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

Recent preclinical research has identified wild-type cystic fibrosis transmembrane conductance regulator (CFTR) in cerebral artery smooth muscle cells as a key protein involved in the myogenic mechanism governing cerebrovascular reactivity and a potential therapeutic target. In experimental models of HF, CFTR-protein expression is downregulated, which is associated with increased vascular tone, reduced cerebral blood flow, increased neuronal damage and poorer scores on functional tests. Treatment with CFTR-correctors reverses the pathology and normalizes cerebral artery CFTR-expression, vascular tone, CBF, neuronal health and functional outcome. Lumacaftor is an existing small-molecule CFTR-corrector that increases the abundance of CFTR-protein at the cell membrane by augmenting its trafficking and stability. It is currently approved as part of a combination therapy (lumacaftor/ivacaftor) in cystic fibrosis patients with the CFTR F508del gene mutation.

The purpose of this trial is to build on the CFTR-stabilizing properties of lumacaftor in HF patients and determine whether clinical application of a CFTR-stabilizing treatment improves cerebral perfusion and cognitive performance. The study is a Phase II proof-of-concept, randomized, parallel group, placebo-controlled, double-blind, longitudinal, single treatment center trial of 60 stable adults with HFrEF (no hospitalization within 3 months) on optimal goal-directed medical therapy treated with lumacaftor vs. identical placebo. This will include participants who are New York Heart Association (NYHA) class II-III, with reduced cardiac output and an EF of <40%.

Following eligibility assessment and consent procedures, participants will undergo screening to measure baseline CBF using perfusion-weighted magnetic resonance imaging (MRI). Participants enrolled in the study will be allocated 1:1 to receive lumacaftor 200 mg q12 or identical placebo for 30 days. A follow-up cerebral MRI will assess the change from baseline at 1 month in global CBF as the primary outcome measure of the trial. In additional to safety metrics, a battery of neurocognitive assessments will be administered using the Montreal Cognitive Assessment (MoCA), Trail Making Test (TMT), the Hospital Anxiety and Depression Scale (HADS) and the Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) to determine changes from baseline, at 1 month and 3 months in cognitive function, mental health, and quality of life as key secondary outcomes.

• Lumacaftor 200 MG (Drug): Lumacaftor 200 mg q12
• Placebo (Drug): Identical placebo

Primary outcomes

• Efficacy of lumacaftor treatment in increasing cerebral blood flow versus placebo in HFrEF patients. [Baseline and 1 month]: Change from baseline in global cerebral blood flow at 1 month using treatment or placebo as assessed by perfusion weighted MRI.

Secondary outcomes

• Rate of treatment-emergent adverse events as assessed by MedDRA. [Baseline up to Day 90]: Number of treatment-emergent AEs by severity and treatment received. This will capture participants who received at least one dose of treatment.
• Number of participants with clinically significant changes from baseline in physical examinations findings at 1 week, 1 month and 3 months. [Baseline, 1 week, 1 month and 3 months]
• Number of participants with clinically significant changes from baseline in vital signs at 1 week, 1 month and 3 months. [Baseline, 1 week, 1 month and 3 months]
• Number of participants with clinically significant changes from baseline in electrocardiograms (ECGs) at 1 week, 1 month and 3 months. [Baseline, 1 week, 1 month and 3 months]
• Number of participants with clinically significant changes from baseline in laboratory test results at 1 week, 1 month and 3 months. [Baseline, 1 week, 1 month and 3 months]
• Number of participants with clinically significant changes from baseline in the Columbia Suicide Severity Rating Scale (C-SSRS) at 1 week, 1 month and 3 months. [Baseline, 1 week, 1 month and 3 months]: The C-SSRS is a questionnaire that captures severity and intensity of suicidal ideation and the number of suicidal behavioural attempts.
• Changes from baseline in Montreal Cognitive Assessment (MoCA) scores at 1 month and 3 months. [Baseline, 1 month and 3 months]: MoCA is a screening tool for global cognitive function over several domains (memory, attention, language, visuospatial skills, and executive function). Scoring is 0-30-points, with higher scores indicating better global cognition function.
• Changes from baseline in the 36-Item Short Form Health Survey (SF-36) scores at 1 month and 3 months. [Baseline, 1 month and 3 months]: The SF-36 is a self-report, general measure of health status and quality of life, assessing eight domains (physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions). Scoring is 0-100 points for each domain, with higher scores indicating a more favourable health state.
• Changes from baseline in the Hospital Anxiety and Depression Scale (HADS) scores at 1 month and 3 months. [Baseline, 1 month and 3 months]: HADS is a self-report, 14-item measure to screen for depression and anxiety disorders among non-psychiatric, medically ill, outpatient populations. Scoring is 7 points for each domain of depression and anxiety, with scores of less than 7 for non-cases, 8-10 for mild cases, 11-14 for moderate cases and 15-21 for severe cases.
• Changes from baseline in the Trail-Making-Test (TMT) scores at 1 month and 3 months. [Baseline, 1 month and 3 months]: The TMT is an attention and task-switching, two-part test to measure executive and psychomotor function by connecting a series of dots accurately. Scoring is based on time to completion, with a score of more than 70-78 seconds deficient for TMT-A and a score of more than 180-273 seconds deficient for TMT-B.

Sex: All, ages: 18 Years to any

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

• Kim Connelly, Principal investigator, Unity Health Toronto