Clinical trial NCT06709612: Postsurgical Analgesia After Hernia Repair
Official title: Pilot Phase II Study of AMT-143 for Postsurgical Analgesia After Hernia Repair
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Hernia
Hernia, Abdominal
Keywords: Abdominal hernia
Pain Control
Lead sponsor: AmacaThera Inc.
Sponsor class: INDUSTRY
First posted: 2024-11-29
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study has 3 cohorts of ascending doses. Each cohort has 3 arms: AMT-143, Ropivacaine Solution and Saline Placebo.

AMT-143 is formulated as 385 mg/mL on a ropivacaine HCl equivalence basis in hydrogel containing sodium hyaluronate and methylcellulose. Each syringe has been filled with 0.52 g hydrogel, and several syringes may be combined to provide each study dose. The dose required for each participant will be prepared in the study site pharmacy prior to surgery following aseptic procedures.

Saline placebo will consist of 0.9% sodium chloride injection USP and will be administered in an amount matching the volume of AMT-143 to be used in each of the Cohorts 1 to 3.

The active comparator, ropivacaine hydrochloride 1% solution will be administered at a volume of 5 mL (50 mg) for all 3 cohorts.
Primary purpose: TREATMENT

Brief summary: The study is designed to evaluate the safety, efficacy, and pharmacokinetics (PK) of three ascending doses of AMT-143 to determine the appropriate dose of AMT-143 for the management of postsurgical pain following inguinal hernia repair. Healthy male and female participants ≥18 years of age scheduled for open inguinal hernia repair surgery will be enrolled. Participants will all receive general anesthesia. The open inguinal hernia repair will be performed by a participating surgeon and the study medication will be administered by the surgeon prior to wound closure. AMT-143 is provided as a hydrogel containing 385 mg/mL ropivacaine (on a ropivacaine HCl equivalence basis). AMT-143 hydrogel will be provided as pre-filled syringes for administration via instillation into the surgical site after surgery and prior to suture. This will be a randomized, single blind, placebo and active controlled, dose escalation study performed at one clinical site to determine optimal doses of AMT-143. The study will consist of 30 participants, 10 per dose. Participants will receive AMT-143, or saline placebo, or ropivacaine 1% solution. Participants will be blinded to treatment. All assessments up to 4 h will be performed in the hospital clinic setting. Post discharge follow-up for the study will be handled on an outpatient basis and will be conducted by a home nurse up to Day 21. The participant will return to the clinical site for a final End of Study visit on Day 28.

Detailed description: This is a Pilot Phase II Study of AMT-143 for Postsurgical Analgesia After Hernia Repair considered Phase IIa. The study is designed to evaluate the safety, efficacy, and pharmacokinetics (PK) of three ascending doses of AMT-143 to determine the appropriate dose of AMT-143 for the management of postsurgical pain following inguinal hernia repair.

This will be a randomized, single blind, placebo and active controlled, dose escalation study performed at one clinical site to determine optimal doses of AMT-143. The study will consist of 30 participants, 10 per dose: 6 participants will receive AMT-143 hydrogel, 2 participants will receive saline placebo, and 2 will receive the active control ropivacaine hydrochloride 1% solution.

The 30 participants will be randomly assigned sequentially to one of 3 treatment cohorts of escalating doses of AMT-143. Participants will receive AMT-143, or saline placebo, or ropivacaine 1% solution. Participants will be blinded to treatment.

Each cohort consists of 10 participants who will be dosed in a sequential manner to evaluate the safety, efficacy, and PK of three ascending doses of AMT-143 hydrogel (concentration 385 mg/mL) at 385, 770, and 1,155 mg ropivacaine. The volume of saline placebo will match the volume of AMT-143 used while the 1% ropivacaine solution active control will be administered at the same volume for each Cohort.

Study drug will be administered via syringe instillation into the surgical site prior to wound closure. Participants will be followed for 28 days, both in-clinic and as outpatients for safety, efficacy, and PK assessments. Safety assessment will include incidence of treatment-emergent adverse events (TEAEs), electrocardiogram (ECG) changes, vital signs, clinical laboratory assessments, and physical examination. Efficacy assessments will include pain intensity assessment using the Numeric Rating Scale (NRS) at rest and with active movement (NRS-A) over 28 days and use of rescue medications. Blood samples will be collected before surgery (pre) and after surgery at 1, 2, 4, 9±1 h and then Days 2, 3, 7, 14, 21 and 28.

All assessments up to 4 h will be performed in the hospital clinic setting. Post discharge follow-up for the study will be handled on an outpatient basis and will be conducted by a home nurse up to Day 21. The participant will return to the clinical site for a final End of Study visit on Day 28.

All postsurgical assessments will be timed from the start of study drug instillation (Time 0) in the surgical site, prior to suturing. Participants will be discharged from the hospital on the same day as the surgery and study procedures will be performed on a home basis for safety and efficacy assessments of AMT-143 hydrogel and additional PK blood draws up to Day 21 as required. An end of study visit is planned for Day 28.

Data will be reviewed by the Safety Evaluation Committee (SEC) after each Cohort to determine if it is safe to move forward to the next dose level.

Participants undergoing primary open hernia repair, will be randomized to one of three treatment cohorts of escalating doses of AMT-143 hydrogel. Saline Placebo will match the volume of AMT-143 hydrogel in each of the 3 cohorts. Ropivacaine 1% solution will remain constant for each cohort.

Cohort 1:

* 6 participants: 1 mL AMT-143 hydrogel containing 385 mg ropivacaine
* 2 participants: 1 mL Saline Placebo
* 2 participants: 5 mL Ropivacaine 10 mg 1% solution

Cohort 2:

* 6 participants: 2 mL AMT-143 hydrogel containing 770 mg ropivacaine
* 2 participants: 2 mL Saline Placebo
* 2 participants: 5 mL Ropivacaine 10 mg/mL (1%) solution

Cohort 3:

* 6 participants: 3 mL AMT-143 hydrogel containing 1,155 mg ropivacaine
* 2 participants: 3 mL Saline Placebo
* 2 participants: 5 mL Ropivacaine 10 mg/mL (1%) solution Study drug will be administered locally (from a syringe) into the surgical site prior to wound closure.

The SEC will monitor safety, efficacy and PK data from each cohort to determine if it is safe to move to the next cohort.

Eligibility criteria: Inclusion Criteria:

1. Provides voluntary written informed consent.
2. Participants are ≥18 years of age at screening.
3. Scheduled to undergo unilateral open inguinal hernia repair.
4. Body mass index (BMI) ≤40.0 kg/m2.
5. Male participants must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control for the duration of the study until at least 1 week after the administration of study medication.
6. Female participants:

   * Not pregnant (female participant of childbearing potential must have a negative urine pregnancy test before surgery).
   * Not lactating.
   * Not planning to become pregnant during the study.
   * Be surgically sterile; or at least two years post-menopausal; or have a monogamous partner who is surgically sterile; or is practicing double-barrier contraception; or practicing abstinence (must agree to use double-barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, or combination oral contraceptive approved by Health Canada for greater than 2 months prior to screening visits and commits to the use of an acceptable form of birth control for the duration of the study.
7. In the opinion of the Investigator, is willing and able to understand the study procedures, and agrees to adhere to the requirements of the study protocol, in order to enable accurate and appropriate responses to pain scales.

Exclusion Criteria:

1. Have chronic pain and have been receiving or have received chronic opioid therapy defined as greater than 15 morphine equivalents units per day for greater than 3 out of 7 days per week over a one-month period within 12 months of study treatment initiation.
2. History of hypersensitivity to any ingredient in the formulation (hyaluronan or methylcellulose).
3. History of hypersensitivity or allergy to amide type local anaesthetics (lidocaine, bupivacaine, or ropivacaine).
4. History of ventricular tachycardia, ventricular fibrillation, or atrioventricular block without a pacemaker.
5. Have a clinically significant abnormal clinical laboratory test value, according to the judgement of the investigator.
6. Have a clinically significant 12-lead ECG abnormality, according to the judgement of the investigator.
7. Have received any medications with a potential for drug interactions with ropivacaine (i.e., amide-type local anaesthetics such as lidocaine, bupivacaine, mepivacaine and prilocaine; antiarrhythmics such as procainamide, disopyramide, tocainide, mexiletine and flecainide; sedative; strong inhibitors of cytochrome P4501A2 such as fluvoxamine enoxacin, theophylline and imipramine for at least 5 half-lives prior to the start of this).
8. Have received any investigational product within 30 days before dosing with study medication.
9. Suspected or known history of substance abuse and/or alcoholism.

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events to determine Safety and tolerability of AMT-143
timeFrame: From surgery to day 28 follow-up
measure: Pharmacokinetics of AMT-143
timeFrame: From surgery to day 28 follow-up
Secondary outcomes:
measure: Analgesic efficacy of AMT-143
timeFrame: From surgery to day 28 follow-up
Other outcomes:
Locations:
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
Study officials:
affiliation: McMaster University
name: James Paul, MD
role: PRINCIPAL_INVESTIGATOR
References: