HypertensionPhase 4ErtugliflozinNCT03640221
Ertugliflozin Versus Hydrochlorothiazide in Reducing Sympathetic Neural Overactivity in Patients With Hypertension and Recently-diagnosed Type 2 Diabetes.
A Phase 4 study testing Ertugliflozin, Hydrochlorothiazide 12.5mg and Microneurography in people with Hypertension and Diabetes Mellitus, Type 2, run by Cedars-Sinai Medical Center at 1 site in United States.
Trial summary
The sodium-glucose cotransporter 2 (SGLT2) inhibitors are an exciting new class of antidiabetic drugs that cause a modest reduction in high blood pressure and large reductions in the risk of cardiovascular disease (CVD) outcomes and renal outcomes in patients with advanced type 2 diabetes and very high CVD risk. Read more about this study
- Who is it for?
- Ages 35 to 65 years
- Conditions the study is for
- Hypertension, Diabetes Mellitus, Type 2
- What is being tested?
- Ertugliflozin, Hydrochlorothiazide 12.5mg and Microneurography
- Type of treatment
- Pill or oral medicine, Injection or infusion, Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Sep 2018to 31 Aug 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of diabetes mellitus established < 24 months before enrollment
- Ages 30-65 years
- Men and women, inclusive or race/ethnic groups
- Background standard-of-care cardiometabolic therapy including a stable dose regimen for 6 weeks of: a) metformin and b) an ACEI or an ARB and c) any statin.
- HBA1C of 6.5 to 8.0
- Urine albumin/creatinine < 300
Show all 13Show fewer
- eGFR > 60
- Systolic BP 130 to 150 mmHg on the first screening visit and a Systolic BP of 130 to 145 mmHg on the second screening visit
- BMI 25 to 35 inclusive
- Normal sinus rhythm by 12-lead ECG with no major conduction abnormalities
- Left ventricular ejection fraction > 50% by transthoracic echocardiogram
- Willing and able to cooperate with all aspects of the protocol;
- Willing and able to give written informed consent for study participation and provide consent for access to medical data according to appropriate local data protection legislation, allowing authorization to access medical records and describe events captured in the endpoints
Who cannot join
- Known history of previous cardiovascular disease (CVD)
- Currently on other diabetes medications such as: insulin analogs, GLP-1 analogs, DPPIV inhibitors, thiazolidinediones, sulfonylureas, meglitinides, alpha glucosidase inhibitors, amylin analogies.
- Any concomitant medications or supplements, with the exception of: aspirin, ACE-I or ARB, and statin therapy
- Diagnosed diabetic peripheral sensory neuropathy or retinopathy
- Orthostatic hypotension defined as standing BP < 100/60 or postural fall of SBP > 20 or DBP > 10
- Female patients who are pregnant, intend to become pregnant during the study, or are nursing
Show all 15Show fewer
- Known hypersensitivity to SGLT-2 inhibitors
- Presence of hepatic disease
- History of diabetic ketoacidosis
- Type 1 diabetes
- Pancreas or beta-cell transplantation
- Pancreatitis or pancreatic surgery
- Unable to communicate or cooperate with the investigator due to language, poor mental development or impaired cerebral function.
- History of illicit drug use
- Any other condition(s) deemed by the physician-investigators to be unsafe to participate
Trial locations and contacts
1 site in 1 country.
United States1 site
Cedars-Sinai Medical Center
Los Angeles, California, 90048
About this study
Official title: A Double-blind, Randomized, Parallel 2- Arm Study to Compare the Efficacy of Ertugliflozin Versus Hydrochlorothiazide in Reducing Sympathetic Neural Overactivity in Patients With Hypertension and Recently-diagnosed Type 2 Diabetes Who Are Receiving Background Standard-of-care Cardio-metabolic Therapy With Metformin, an Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker, and a Statin.
The sodium-glucose cotransporter 2 (SGLT2) inhibitors are an exciting new class of antidiabetic drugs that cause a modest reduction in high blood pressure and large reductions in the risk of cardiovascular disease (CVD) outcomes and renal outcomes in patients with advanced type 2 diabetes and very high CVD risk. However, the mechanistic underpinning of these CVD benefits is not well understood. Mechanistic studies are needed to define specific biologic targets and thus optimize therapeutic benefits.
Type 2 diabetes mellitus is firmly established as a state of sympathetic neural overactivity, which may contribute to coexistent hypertension, heart failure, sudden cardiac death, macro- and micro-vascular complications of diabetes, and diabetic nephropathy. In patients recently diagnosed with Type 2 diabetes, microelectrode recordings of sympathetic nerve activity (SNA) targeted to the skeletal muscle circulation have shown both:
Read more
- abnormally high resting (ambient) levels of sympathetic nerve activity; and
- greatly exaggerated increases in sympathetic nerve activity during isometric (static) handgrip exercise.
The purpose of the proposed study is to determine if Ertugliflozin, a SGLT2 inhibitor, constitutes an effective countermeasure against sympathetic overactivity in patients with diagnosed hypertension and recently diagnosed type 2 diabetes by normalizing the high resting level of muscle sympathetic nerve activity (SNA) as measured by intraneural microelectrodes in the peroneal nerve.
Thus, an effective countermeasure is an urgent unmet medical need. The SGLT2 inhibitors hold exciting promise to address this need.
Read the detailed description
Static handgrip provides unique mechanistic insights into putative therapeutic targets (in this case the SGLT2 inhibitors) within the human autonomic nervous system include examining the reflexes within the nervous system and its response as a result. Static handgrip will require that patients lay down and with the use of a dyanometer (handgrip device which measures the force output generated from the handgrip exercise) and they will squeeze to the maximum of their ability for 30 seconds, then have a relaxation period, and grip again.
Typically responses to the nervous system travel via unmyelinated skeletal muscle nerve fibers (afferent signals) and the brain responds via the central motor command (or voluntary motor effort) which is its communication to the body to indicate the perception of effort needed in order to complete the task at hand. This volitional component of exercise- is the main mechanism driving heart rate during static handgrip.
When activated by exercise-induced skeletal muscle acidosis (as with static handgrip), muscle afferents signal the brain of a mismatch between muscle perfusion and metabolic demand and trigger a reflex increase in sympathetic nerve activity to non-exercising skeletal muscles. This raises blood pressure and shunts blood to the metabolically active muscle groups. Also, with voluntary exercise, the activation of brain pathways leading to the engagement of parallel central inhibition of the vagus nerve. The result is an increase in cardiac sympathetic nerve activity but it has an an insignificant effect on muscle sympathetic nerve activity, which is driven almost entirely by direct input from the afferent signals.
Thus, the investigators hypothesize that, in type 2 diabetes, impaired skeletal muscle energetics requires patients to use excessive voluntary motor effort to perform routine static handgrip, resulting in a parallel augmentation in cardiac sympathetic nerve activity. If Ertugliflozin improves skeletal muscle energetics, the same isometric exercise will require less motor effort which should result in smaller increases in cardiac sympathetic nerve activity and heart rate as well as a lower rating of perceived exertion on the Borg scale (an established index of central command).
The proposed work stands to advance several innovative concepts that could change the clinical approach to the early management of type 2 diabetes:
- The sympathetic nervous system as a novel therapeutic target in the mechanistic underpinning of how SGLT2 inhibitors protect against major CVD.
- Hyperfunction of unmyelinated autonomic (skeletal muscle) sensory nerves as a putative abnormal indicator of diabetic autonomic cardiovascular neuropathy.
- Early SGLT2-mediated correction of sympathetic overactivity in patients with type 2 diabetes could favorably alter the natural history of diabetic autonomic neuropathy.
The proposed methodology incorporates several scientific rigors:
- Direct measurement of sympathetic nerve action potentials in human patients using intraneural microelectrodes. This is the gold standard for studying the regulation of the sympathetic nervous system in patients.
- This microneurographic technique is highly quantitative and remarkably reproducible when a given subject is studied repeatedly without intervention. The spatial resolution is a major advantage by permitting recording of postganglionic fibers innervating the skeletal muscle circulation without "interfering noise" from surrounding postganglionic fibers innervating the skin and from muscle spindles. The temporal resolution permits calculation of the primary endpoint which relates sympathetic discharge rate to the cardiac cycle, providing the best indicator that sympathetic regulation is altered by an SGLT2 inhibitor.
- Skin sympathetic nerve activity recorded using standard ECG chest leads. The rationale is that the stellate ganglion gives off parallel sympathetic fibers to the heart and to the skin of the chest wall. Conscious dog studies in Dr. Peng-Shen Chen's lab at Indiana University show > 70% concordance of bursts in simultaneous recordings from the stellate ganglion, the cardiac sympathetics, and the chest wall skin sympathetics; similar data are obtained from standard non-invasive ECG chest leads using appropriate bandpass filtering and amplification. Collaborative translational data on healthy human subjects in my lab at Cedars-Sinai show that Skin sympathetic nerve activity displays characteristic discharge properties of Skin sympathetic nerve activity recorded with our intraneural microelectrodes: large non-pulse synchronous bursts of activity that increase immediately with the onset of static handgrip preceded by clear anticipatory bursts. Thus, Skin sympathetic nerve activity provides in conscious human patients a novel quantitative measurement of the centrally-influenced/baroreceptor-insensitive component of cardiac sympathetic nerve activity. Dr. Chen has shown large bursts of Skin sympathetic nerve activity trigger episodes of ventricular tachycardia (VT) in some VT patients with implanted automatic defibrillators. So, if SGLT2 inhibitors buffer excessive increases in Skin sympathetic nerve activity at rest or during static handgrip in patients with type 2 diabetes, this could potentially protect against one form of catecholamine-induced sudden cardiac death.
- CleverCaps Pill Dispensing System- this unique electronic pill bottle system incorporates wireless technology and state-of-the-art methodology for quantifying and optimizing medication compliance. The system sends reminders for each scheduled dose of each pill type and tracks opening and closing of the bottles in real time as well as the weight of the remaining pills.
- Welch Allyn Spot Vital Signs Monitor-- provides vital signs in seconds with hospital-grade technology and received an AA rating for continuous inflation mode which takes 6 readings per inflation sequence. This will allow for close titration of medications to induce a 10mmHg bidirectional changes in the mean arterial pressure.
- the investigators will conduct careful pharmacologic quantitative testing of the baroreceptor reflex.
- Conditions
- Hypertension, Diabetes Mellitus, Type 2
- Being tested
- Ertugliflozin, Hydrochlorothiazide 12.5mg, Microneurography, SKNA recordings, Static Handgrip
- Keywords
- Hypertension, Diabetes
- Medical subject headings
- Hypertension, Diabetes Mellitus, Type 2, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ErtugliflozinDrug
Also called SGLT2 inhibitor
The sodium-glucose cotransporter 2 (SGLT2) inhibitors are an exciting new class of antidiabetic drugs that cause a modest reduction in high blood pressure and large reductions in the risk of cardiovascular disease (CVD) outcomes and renal outcomes in patients with advanced type 2 diabetes and very high CVD risk. However, the mechanistic underpinning of these CVD benefits is not well understood. this arm will allow us to test our hypothesis.
Hydrochlorothiazide 12.5mgDrug
Also called mild antihypertensive comparator
comparator arm allow us to mimic the mild anti hypertensive effect seen with the SGLT-2 inhibitors in order to enable us to differentiate whether the cardiovascular protection seen with the SGLT-2 inhibitors is secondary to its antihypertensive effects vs the potential decrease in sympathetics.
MicroneurographyDevice
Multiunit recordings of postganglionic sympathetic nerve activity will be obtained with unipolar tungsten microelectrodes inserted selectively into skeletal muscle nerve fascicles of the peroneal nerve. The nerve signals are amplified, filtered (bandwidth 700-2000 Hz), rectified and integrated to obtain a mean voltage display of sympathetic nerve activity. Sympathetic bursts are counted by inspection of the neurograms. A deflection on the mean voltage display is counted as a "burst" if it has a minimal signal to noise ratio of 2:1. The interobserver and intraobserver variations in identifying bursts are <10% and < 5%, respectively.
SKNA recordingsOther
SKNA recordings will be captured by placing ECG electrodes on the chest wall. Recordings will be obtained simultaneously with microneurographic recording. The two techniques will undergo identical filtering and processing of the neurophysiologic inputs which are then displayed simultaneously using identical output functions.
Static HandgripOther
Subjects will perform static handgrip at 33% MVC for 2 minutes, using a Stoelting recording handgrip dynamometer. Force output will be recorded continuously and displayed on the computer screen in real time to provide the subject with visual feedback. MVC will be determined for each subject at the beginning of each experiment. Subjects will be instructed to avoid straining maneuvers, changes in breathing, and contraction of non-exercising muscles during the experimental protocols. Ratings of perceived exertion (RPE) will be obtained at the end of each exercise by using a 6- to 20-unit Borg scale. Static handgrip at 33% MVC is accompanied by reflex increases in muscle sympathetic nerve activity caused by activation of the acid-sensing unmyelinated muscle afferents.
Post-handgrip forearm vascular occlusionOther
This will be performed by inflating a pneumatic cuff on the upper exercising arm to suprasystolic pressure (220 mmHg) beginning 10 seconds before the subject stops gripping and ending 2 minutes into the post-exercise period. The vascular occlusion maintains intramuscular acidosis and thus the stimulation of acid-sensing unmyelinated skeletal muscle afferents and their reflex increase in muscle sympathetic nerve activity and BP, while the muscular relaxation eliminates central command and the attendant increase in heart rate (which returns to the baseline level). As soon as the cuff is release and the forearm circulation is restored, muscle sympathetic nerve activity quickly returns to the baseline level and BP soon follows.
Testing of the Arterial Baroreflex FunctionOther
We will compare effects of Ertugliflozin vs. low-dose HCTZ on sinoaortic baroreflex function in hypertensive diabetic subjects during both spontaneous fluctuations in arterial pressure and during decreases and increases in arterial pressure induced by the Valsalva maneuver. The aim of this protocol is to determine if the sympathetic nerve, as well as the heart rate, component of the sinoaortic baroreflex can be augmented by the SGLT2 inhibitor. After obtaining stable baseline recordings, arterial pressure, heart rate, and muscle sympathetic nerve activity will recorded during spontaneous fluctuations in BP over 5 minutes and during both decreases in BP during phase III of the Valsavla maneuver and during the phase IV overshoot in BP upon its release. Frequent accurate measurement of arterial pressure will be obtained with a highly-rated oscillometric arm monitor that records 6 BP readings per minute (Welch Allyn Vital Signs Monitor).
| Study group | Role | What they receive |
|---|---|---|
| Experimental | Experimental | will receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide. Receives: Drug: Ertugliflozin; Device: Microneurography; Other: SKNA recordings; Other: Static Handgrip; Other: Post-handgrip forearm vascular occlusion; Other: Testing of the Arterial Baroreflex Function |
| Active Comparator | Active comparator | will receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug) Receives: Drug: Hydrochlorothiazide 12.5mg; Device: Microneurography; Other: SKNA recordings; Other: Static Handgrip; Other: Post-handgrip forearm vascular occlusion; Other: Testing of the Arterial Baroreflex Function |
What is being measured
The primary outcome is the main question the study is designed to answer.
Muscle sympathetic nerve activity (bursts/minute)
The primary outcome is the change from baseline in muscle sympathetic nerve activity after 3 months of daily treatment with either Ertugliflozin or hydrochlorothiazide. Muscle sympathetic nerve activity will be measured with microelectrodes inserted into the peroneal nerve (microneurography).
Measured: 3 months
Secondary outcomes (4)
Outcome 2 is the increase in muscle sympathetic nerve activity in bursts/minute induced by static handgrip.
Muscle sympathetic nerve activity will be measured at rest and after 2 minutes of static (isometric) handgrip at 33% maximum voluntary contraction. This exercised-induced response will be measured at baseline and after 3 months of Ertugliflozin or HCTZ.
Measured: 3 months
Increase in muscle sympathetic nerve activity induced by post-hand grip forearm vascular occlusion
Muscle sympathetic nerve activity will be measured at rest and after 2 minutes of by post-handgrip forearm vascular occlusion. After 2 minutes of static handgrip at 33% maximum, a pneumatic cuff will be inflated on the upper exercised arm for 2 minutes. This response will be measured at baseline and after 3 months of Ertugliflozin or HCTZ.
Measured: 3 months
Change in chest wall skin sympathetic nerve activity in bursts per minute.
Chest wall skin sympathetic nerve activity, a non-invasive measure of cardiac sympathetic nerve activity, will be measured from standard surface ECG leads using appropriate filtering and amplification.
Measured: 3 months
Arterial baroreflex gain.
Baroreflex gain will be measured as the reflex increase in muscle sympathetic nerve activity in bursts/minutes per mm Hg peak decrease in mean arterial pressure induced by Valsalva strain (Phase III) and the reflex decrease in muscle sympathetic nerve activity per mm Hg during the peak overshoot in mean arterial pressure upon release of the Valsalva maneuver (Phase IV).
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Aug 2018
- Study start1 Sep 2018 (estimated)
- Primary completion31 May 2020 (estimated)
- Study completion31 Aug 2020 (estimated)
Why it stopped: Study withdrawn prior to IRB approval and enrollment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HypertensionStudies of the same condition, open and under way.
- More trials run by Cedars-Sinai Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A double-blind, randomized, parallel 2- arm study, therapy will be randomly allocated 2:1 to Ertugliflozin oral tablet daily (n=20) or hydrochlorothiazide 12.5mg oral tablet (n=10) and followed for three months.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Cedars-Sinai Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03640221
- Sponsor's protocol ID
- 51991
- Acronym
- Ertugliflozin
- Status last verified
- Aug 2018
- First submitted
- 1 Aug 2018
- Last updated
- 14 Jan 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double-blind, Randomized, Parallel 2- Arm Study to Compare the Efficacy of Ertugliflozin Versus Hydrochlorothiazide in Reducing Sympathetic Neural Overactivity in Patients With Hypertension and Recently-diagnosed Type 2 Diabetes Who Are Receiving Background Standard-of-care Cardio-metabolic Therapy With Metformin, an Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker, and a Statin.
- ClinicalTrials.gov ID
- NCT03640221
- Acronym / sponsor ID
- Ertugliflozin / 51991
- Conditions
- Hypertension, Diabetes Mellitus, Type 2
- Keywords
- Hypertension, Diabetes
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Study withdrawn prior to IRB approval and enrollment
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Cedars-Sinai Medical CenterUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 1 Sep 2018 (estimated)
- Primary completion
- 31 May 2020 (estimated)
- Study completion
- 31 Aug 2020 (estimated)
- First posted
- 21 Aug 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The sodium-glucose cotransporter 2 (SGLT2) inhibitors are an exciting new class of antidiabetic drugs that cause a modest reduction in high blood pressure and large reductions in the risk of cardiovascular disease (CVD) outcomes and renal outcomes in patients with advanced type 2 diabetes and very high CVD risk. However, the mechanistic underpinning of these CVD benefits is not well understood. Mechanistic studies are needed to define specific biologic targets and thus optimize therapeutic benefits.
Type 2 diabetes mellitus is firmly established as a state of sympathetic neural overactivity, which may contribute to coexistent hypertension, heart failure, sudden cardiac death, macro- and micro-vascular complications of diabetes, and diabetic nephropathy. In patients recently diagnosed with Type 2 diabetes, microelectrode recordings of sympathetic nerve activity (SNA) targeted to the skeletal muscle circulation have shown both:
- abnormally high resting (ambient) levels of sympathetic nerve activity; and
- greatly exaggerated increases in sympathetic nerve activity during isometric (static) handgrip exercise.
The purpose of the proposed study is to determine if Ertugliflozin, a SGLT2 inhibitor, constitutes an effective countermeasure against sympathetic overactivity in patients with diagnosed hypertension and recently diagnosed type 2 diabetes by normalizing the high resting level of muscle sympathetic nerve activity (SNA) as measured by intraneural microelectrodes in the peroneal nerve.
Thus, an effective countermeasure is an urgent unmet medical need. The SGLT2 inhibitors hold exciting promise to address this need.
Detailed description
Static handgrip provides unique mechanistic insights into putative therapeutic targets (in this case the SGLT2 inhibitors) within the human autonomic nervous system include examining the reflexes within the nervous system and its response as a result. Static handgrip will require that patients lay down and with the use of a dyanometer (handgrip device which measures the force output generated from the handgrip exercise) and they will squeeze to the maximum of their ability for 30 seconds, then have a relaxation period, and grip again.
Typically responses to the nervous system travel via unmyelinated skeletal muscle nerve fibers (afferent signals) and the brain responds via the central motor command (or voluntary motor effort) which is its communication to the body to indicate the perception of effort needed in order to complete the task at hand. This volitional component of exercise- is the main mechanism driving heart rate during static handgrip.
When activated by exercise-induced skeletal muscle acidosis (as with static handgrip), muscle afferents signal the brain of a mismatch between muscle perfusion and metabolic demand and trigger a reflex increase in sympathetic nerve activity to non-exercising skeletal muscles. This raises blood pressure and shunts blood to the metabolically active muscle groups. Also, with voluntary exercise, the activation of brain pathways leading to the engagement of parallel central inhibition of the vagus nerve. The result is an increase in cardiac sympathetic nerve activity but it has an an insignificant effect on muscle sympathetic nerve activity, which is driven almost entirely by direct input from the afferent signals.
Thus, the investigators hypothesize that, in type 2 diabetes, impaired skeletal muscle energetics requires patients to use excessive voluntary motor effort to perform routine static handgrip, resulting in a parallel augmentation in cardiac sympathetic nerve activity. If Ertugliflozin improves skeletal muscle energetics, the same isometric exercise will require less motor effort which should result in smaller increases in cardiac sympathetic nerve activity and heart rate as well as a lower rating of perceived exertion on the Borg scale (an established index of central command).
The proposed work stands to advance several innovative concepts that could change the clinical approach to the early management of type 2 diabetes:
- The sympathetic nervous system as a novel therapeutic target in the mechanistic underpinning of how SGLT2 inhibitors protect against major CVD.
- Hyperfunction of unmyelinated autonomic (skeletal muscle) sensory nerves as a putative abnormal indicator of diabetic autonomic cardiovascular neuropathy.
- Early SGLT2-mediated correction of sympathetic overactivity in patients with type 2 diabetes could favorably alter the natural history of diabetic autonomic neuropathy.
The proposed methodology incorporates several scientific rigors:
- Direct measurement of sympathetic nerve action potentials in human patients using intraneural microelectrodes. This is the gold standard for studying the regulation of the sympathetic nervous system in patients.
- This microneurographic technique is highly quantitative and remarkably reproducible when a given subject is studied repeatedly without intervention. The spatial resolution is a major advantage by permitting recording of postganglionic fibers innervating the skeletal muscle circulation without "interfering noise" from surrounding postganglionic fibers innervating the skin and from muscle spindles. The temporal resolution permits calculation of the primary endpoint which relates sympathetic discharge rate to the cardiac cycle, providing the best indicator that sympathetic regulation is altered by an SGLT2 inhibitor.
- Skin sympathetic nerve activity recorded using standard ECG chest leads. The rationale is that the stellate ganglion gives off parallel sympathetic fibers to the heart and to the skin of the chest wall. Conscious dog studies in Dr. Peng-Shen Chen's lab at Indiana University show > 70% concordance of bursts in simultaneous recordings from the stellate ganglion, the cardiac sympathetics, and the chest wall skin sympathetics; similar data are obtained from standard non-invasive ECG chest leads using appropriate bandpass filtering and amplification. Collaborative translational data on healthy human subjects in my lab at Cedars-Sinai show that Skin sympathetic nerve activity displays characteristic discharge properties of Skin sympathetic nerve activity recorded with our intraneural microelectrodes: large non-pulse synchronous bursts of activity that increase immediately with the onset of static handgrip preceded by clear anticipatory bursts. Thus, Skin sympathetic nerve activity provides in conscious human patients a novel quantitative measurement of the centrally-influenced/baroreceptor-insensitive component of cardiac sympathetic nerve activity. Dr. Chen has shown large bursts of Skin sympathetic nerve activity trigger episodes of ventricular tachycardia (VT) in some VT patients with implanted automatic defibrillators. So, if SGLT2 inhibitors buffer excessive increases in Skin sympathetic nerve activity at rest or during static handgrip in patients with type 2 diabetes, this could potentially protect against one form of catecholamine-induced sudden cardiac death.
- CleverCaps Pill Dispensing System- this unique electronic pill bottle system incorporates wireless technology and state-of-the-art methodology for quantifying and optimizing medication compliance. The system sends reminders for each scheduled dose of each pill type and tracks opening and closing of the bottles in real time as well as the weight of the remaining pills.
- Welch Allyn Spot Vital Signs Monitor-- provides vital signs in seconds with hospital-grade technology and received an AA rating for continuous inflation mode which takes 6 readings per inflation sequence. This will allow for close titration of medications to induce a 10mmHg bidirectional changes in the mean arterial pressure.
- the investigators will conduct careful pharmacologic quantitative testing of the baroreceptor reflex.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- A double-blind, randomized, parallel 2- arm study, therapy will be randomly allocated 2:1 to Ertugliflozin oral tablet daily (n=20) or hydrochlorothiazide 12.5mg oral tablet (n=10) and followed for three months.
| Arm | Type | Receives |
|---|---|---|
| Experimental | Experimental | Drug: Ertugliflozin, Device: Microneurography, Other: SKNA recordings, Other: Static Handgrip, Other: Post-handgrip forearm vascular occlusion, Other: Testing of the Arterial Baroreflex Functionwill receive two bottles of Ertugliflozin 15mg tablets (active drug) and a placebo for hydrochlorothiazide. |
| Active Comparator | Active comparator | Drug: Hydrochlorothiazide 12.5mg, Device: Microneurography, Other: SKNA recordings, Other: Static Handgrip, Other: Post-handgrip forearm vascular occlusion, Other: Testing of the Arterial Baroreflex Functionwill receive two bottles of Placebo for ertugliflozin and hydrochlorthiazide 12.5mg capsules (active drug) |
Who may qualify
- Ages
- 35 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Diagnosis of diabetes mellitus established < 24 months before enrollment
- Ages 30-65 years
- Men and women, inclusive or race/ethnic groups
- Background standard-of-care cardiometabolic therapy including a stable dose regimen for 6 weeks of: a) metformin and b) an ACEI or an ARB and c) any statin.
- HBA1C of 6.5 to 8.0
Key exclusion criteria (15 listed)
- Known history of previous cardiovascular disease (CVD)
- Currently on other diabetes medications such as: insulin analogs, GLP-1 analogs, DPPIV inhibitors, thiazolidinediones, sulfonylureas, meglitinides, alpha glucosidase inhibitors, amylin analogies.
- Any concomitant medications or supplements, with the exception of: aspirin, ACE-I or ARB, and statin therapy
- Diagnosed diabetic peripheral sensory neuropathy or retinopathy
- Orthostatic hypotension defined as standing BP < 100/60 or postural fall of SBP > 20 or DBP > 10
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ErtugliflozinAlso: SGLT2 inhibitorThe sodium-glucose cotransporter 2 (SGLT2) inhibitors are an exciting new class of antidiabetic drugs that cause a modest reduction in high blood pressure and large reductions in the risk of cardiovascular disease (CVD) outcomes and renal outcomes in patients with advanced type 2 diabetes and very high CVD risk. However, the mechanistic underpinning of these CVD benefits is not well understood. this arm will allow us to test our hypothesis. | Drug | Experimental |
| Hydrochlorothiazide 12.5mgAlso: mild antihypertensive comparatorcomparator arm allow us to mimic the mild anti hypertensive effect seen with the SGLT-2 inhibitors in order to enable us to differentiate whether the cardiovascular protection seen with the SGLT-2 inhibitors is secondary to its antihypertensive effects vs the potential decrease in sympathetics. | Drug | Active Comparator |
| MicroneurographyMultiunit recordings of postganglionic sympathetic nerve activity will be obtained with unipolar tungsten microelectrodes inserted selectively into skeletal muscle nerve fascicles of the peroneal nerve. The nerve signals are amplified, filtered (bandwidth 700-2000 Hz), rectified and integrated to obtain a mean voltage display of sympathetic nerve activity. Sympathetic bursts are counted by inspection of the neurograms. A deflection on the mean voltage display is counted as a "burst" if it has a minimal signal to noise ratio of 2:1. The interobserver and intraobserver variations in identifying bursts are <10% and < 5%, respectively. | Device | Active Comparator, Experimental |
| SKNA recordingsSKNA recordings will be captured by placing ECG electrodes on the chest wall. Recordings will be obtained simultaneously with microneurographic recording. The two techniques will undergo identical filtering and processing of the neurophysiologic inputs which are then displayed simultaneously using identical output functions. | Other | Active Comparator, Experimental |
| Static HandgripSubjects will perform static handgrip at 33% MVC for 2 minutes, using a Stoelting recording handgrip dynamometer. Force output will be recorded continuously and displayed on the computer screen in real time to provide the subject with visual feedback. MVC will be determined for each subject at the beginning of each experiment. Subjects will be instructed to avoid straining maneuvers, changes in breathing, and contraction of non-exercising muscles during the experimental protocols. Ratings of perceived exertion (RPE) will be obtained at the end of each exercise by using a 6- to 20-unit Borg scale. Static handgrip at 33% MVC is accompanied by reflex increases in muscle sympathetic nerve activity caused by activation of the acid-sensing unmyelinated muscle afferents. | Other | Active Comparator, Experimental |
| Post-handgrip forearm vascular occlusionThis will be performed by inflating a pneumatic cuff on the upper exercising arm to suprasystolic pressure (220 mmHg) beginning 10 seconds before the subject stops gripping and ending 2 minutes into the post-exercise period. The vascular occlusion maintains intramuscular acidosis and thus the stimulation of acid-sensing unmyelinated skeletal muscle afferents and their reflex increase in muscle sympathetic nerve activity and BP, while the muscular relaxation eliminates central command and the attendant increase in heart rate (which returns to the baseline level). As soon as the cuff is release and the forearm circulation is restored, muscle sympathetic nerve activity quickly returns to the baseline level and BP soon follows. | Other | Active Comparator, Experimental |
| Testing of the Arterial Baroreflex FunctionWe will compare effects of Ertugliflozin vs. low-dose HCTZ on sinoaortic baroreflex function in hypertensive diabetic subjects during both spontaneous fluctuations in arterial pressure and during decreases and increases in arterial pressure induced by the Valsalva maneuver. The aim of this protocol is to determine if the sympathetic nerve, as well as the heart rate, component of the sinoaortic baroreflex can be augmented by the SGLT2 inhibitor. After obtaining stable baseline recordings, arterial pressure, heart rate, and muscle sympathetic nerve activity will recorded during spontaneous fluctuations in BP over 5 minutes and during both decreases in BP during phase III of the Valsavla maneuver and during the phase IV overshoot in BP upon its release. Frequent accurate measurement of arterial pressure will be obtained with a highly-rated oscillometric arm monitor that records 6 BP readings per minute (Welch Allyn Vital Signs Monitor). | Other | Active Comparator, Experimental |
Primary outcome
Muscle sympathetic nerve activity (bursts/minute)
Time frame: 3 months
The primary outcome is the change from baseline in muscle sympathetic nerve activity after 3 months of daily treatment with either Ertugliflozin or hydrochlorothiazide. Muscle sympathetic nerve activity will be measured with microelectrodes inserted into the peroneal nerve (microneurography).
4 secondary outcomes
Outcome 2 is the increase in muscle sympathetic nerve activity in bursts/minute induced by static handgrip.
Time frame: 3 months
Increase in muscle sympathetic nerve activity induced by post-hand grip forearm vascular occlusion
Time frame: 3 months
Change in chest wall skin sympathetic nerve activity in bursts per minute.
Time frame: 3 months
Arterial baroreflex gain.
Time frame: 3 months
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jan 2020.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ertugliflozin, Hydrochlorothiazide 12.5mg and Microneurography in people with Hypertension and Diabetes Mellitus, Type 2, run by Cedars-Sinai Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 14 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Muscle sympathetic nerve activity (bursts/minute) (time frame: 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jan 2020.