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

Primary Purpose

Pulmonary Arterial Hypertension

Status

Unknown status

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

Morphine Sulfate

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

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

Sites / Locations

University Health Network, Toronto General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Morphine sulfate - Visit 1

Morphine sulfate - Visit 2

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Change in Borg Dyspnea Score

Change in peak Borg dyspnea score (morphine versus control)

Secondary Outcome Measures

Change in 6-Minute Walk Distance

Change in six-minute walk distance (morphine versus control)

Full Information

NCT ID

NCT03401476

First Posted

April 30, 2017

Last Updated

January 16, 2018

Sponsor

John Granton

1. Study Identification

Unique Protocol Identification Number

NCT03401476

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2018

Overall Recruitment Status

Unknown status

Study Start Date

May 8, 2017 (Actual)

Primary Completion Date

December 31, 2018 (Anticipated)

Study Completion Date

December 31, 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

John Granton

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Arterial Hypertension

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Morphine sulfate - Visit 1

Arm Type

Active Comparator

Arm Description

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.

Arm Title

Morphine sulfate - Visit 2

Arm Type

Active Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Morphine Sulfate

Other Intervention Name(s)

Statex

Intervention Description

Morphine Sulfate Tablets

Primary Outcome Measure Information:

Title

Change in Borg Dyspnea Score

Description

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 Outcome Measure Information:

Title

Change in 6-Minute Walk Distance

Description

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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: 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

John Granton, MD, FRCPC

Organizational Affiliation

University Health Network, Toronto

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Health Network, Toronto General Hospital

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2N2

Country

Canada

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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