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

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)

Overview

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.

Interventions

• Drug Morphine Sulphate
  Oral morphine sulphate given up to 5 mg twice daily.
• 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).
• Drug Pregabalin
  Oral pregabalin given up to a maximum tolerated dose of 150 mg twice daily.
• 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).

Primary outcome measures

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

Secondary outcome measures (9)

• Change from baseline in awake cough frequency (coughs/hour) measured by the VitaloJAK ambulatory cough monitor at 6 weeks [Time frame: 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]
• 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]
• Change from baseline in cough severity on the McMaster Cough Severity Questionnaire at 6 weeks [Time frame: 6 weeks]
• Change from baseline in cough severity on the 100-mm visual analogue scale at 6 weeks [Time frame: 6 weeks]
• Change from baseline in cough-specific quality of life on the Leicester Cough Questionnaire at 6 weeks [Time frame: 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]
• 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]
• 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]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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:

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 5 centers

• Respiratory Clinical Trials Centre, University of Calgary — Calgary
• Respiratory Research Lab, McMaster University — Hamilton
• St Joseph's Health Care London — London
• Institut universitaire de cardiologie et de pneumologie de Quebec - University Laval — Québec
• Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke — Sherbrooke

Identifiers

NCT: NCT07288528 · FORTITUDE-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗