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

NCT07288528 | Not Yet Recruiting Phase 4

• 1 other identifier: FORTITUDE-01
• Study Type: interventional
• Target: 124
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Cough; Refractory Chronic Cough; Chronic Cough; Unexplained Chronic Cough; Cough Hypersensitivity Syndrome

Keywords

Cough; Chronic Cough; Morphine; Pregabalin; Non-Pharmacologic Therapy; Refractory Chronic Cough; Unexplained Chronic Cough

Outcome Measures

Primary Outcomes (1)

• Change from baseline in 24-hour cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 6 weeks

  6 weeks

Secondary Outcomes (9)

• Change from baseline in awake cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 6 weeks

  6 weeks

• Change from baseline in sleep cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 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

  6 weeks

• Change from baseline in cough severity on the McMaster Cough Severity Questionnaire at 6 weeks

  6 weeks

• Change from baseline in cough severity on the 100-mm visual analogue scale at 6 weeks

  6 weeks

Other Outcomes (4)

• Proportion of patients with any adverse event for each intervention at 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

  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

  6 weeks, 6 months, and 12 months

Study Arms (4)

Morphine Sulphate

EXPERIMENTAL

Oral morphine sulphate given up to 5 mg twice daily.

Drug: Morphine Sulphate

Morphine Sulphate + Cough Control Therapy

EXPERIMENTAL

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

Pregabalin

EXPERIMENTAL

Oral pregabalin given up to a maximum tolerated dose of 150 mg twice daily.

Drug: Pregabalin

Pregabalin + Cough Control Therapy

EXPERIMENTAL

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

Interventions

Morphine Sulphate DRUG

Oral morphine sulphate given up to 5 mg twice daily.

Morphine Sulphate

Morphine Sulphate + Cough Control Therapy COMBINATION_PRODUCT

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).

Morphine Sulphate + Cough Control Therapy

Pregabalin DRUG

Oral pregabalin given up to a maximum tolerated dose of 150 mg twice daily.

Pregabalin

Pregabalin + Cough Control Therapy COMBINATION_PRODUCT

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).

Pregabalin + Cough Control Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults (≥18 years old) with either:
• 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
• 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.

You may not qualify if:

• 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;
• Are currently taking morphine or pregabalin for the treatment of any indication (i.e., RCC/UCC or chronic pain);\*
• 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);\*
• Have a history of opioid or substance abuse that, in the opinion of the investigator, may interfere with the conduct of the study;
• Are a current smoker, or ex-smoker with a \>20 pack-year history who have abstained from smoking for \<6 months;
• Have cough due to angiotensin-converting enzyme inhibitor use;
• Have symptoms of an upper respiratory infection within the last month that have not resolved;
• Had an asthma exacerbation within the last month that requires an increase or start of an oral corticosteroid;
• Have other primary pulmonary disorders, including pulmonary embolism, pulmonary hypertension, lung cancer, cystic fibrosis, radiologically-proven emphysema, interstitial lung disease, or severe bronchiectasis;
• Have language, memory, cognitive, or psychiatric issues that may prevent optimal participation;
• Have creatinine clearance \<15 mL/min, including individuals with end-stage renal disease who require hemodialysis or peritoneal dialysis;
• 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;
• Have participated in another clinical trial of an investigational medicinal product within 30 days;
• Pregnant or breastfeeding; or
• Females of child-bearing potential who:

Sponsors & Collaborators

• McMaster University: lead

Study Sites (5)

Respiratory Clinical Trials Centre, University of Calgary

Calgary, Alberta, T2N 4Z6, Canada

Location

Respiratory Research Lab, McMaster University

Hamilton, Ontario, L8N 3Z5, Canada

Location

St Joseph's Health Care London

London, Ontario, N6A 4V2, Canada

Location

Institut universitaire de cardiologie et de pneumologie de Quebec - University Laval

Québec, Quebec, G1V 4G5, Canada

Location

Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke

Sherbrooke, Quebec, J1H 5N4, Canada

Location

MeSH Terms

Conditions

Cough; Chronic Cough; cough hypersensitivity syndrome

Interventions

Morphine; Pregabalin

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; gamma-Aminobutyric Acid; Aminobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Imran Satia, MD PhD

  McMaster University

  PRINCIPAL INVESTIGATOR

• Wafa Hassan, MD

  McMaster University

  STUDY CHAIR

• Elena Kum

  McMaster University

  STUDY CHAIR

Central Study Contacts

Imran Satia, MD PhD

CONTACT

905-521-2100; satiai@mcmaster.ca

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 4, 2025
• First Posted: December 17, 2025
• Study Start: April 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): July 1, 2029
• Last Updated: December 17, 2025

Record last verified: 2025-12

Locations

CA (5)