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

NCT ID: NCT07288528

Last Updated: 2025-12-17

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 124 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-04-01
• Study Completion Date: 2029-07-01

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.

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.

Conditions

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

Keywords

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Morphine Sulphate

Oral morphine sulphate given up to 5 mg twice daily.

Group Type: EXPERIMENTAL

Morphine Sulphate

Intervention Type: DRUG

Oral morphine sulphate given up to 5 mg twice daily.

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).

Group Type: EXPERIMENTAL

Morphine Sulphate + Cough Control Therapy

Intervention Type: 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).

Pregabalin

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

Group Type: EXPERIMENTAL

Pregabalin

Intervention Type: DRUG

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

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).

Group Type: EXPERIMENTAL

Pregabalin + Cough Control Therapy

Intervention Type: 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).

Interventions

Morphine Sulphate

Oral morphine sulphate given up to 5 mg twice daily.

Intervention Type: DRUG

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).

Intervention Type: COMBINATION_PRODUCT

Pregabalin

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

Intervention Type: DRUG

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).

Intervention Type: COMBINATION_PRODUCT

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

McMaster University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Imran Satia, MD PhD

Role: PRINCIPAL_INVESTIGATOR

McMaster University

Wafa Hassan, MD

Role: STUDY_CHAIR

McMaster University

Elena Kum

Role: STUDY_CHAIR

McMaster University

Locations

Respiratory Clinical Trials Centre, University of Calgary

Calgary, Alberta, Canada

Respiratory Research Lab, McMaster University

Hamilton, Ontario, Canada

St Joseph's Health Care London

London, Ontario, Canada

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

Québec, Quebec, Canada

Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke

Sherbrooke, Quebec, Canada

Countries

Canada

Central Contacts

Imran Satia, MD PhD

Role: CONTACT

Phone: 905-521-2100

Email: satiai@mcmaster.ca

Facility Contacts

Stephen Field, MD

Role: primary

Imran Satia, MD PhD

Role: primary

Anurag Bhalla, MD

Role: primary

Andreanne Cote, MD MA

Role: primary

Simon Couillard, MD MSc

Role: primary

Other Identifiers

FORTITUDE-01

Identifier Type: -

Identifier Source: org_study_id