AzTrials
AzTrials

Intestinal ObstructionPhase 1LOP-MNTX-2009NCT01596777

Effects of 500 mg Immediate Release and Extended Release Methylnaltrexone on Loperamide-induced Delay of the Oro-cecal and Whole-gut Transit Time in Healthy Subjects

A Phase 1 study testing Loperamide, Methylnaltrexone 12 mg sc. and Methylnaltrexone IR capsule in people with Intestinal Obstruction, run by University Medicine Greifswald at 1 site in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The purpose of this study is to describe the effects of methylnaltrexone in preventing loperamide-induced delay of the oro-cecal and whole-gut transit time and measure pharmacokinetics of methylnaltrexone after subcutaneous and oral administration of immediate release and extended release capsules. Read more about this study

Who is it for?
Ages 18 to 45 yearsHealthy volunteers can take part
Conditions the study is for
Intestinal Obstruction
What is being tested?
Loperamide, Methylnaltrexone 12 mg sc. and Methylnaltrexone IR capsule
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
15 participants
Where
1 siteGermany
Study dates
Jan 2010to May 2010
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 45 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • age: 18 - 45 years
  • sex: male and female
  • ethnic origin: Caucasian
  • minimal body weight: 62 kg
  • body mass index: ≥ 19 kg/m² and ≤ 27 kg/m²
  • good health as evidenced by the results of the clinical examination, ECG, and the laboratory check-up, which were judged by the clinical investigator not to differ in a clinical relevant way from the normal state
  • written informed consent

Who cannot join

  • hepatic and renal diseases and/or pathological findings, which might interfere with pharmacokinetics and pharmacodynamics of the study medication
  • gastrointestinal diseases and/or pathological findings, which might interfere with pharmacokinetics and pharmacodynamics of the study medication
  • drug or alcohol dependence
  • positive drug or alcohol screening
  • smokers of 10 or more cigarettes per day
  • positive results in HIV, HBV and HCV screenings
Show all 20Show fewer
  • volunteers who were on a diet which could affect the pharmacokinetics of the drug
  • heavy tea or coffee drinkers (more than 1 L per day)
  • lactation, pregnancy test positive or not performed or women of child-bearing age without safe contraception
  • volunteers suspected or known not to follow instructions of the clinical investigators
  • volunteers who were unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they would have been exposed to as a result of their participation in the study
  • volunteers liable to orthostatic dysregulation, fainting or blackouts
  • participation in a clinical trial during the last 3 months prior to the start of the study
  • less than 14 days after last acute disease
  • less than 3 months after last blood donation
  • any medication within 4 weeks prior to the intended first administration of the study medication which might have influenced functions of the gastrointestinal tract (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists, proton pump inhibitors)
  • any other medication within two weeks prior to the first administration of the study medication, but at least 10-time the half-live of the respective drug (except oral contraceptives)
  • intake of grapefruit containing food or beverages within 14 days prior to administration of the study medication
  • known allergic reactions to the active ingredients used or to constituents of the study medication
  • deficiency of glucose-6-phosphate dehydrogenase

Trial locations and contacts

1 site in 1 country.

Germany1 site
  • Department of Clinical Pharmacology, Ernst-Moritz-Arndt-University Greifswald

    Greifswald, Mecklenburg-Vorpommern

Other trials in Germany

About this study

The purpose of this study is to describe the effects of methylnaltrexone in preventing loperamide-induced delay of the oro-cecal and whole-gut transit time and measure pharmacokinetics of methylnaltrexone after subcutaneous and oral administration of immediate release and extended release capsules.

Read the detailed description

The increasing prevalence of opioid use and consequently, opioid-induced bowel dysfunction has prompted interest in identifying effective treatment options. Until now, the treatment of opioid-induced constipation (OIC) has been viewed as an extension of constipation in general. Traditional therapies for constipation such as bulking agents, stool softeners, stimulant laxatives, and osmotic agents are commonly utilized, but the effects of such therapies are nonspecific and are often generating diarrhea or cramps and some of these drugs cause severe side effects. Furthermore, these conventional measures are sometimes insufficient in some patients, especially those requiring increasing doses of opioids.

Opioid-induced constipation is predominantly mediated by gastrointestinal μ-opioid receptors. Selective blockade of these peripheral receptors might relieve constipation without compromising centrally mediated effects of opioid analgesia or precipitating withdrawal.

Naloxone is a competitive antagonist of opioid receptors inside and outside the central nervous system used as a solution for injection in the treatment of opioid overdose. When administered orally, it can reduce opioid-induced constipation due to a local action in the gut.

Another way to prevent central actions is the use of opioid antagonists which can't penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Their antagonism of μ-opioid receptors in the gastrointestinal tract seems to reverse opioid-induced gut hypomotility.

It is assumed that methylnaltrexone after oral administration influences intestinal motility by local blockade of opioid receptors along the luminal surface of the gut. Because methylnaltrexone seems to have an absorption window in the proximal small intestine as caused by lower activity of P-glycoprotein in that region (similar to other quaternary compounds, eg. trospium chloride), immediate release (uncoated) methylnaltrexone is better absorbed form the small intestine and might therefore be less active than the enteric-coated drug.

However, the pharmacokinetic and pharmacodynamic data on oral methylnaltrexone are very preliminarily so far. Furthermore, intestinal transit time has been measured using lactulose as a probe compound that has an own laxative effect.

Therefore, the following clinical study was initiated to proof the concept in a controlled clinical trial in healthy subjects, whether methylnaltrexone antagonizes the loperamide induced delay of oro-cecal and whole-gut transit time after oral administration of immediate and extended release capsules in comparison to subcutaneous administration.

Loperamide is an opioid agonist and acts on the µ-receptors in the myenteric plexus. It does not affect the central nervous system like other opioids. Loperamide significantly prolongs the mouth-to-cecum transit time as evaluated by the lactulose hydrogen breath test. This effect may be antagonized by the concomitant administration of naloxone.

Being tested
Loperamide, Loperamide placebo, Methylnaltrexone placebo, Methylnaltrexone 12 mg sc., Methylnaltrexone IR capsule
Keywords
Loperamide-induced obstipation, Methylnaltrexone, oro-cecal transit time, whole gut transit time, Pharmacokinetics
Medical subject headings
Intestinal Obstruction

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LoperamideDrug

    Also called LOP 4 mg

    20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration

  • Loperamide placeboDrug

    Also called LOP placebo

    200 ml apple juice

  • Methylnaltrexone placeboDrug

    Also called MNTX placebo

    Methylnaltrexone placebo capsule (identical to MNTX IR and MNTX ER)

  • Methylnaltrexone 12 mg sc.Drug

    Also called MNTX 12 mg sc.

    RELISTOR 12 mg/0.6 ml Injektionslösung (Wyeth)

  • Methylnaltrexone IR capsuleDrug

    Also called MNTX IR

    Methylnaltrexone bromide 500 mg IR capsule

  • Methylnaltrexone ER capsuleDrug

    Also called MNTX ER

    Methylnaltrexone bromide 500 mg ER capsule

  • Colon TransitDevice

    3x1 capsules containing radio-opaque marker of 6 different shapes (in two consecutive study periods, capsules with different shapes of the markers are given)

  • SulfasalazineDrug

    Also called SSP

    500 mg Azulfidine® (Pharmacia)

Study groups in NCT01596777
Study groupRoleWhat they receive
Treatment APlacebo comparatorAdministration of LOP placebo (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX placebo (0 h). To asses the oro-cecal and whole-gut transit time under placebo condition.
Receives: Drug: Loperamide placebo; Drug: Methylnaltrexone placebo; Device: Colon Transit; Drug: Sulfasalazine
Treatment BPlacebo comparatorAdministration of LOP 4 mg (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX placebo (0 h). To asses the oro-cecal and whole-gut transit time under loperamide-induced obstipation condition.
Receives: Drug: Loperamide; Drug: Methylnaltrexone placebo; Device: Colon Transit; Drug: Sulfasalazine
Treatment CActive comparatorAdministration of LOP 4 mg (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX 12 mg sc. (0 h). To assess the effects of methylnaltrexone in preventing loperamide-induced delay of the oro-cecal and whole-gut transit time and to measure pharmacokinetics of methylnaltrexone after subcutaneous administration.
Receives: Drug: Loperamide; Drug: Methylnaltrexone 12 mg sc.; Device: Colon Transit; Drug: Sulfasalazine
Treatment DActive comparatorAdministration of LOP 4 mg (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX IR (0 h). To assess the effects of methylnaltrexone in preventing loperamide-induced delay of the oro-cecal and whole-gut transit time and to measure pharmacokinetics of methylnaltrexone after oral administration of immediate release capsule.
Receives: Drug: Loperamide; Drug: Methylnaltrexone IR capsule; Device: Colon Transit; Drug: Sulfasalazine
Treatment EActive comparatorAdministration of LOP 4 mg (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX ER (0 h). To assess the effects of methylnaltrexone in preventing loperamide-induced delay of the oro-cecal and whole-gut transit time and to measure pharmacokinetics of methylnaltrexone after oral administration of extended release capsule.
Receives: Drug: Loperamide; Drug: Methylnaltrexone ER capsule; Device: Colon Transit; Drug: Sulfasalazine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Oro-cecal transit time

    Oro-cecal transit time (OCT) was defined as the first appearance of sulfapyridine in the blood after oral administration of 500 mg sulfasalazine immediate release tablets. Because of the high sensitivity of the analytical assay, the OCT was defined as the average of the times needed after sulfasalazine administration to exceed serum concentrations (cut-off) of 50 ng/ml (t50) and of 100 ng/ml (t100).

    Measured: up to 24 h after administration of sulfasalazine

  2. Average whole-gut transit time

    Whole-gut transit time (WGT) was assessed by counting the appearance of radio-opaque markers of different shapes (Colon transit capsules) to different time pints in the stool, which were administered 24 h, 12 h and 1 h before administration of the methylnaltrexone study medication. The radio-opaque markers in the stool inside the sampling containers were visualized with an X-ray device (Philips Optimus, Philips Healthcare, Hamburg, Germany, CE 257303004) The images were stored and evaluated using the Agfa PACS Workstation, Impact-Version 5.2 (Agfa-Healthcare, Cologne, Germany).

    Measured: up to 6 days after administration of methylnaltrexone

  3. renal clearances (CLR)

    Measured: blood sampling at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h and urine sampling in 24 hours interval for 3 days after administration of methylnaltrexone

  4. area under the concentrations-time curve (AUC)

    Measured: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone

  5. maximum concentration (Cmax)

    Measured: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone

  6. time of maximum concentration (Tmax)

    Measured: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone

  7. terminal half-life (t1/2)

    Measured: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone

  8. mean residence time (MRT)

    Measured: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone

  9. distribution volume at steady-state (Vss)

    Measured: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone

  10. total body clearance (CLtot)

    Measured: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone

  11. relative bioavailability (F)

    Ratio AUC of IR and ER formulation over subcutaneous administration

    Measured: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 May 2012 (estimated)
  2. Study startJan 2010
  3. Primary completionMar 2010
  4. Study completionMay 2010

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01596777
Sponsor's protocol ID
LOP-MNTX-2009
Acronym
LOP-MNTX-2009
Status last verified
Oct 2016
First submitted
7 May 2012
Last updated
26 Oct 2016
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Loperamide, Methylnaltrexone 12 mg sc. and Methylnaltrexone IR capsule in people with Intestinal Obstruction, run by University Medicine Greifswald at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Oct 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Oro-cecal transit time (time frame: up to 24 h after administration of sulfasalazine). The study lists 11 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Oct 2016.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in