Status unknownNCT03401476Updated Jan 18, 2018

Effect of Morphine on Dyspnea and 6-Minute Walk Distance in Pulmonary Arterial Hypertension

A Phase 2 interventional study of Morphine Sulfate in Pulmonary Arterial Hypertension, sponsored by John Granton. Status unknown at 1 site in Canada. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-01-18.

Sponsored by John Granton · Phase 2, Interventional, and Treatment

The sponsor has not verified this record recently (last verified Jan 2018), so the status shown — last known as Enrolling by invitation — may be out of date.

Phase: Phase 2
Study type: Interventional
Enrollment: 15
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study summary

Despite advances in treatment and corresponding improvements in survival, patients with pulmonary arterial hypertension (PAH) remain highly symptomatic. In one survey of 315 patients with PAH, sixty-eight percent had moderate or severe dyspnea on exertion and 40% had a profound and clinically significant deficit in quality of life. Palliative care is being increasingly investigated in life-limiting cardiovascular diseases to alleviate symptoms. In PAH, its implementation is frequently delayed until end-of-life. Opioids are a common palliative care intervention, however the efficacy and safety of opioids for symptom relief in PAH has not been evaluated.

Read the detailed description

There is biologic plausibility for opioids in the treatment of dyspnea in PAH. Opioids have widespread effects including venodilation, vasodilation, reducing sympathetic outflow, blunting hypercapnic and hypoxic ventilatory responses, and altering the central perception of dyspnea. Although the origins of dyspnea in PAH are incompletely understood and multifactorial, right ventricular dysfunction reduces exercise capacity and likely also plays a role in the development of dyspnea. Mechanoreceptors situated in the right atrium and right ventricle sense elevated pressures and via sympathetic afferents may lead to an augmentation of ventilatory response and hence dyspnea. Morphine may specifically antagonize this feedback loop by causing venodilation and blunting sympathetics. Morphine also reduces central chemosensitivity and perceptions of dyspnea. Therefore, the drug may antagonize both peripheral and central drivers of dyspnea in PAH.

Investigators will conduct a single-center feasibility study of morphine for treatment of dyspnea and exercise intolerance in PAH. Participants will complete two 6-minute walk tests (6MWT) within one week. Participants will be randomly assigned to receive morphine prior to either the first or second 6MWT. Symptoms and 6-minute walk distance (6MWD) will be compared between the two tests.

Conditions studied

Pulmonary Arterial Hypertension

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Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Aged 18 or older
Diagnosis of Group 1 pulmonary hypertension including idiopathic PAH, heritable PAH, and PAH that is drug- or toxin-induced, associated with connective tissue disease, human immunodeficiency virus (HIV) infection, congenital heart disease, or schistosomiasis23
PAH confirmed by means of a right heart catheterization demonstrating:24
- Mean pulmonary arterial pressure of ≥ 25 mmHg
- Pulmonary capillary wedge pressure ≤ 15 mmHg
- Pulmonary vascular resistance of ≥ 3 Wood units
World Health Organization (WHO) Functional Class III or ambulatory Class IV
Six-minute walk test performed within the past 6 months demonstrating a distance of at least 50 metres.
Unchanged PAH medication regimen for 30 days prior to enrolment. Therapy may include endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, or oral or parenteral prostacyclin analogues. Diuretic doses may change.

Exclusion criteria

Exclusion Criteria:

Group 1 pulmonary hypertension due to portal hypertension
Group 1 pulmonary hypertension due to pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis
Groups 2, 3, 4, or 5 pulmonary hypertension
Severe renal impairment (estimated glomerular filtration rate \< 30 mL/minute/1.73m2 measured within 6 months)
Severe hepatic impairment (INR > 2.0 in absence of vitamin K antagonist therapy, serum bilirubin > 50mmol/L, cirrhosis on imaging or liver biopsy, prior hepatic encephalopathy, or Model for End-Stage Liver Disease (MELD) score > 19, measured within 6 months, as required based on clinical suspicion)
Women who are pregnant or breastfeeding (beta-human chorionic gonadotropin (hCG) to confirm non-pregnant status in all females below age 50)
Hypersensitivity to opioid analgesic, concomitant use with Monoamine Oxidase (MAO) inhibitor or within 14 days of such treatment, concomitant use with barbiturates. Concomitant use with benzodiazepines and/or antipsychotics is permissible provided doses are stable over preceding 1 month.
Daily use of an opioid-containing medication
Unstable condition that is a contraindication to opioid use: Central Nervous System (CNS) depression, acute respiratory disease or impairment (acute hypoxia or hypercapnia), acute asthma or Chronic Obstructive Pulmonary Disease (COPD) exacerbation, untreated symptomatic obstructive sleep apnea, unstable cardiac arrhythmias, suspected hypovolemia, recent seizures (within 1 month), active drug abuse, abdominal disease and/or recent GI surgery (within 1 month), active gallbladder disease/biliary colic, untreated depression/suicidality, recent head injury (within 1 month), pre-existing intracranial lesion or increased intracranial pressure, untreated urinary tract obstruction, untreated hypothyroidism, hypopituitarism or Addison's disease.
Hypotension (resting systolic blood pressure less than or equal to 80mmHg)
Active or unstable coronary artery disease

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover assignment
Masking: None (open label)
Enrollment: 15 participants (estimated)

Study arms

Active comparator
Morphine sulfate - Visit 1
Patients who are randomized to this group will be administered a fixed 5mg dose of oral morphine sulfate prior to performing their 6MWT at Visit 1.
Drug: Morphine Sulfate
Active comparator
Morphine sulfate - Visit 2
Patients who are randomized to this group will be administered a fixed 5mg dose of oral morphine sulfate prior to performing their 6MWT at Visit 2.
Drug: Morphine Sulfate

Interventions

DrugMorphine Sulfate
Morphine Sulfate Tablets
Also known as: Statex

What researchers measure

Primary outcomes

Change in Borg Dyspnea Score
Change in peak Borg dyspnea score (morphine versus control)
Time frame: The Peak Borg Dyspnea Score will be determined over 6 minutes of observation during the conduct of each 6-minute walk test. The 6-minute walk tests and assessments of the peak Borg Dyspnea Score will be recorded within 1 and 7 days of each other.

Secondary outcomes

Change in 6-Minute Walk Distance
Change in six-minute walk distance (morphine versus control)
Time frame: The distance travelled during each 6 minute walk will be determined at completion of the 6-minute walk test. The distance travelled during the 6-minute walk test will be recorded within 1 and 7 days of each other.

Study locations

1 site

University Health Network, Toronto General Hospital
Toronto, Ontario M5G 2N2, Canada

References and documents

Individual participant data

Plan to share: No

No publications or documents are linked to this record.

Registry details

Key details

Study ID: NCT03401476
Lead sponsor: John Granton
Responsible party: John Granton (Principal Investigator, University Health Network, Toronto) — Sponsor-investigator
First posted: Jan 17, 2018
Start date: May 8, 2017
Primary completion: Dec 31, 2018 (estimated)
Completion: Dec 31, 2019 (estimated)
Last update: Jan 18, 2018

Study contacts

John Granton, MD, FRCPC

principal investigator · University Health Network, Toronto

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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