A Clinical Study of Alanyl-Glutamine for Reduction of Post-Myomectomy Adhesions

Study Overview
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Brief Summary
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This study evaluates whether L-Alanyl-L-Glutamine can reduce the incidence, extent and severity of adhesions after myomectomy. Half of the participants will receive L-Alanyl-L-Glutamine and the other half of participants will receive a saline placebo at the time of myomectomy.

Detailed Description
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The myriad medical and financial burdens of post-operative adhesions are well documented; however, treatment options are limited and controversial. Implantable physical barriers to prevent adhesions are commercially available, but most trials have failed to demonstrate compelling evidence to support widespread use. In recent years, advances have been made in our understanding of the cellular mechanisms underlying adhesiogenesis, raising the prospect of targeting these pathways to prevent post-surgical adhesions. However, to date, no drug has received regulatory approval for this purpose in any jurisdiction. Our study was designed to evaluate the efficacy and safety of a single intraoperative intraperitoneal dose of L-Alanyl-L-Glutamine (AG), an agent which has been shown to act upon key mediators in the adhesion formation pathway. Methods: This was a randomized, double-blind, placebo-controlled study (DBRCT) of 47 women who underwent myomectomies by laparoscopy (N=37; AG-18 vs Placebo-19) or laparotomy (N=10; AG-5 vs Placebo-5) with a scheduled clinically necessary second-look laparoscopy (SLL) 6 - 8 weeks later. Digital recordings were obtained for all procedures. The primary endpoint was reduction in the incidence, severity and extent of post-operative adhesions, as analyzed by intention-to-treat (ITT) approach. Three independent, blinded reviewers evaluated the operative video recordings to assess for presence of adhesions. Secondary endpoints assessed the safety and tolerability of AG. Post-hoc analysis assessed presence or absence of adhesions in the peritoneal cavity. Patients included those with previous history of surgery, endometriosis, and adhesiolysis was permitted at myomectomy.

Official Title
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A Randomized Double-Blind Controlled Proof-of-Concept Study of Alanyl-Glutamine for Reduction of Post-Myomectomy Adhesions

Conditions
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Pelvic Adhesions

Intervention / Treatment
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* Drug: L-Alanyl/L-Glutamine
* Drug: Physiologic saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects are female Subjects are 18 years of age or older at the time of consent Subjects have a BMI between 17-40 Subjects must have signed informed consent form Subjects have a preoperative diagnosis of uterine fibroids and plan to have a myomectomy completed surgically as part of their standard of care Subjects must have a physical examination and compliance assessment Exclusion Criteria: Subjects whose BMI is outside the range of 17-40 Subjects participating in another clinical trial with a drug or device Subjects who have participated in a clinical trial with a drug or device within 30 days prior to this study Subjects with suspected or diagnosed pregnancy Subjects with suspected intraabdominal infection Subjects who are immunocompromised Subjects diagnosed with cancer Subjects treated with hemostatic agents (e.g. fibrin sealant, collagen, oxidized cellulose) Subjects treated with adhesion prevention agents other than the Anti-Adhesion product (APP) (e.g. Intergel ® Adhesion Prevention Solution, Seprafilm ® Membrane) Subjects taking anti-epileptic medication Subjects who have been treated with Methotrexate or other chemotherapeutics agents Subjects with an American Fertility Society score of Stage D at the time of myomectomy as determined by the surgeon Positive viral serology screening results for hepatitis B surface antigen, antibodies to hepatitis C virus or human immunodeficiency

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Physiological saline- Laparoscopic<br>Participants receiving intraperitoneal administration of physiological saline at the time of laparoscopic myomectomy. | Drug: Physiologic saline<br>* Placebo<br>|
| Experimental: L-Alanyl/L-Glutamine- Laparoscopic<br>Participants receiving intraperitoneal administration of L-Alanyl-L-Glutamine at the time of laparoscopic myomectomy. | Drug: L-Alanyl/L-Glutamine<br>* Sterile solution of L-Alanyl-L-Glutamine, 400mg/mL in water for injection. It is dosed at 1g/kg of body weight and is instilled into the peritoneum at the time of surgery. The active ingredient, glutamine, is a conditionally essential amino acid component of nutritional supplements.<br>* Other names: Evitar;|
| Placebo Comparator: Physiological saline- Laparotomy<br>Participants receiving intraperitoneal administration of physiological saline at the time of myomectomy (laparotomy). | Drug: Physiologic saline<br>* Placebo<br>|
| Experimental: L-Alanyl/L-Glutamine- Laparotomy<br>Participants receiving intraperitoneal administration of L-Alanyl-L-Glutamine at the time of myomectomy (laparotomy). | Drug: L-Alanyl/L-Glutamine<br>* Sterile solution of L-Alanyl-L-Glutamine, 400mg/mL in water for injection. It is dosed at 1g/kg of body weight and is instilled into the peritoneum at the time of surgery. The active ingredient, glutamine, is a conditionally essential amino acid component of nutritional supplements.<br>* Other names: Evitar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Which Adhesions Were Prevented. | The American Fertility Society (AFS) grading system for adhesions was used to assess incidence of adhesions. Adhesion prevention was determined through grading of adhesions at the time of myomectomy (initial surgery) and at the time of second look surgery and compared. | 6-8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events, Adverse Drug Reactions and Clinical Laboratory Abnormalities. | Participants With Treatment-related Adverse Events as Assessed by Clinical Blood Work Abnormalities and Physical Examination. | 8 weeks |