Clinical trial NCT06800092: Sildenafil to Prevent and Reduce Cancer Related Cognitive Impairment
Official title: Sildenafil to Prevent and Reduce Cancer Related Cognitive Impairment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Cancer
Keywords: Fatigue
Brain Fog
Lead sponsor: The University of Texas Medical Branch, Galveston
Sponsor class: OTHER
First posted: 2025-01-29
Enrollment: 30
Sex: FEMALE
Minimum age (years): 30
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: This study is examining the effects of standard of care cancer treatment as well as a medication called Sildenafil, on the cancer associated fatigue, cognition and the gut microbiome.

Detailed description: Cancer related cognitive impairment (CRCI) severely impacts neurocognitive function and is characterized by deficits in memory, learning, processing speed, and executive function. This cognitive impairment commonly referred to as "brain fog" or "chemo-brain," often co-occurs with central and peripheral fatigue. Symptoms typically begin acutely with the initiation of therapy, and persist chronically throughout prolonged treatment. Despite advancements in cytotoxic chemotherapies, CRCI plagues 75% of breast cancer patients during treatment, and development of new therapeutic options have been hampered by an incomplete understanding of the underlying mechanisms that cause CRCI. Although the etiology is not clear, CRCI is known to be associated with oxidative stress, increased inflammation, and disruption to the blood-brain barrier (BBB). Importantly, the endothelial cells of the BBB protect the central nervous system (CNS) from harmful and inflammatory bloodborne factors. Similarly, endothelial and epithelial barriers in the gut prevent microbial invasion and resulting regional and systemic inflammatory signaling. Thus, gut and brain barriers regulate exposure of the CNS to inflammatory factors and represent an important source of communication in the gut-brain axis. Research suggests that cytotoxic chemotherapeutic agents compromise both brain and gut endothelial and epithelial barrier integrity, leading to extravasation of toxins and immune cells into the CNS, causing neuroinflammation and CRCI. This study proposes that sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, will preserve barrier integrity during chemotherapy by downregulating oxidative and nitrosative stress that leads to endothelial dysfunction via multiple pathways. Thus, the goal of this project is to interrogate how chemotherapy-induced brain and gut barrier dysfunction mediate CRCI, neurotoxicity, and neuro- and systemic inflammation. Outcomes will be measured at baseline and throughout standard of care treatment, specifically after neoadjuvant chemotherapy, surgery, radiation treatment, chemotherapy treatment and after 24 weeks of endocrine treatment.

Eligibility criteria: Inclusion Criteria:

* Female
* Ages 30 - 50 years
* Self-reported menses occurrence within past 12 months
* Diagnosis of ER+/HER2- breast cancer
* Willing and able to comply with study procedures
* Willing and able to provide consent

Exclusion Criteria:

* Untreated thyroid disorder
* Untreated diabetes
* BMI \>30
* Current treatment with metformin
* Diagnosed neuromuscular disease
* Diagnosed neurovascular disease
* Prior history of cognitive impairment
* Prior history of chemotherapy treatment
* HIV, Hepatitis B or Hepatitis C
* Systolic blood pressure \<90 or \>170, diastolic blood pressure \<50 or \>110 after repeated evaluation with proper cuff. This range is the acceptable range stated in the prescribing information for sildenafil (\>90/50 and \<170/110)
* Use of alpha blockers in the past 2 weeks
* Use of PDE5 inhibitors in the past 2 weeks
* Use of nitrates
* Subjects with MRI incompatible devices
* Subjects with severe claustrophobia
* Any medical condition that, in the opinion of the investigator, would place the subject at increased risk for participation

Primary outcomes:
measure: Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale at baseline
timeFrame: Baseline
measure: Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after neoadjuvant chemotherapy treatment
timeFrame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
measure: Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after surgery
timeFrame: through completion of surgery, average of 24 weeks from baseline
measure: Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after radiation treatment
timeFrame: through radiation treatment completion, average of 30 weeks from baseline
measure: Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after chemotherapy treatment
timeFrame: through chemotherapy treatment completion, average of 50 weeks from baseline
measure: Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after 24 weeks of endocrine treatment
timeFrame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline
measure: Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) at baseline
timeFrame: baseline
measure: Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after neoadjuvant chemotherapy treatment
timeFrame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
measure: Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after surgery
timeFrame: through completion of surgery, average of 24 weeks from baseline
measure: Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after radiation treatment
timeFrame: through radiation treatment completion, average of 30 weeks from baseline
measure: Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after chemotherapy treatment
timeFrame: through chemotherapy treatment completion, average of 50 weeks from baseline
measure: Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after 24 weeks of endocrine therapy treatment
timeFrame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline
measure: Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) at baseline
timeFrame: baseline
measure: Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after neoadjuvant chemotherapy treatment
timeFrame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
measure: Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after surgery
timeFrame: through completion of surgery, average of 24 weeks from baseline
measure: Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after radiation treatment
timeFrame: through radiation treatment completion, average of 30 weeks from baseline
measure: Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after chemotherapy treatment
timeFrame: through chemotherapy treatment completion, average of 50 weeks from baseline
measure: Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after 24 weeks of endocrine treatment
timeFrame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline
Secondary outcomes:
measure: Quantify absolute abundance of gut microbiome using using metagenomic analysis at baseline
timeFrame: baseline
measure: Quantify absolute abundance of gut microbiome using metagenomic analysis after neoadjuvant chemotherapy treatment
timeFrame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
measure: Quantify absolute abundance of gut microbiome using metagenomic analysis after surgery
timeFrame: through completion of surgery, average of 24 weeks from baseline
measure: Quantify absolute abundance of gut microbiome using metagenomic analysis after radiation treatment
timeFrame: through radiation treatment completion, average of 30 weeks from baseline
measure: Quantify absolute abundance of gut microbiome using metagenomic analysis after chemotherapy treatment
timeFrame: through chemotherapy treatment completion, average of 50 weeks from baseline
measure: Quantify absolute abundance of gut microbiome using metagenomic analysis after 24 weeks of endocrine treatment
timeFrame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline
measure: Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after neoadjuvant chemotherapy treatment
timeFrame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
measure: Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after surgery
timeFrame: through completion of surgery, average of 24 weeks from baseline
measure: Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after radiation treatment
timeFrame: through radiation treatment completion, average of 30 weeks from baseline
measure: Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after chemotherapy treatment
timeFrame: through chemotherapy treatment completion, average of 50 weeks from baseline
measure: Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after 24 weeks of endocrine treatment
timeFrame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline
Other outcomes:
Locations:
city: Galveston
country: United States
facility: The University of Texas Medical Branch
state: Texas
Study officials:
affiliation: University of Texas
name: Melinda Sheffield-Moore, PhD
role: PRINCIPAL_INVESTIGATOR
References: