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Metoclopramide, Azithromycin, or Nondrug Pretreatment for UGIB to Reduce Second Endoscopy (MANPURSE)

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ClinicalTrials.gov Identifier: NCT03840057
Recruitment Status : Not yet recruiting
First Posted : February 15, 2019
Last Update Posted : August 14, 2019
Sponsor:
Information provided by (Responsible Party):
Waihong Chung, Lifespan

Brief Summary:
Early endoscopy is an integral part of the management plan for patients presenting with clinical signs of severe or ongoing UGIB. An accurate endoscopic diagnosis and successful endoscopic hemostasis is highly dependent on adequate visualization of the entire gastric mucosa. Metoclopramide has previously been investigated as a prokinetic agent to aid gastric emptying prior to endoscopy, but its widespread adoption is limited by a lack of high quality clinical evidence as well as concerns regarding side effects. Erythromycin is currently the only prokinetic agent recommended by the American and the European guidelines for use in selected patients in order to reduce the need for second endoscopy. Its clinical application, however, is limited by risk of arrhythmia, significant drug interactions, and frequent drug shortages. Azithromycin is structurally related to erythromycin, but is devoid of most adverse side effects associated with erythromycin use. Early evidence suggests that azithromycin may be an effective alternative to erythromycin in the treatment of gastroparesis. The current study, an interventional, randomized, triple-blinded, placebo-controlled clinical trial, is primarily aimed to evaluate the effectiveness of azithromycin as a prokinetic agent in the management of UGIB. It is also aimed to further evaluate the role of metoclopramide as a prokinetic agent in this setting. Outcome measures to be collected in this study include the need for secondary endoscopy, overall mortality, transfusion requirement, length of stay, requirement for surgery, and incidence of adverse side effects. Results from this study would help identify a safe, effective, and readily available prokinetic agent to be used prior to endoscopy.

Condition or disease Intervention/treatment Phase
Gastro Intestinal Bleeding Upper Gastrointestinal Bleeding Drug: Azithromycin Injection Drug: Metoclopramide Injectable Solution Drug: Sodium chloride 0.9% Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 435 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: The study is comprised of two intervention arms, namely the azithromycin arm and the metoclopramide arm, as well as one placebo arm. The two interventions would be studied sequentially in order to simplify the logistical challenges of the blinding and placebo-control processes. The current study is comprised to two parts. During Part 1 of the study, participants are randomized to either azithromycin 500mg intravenous infusion or equivalent volume of 0.9% sodium chloride infusion in a 2-to-1 ratio. During Part 2 of the study, participants are randomized to either metoclopramide 10mg intravenous injection or equivalent volume of 0.9% sodium chloride injection in a 2-to-1 ratio. The 0.9% sodium chloride arm from the two parts of the study are pooled together to form the placebo arm during final analysis.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Initial management of UGIB would be performed by the primary team without interference from the investigator. If a gastroenterology consult were placed by the primary team, the endoscopist on-call would evaluate the patient per routine care. If an early endoscopy is deemed appropriate and necessary based on the patient's clinical status, the participant is registered to a central electronic database, which would assign participants to the intervention arm or the placebo arm using a permuted block randomization process. The appropriate medication or placebo is prepared and distributed by the central inpatient pharmacy. The investigator, the endoscopist, the study participant, and the primary team are all blinded to the assignment.
Primary Purpose: Treatment
Official Title: Metoclopramide, Azithromycin, or Nondrug Pretreatment for Upper Gastrointestinal Bleeding to Reduce Second Endoscopy
Estimated Study Start Date : December 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Azithromycin
Participants randomized to the azithromycin arm would receive 250mL of reconstituted solution containing 500mg of generic azithromycin to be administered as a slow intravenous infusion over 1 hour by the primary team 30-120 minutes prior to endoscopy. No dosage adjustment is made for those with hepatic or renal impairment. No dose adjustment is made for geriatric population.
Drug: Azithromycin Injection
Azithromycin, a semi-synthetic macrolide antibiotic derived from erythromycin. The role of azithromycin as a prokinetic agent was first reported in a retrospective cohort study, which showed azithromycin to be equivalent to erythromycin in accelerating gastric emptying in patients with gastroparesis. The aim of this intervention arm is to evaluate the effectiveness of azithromycin as a prokinetic agent in the management of UGIB.

Experimental: Metoclopramide
Participants randomized to the metoclopramide arm would receive 2mL of solution containing 10mg of generic metoclopramide to be administered as a direct intravenous push by the primary team 5-60 minutes prior to endoscopy. No dosage adjustment is made for those with hepatic impairment. A 50% dose reduction is made for those with creatinine clearance of less than 40mL/minute. No dose adjustment is made for geriatric population.
Drug: Metoclopramide Injectable Solution
Metoclopramide, a 5-HT4 agonist and a dopamine D2-receptor antagonist, is approved for short-term treatment of gastroparesis. The use of metoclopramide as a prokinetic agent in the setting of UGIB has been previously studied, but the number of subject involved was too low to adequately power the studies. The aim of this intervention arm is to further evaluate the effectiveness of metoclopramide as a prokinetic agent in the management of UGIB.

Placebo Comparator: Placebo
Participants randomized to the placebo arm during Part 1 (azithromycin) of the study would receive 250mL of 0.9% sodium chloride solution to be administered as a slow intravenous infusion over 1 hour by the primary team 30-120 minutes prior to endoscopy. Participants randomized to the placebo arm during Part 2 (metoclopramide) of the current study would receive 2mL of 0.9% sodium chloride solution to be administered as a direct intravenous push by the primary team 5-60 minutes prior to endoscopy.
Drug: Sodium chloride 0.9%
Normal saline is used as a placebo control.




Primary Outcome Measures :
  1. Rate of Reduction in the Need for Second Endoscopy [ Time Frame: 48 hours ]
    The primary outcome measure of effectiveness is a reduction in the need for second endoscopy within 48 hours of the first endoscopy. This primary outcome measure is chosen because it represents the basis of current American and European guideline recommendations regarding erythromycin.

  2. Adverse Cardiac Side Effects related to Intervention [ Time Frame: 5 days ]
    The primary cardiac outcome measure is the incidence of unstable arrhythmia, occurring within 5 days of azithromycin administration, requiring cardioversion or resulting in cardiac arrest.

  3. Adverse Infectious Disease Side Effects related to Intervention [ Time Frame: 30 days ]
    The primary infectious disease outcome measure is the incidence of C. difficile infection, occurring within 30 days of azithromycin administration.

  4. Adverse Neurological Side Effects related to Intervention [ Time Frame: 48 hours ]
    The primary neurological outcome measure is the incidence of any reversible or irreversible extrapyramidal symptom, such as acute dystonic reactions, akathisia, drug-induced Parkinsonism, and tardive dyskinesia, within 48 hours of metoclopramide administration.


Secondary Outcome Measures :
  1. Quality of Endoscopic Visualization [ Time Frame: 48 hours ]
    Endoscopic visibility is graded using the standard 4-point objective scoring system as described in most endoscopy literature. The corpus, fundus, and duodenal bulb are scored separately based on an independent review of the images captured by the endoscopist. If a second endoscopy is performed within 48 hours of the initial endoscopy, the presence of clinically significant lesions not identified during the first endoscopy is also measured.

  2. All-Cause Mortality [ Time Frame: 30 days. ]
    All-Cause Mortality within 30 days.

  3. Number of Unit of Transfusion [ Time Frame: 30 days ]
    Number of units of packed red blood cells transfused before hemostasis has been achieved or death.

  4. Length of Hospital Stay [ Time Frame: 30 days ]
    Length of hospital stay since admission for current episode of GIB.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1. Adult patients ≥ 18 years of age at the time of presentation;
  • 2. Admitted to Rhode Island Hospital (RIH) emergency room or inpatient services;
  • 3. Presented with hematemesis, coffee ground emesis, or melena;
  • 4. Upper endoscopy is planned within 24 hours of presentation or onset of bleeding.

Exclusion Criteria:

  • 1. Known anaphylactic allergic reaction to erythromycin, azithromycin, and/or metoclopramide;
  • 2. Concurrent use of certain medications associated with tardive dyskinesia (TD):
  • a. Fluphenazine,
  • b. Haloperidol,
  • c. Loxapine,
  • d. Paliperidone,
  • e. Perphenazine,
  • f. Pimozide,
  • g. Risperidone,
  • h. Thiothixene,
  • i. Trifluoperazine;
  • 3. Concurrent use of certain medications associated with torsade de pointes:
  • a. Amiodarone,
  • b. Chlorpromazine,
  • c. Disopyramide,
  • d. Dofetilide,
  • e. Methadone,
  • f. Procainamide,
  • g. Quinidine,
  • h. Sotalol;
  • 4. Known history of TD, ventricular arrhythmias , or long QT syndrome;
  • 5. Already received erythromycin and/or azithromycin within the past 10 days, or metoclopramide within the past 4 days for other indications;
  • 6. Recipient of hematopoietic stem cell transplant;
  • 7. History of Neisseria gonorrhoeae infection;
  • 8. Pregnancy;
  • 9. Prior gastrectomy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03840057


Contacts
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Contact: Waihong Chung, MD PhD 401-444-5280 waihong.chung@lifespan.org

Sponsors and Collaborators
Waihong Chung

Publications:

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Responsible Party: Waihong Chung, Fellow, Lifespan
ClinicalTrials.gov Identifier: NCT03840057     History of Changes
Other Study ID Numbers: 1
First Posted: February 15, 2019    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Waihong Chung, Lifespan:
GIB
UGIB

Additional relevant MeSH terms:
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Gastrointestinal Hemorrhage
Hemorrhage
Pathologic Processes
Gastrointestinal Diseases
Digestive System Diseases
Metoclopramide
Pharmaceutical Solutions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Dopamine D2 Receptor Antagonists
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action