Pelvic Adhesions
Conditions
Brief summary
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
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.
Interventions
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.
Placebo
Sponsors
Temple Therapeutics BV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants in Which Adhesions Were Prevented. | 6-8 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events, Adverse Drug Reactions and Clinical Laboratory Abnormalities. | 8 weeks | Participants With Treatment-related Adverse Events as Assessed by Clinical Blood Work Abnormalities and Physical Examination. |
Countries
Ukraine
Participant flow
Recruitment details
This was a single-center study at a private hospital clinic. Recruitment was between February 2015 and October 2016. Subjects were adult women planned for myomectomy with a scheduled clinically necessary second look laparoscopy. The study and consent form were approved by the Institutional Review Board/Ethics Committee and the Investigator's IRB/EC (Ethics Committee of Kharkiv City Clinical Multi-field Hospital,Kharkiv, Ukraine). Participants were not compensated to participate in this trial.
Participants by arm
| Arm | Count |
|---|---|
| L-Alanyl/L-Glutamine- Laparoscopic Participants receiving intraperitoneal administration of L-Alanyl-L-Glutamine at the time of laparoscopic myomectomy.
L-Alanyl/L-Glutamine: 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. | 18 |
| Physiological Saline- Laparoscopic Participants receiving intraperitoneal administration of physiological saline at the time of laparoscopic myomectomy.
Physiologic saline: Placebo | 19 |
| L-Alanyl/L-Glutamine- Laparotomy Participants receiving intraperitoneal administration of L-Alanyl-L-Glutamine at the time of myomectomy (laparotomy).
L-Alanyl/L-Glutamine: 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. | 5 |
| Physiological Saline- Laparotomy Participants receiving intraperitoneal administration of physiological saline at the time of myomectomy (laparotomy).
Physiologic saline: Placebo | 5 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 1 | 2 |
Baseline characteristics
| Characteristic | L-Alanyl/L-Glutamine- Laparoscopic | Physiological Saline- Laparoscopic | L-Alanyl/L-Glutamine- Laparotomy | Physiological Saline- Laparotomy | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 19 Participants | 5 Participants | 5 Participants | 47 Participants |
| BMI (kg/m^2) | 23.5 kg/m^2 STANDARD_DEVIATION 4.3 | 22.3 kg/m^2 STANDARD_DEVIATION 3 | 24.5 kg/m^2 STANDARD_DEVIATION 7.9 | 23.5 kg/m^2 STANDARD_DEVIATION 3.5 | 23.5 kg/m^2 STANDARD_DEVIATION 0.9 |
| Diastolic BP (mmHg) | 70.0 mmHg STANDARD_DEVIATION 5 | 70.3 mmHg STANDARD_DEVIATION 6.1 | 71 mmHg STANDARD_DEVIATION 2.2 | 67 mmHg STANDARD_DEVIATION 6.7 | 69.6 mmHg STANDARD_DEVIATION 1.8 |
| Heart rate (bpm) | 79.8 beats per minute STANDARD_DEVIATION 8.6 | 79.4 beats per minute STANDARD_DEVIATION 7.6 | 79 beats per minute STANDARD_DEVIATION 1.8 | 73 beats per minute STANDARD_DEVIATION 8.3 | 77.8 beats per minute STANDARD_DEVIATION 3.2 |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 18 Participants | 19 Participants | 5 Participants | 5 Participants | 47 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Systolic BP (mmHg) | 113.9 mmHg STANDARD_DEVIATION 9.5 | 113.9 mmHg STANDARD_DEVIATION 8.6 | 117 mmHg STANDARD_DEVIATION 5.7 | 110 mmHg STANDARD_DEVIATION 10 | 113.7 mmHg STANDARD_DEVIATION 2.9 |
| Temperature (Degrees Celsius) | 36.7 Degrees Celsius STANDARD_DEVIATION 0.1 | 36.3 Degrees Celsius STANDARD_DEVIATION 0.1 | 36.7 Degrees Celsius STANDARD_DEVIATION 0.1 | 36.6 Degrees Celsius STANDARD_DEVIATION 0.1 | 36.5 Degrees Celsius STANDARD_DEVIATION 0.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 19 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 3 / 18 | 6 / 19 | 1 / 5 | 1 / 5 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 | 0 / 5 | 0 / 5 |
Outcome results
Primary
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.
Time frame: 6-8 weeks
Population: The number of subjects in each study group (Control \[N=20\] and AG \[N=19\]) was lower at the second look laparoscopic (SLL) compared to the number of subjects originally enrolled in each study group. The difference between groups numbers is a result of dropouts, including subjects who failed criteria for SLL or who elected not to continue the study. The laparotomy group, given the small sample size, was primary used to gather safety data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-Alanyl/L-Glutamine- Laparoscopic | Number of Participants in Which Adhesions Were Prevented. | 15 Participants |
| Physiological Saline- Laparoscopic | Number of Participants in Which Adhesions Were Prevented. | 5 Participants |
| L-Alanyl/L-Glutamine- Laparotomy | Number of Participants in Which Adhesions Were Prevented. | 4 Participants |
| Physiological Saline- Laparotomy | Number of Participants in Which Adhesions Were Prevented. | 3 Participants |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| L-Alanyl/L-Glutamine- Laparoscopic | Adverse Events, Adverse Drug Reactions and Clinical Laboratory Abnormalities. | 3 Participants |
| Physiological Saline- Laparoscopic | Adverse Events, Adverse Drug Reactions and Clinical Laboratory Abnormalities. | 6 Participants |
| L-Alanyl/L-Glutamine- Laparotomy | Adverse Events, Adverse Drug Reactions and Clinical Laboratory Abnormalities. | 1 Participants |
| Physiological Saline- Laparotomy | Adverse Events, Adverse Drug Reactions and Clinical Laboratory Abnormalities. | 1 Participants |