CoughPhase 4FORTITUDENCT07288528
A 2x2 Factorial, Randomized, Open-label Trial to Evaluate Neuromodulators and Cough Control Therapy in Patients With Refractory or Unexplained Chronic Cough
A Phase 4 study testing Morphine Sulphate and Pregabalin in people with Cough and Refractory Chronic Cough, run by McMaster University at 5 sites in Canada.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cough, Refractory Chronic Cough, Unexplained Chronic Cough
- What is being tested?
- Morphine Sulphate and Pregabalin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 124 participants
- Where
- 5 sitesCanada
- Study dates
- 30 Sep 2026to 1 Oct 2029
- Phase
- Phase 4
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
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- 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:
- 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.
- 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.
- 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.
Trial locations and contacts
5 sites in 1 country. Contact the study team or a site near you to ask about taking part.
5 sites in 1 country
Canada5 sites
Respiratory Clinical Trials Centre, University of Calgary
Calgary, Alberta, T2N 4Z6
Stephen Field, MD, 403-220-8722, sfield@ucalgary.ca
Stephen Field, MD
Respiratory Research Lab, McMaster University
Hamilton, Ontario, L8N 3Z5
Imran Satia, MD PhD, 905-521-2100 ext. 76228, satai@mcmaster.ca
Imran Satia, MD PhD
St Joseph's Health Care London
London, Ontario, N6A 4V2
Anurag Bhalla, MD, 519-646-6100 ext. 61352, anurag.bhalla@sjhc.london.on.ca
Anurag Bhalla, MD MSc
Institut universitaire de cardiologie et de pneumologie de Quebec - University Laval
Québec, Quebec, G1V 4G5
Andreanne Cote, MD MA, 418-656-4747, andreanne.cote@criucpq.ulaval.ca
Andreanne Cote, MD MA
Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke, Quebec, J1H 5N4
Simon Couillard, MD MSc, 819-436-1110 ext. 15037, simon.couillard2@usherbrooke.ca
Simon Couillard, MD MSc
About this study
Official title: 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.
Read the 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 independent 1:1 randomization to pharmacotherapy-either low-dose morphine (up to 5 mg twice daily) or pregabalin (up to 150 mg twice daily)-and concurrent cough control therapy (CCT) or no CCT. 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.
- Conditions
- Cough, Refractory Chronic Cough, Unexplained Chronic Cough, Cough Hypersensitivity Syndrome, Chronic Cough
- Being tested
- Morphine Sulphate, Morphine Sulphate + Cough Control Therapy, Pregabalin, Pregabalin + Cough Control Therapy
- Keywords
- Cough, Chronic Cough, Morphine, Pregabalin, Non-Pharmacologic Therapy, Refractory Chronic Cough, Unexplained Chronic Cough
- Medical subject headings
- Cough, Chronic Cough, cough hypersensitivity syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Morphine SulphateDrug
Oral morphine sulphate given up to 5 mg twice daily.
Morphine Sulphate + Cough Control TherapyCombination 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).
PregabalinDrug
Oral pregabalin given up to a maximum tolerated dose of 150 mg twice daily.
Pregabalin + Cough Control TherapyCombination 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).
| Study group | Role | What they receive |
|---|---|---|
| Morphine Sulphate | Experimental | Oral morphine sulphate given up to 5 mg twice daily. Receives: 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). Receives: Combination Product: Morphine Sulphate + Cough Control Therapy |
| Pregabalin | Experimental | Oral pregabalin given up to a maximum tolerated dose of 150 mg twice daily. Receives: 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). Receives: Combination Product: Pregabalin + Cough Control Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from baseline in 24-hour cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 6 weeks
Measured: 6 weeks
Secondary outcomes (12)
Change from baseline in awake cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 6 weeks
Measured: 6 weeks
Change from baseline in sleep cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 6 weeks
Measured: 6 weeks
Change from baseline in cough bouts (defined by inter-cough intervals) measured by the VitaloJAK ambulatory cough monitor at 6 weeks
Measured: 6 weeks
Change from baseline in cough severity on the McMaster Cough Severity Questionnaire at 6 weeks
Measured: 6 weeks
Change from baseline in cough severity on the 100-mm visual analogue scale at 6 weeks
Measured: 6 weeks
Change from baseline in cough-specific quality of life on the Leicester Cough Questionnaire at 6 weeks
Measured: 6 weeks
Proportion of patients achieving a ≥30% reduction in 24-hour cough frequency at 6 weeks
Measured: 6 weeks
Proportion of patients achieving a ≥30-mm reduction on the 100-mm cough severity visual analogue scale at 6 weeks
Measured: 6 weeks
Proportion of patients achieving a ≥1.3-point improvement on the Leicester Cough Questionnaire at 6 weeks
Measured: 6 weeks
Change from week 6 (end of randomized phase) in cough severity on the McMaster Cough Severity Questionnaire at 6 and 12 months
Measured: 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
Measured: 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
Measured: 6 and 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Dec 2025
- Study start30 Sep 2026 (estimated)
- Primary completion1 Sep 2029 (estimated)
- Study completion1 Oct 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for CoughStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 124 participants (estimated)
Sponsor and investigators
- Lead sponsor
- McMaster University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Imran Satia, MD PhD, Principal investigator, McMaster University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07288528
- Sponsor's protocol ID
- FORTITUDE-01
- Acronym
- FORTITUDE
- Status last verified
- Dec 2025
- First submitted
- 4 Dec 2025
- Last updated
- 19 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The Principal Investigator and Steering Committee will review requests for data sharing on an individual basis. After the main publication of the FORTITUDE trial, there may be opportunities to conduct additional analyses on the data collected. Formal requests for additional analyses with a submitted rationale and analysis plan will be made to the Principal Investigator and reviewed with the Steering Committee.
Publications
Kum E, Hassan W, Beaudin S, Strong G, Smith K, Oliveira A, Al-Saiedy M, Mancopes R, Grave AS, Bernier M, Bhalla A, Brister DL, Cote A, Couillard S, Field SK, Johnston F, Newman R, Popovic N, Kaplan AG, Brooks D, Guyatt G, Satia I. Multicentre, 2x2 factorial, randomised, open-label trial of neuromodulators and cough control therapy for refractory or unexplained chronic cough: the FORTITUDE trial protocol. BMJ Open. 2026 Sep 18;16(9):e126545. doi: 10.1136/bmjopen-2026-126545.
PubMed 42760069