Lumacaftor Yields Reversal of Impaired Cerebral Blood Flow in Heart Failure Patients

Inclusion Criteria Participants screened for enrolment must meet all of the following criteria to be eligible for study participation: 1. Provide written informed consent 2. Aged 18 years or older with stable heart failure NYHA class II-III, with reduced cardiac output and an EF of \<40% on optimal goal directed medical therapy as per CCS Guidelines and the AHA/ACC/HFSA Guidelines for the Management of Heart Failure 3. No hospital admissions for inpatient care in 3 months prior to study 4. CBF at screening of ≤45 mL/100g/min 5. Able to comply with study procedures 6. Female participants must fulfill at least one of the following: 1. Negative serum pregnancy (β-hCG) test at screening if participant is of childbearing potential (defined as having gone through menarche and not postmenopausal) 2. Post-menopausal for a minimum of 1 year (defined as 12 consecutive months with no menses without an alternative medical cause) Be surgically sterile for a minimum of 6 months (achieved through partial/total hysterectomy, bilateral oophorectomy, or bilateral salpingectomy; note that tubal ligation is not considered a method of permanent sterilization) 7. Agree to avoid pregnancy and be willing to use medically acceptable methods of contraception for the duration of study and for 1 month after the last dose of the IMP (for females) and for 3 months after the last dose (for males) Exclusion criteria Participants screened for enrolment, meeting any of the following criteria are not eligible for study participation: 1. Participants with symptomatic HF who have non-MRI compatible cardiac implantable electronic devices (CIEDs), such as a cardiac defibrillator or pacemaker, or in whom this is required within 3 months of the study 2. Those requiring coronary revascularisation in 6 months following the study 3. Participants with cystic fibrosis (CF) or any other condition that may require use of CFTR modulating agents 4. Participants using antiallergics (e.g., montelukast), antibiotics (e.g., clarithromycin), anticoagulants (e.g., warfarin), anticonvulsants (e.g., carbamazepine), antidepressants (e.g., citalopram), antifungals (e.g., fluconazole), anti-mycobacterials (e.g., rifabutin), barbituates, benzodiazepines (e.g., midazolam), immunosuppressants (e.g., cyclosporine), proton pump inhibitors (e.g., esomeprazole) within 30 days of trial start 5. A history of or known seropositivity for human immunodeficiency virus (HIV) and active hepatitis B and/or C infection 6. Participants with moderate or severe hepatic disease (such as cirrhosis), or impaired liver function tests defined as serum ALT and/or AST \>3 x the upper limit of normal (ULN) or total bilirubin \>2 x ULN 7. Resting heart rate of \>100 bpm 8. Symptomatic blood pressure \<90 mmHg systolic 9. Any major deviation in clinical lab values and/or electrocardiograms deemed clinically significant at baseline that in the opinion of the investigator would compromise the outcome of the trial as it relates to the active therapy 10. Any clinically significant abnormalities in physical examination, neurological examination, vital signs, safety laboratory tests, and/or electrocardiograms that may impact the safety of the participant, in the opinion of the investigator 11. Any suicidal behaviour in the past 2 years (i.e., actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behaviour), or any suicidal ideation (type 4 or 5) in the last 6 months (i.e., active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent), as defined by the C-SSRS 12. Participants currently experiencing any clinically significant or unstable medical condition that in the opinion of the investigator might limit their ability to complete the study, or to comply with the requirements of the protocol, including dermatologic disease, haematological disease, pulmonary disease, kidney disease, hepatic disease, gastrointestinal disease, genitourinary disease, endocrine disease, neurological disease, and psychiatric disease 13. Participants with severe chronic obstructive pulmonary disease (COPD), or demonstrating a significant degree of pulmonary obstruction with a forced expiratory volume in the first second (FEV1) or forced vital capacity (FVC) that is \<70% of the predicted normal value, or FEV/FVC ratio that is \<65% 14. Females having used implanted, injected, intravaginal, or intrauterine hormonal contraceptive within 6 months prior to first study drug administration. 15. Females taking oral or transdermal hormonal contraceptives within 30 days prior to first study drug administration 16. Female participants who are currently breastfeeding or planning to breastfeed 17. Any malignancy not considered cured (except basal cell carcinoma of the skin). A participant is considered cured if there has been no evidence of cancer recurrence for the 5 years prior to screening 18. Unstable coronary syndromes 19. Moderate or severe valvular disease 20. Body mass index \>40 kg/m2 21. Estimated glomerular filtration rate (eGFR) of \<30 ml/m2 22. Participants with a ferro-magnetic aneurysm clip or vascular clamp that is non-MRI compatible 23. Claustrophobia or inability to undergo MRI without sedation 24. Any other recognized CMRI contraindication as per local guidelines 25. Participants that have participated in a clinical study during the 3 months prior to screening, or that plan to participate in another clinical study