same knee. A passive range-of-motion (PRM) will be used before the 12-hour study period is complete Patient has previously not responded to opioid analgesics for treatment of pain. Patient is currently taking or has taken an opioid for more than 30 consecutive days of daily use at a daily dose equivalent to greater than 15 mg morphine within the past 3 months prior to surgery (e.g. more than 3 doses per day of Vicodin®, Norco®, Lortab® with 5 mg hydrocodone per tablet). Patient has an allergy or hypersensitivity to opioids. Patient currently has sleep apnea that has been documented by a sleep laboratory study. Patient has any screening laboratory test value outside the laboratory normal range which is considered clinically significant by the Investigator. Patient has a contraindication to the use of general anesthesia. Patient is a woman who is pregnant or lactating. Patient has psychiatric disease or encephalopathy severe enough to prevent patient from providing reliable study documentation. Patient, in the Investigator's judgment, does not have adequate ability to read and understand English. Patient has a medical condition that, in the Investigator's opinion, could adversely impact the patient's participation or safety, conduct of the study, or interfere with the pain assessments, including fracture or active infection. Patient has clinically significant renal or liver impairment which could affect metabolism or clearance of sufentanil. Patient has a painful physical condition other than knee arthritis that, in the opinion of the Investigator, may confound post-operative pain assessments. Patient has a history of drug, prescription medicine, or alcohol abuse within the past 2 years or a positive test for drugs of abuse at screening. Patient is receiving oxygen therapy at the time of screening. Patient participated in a clinical trial of an investigational drug or device within 30 days of screening visit or is scheduled to receive an investigational product other than ARX-F01 while participating in this study. Exclusion Criteria at Randomization (during early PACU time period): Patient has a respiratory rate that is less than 8 breaths per minute or greater than 24 breaths per minute, Patient has arterial oxygen saturation by pulse oximetry (SpO2) of less than 90% with supplemental oxygen. Patient is not able to answer questions and follow commands. Patient has vomiting that is not responsive to standard treatment. The surgical procedure from incision to closure was longer than 3 hours. There have been any deviations from the surgical or anesthetic protocols as specified in the protocol.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Sufentanil NanoTab<br>* 5 mcg Sufentanil NanoTab taken sublingually q 20 minutes as needed for pain for 12 hours<br>* Other names: ARX-F01;|
| Experimental: 2<br> | Drug: Sufentanil NanoTab<br>* 10 mcg Sufentanil NanoTab taken sublingually q 20 minutes as needed for pain for 12 hours<br>* Other names: ARX-F01;|
| Experimental: 3<br> | Drug: Sufentanil NanoTab<br>* 15 mcg Sufentanil NanoTab taken sublingually q 20 minutes as needed for pain for 12 hours<br>* Other names: ARX-F01;|
| Placebo Comparator: 4<br> | Drug: Placebo NanoTab<br>* Placebo NanoTab taken sublingually q 20 minutes as needed for pain for 12 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SPID-12 | SPID-12 is the sum of the pain intensity difference (PID) over the 12 hour time period. A pain intensity score of 0 (no pain) to 10 (worst possible pain) is obtained before starting the study and throughout the 12 hour time period. The pain score at each assessment time point is subtracted from the baseline pain score (starting point) to provide the total sum score or SPID-12. A higher SPID-12 score is better and indicates a reduction in pain intensity compared to the baseline score. Per protocol, pain scores are collected at 15 different time points. If all scores are collected, the full range of SPID-12 scores could be -150 to 150. | 12 hours after first dose |