A 2x2 Factorial, Randomized, Open-label Trial to Evaluate Neuromodulators and Cough Control Therapy in Patients With Refractory or Unexplained Chronic Cough (FORTITUDE)

December 4, 2025 updated by: McMaster University

A 2x2 Factorial, Randomized, Open-label Trial to Evaluate Neuromodulators and Cough Control Therapy in Patients With Refractory or Unexplained Chronic Cough (FORTITUDE)

The FORTITUDE trial will provide head-to-head evidence on the benefits and harms of two commonly prescribed neuromodulators (low-dose morphine and pregabalin), the effectiveness of a virtual cough control therapy, exploratory assessment of potential synergy in combining these interventions, and the long-term outcomes of these treatments in patients with refractory or unexplained chronic cough.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

FORTITUDE (FactOrial Randomized TrIal To evalUate neuromoDulators and cough control thErapy) is a 6-week, 2x2 factorial, randomized, open-label trial with an extension observational phase up to 1 year. The trial will include Canadian hospital sites enrolling 124 patients. Patients ≥18 years old with either refractory or unexplained chronic cough will undergo 1:1:1:1 randomization to receive either low-dose morphine (up to 5 mg twice daily) or pregabalin (up to a maximum tolerated dose of 150 mg twice daily) with or without cough control therapy. The cough control therapy will consist of five virtual sessions delivered over 6 weeks by a trained physiotherapist and speech-language pathologist. Change from baseline in 24-hour cough frequency at 6 weeks represents the primary outcome.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
124

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T2N 4Z6
        • Respiratory Clinical Trials Centre, University of Calgary
        • Contact:
        • Principal Investigator:
          • Stephen Field, MD
        • Principal Investigator:
          • Danica Brister, MD
    • Ontario
      • Hamilton, Ontario, Canada, L8N 3Z5
        • Respiratory Research Lab, McMaster University
        • Contact:
        • Principal Investigator:
          • Elena Kum
        • Principal Investigator:
          • Wafa Hassan, MD
      • London, Ontario, Canada, N6A 4V2
    • Quebec
      • Québec, Quebec, Canada, G1V 4G5
        • Institut universitaire de cardiologie et de pneumologie de Quebec - University Laval
        • Contact:
      • Sherbrooke, Quebec, Canada, J1H 5N4
        • Centre de recherche du Centre hospitalier Universitaire de Sherbrooke
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Adults (≥18 years old) with either:
  2. Refractory chronic cough (RCC), defined as having one or more identifiable causes of cough (asthma, allergic rhinitis, and/or GERD), but with previous trials of treatment targeting the underlying condition leading to no cough resolution; OR
  3. Unexplained chronic cough (UCC), defined as having a cough lasting >8 weeks with (i) a normal chest X-ray/CT in the last 5 years and since the onset of chronic cough; (ii) FEV1 and FVC ≥80% predicted or >lower limit of normal (LLN); (iii) FEV1/FVC ≥0.7 or >LLN; (iv) no evidence of asthma; and (vi) no regular symptoms of nasal/reflux disease.

Exclusion Criteria:

  1. Those who, in the opinion of the investigator, have previously tried low-dose morphine, pregabalin, and/or CCT with full intervention fidelity for the treatment of RCC/UCC;
  2. Are currently taking morphine or pregabalin for the treatment of any indication (i.e., RCC/UCC or chronic pain);*
  3. Are currently taking other centrally-acting medication (i.e., gabapentin, amitriptyline, dextromethorphan) for the treatment of any indication (i.e., RCC/UCC, seizures, or depression);*
  4. Have a history of opioid or substance abuse that, in the opinion of the investigator, may interfere with the conduct of the study;
  5. Are a current smoker, or ex-smoker with a >20 pack-year history who have abstained from smoking for <6 months;
  6. Have cough due to angiotensin-converting enzyme inhibitor use;
  7. Have symptoms of an upper respiratory infection within the last month that have not resolved;
  8. Had an asthma exacerbation within the last month that requires an increase or start of an oral corticosteroid;
  9. Have other primary pulmonary disorders, including pulmonary embolism, pulmonary hypertension, lung cancer, cystic fibrosis, radiologically-proven emphysema, interstitial lung disease, or severe bronchiectasis;
  10. Have language, memory, cognitive, or psychiatric issues that may prevent optimal participation;
  11. Have creatinine clearance <15 mL/min, including individuals with end-stage renal disease who require hemodialysis or peritoneal dialysis;
  12. Have any other condition that, in the opinion of the qualified investigator, may adversely affect the participant's ability to complete the study or its measures or pose significant risk to the participant;
  13. Have participated in another clinical trial of an investigational medicinal product within 30 days;
  14. Pregnant or breastfeeding; or

  15. Females of child-bearing potential who:

    1. Do not agree to use a medically approved method of birth control for the duration of the study. All hormonal birth control must have been in use for a minimum of 3 months.
    2. Acceptable methods of birth control include oral contraceptives, hormone birth control patch, vaginal contraceptive ring, injectable contraceptives, or hormone implant, double-barrier method, intrauterine devices, non-heterosexual lifestyle or agrees to use contraception if planning on changing to heterosexual partner(s), vasectomy of partner at least 6 months prior to screening.

    3. Females who are not of child-bearing potential will be defined as females who have undergone a sterilization procedure (e.g., hysterectomy, bilateral oophorectomy, bilateral tubal ligation, complete endometrial ablation) or have been post-menopausal for at least 1 year prior to screening.

      • Participants taking any of the above medications at baseline will only be eligible if they are willing and medically able to safely discontinue them at least 2 weeks prior to the first study visit. Eligibility will be confirmed by the local study investigator prior to enrolment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Morphine Sulphate
Oral morphine sulphate given up to 5 mg twice daily.
Drug: Morphine Sulphate
Oral morphine sulphate given up to 5 mg twice daily.
Experimental: Morphine Sulphate + Cough Control Therapy
Oral morphine sulphate given up to 5 mg twice daily and cough control therapy (5 virtual sessions delivered over 6 weeks by a trained physiotherapist and speech-language pathologist).
Combination product: Morphine Sulphate + Cough Control Therapy
Oral morphine sulphate given up to 5 mg twice daily and cough control therapy (5 virtual sessions delivered over 6 weeks by a trained physiotherapist and speech-language pathologist).
Experimental: Pregabalin
Oral pregabalin given up to a maximum tolerated dose of 150 mg twice daily.
Drug: Pregabalin
Oral pregabalin given up to a maximum tolerated dose of 150 mg twice daily.
Experimental: Pregabalin + Cough Control Therapy
Oral pregabalin given up to a maximum tolerated dose of 150 mg twice daily and cough control therapy (5 virtual sessions delivered over 6 weeks by a trained physiotherapist and speech-language pathologist).
Combination product: Pregabalin + Cough Control Therapy
Oral pregabalin given up to a maximum tolerated dose of 150 mg twice daily and cough control therapy (5 virtual sessions delivered over 6 weeks by a trained physiotherapist and speech-language pathologist).

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Change from baseline in 24-hour cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 6 weeks
Time Frame: 6 weeks
6 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Change from baseline in awake cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 6 weeks
Time Frame: 6 weeks
6 weeks
Change from baseline in sleep cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 6 weeks
Time Frame: 6 weeks
6 weeks
Change from baseline in cough bouts (defined by inter-cough intervals) measured by the VitaloJAK ambulatory cough monitor at 6 weeks
Time Frame: 6 weeks
6 weeks
Change from baseline in cough severity on the McMaster Cough Severity Questionnaire at 6 weeks
Time Frame: 6 weeks
6 weeks
Change from baseline in cough severity on the 100-mm visual analogue scale at 6 weeks
Time Frame: 6 weeks
6 weeks
Change from baseline in cough-specific quality of life on the Leicester Cough Questionnaire at 6 weeks
Time Frame: 6 weeks
6 weeks
Change from week 6 (end of randomized phase) in cough severity on the McMaster Cough Severity Questionnaire at 6 and 12 months
Time Frame: 6 and 12 months
6 and 12 months
Change from week 6 (end of randomized phase) in cough severity on the 100-mm visual analogue scale at 6 and 12 months
Time Frame: 6 and 12 months
6 and 12 months
Change from week 6 (end of randomized phase) in cough-specific quality of life on the Leicester Cough Questionnaire at 6 and 12 months
Time Frame: 6 and 12 months
6 and 12 months

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Time Frame
Proportion of patients with any adverse event for each intervention at 6 weeks, 6 months, and 12 months
Time Frame: 6 weeks, 6 months, and 12 months
6 weeks, 6 months, and 12 months
Proportion of patients with treatment-related adverse events for each intervention at 6 weeks, 6 months, and 12 months
Time Frame: 6 weeks, 6 months, and 12 months
6 weeks, 6 months, and 12 months
Proportion of patients with serious adverse events for each intervention at 6 weeks, 6 months, and 12 months
Time Frame: 6 weeks, 6 months, and 12 months
6 weeks, 6 months, and 12 months
Proportion of patients with adverse events leading to treatment discontinuation for each intervention at 6 weeks, 6 months, and 12 months
Time Frame: 6 weeks, 6 months, and 12 months
6 weeks, 6 months, and 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
McMaster University

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Imran Satia, MD PhD, McMaster University
  • Study Chair: Wafa Hassan, MD, McMaster University
  • Study Chair: Elena Kum, McMaster University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 1, 2029

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2029

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 4, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 4, 2025

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 17, 2025

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 17, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 4, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • FORTITUDE-01

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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