Metabolic Effects of Metformin Therapy in Obstructive Sleep Apnea

Status

Terminated

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04530747

Acronym

MET-OSA

Enrollment

Registered

2020-08-28

Start date

2021-01-28

Completion date

2021-11-30

Last updated

2023-01-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Sleep Apnea, Obstructive

Keywords

Obstructive Sleep Apnea, Metformin

Brief summary

The purpose of the study is to see if metformin improves metabolism in patients with obstructive sleep apnea (OSA) using positive airway pressure (PAP) therapy. Metformin is approved by the Food and Drug Administration (FDA) for the treatment and prevention of diabetes. It is not approved for use in patients with OSA.

Detailed description

Positive airway pressure (PAP) is standard therapy for obstructive sleep apnea (OSA) but has shown mixed results for improvement of insulin sensitivity and does not reduce cardiovascular (CV) events and mortality, even in patients with established CV disease. Hence, eliminating intermittent hypoxia alone with standard PAP therapy may not be sufficient to restore metabolism. Additional adjunct strategies (such as metformin) known to improve metabolism may be required to reduce metabolic burden and CV risk in OSA patients. The aim of this study is to examine the longitudinal changes in metabolism of OSA patients receiving both PAP and metformin treatment. The MET-OSA study will last about 4 months. After screening the participants to determine eligibility, baseline study measures will be obtained and the participants will be provided with standard PAP for OSA treatment. Participants will also be randomized to receive either placebo or metformin treatment for 3 months. Compliance to study drug will be determined during monthly follow-up visits. Final study visit will include assessment of all baseline study measures.

Interventions

DRUGMetformin + PAP

Subjects randomized to this arm will receive 500 mg capsules containing metformin extended release (XR). Metformin XR dosing will be 500 mg (1 x 500 mg) every evening (qPM) during Week 1, 1000 mg (2 x 500 mg) qPM during Week 2, 1500 mg (3 x 500 mg) qPM during Week 3, and 2000 mg (4 x 500 mg) qPM from Week 4 onwards. Subjects will also be provided PAP (positive airway pressure) device for standard management of obstructive sleep apnea.

DRUGPlacebo oral capsule + PAP

Subjects randomized to this arm will receive 500 mg capsules containing placebo. Placebo dosing will be 500 mg (1 x 500 mg) qPM during Week 1, 1000 mg (2 x 500 mg) qPM during Week 2, 1500 mg (3 x 500 mg) qPM during Week 3, and 2000 mg (4 x 500 mg) qPM from Week 4 onwards. Subjects will also be provided PAP (positive airway pressure) device for standard management of obstructive sleep apnea.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

35 Years to 65 Years

Healthy volunteers

Inclusion criteria

* Body mass index (BMI) ≥ 30-50 kg/m\^2 (inclusive). * Apnea-Hypopnea Index ≥ 15 events/h. * Must be able to provide written informed consent. * Willing to participate and adhere to study procedures (video recorded in-lab sleep studies, positive airway pressure (PAP) treatment, take study drug, have adipose tissue and skeletal muscle biopsies). * Women of child-bearing potential must agree to use appropriate contraception to avoid pregnancy throughout the study. * Willing to have blood, as well as adipose and muscle tissue stored for future use.

Exclusion criteria

* HbA1c \> 6.4%. * Severe or uncontrolled hypertension defined as systolic blood pressure (BP) ≥180 mmHg and/or diastolic BP ≥110 mmHg on the average of three seated measurements after being at rest for at least 5 minutes. * Significant cardiovascular, hepatic, renal, neurologic, or psychiatric disease as determined by the study physician. * Pregnancy, breast feeding or planning pregnancy in the coming 4 months. * Impaired renal function defined as estimated glomerular filtration rate (eGFR) \<60ml/min/1.73m2 (estimated with Chronic Kidney Disease Epidemiology Collaboration equation 1 method). * Known hypersensitivity to metformin. * Currently taking a glucose lowering or weight loss medications. * Current PAP use or use of PAP in the past 6 months. * Currently taking antihypertensive and lipid-lowering medications known to affect adipose tissue and skeletal muscle metabolism. For example, statins and drugs targeting renin-angiotensin system will not be allowed. However, use of diuretics, beta-blockers, alpha-blockers and calcium channel blockers may be allowed provided the participant is on a stable dose for at least 3 months prior to the study visit. * Oxygen desaturation index \<15 events/h of sleep. * Any medication or condition that, in the opinion of the medical investigator, could interfere with the study outcomes or put the subject at risk by participating in the study.

Design outcomes

Primary

Measure	Time frame	Description
Changes in Matsuda Index	approximately 4 months, includes measures obtained at baseline and 3 month follow-up.	Comparison of change in Matsuda Index as determined by 2-h oral glucose tolerance test (OGTT). During OGTT, response to oral 75g glucose intake is determined by measuring insulin and glucose in timed samples obtained at -5, 10, 20, 30, 60, 90 and 120 min. Matsuda index is a commonly used composite index to estimate whole-body insulin sensitivity. Matsuda index is calculated as (10,000/ square root of \[fasting glucose X fasting insulin\] X \[mean OGTT glucose X mean OGTT insulin\]). Increase in scores reflect improvement in whole body insulin sensitivity.

Secondary

Measure	Time frame	Description
Changes in Insulin Area Under the Curve (AUC) During 2-h Oral Glucose Tolerance Test (OGTT)	approximately 4 months, includes measures obtained at baseline and 3 month follow-up.	Comparison of change in insulin AUC (area under the curve) as derived from 2-h oral glucose tolerance test (OGTT). During OGTT, response to oral 75g glucose intake is determined by measuring insulin and glucose in timed samples obtained at -5, 10, 20, 30, 60, 90 and 120 min. 2-h insulin AUC is calculated using trapezoid method. Higher AUC indicates higher insulin secretion.
Changes in Glucose Area Under the Curve (AUC) During 2-h Oral Glucose Tolerance Test (OGTT)	approximately 4 months, includes measures obtained at baseline and 3 month follow-up.	Comparison of change in glucose AUC (area under the curve) as derived from 2-h oral glucose tolerance test (OGTT). During OGTT, response to oral 75g glucose intake is determined by measuring insulin and glucose in timed samples obtained at -5, 10, 20, 30, 60, 90 and 120 min. 2-h glucose AUC is calculated using trapezoid method. Higher AUC indicates higher levels of circulating glucose.
Changes in Insulinogenic Index	approximately 4 months, includes measures obtained at baseline and 3 month follow-up.	Comparison of insulinogenic index derived from the initial 30 min data from the 2-h oral glucose tolerance test (OGTT). Insulinogenic index measures the early insulin response during the oral glucose challenge. The index is calculated as ratio of change in insulin to glucose from 0 to 30 min values derived from OGTT. Decrease in scores reflect improvement in insulin sensitivity.
Changes in Disposition Index	approximately 4 months, includes measures obtained at baseline and 3 month follow-up.	Comparison of change in disposition index as derived from 2-h oral glucose tolerance test. Disposition index measures beta-cell function and is calculated as product of Matsuda index and Insulinogenic index values. Increase in scores reflect improvement in glucose metabolism.
Changes in Homeostasis Model Assessment for Insulin Resistance (HOMA-IR)	approximately 4 months, includes measures obtained at baseline and 3 month follow-up.	Comparison of change in HOMA-IR value derived from fasting insulin and glucose. HOMA-IR is a simple index for insulin resistance based on fasting measures of glucose and insulin which is a commonly used end-point for assessment of insulin resistance in clinical trials. HOMA-IR is calculated as \[(fasting insulin X fasting glucose)/ 22.5\]. Higher values indicate higher insulin resistance. An increase will suggest a detrimental effect on glucose metabolism. Individuals with HOMA-IR \< 5.7% are considered healthy, between 5.7 and 6.4% are considered prediabetic, and more than 6.4% are considered diabetic.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Metformin + PAP Subjects randomized to this arm will be orally given 2000 mg metformin daily. Metformin dosage will be slowly increased to improve tolerance. Metformin: Subjects randomized to this arm will receive 500 mg capsules containing metformin XR. Metformin XR dosing will be 500 mg (1 x 500 mg) qPM during Week 1, 1000 mg (2 x 500 mg) qPM during Week 2, 1500 mg (3 x 500 mg) qPM during Week 3, and 2000 mg (4 x 500 mg) qPM from Week 4 onwards. Subjects will also be provided PAP (positive airway pressure) device for standard management of obstructive sleep apnea.	8
Placebo Oral Capsule + PAP Subjects randomized to this arm will receive placebo matching study drug. Placebo oral capsule: Subjects randomized to this arm will receive 500 mg capsules containing placebo. Placebo dosing will be 500 mg (1 x 500 mg) qPM during Week 1, 1000 mg (2 x 500 mg) qPM during Week 2, 1500 mg (3 x 500 mg) qPM during Week 3, and 2000 mg (4 x 500 mg) qPM from Week 4 onwards. Subjects will also be provided PAP (positive airway pressure) device for standard management of obstructive sleep apnea.	8
Total	16

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Metformin + PAP	Placebo Oral Capsule + PAP	Total
Age, Continuous	50.25 years STANDARD_DEVIATION 8.31	51.5 years STANDARD_DEVIATION 5.04	50.88 years STANDARD_DEVIATION 6.67
Apnea Hypopnea Index	54.4 event/h of sleep STANDARD_DEVIATION 22.5	52.1 event/h of sleep STANDARD_DEVIATION 21	53.3 event/h of sleep STANDARD_DEVIATION 21.1
Body mass index	36.63 Kg/m^2 STANDARD_DEVIATION 2.34	36.31 Kg/m^2 STANDARD_DEVIATION 3.48	36.47 Kg/m^2 STANDARD_DEVIATION 2.87
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	7 Participants	8 Participants	15 Participants
Region of Enrollment United States	8 participants	8 participants	16 participants
Sex: Female, Male Female	1 Participants	2 Participants	3 Participants
Sex: Female, Male Male	7 Participants	6 Participants	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 8	0 / 8
other Total, other adverse events	0 / 8	0 / 8
serious Total, serious adverse events	0 / 8	0 / 8

Outcome results

Primary

Changes in Matsuda Index

Comparison of change in Matsuda Index as determined by 2-h oral glucose tolerance test (OGTT). During OGTT, response to oral 75g glucose intake is determined by measuring insulin and glucose in timed samples obtained at -5, 10, 20, 30, 60, 90 and 120 min. Matsuda index is a commonly used composite index to estimate whole-body insulin sensitivity. Matsuda index is calculated as (10,000/ square root of \[fasting glucose X fasting insulin\] X \[mean OGTT glucose X mean OGTT insulin\]). Increase in scores reflect improvement in whole body insulin sensitivity.