Clinical trial NCT05571670: Bile Acids in Acute Insulin Resistance
Official title: Bile Acid and Lipid Metabolism in Patients With Drug-induced Acute Insulin Resistance
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: PI3K Gene Mutation
AKT Gene Mutation
MTOR Gene Mutation
Cancer
Insulin Resistance
Keywords: Insulin resistance
Bile acids
Cardiovascular disease
Dyslipidemia
Lead sponsor: Columbia University
Sponsor class: OTHER
First posted: 2022-10-07
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adult patients of any gender, without pre-existing diabetes, treated with PI3K/AKT/mTOR inhibitors for cancer according to standard of care.

Brief summary: This is a prospective observational study with a primary goal of monitoring changes in circulating bile acid profiles and parameters of glucose and lipid metabolism prior, during, and after cancer treatment with agents that directly impair insulin action: PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. Patients will not receive any cancer treatment specifically for the purposes of this study. Rather, this study will be based on treatment decisions made independently by participants' oncologists according to standard of care or other clinical trial protocol. This study seeks to enroll at least 25 participants each for PI3K inhibitors, mTOR inhibitors and, once available for open-label treatment, AKT inhibitors.

Detailed description: The primary objective of this study is to determine the effect of drug-induced acute insulin resistance (diaIR) on the ratio of 12α-hydroxylated bile acids (12-HBA) to 12α-hydroxylated bile acids (non-12-HBA) in cancer patients treated with phosphatidylinositol-4,5-bisphosphate kinase (PI3K) inhibitors (PI3Ki), mammalian target of rapamycin (mTOR) inhibitors (mTORi), and AKT inhibitors (AKTi) once possible. Specifically, this study will: (1) verify the induction of diaIR by monitoring changes in fasting ± postprandial blood glucose, insulin/c-peptide, and fructosamine; and (2) assess qualitative and quantitative changes in the circulating bile acid (BA) pool (including bile acid intermediary metabolites) by mass spectrometry in the fasting ± postprandial states prior to and then at 2 and 4 weeks after starting treatment. This study focuses in particular on determining changes in the 12α-hydroxylated bile acids to 12α-hydroxylated bile acids, as well as each of these subclasses and their individual substituents as a proportion of the overall BA pool.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Speaks English and/ or Spanish
* Any cancer diagnosis
* Planned for treatment with:

  * PI3K inhibitors

    * Alpelisib
    * Inavolisib
    * Any experimental PI3K inhibitor
  * AKT inhibitors (if these become available for open-label use during the study course)

    * Afuresertib
    * Capivasertib
    * Ipatasertib
    * Miransertib
    * Uposertib
  * mTOR inhibitors

    * Everolimus
    * Sirolimus
    * Temsirolimus
* Signed informed consent

Exclusion Criteria:

* Known dysglycemia
* Known diagnosis of diabetes mellitus
* Treatment with glucose-lowering medications at baseline

  * Insulin
  * Sulfonylureas or meglitinides
  * Metformin \>1000mg total daily dose
  * Thiazolidinediones
  * SGLT2 inhibitors
  * GLP-1 receptor agonists
  * DPP4 inhibitors
  * Amylin mimetics
  * Acarbose
* Significant biochemical evidence of liver dysfunction on lab tests within 30 days before starting drug that have not fallen to below the following thresholds prior to starting drug
* Significant functional or anatomical abnormalities of the small intestine
* Use of certain medications at baseline, within 7 days of starting cancer drug
* Allergy to cow dairy or soy (only excludes from MMTT, does not exclude from fasting blood draws)
* Inability to provide informed consent

Primary outcomes:
measure: Ratio of 12-HBA to non-12-HBA
timeFrame: 1-2 Months
measure: Insulin resistance
timeFrame: 1-2 months
Secondary outcomes:
measure: Lipid profile
timeFrame: 1-2 months
measure: Surrogate markers of BA signaling
timeFrame: 1-2 months
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
Study officials:
References: