NCT04428723

Brief Summary

The goal of this study is to identify physiologic and molecular mechanisms that underlie hypoglycemia in the absence of diabetes (or medications that can cause hypoglycemia) and to investigate potential genetic and microbiome differences which contribute to hypoglycemia. We will test the hypothesis that hypoglycemia in the absence of diabetes is linked to genetic variation or the microbiome, and identify whether additional medical history or diagnoses are enriched in the population of patients with hypoglycemia.

Trial Health

75
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
33

participants targeted

Target at P25-P50 for all trials

Timeline
7mo left

Started Aug 2020

Longer than P75 for all trials

Geographic Reach
1 country

1 active site

Status
active not recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress91%
Aug 2020Dec 2026

First Submitted

Initial submission to the registry

May 27, 2020

Completed
15 days until next milestone

First Posted

Study publicly available on registry

June 11, 2020

Completed
2 months until next milestone

Study Start

First participant enrolled

August 11, 2020

Completed
6.3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2026

Expected
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2026

Last Updated

February 6, 2026

Status Verified

February 1, 2026

Enrollment Period

6.3 years

First QC Date

May 27, 2020

Last Update Submit

February 4, 2026

Conditions

Hypoglycemia

Keywords

MicrobiomeDNAHormonesGenetics

Outcome Measures

Primary Outcomes (10)

  • Entry of medical history data into a deidentified database.

    Medical history data will be entered into RedCap for analysis.

    March 2020 through March 2025

  • Entry of physical exam data into a deidentified database.

    Pertinent physical exam data will be entered into RedCap for analysis.

    March 2020 through March 2025

  • Entry of laboratory data into a deidentified database.

    Laboratory data will be entered into RedCap for analysis.

    March 2020 through March 2025

  • Entry of demographic data into a deidentified database.

    Demographic data will be entered into RedCap for analysis.

    March 2020 through March 2025

  • Analysis of participant demographics and medical history, comparing the 3 study groups.

    Demographic and medical history data will be summarized in RedCap and compared between groups using ANOVA or chi-square testing, depending on the variable analyzed.

    March 2025

  • Targeted resequencing of DNA to identify variants associated with hypoglycemia, comparing patients with hypoglycemia (both surgical and non-surgical) and healthy controls.

    Sequence variants identified during targeted resequencing will be summarized and prevalence will be compared between groups and with population databases. Depending on results of targeted resequencing, additional expanded genotyping may be performed.

    March 2025

  • Analysis of microbiome, comparing study groups.

    Microbiome will be characterized by sequencing to obtain metagenomic data and pathway analysis; all data will be adjusted for multiple comparisons.

    March 2025

  • Analysis of glucose patterns during masked continuous glucose monitoring (CGM), including time in range, time in hypoglycemia, time in hyperglycemia, comparing the study groups.

    For a subset of participants who consent to participate in optional Visit 2, CGM data will be analyzed to assess mean, median, peak, and nadir sensor glucose values, glycemic variability (GV), severity and length of hypoglycemia (% time glucose \<70, \<60, \<54 mg/dL), and number and duration of severe hypoglycemia (sensor glucose \<54, duration \>15 minutes) will be quantified. Metrics will be assessed over 24 hours and during daytime (6 AM to midnight) and nighttime (midnight to 6 AM) independently.

    March 2025

  • Analysis of metabolic responses during mixed meal testing.

    For a subset of participants who consent to participate in optional Visit 2, magnitude of hypoglycemia will be correlated with metabolite levels during meal testing. Metabolites will be measured at set time points after the start of the mixed meal. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in metabolic responses. Data will be checked to ensure variables conform to assumptions of the analysis. Sensitivity analysis will determine whether missing data are randomly associated with clinical or experimental phenotypes, and assess the impact of missing data on conclusions. The relationship between clinical and metabolic variables will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.

    March 2025

  • Analysis of hormonal responses during mixed meal testing.

    For a subset of participants who consent to participate in optional Visit 2, magnitude of hypoglycemia will be correlated with hormone levels during meal testing. Counterregulatory hormones will be measured at set time points after the start of the mixed meal. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in counterregulatory hormone responses. Data will be checked to ensure variables conform to assumptions of the analysis. Sensitivity analysis will determine whether missing data are randomly associated with clinical or experimental phenotypes, and assess the impact of missing data on conclusions. The relationship between clinical and hormonal variables will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.

    March 2025

Secondary Outcomes (4)

  • Relationship between metabolic responses and magnitude of hypoglycemia as determined by CGM.

    March 2025

  • Relationship between hormonal responses and magnitude of hypoglycemia as determined by CGM.

    March 2025

  • Relationship between metabolic responses and microbiome.

    March 2025

  • Relationship between hormonal responses and microbiome.

    March 2025

Other Outcomes (1)

  • Safety outcome- hyperglycemia and hypoglycemia during the study

    March 2025

Study Arms (3)

Hypoglycemia, no upper gastrointestinal (GI) surgery

Males or females with hypoglycemia with neuroglycopenia, but no history of upper GI surgery, diabetes or prediabetes

Other: Entry of demographic and medical history data into a deidentified databaseGenetic: Blood sample for DNA analysisDiagnostic Test: Stool sample for microbiome analysisDiagnostic Test: Mixed meal tolerance testDiagnostic Test: Continuous glucose monitoringDiagnostic Test: activity monitor

Hypoglycemia, with history of upper GI surgery

Males or females with hypoglycemia with neuroglycopenia, with history of upper GI surgery

Other: Entry of demographic and medical history data into a deidentified databaseGenetic: Blood sample for DNA analysisDiagnostic Test: Stool sample for microbiome analysisDiagnostic Test: Mixed meal tolerance testDiagnostic Test: Continuous glucose monitoringDiagnostic Test: activity monitor

Controls, without hypoglycemia or upper GI surgery

Males or females with no history of upper gastrointestinal surgery, hypoglycemia, or diabetes.

Other: Entry of demographic and medical history data into a deidentified databaseGenetic: Blood sample for DNA analysisDiagnostic Test: Stool sample for microbiome analysisDiagnostic Test: Mixed meal tolerance testDiagnostic Test: Continuous glucose monitoringDiagnostic Test: activity monitor

Interventions

Blood sample for DNA analysisGENETIC

Targeted resequencing of DNA to identify variants associated with hypoglycemia, comparing participants with hypoglycemia (both surgical and non-surgical) and healthy controls.

Controls, without hypoglycemia or upper GI surgeryHypoglycemia, no upper gastrointestinal (GI) surgeryHypoglycemia, with history of upper GI surgery
Stool sample for microbiome analysisDIAGNOSTIC_TEST

Participants will be asked to provide a fecal sample, collected at home, which will be analyzed to determine the types of bacteria present in the feces.

Controls, without hypoglycemia or upper GI surgeryHypoglycemia, no upper gastrointestinal (GI) surgeryHypoglycemia, with history of upper GI surgery
Mixed meal tolerance testDIAGNOSTIC_TEST

For a subset of participants: After an overnight fast, participants will be given a standard liquid mixed meal; blood samples will be collected at baseline (fasting) and at defined time points after a meal for metabolic and hormonal analyses.

Also known as: Meal Testing
Controls, without hypoglycemia or upper GI surgeryHypoglycemia, no upper gastrointestinal (GI) surgeryHypoglycemia, with history of upper GI surgery
Continuous glucose monitoringDIAGNOSTIC_TEST

A CGM sensor (Dexcom G4 or other professional version available at onset of study) will be placed in blinded (masked) mode, and will be worn for 10 days. Data will be analyzed to determine patterns of glucose during both day and night intervals.

Controls, without hypoglycemia or upper GI surgeryHypoglycemia, no upper gastrointestinal (GI) surgeryHypoglycemia, with history of upper GI surgery
activity monitorDIAGNOSTIC_TEST

The activity monitor (Fitbit Charge 2) will be worn by participants for 10 days, to assess activity, concurrent with CGM sensor wear.

Controls, without hypoglycemia or upper GI surgeryHypoglycemia, no upper gastrointestinal (GI) surgeryHypoglycemia, with history of upper GI surgery
Entry of demographic and medical history data into a deidentified databaseOTHER

Entry into repository for analysis.

Controls, without hypoglycemia or upper GI surgeryHypoglycemia, no upper gastrointestinal (GI) surgeryHypoglycemia, with history of upper GI surgery

Eligibility Criteria

Age18 Years - 70 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64), Older Adult (65+)
Sampling MethodNon-Probability Sample
Study Population

3 groups: (1) patients with hypoglycemia, but without a history of bariatric or other gastrointestinal surgery, recruited from the Joslin Hypoglycemia Clinic, (2) patients with hypoglycemia and history of upper gastrointestinal surgery, recruited from the Joslin Hypoglycemia Clinic,(3) controls without hypoglycemia or surgery, recruited by local advertisement or from family members of patients with hypoglycemia. We plan to enroll patients with hypoglycemia continuously over the next 5 years.

You may qualify if:

  • For hypoglycemia group without a history of bariatric surgery: Males or females diagnosed with hypoglycemia with prior episodes of neuroglycopenia.
  • For hypoglycemia group with history of upper gastrointestinal surgery: Males or females diagnosed with ongoing hypoglycemia with prior episodes of neuroglycopenia.
  • For non-surgical controls only: Males or females with no history of upper gastrointestinal surgery and no history of hypoglycemia or diabetes.
  • Age 18-70 years of age, inclusive, at screening.
  • Willingness to provide informed consent and attend one study visit, with option to attend a second visit with mixed meal test, and follow all study procedures

You may not qualify if:

  • Active treatment with any diabetes medications except for acarbose;
  • Known insulinoma, gastrinoma, or other neuroendocrine tumor;
  • Chronic kidney disease stage 4 or 5 (including end-stage renal disease);
  • Hepatic disease, including serum alanine transaminase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as serum albumin \< 3.0 g/dL; or serum bilirubin \> 2.0;
  • Congestive heart failure, New York Hear Association (NYHA) class II, III or IV;
  • History of myocardial infarction, unstable angina or revascularization within the past 6 months or 2 or more risk factors for coronary artery disease including diabetes, uncontrolled hypertension, uncontrolled hyperlipidemia, and active tobacco use;
  • History of syncope (unrelated to hypoglycemia) or diagnosed cardiac arrhythmia;
  • Concurrent administration of β-blocker therapy;
  • History of a cerebrovascular accident;
  • Seizure disorder (other than with suspect or documented hypoglycemia);
  • Active malignancy, except basal cell or squamous cell skin cancers;
  • Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease);
  • Major surgical operation within 30 days prior to screening;
  • Hematocrit \< 33% (women) or \<36% (men);
  • Bleeding disorder, treatment with warfarin, or platelet count \<50,000;
  • +6 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Joslin Diabetes Center

Boston, Massachusetts, 02215, United States

Location

Related Links

Biospecimen

Retention: SAMPLES WITH DNA

Blood and fecal samples will be stored for up to 5 years for future analyses of additional blood proteins and metabolites and microbiome species which may contribute to hypoglycemia. DNA will be stored for additional expanded genotyping, depending on results of targeted resequencing. Fecal samples and /or cultures from them may be used for mouse transfer experiments in the future. All samples will be labeled only with the study identifier (ID) and acrostic unique to each participant.

MeSH Terms

Conditions

Hypoglycemia

Interventions

Blood Specimen CollectionContinuous Glucose Monitoring

Condition Hierarchy (Ancestors)

Glucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Specimen HandlingClinical Laboratory TechniquesDiagnostic Techniques and ProceduresDiagnosisPuncturesSurgical Procedures, OperativeInvestigative TechniquesBlood Chemical AnalysisClinical Chemistry TestsDiagnostic Techniques, EndocrineMonitoring, Physiologic

Study Officials

  • Mary Elizabeth Patti, MD

    Joslin Diabetes Center

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
observational
Observational Model
COHORT
Time Perspective
CROSS SECTIONAL
Target Duration
3 Weeks
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

May 27, 2020

First Posted

June 11, 2020

Study Start

August 11, 2020

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

December 1, 2026

Last Updated

February 6, 2026

Record last verified: 2026-02

Data Sharing

IPD Sharing
Will share

Deidentified participant data may be shared with other researchers with permission of local institutional review boards.

Shared Documents
STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
Time Frame
6 months after publication of study results.
Access Criteria
Data will be shared with academic investigators with approval of local institutional review boards.

Locations

US(1)