- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04569630
The HEADWIND Study - Part 2 (HEADWIND)
Non-randomised, Controlled, Interventional Single-centre Study for the Design and Evaluation of an In-vehicle Hypoglycaemia Warning System in Diabetes - The HEADWIND Study Part 2
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Hypoglycaemia is among the most relevant acute complications of diabetes mellitus. During hypoglycaemia physical, psychomotor, executive and cognitive function significantly deteriorate. These are important prerequisites for safe driving. Accordingly, hypoglycaemia has consistently been shown to be associated with an increased risk of driving accidents and is, therefore, regarded as one of the relevant factors in traffic safety. Despite important developments in the field of diabetes technology, the problem of hypoglycaemia during driving persists. Automotive technology is highly dynamic, and fully autonomous driving might, in the end, resolve the issue of hypoglycemia-induced accidents. However, autonomous driving (level 4 or 5) is likely to be broadly available only to a substantially later time point than previously thought due to increasing concerns of safety associated with this technology. Therefore, solutions bridging the upcoming period by more rapidly and directly addressing the problem of hypoglycemia-associated traffic incidents are urgently needed.
On the supposition that driving behaviour differs significantly between euglycaemic state and hypoglycaemic state, the investigators assume that different driving patterns in hypoglycemia compared to euglycemia can be used to generate hypoglycemia detection models using machine learning neural networks (deep machine learning classifiers).
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
-
Bern, Switzerland
- Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Informed consent as documented by signature
- Type 1 Diabetes mellitus as defined by WHO for at least 1 year or confirmed C-peptide negative (<100pmol/l with concomitant blood glucose >4 mmol/l)
- Age between 21-60 years
- HbA1c ≤ 9.0 %
- Functional insulin treatment with good knowledge of insulin self- management
- Passed driver's examination at least 3 years before study inclusion. Possession of a valid, definitive Swiss driver's license.
- Active driving in the last 6 months.
Exclusion Criteria:
- Contraindications to the drug used to induce hypoglycaemia (insulin aspart), known hypersensitivity or allergy to the adhesive patch used to attach the glucose sensor.
- Pregnancy or intention to become pregnant during the course of the study, lactating women or lack of safe contraception
- Other clinically significant concomitant disease states as judged by the investigator
- Physical or psychological disease likely to interfere with the normal conduct of the study and interpretation of the study results as judged by the investigator
- Renal failure
- Hepatic dysfunction
- Coronary heart disease
- Other cardiovascular disease
- Epilepsy
- Drug or alcohol abuse
- Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant
- Participation in another study with an investigational drug within the 30 days preceding and during the present study
- Total daily insulin dose >2 IU/kg/day
- Specific concomitant therapy washout requirements prior to and/or during study participation
- Current treatment with drugs known to interfere with metabolism or driving performance
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Intervention group
|
Participants will drive on a designated circuit with a real car on a test track accompanied by a driving instructor.
Driving data will be recorded in 4 subsequent glycemic states using an adapted hypoglycemic clamp protocol: euglycemia (d1, 5-8 mmol/l), progressive hypoglycaemia (d2, declining from 4.5 to 2.5 mmol/l), stable hypoglycemia (d3, 2.0-2.5 mmol/l), and again in euglycaemia (d4, 5-8 mmol/l).
Patients will be blinded to their glucose levels.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Accuracy of the HEADWIND-model: Diagnostic accuracy of the hypoglycemia warning system (HEADWIND) in detecting hypoglycemia (blood glucose < 3.9 and < 3.0 mmol/l) quantified as the area under the receiver operator characteristics curve (AUC ROC).
Time Frame: 240 minutes
|
Accuracy of the HEADWIND-model will be assessed using real car driving data recorded in progressive hypoglycemia and driving data will be analysed using applied machine learning technology for hypoglycemia detection.
|
240 minutes
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Glycemic level at time point of hypoglycemia detection by the HEADWIND-model
Time Frame: 240 minutes
|
Blood glucose at time point of hypoglycemia detection by the HEADWIND-model will be determined.
|
240 minutes
|
Comparison CGM and HEADWIND-model regarding time-point of hypoglycemia detection
Time Frame: 240 minutes
|
Time point of hypoglycemia detection by CGM will be compared to time point of hypoglycemia detection by the HEADWIND-model.
|
240 minutes
|
Comparison CGM and HEADWIND-model regarding glycemia
Time Frame: 240 minutes
|
Blood glucose at time point of hypoglycemia detection by the HEADWIND- model compared to glucose value of CGM at same time point will be assessed.
|
240 minutes
|
Time point of need-to-treat
Time Frame: 240 minutes
|
Time point of self-perceived need-to-treat (hypoglycemia) compared to time point of hypoglycemia detection by the HEADWIND-model and CGM.
|
240 minutes
|
Change of swerving
Time Frame: 240 minutes
|
Change of swerving during driving in hypoglycemia (< 3.9mmol/L) will be compared to euglycemia (5.5 mmol/L).
Driving parameters will be recorded by the study car.
|
240 minutes
|
Change of spinning
Time Frame: 240 minutes
|
Change of spinning during driving in hypoglycemia (< 3.9mmol/L) will be compared to euglycemia (5.5 mmol/L).
Driving parameters will be recorded by the study car.
|
240 minutes
|
Change of velocity
Time Frame: 240 minutes
|
Change of velocity during driving in hypoglycemia (< 3.9mmol/L) will be compared to euglycemia (5.5 mmol/L).
Driving parameters will be recorded by the study car.
|
240 minutes
|
Change of steer
Time Frame: 240 minutes
|
Change of steer during driving in hypoglycemia (< 3.9mmol/L) will be compared to euglycemia (5.5 mmol/L).
Driving parameters will be recorded by the study car.
|
240 minutes
|
Change of brake
Time Frame: 240 minutes
|
Change of brake during driving in hypoglycemia (< 3.9mmol/L) will be compared to euglycemia (5.5 mmol/L).
Driving parameters will be recorded by the study car.
|
240 minutes
|
Change of steer torque
Time Frame: 240 minutes
|
Change of steer torque during driving in hypoglycemia (< 3.9mmol/L) will be compared to euglycemia (5.5 mmol/L).
Driving parameters will be recorded by the study car.
|
240 minutes
|
Change of steer speed
Time Frame: 240 minutes
|
Change of steer speed during driving in hypoglycemia (< 3.9mmol/L) will be compared to euglycemia (5.5 mmol/L).
Driving parameters will be recorded by the study car.
|
240 minutes
|
Defining the glycemic level when driving performance is decreased
Time Frame: 240 minutes
|
Plasma-glucose level (mmol/L) when driving performance begins to be impaired will be assessed based on significantly altered driving parameters in serious hypoglycemia (< 3.0 mmol/L) compared to euglycemia (5.5mmol/L).
|
240 minutes
|
Driving performance before and after hypoglycemia based on driving parameters (swerving, spinning, velocity, steer, brake, steer torque, steer speed)
Time Frame: 240 minutes
|
Based on significantly altered driving parameters in serious hypoglycemia (< 3.0 mmol/L) driving performance based on swerving, spinning, velocity, steer, brake, steer torque and steer speed, before and after hypoglycemia will be assessed
|
240 minutes
|
Change of heart-rate
Time Frame: 240 minutes
|
Change of heart-rate during driving in hypoglycemia will be compared to euglycemia.
Change of heart-rate will be measured with a holter-ecg and wearable devices.
|
240 minutes
|
Change of heart-rate variability
Time Frame: 240 minutes
|
Change of heart-rate variability during driving in hypoglycemia will be compared to euglycemia.
Heart-rate variability will be measured with a holter-ecg and wearable devices.
|
240 minutes
|
Change of electrodermal activity (EDA)
Time Frame: 240 minutes
|
Change of EDA during driving in hypoglycemia will be compared to euglycemia.
EDA will be measured with wearable devices.
|
240 minutes
|
Change of skin temperature
Time Frame: 240 minutes
|
Change of skin temperature during driving in hypoglycemia will be compared to euglycemia.
Change of skin temperature will be measured with wearable devices and a thermal camera.
|
240 minutes
|
Change of eye movement
Time Frame: 240 minutes
|
Change of eye movement and gaze behaviour during driving in hypoglycemia will be compared to euglycemia.
Eye movement of the participant will be recorded by a camera and an eye-tracker.
|
240 minutes
|
Change of facial expression
Time Frame: 240 minutes
|
Change of facial expression during driving in hypoglycemia will be compared to euglycemia.
Facial expression will be recorded by a camera.
|
240 minutes
|
Diagnostic accuracy in detecting hypoglycemia (blood glucose <3.9 mmol/l and <3.0 mmol/l) and hyperglycemia (blood glucose >13.9 mmol/l and >16.7 mmol/l) quantified as the area under the receiver operator characteristics curve using physiological data
Time Frame: Throughout the study, expected to be up to 12 months
|
Accuracy of dysglycemia detection using physiological data (heart-rate, heart-rate variability, skin temperature, EDA) recorded with wearable devices during the study period will be analysed using applied machine learning technology.
|
Throughout the study, expected to be up to 12 months
|
Diagnostic accuracy in detecting hypoglycemia (blood glucose < 3.9 mmol/l and < 3.0 mmol/l) quantified as the area under the receiver operator curve (AUC-ROC) using video data
Time Frame: Throughout the study, expected to be up to 12 months
|
Using video data recorded by a camera and a thermal camera accuracy in hypoglycaemia detection will be analysed with applied machine learning technology.
|
Throughout the study, expected to be up to 12 months
|
Diagnostic accuracy in detecting hypoglycemia (blood glucose < 3.9 mmol/l and < 3.0 mmol/l) quantified as the area under the receiver operator curve (AUC-ROC) using eye-tracking data
Time Frame: Throughout the study, expected to be up to 12 months
|
Using eye-tracking data recorded by a camera and an eye-tracker (to record gaze behaviour) accuracy in hypoglycemia detection will be analysed with applied machine learning technology.
|
Throughout the study, expected to be up to 12 months
|
CGM accuracy during the controlled hypoglycemic state
Time Frame: 240 minutes
|
Accuracy (mean absolute relative difference, MARD) of CGM Sensor (Dexcom G6) in euglycemia (3.9 - 10 mmol/L), hypoglycemia (3.0 - 3.9mmol/L) and severe hypoglycemia (< 3.0 mmol/L) will be assessed based on plasma glucose measurements
|
240 minutes
|
CGM time-delay during the controlled hypoglycemic state
Time Frame: 240 minutes
|
Time-delay (minutes) of CGM Sensor (Dexcom G6) during progressive hypoglycemia (hypoglycemic clamp) will be assessed compared to plasma glucose.
|
240 minutes
|
Change of glucagon
Time Frame: 240 minutes
|
Change of glucagon before driving, during driving in euglycemia (5.5mmol/L), in hypoglycemia (< 3.9mmol/L), severe hypoglycemia (< 3mmol/L) and after hypoglycemia will be assessed.
|
240 minutes
|
Change of growth hormone (GH)
Time Frame: 240 minutes
|
Change of GH before driving, during driving in euglycemia (5.5mmol/L), in hypoglycemia (< 3.9mmol/L), severe hypoglycemia (< 3mmol/L) and after hypoglycemia will be assessed.
|
240 minutes
|
Change of catecholamines
Time Frame: 240 minutes
|
Change of catecholamines before driving, during driving in euglycemia (5.5mmol/L), in hypoglycemia (< 3.9mmol/L), severe hypoglycemia (< 3mmol/L) and after hypoglycemia will be assessed.
|
240 minutes
|
Change of cortisol
Time Frame: 240 minutes
|
Change of cortisol before driving, during driving in euglycemia (5.5mmol/L), in hypoglycemia (< 3.9mmol/L), severe hypoglycemia (< 3mmol/L) and after hypoglycemia will be assessed.
|
240 minutes
|
Change of insulin
Time Frame: 240 minutes
|
Insulin levels will be measured before driving, during driving in euglycemia (5.5mmol/L), in hypoglycemia (< 3.9mmol/L), serious hypoglycemia (< 3mmol/L) and after hypoglycemia will be assessed.
|
240 minutes
|
Accuracy-comparison of HEADWIND-model and HEADWINDplus-model
Time Frame: 240 minutes
|
Diagnostic accuracy of the hypoglycaemia warning system (HEADWIND) to detect hypoglycaemia (blood glucose < 3.9 mmol/l and < 3.0 mmol/l) quantified as the area under the receiver operator characteristics curve (AUC ROC) using only driving parameters (HEADWIND-model) will be compared to the HEADWIND-model with the additional integration of physiological parameters, video and eye tracker data, in particular heart-rate, heart-rate variability, electrodermal activity (EDA), skin temperature and facial expression (HEADWINDplus-model)
|
240 minutes
|
Self-estimation of glucose and hypoglycemia
Time Frame: 240 minutes
|
Evaluation of self-estimated glucose during progressive hypoglycemia and correlation with measured blood glucose.
|
240 minutes
|
Self-estimation of driving performance
Time Frame: 240 minutes
|
Evaluation of self-estimated driving-performance in severe hypoglycemia (< 3.0 mmol/L) compared to euglycemia (5.5mmol/L).
Self-estimated driving performance will be assessed on a absolute 7-point scale from 0-6 (a lower value means better outcome).
|
240 minutes
|
Self-perception of hypoglycemia symptoms
Time Frame: 240 minutes
|
Correlation of perceived hypoglycemia symptoms on a scale from 0-6 (0 means better outcome) to measured blood glucose.
|
240 minutes
|
Self-perception of hypoglycemia symptoms compared to baseline hypoglycemia awareness
Time Frame: 240 minutes
|
Correlation and comparison of perceived hypoglycemia symptoms on a scale from 0-6 (0 means better outcome) to baseline hypoglycemia awareness (Clarke-Score and Gold-Score, for both tests a score of higher or equal to 4 points indicates impaired awareness of hypoglycemia).
|
240 minutes
|
Driving mishaps and interventions by the driving instructor in euglycaemia (5-8 mmol/l), hypoglycaemia (< 3.9 mmol/l) and severe hypoglycaemia (< 3.0 mmol/l).
Time Frame: 240 minutes
|
Driving mishaps and interventions will be assessed by the driving instructor using an assessment questionnaire with 4 questions on a 7 point Likert scale (lower value means worse outcome)
|
240 minutes
|
Direct comparison of driving performance scores assessed by the driving instructor in euglycemia (5-8 mmol/l), hypoglycaemia (<3.9 mmol/l) and severe hypoglycaemia (< 3.0 mmol/l)
Time Frame: 240 minutes
|
Driving performance will be assessed by the driving instructor using an assessment questionnaire with a score from 1 to 7 (7 means the best outcome)
|
240 minutes
|
Incidence of Adverse Events (AEs)
Time Frame: Throughout the study, expected to be up to 12 months
|
Adverse Events will be recorded at each study visit.
|
Throughout the study, expected to be up to 12 months
|
Incidence of Serious Adverse Events (SAEs
Time Frame: Throughout the study, expected to be up to 12 months
|
Serious Adverse Events will be recorded at each study visit.
|
Throughout the study, expected to be up to 12 months
|
Pre-test perception of technology in general
Time Frame: Throughout the study, expected to be up to 12 months
|
Perception of technology in general will be assessed via questionnaire based self-reports (technology readiness index) measures on the 5-point Likert Scale ranging from "strongly disagree" to "strongly agree" with a scale ranging from -2 to 2 with higher values representing a better outcome (after inversion of negative items).
The total score will be averaged across participants and used individually to support the interview responses when necessary.
|
Throughout the study, expected to be up to 12 months
|
Pre-test experience with in-vehicle voice assistants (IVAs) and technology in general
Time Frame: Throughout the study, expected to be up to 12 months
|
Pre-test experience with IVAs and technology in general will be assessed via questionnaire based self-reports (questionnaire of technology use and acceptance).
The constructs Performance expectancy, Effort expectancy, Social influence, Facilitating conditions, Hedonic motivation, and Behavioural intention are measured on the 7-point Likert scale from "strongly disagree" to "strongly agree" with a scale range from -3 to 3 with higher values representing a better outcome.
The construct Use is measured on the 7-point Likert scale ranging from "never" to "always" with a scale range from -3 to 3. The total score will be averaged per construct and across participants and used individually to support the interview responses when necessary.
|
Throughout the study, expected to be up to 12 months
|
Direct comparison between IVA's prompts and the behavioral responses
Time Frame: 240 minutes
|
Direct comparison of conversational turns between IVA and patient during the ecological momentary assessment and the hypoglycaemia support.
|
240 minutes
|
Self-report of blood sugar level while driving (i.e. ecological momentary assessment)
Time Frame: 240 minutes
|
Comparison of perceived blood sugar level to measured blood glucose, perceived blood sugar level between drives (see outcome 21), and baseline hypoglycemia awareness (Clarke-Score and Gold-Score, for both tests a score of higher or equal to 4 points indicates impaired awareness of hypoglycemia).
|
240 minutes
|
Comparison of cognitive trust in competence and session alliance with IVA to warning type
Time Frame: 240 minutes
|
Cognitive trust in competence with IVA will be assessed via questionnaire based self-reports (Cognitive trust in competence construct from Trust and adoption of recommendations agents questionnaire), measured on the 7-point Likert scale from "strongly disagree" to "strongly agree" with a scale range from -3 to 3 and with higher values representing a better outcome.
Session alliance with IVA will be assessed via questionnaire based self-reports (item from Session Alliance Inventory), measured on the 6-point Likert scale from "not at all" to "completely" with a scale range from 0 to 5 and with higher values representing a better outcome.
The questionnaire will be submitted after delivering IVA's support intervention and will be compared with the type of warning delivered (i.e.
disclosure vs no disclosure).
|
240 minutes
|
General user experience of the early hypoglycaemia warning system (EWS)
Time Frame: Throughout the study, expected to be up to 12 months
|
General user experience of the EWS will be assessed via questionnaire based self-reports (questionnaire for User experience questionnaire and van der Laan scale) measured on an analogue scale with adjective at its extremes (e.g.
easy to learn-hard to learn, boring-exciting, good-bad, etc.) with a scale range from 0 to 100.
The scores will be averaged for each scale across participants and used individually to support the interview responses when necessary.
|
Throughout the study, expected to be up to 12 months
|
Acceptance and use of the EWS
Time Frame: Throughout the study, expected to be up to 12 months
|
Acceptance and use of the EWS will be assessed via questionnaire based self-reports (questionnaire of technology use and acceptance) measured on the 7-point Likert scale from "strongly disagree" to "strongly agree" with a scale range from -3 to 3 with higher values representing a better outcome.
The total score will be averaged per construct and across participants and used individually to support the interview responses when necessary.
|
Throughout the study, expected to be up to 12 months
|
Cognitive trust in competence and emotional trust in the recommendations from IVA
Time Frame: Throughout the study, expected to be up to 12 months
|
Cognitive trust in competence and emotional trust in the recommendations from IVA will be assessed via questionnaire based self-reports (Cognitive trust in competence and emotional trust constructs from Trust and adoption of recommendations agents questionnaire) measured on the 7-point Likert scale from "strongly disagree" to "strongly agree" with a scale range from -3 to 3 and with higher values representing a better outcome.
The total score will be averaged per construct and across participants and used individually to support the interview responses when necessary
|
Throughout the study, expected to be up to 12 months
|
Perceived working alliance with IVA
Time Frame: Throughout the study, expected to be up to 12 months
|
Perceived working alliance with the IVA will be assessed via questionnaire based self-reports (session alliance inventory) measured on the 6-point Likert scale from "not at all" to "completely" with a scale range from 0 to 5 and with higher values representing a better outcome.
The total score will be averaged per construct and across participants and used individually to support the interview responses when necessary
|
Throughout the study, expected to be up to 12 months
|
Collaborators and Investigators
Investigators
- Principal Investigator: Christoph Stettler, Prof. MD, Inselspital, Bern University Hospital, University of Bern
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- HEADWIND 2
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Diabetes
-
University of Colorado, DenverMassachusetts General Hospital; Beta Bionics, Inc.CompletedDiabetes Mellitus, Type 1 | Type 1 Diabetes | Diabetes type1 | Type 1 Diabetes Mellitus | Autoimmune Diabetes | Diabetes Mellitus, Insulin-Dependent | Juvenile-Onset Diabetes | Diabetes, Autoimmune | Insulin-Dependent Diabetes Mellitus 1 | Diabetes Mellitus, Insulin-Dependent, 1 | Diabetes Mellitus, Brittle | Diabetes Mellitus, Juvenile-Onset and other conditionsUnited States
-
Guang NingRecruitingType 2 Diabetes Mellitus | Type1 Diabetes Mellitus | Monogenetic Diabetes | Pancreatogenic Diabetes | Drug-Induced Diabetes Mellitus | Other Forms of Diabetes MellitusChina
-
University of Trás-os-Montes and Alto DouroCompletedType 2 Diabetes Mellitus | Diabetes-Related ComplicationsPortugal
-
Northern Care Alliance NHS Foundation TrustBrighter ABCompletedDiabetes type1 | Diabetes type2United Kingdom
-
VeraLight, Inc.InLight SolutionsUnknownGestational Diabetes | Insulin Dependent Diabetes | Non Insulin Dependent DiabetesUnited States
-
Garvan Institute of Medical ResearchWeizmann Institute of ScienceActive, not recruitingType 2 Diabetes Mellitus | Pre DiabetesAustralia
-
Oregon State UniversitySanofiCompletedType I or Type II Diabetes (Excludes Gestational Diabetes)
-
Taichung Veterans General HospitalNational Health Research Institutes, TaiwanRecruitingDiabetes Complications | Type 2 Diabetes | Maturity-Onset Diabetes of the Young (MODY)Taiwan
-
Peking Union Medical College HospitalUnknownType 2 Diabetes Mellitus | Type 1 Diabetes Mellitus | Gestational Diabetes Mellitus | Pancreatogenic Diabetes Mellitus | Pregestational Diabetes Mellitus | Diabetes Patients in Perioperative PeriodChina
-
University of RoehamptonRecruitingType2 Diabetes Mellitus | Pre DiabetesUnited Kingdom
Clinical Trials on Controlled hypoglycaemic state while driving
-
University Hospital Inselspital, BerneSwiss Federal Institute of Technology; University of St.GallenCompleted
-
University Hospital Inselspital, BerneETH Zurich; University of St.GallenCompleted
-
University Hospital Inselspital, BerneETH Zurich; University of St.GallenCompleted
-
University of PennsylvaniaWithdrawnAutomobile Accident
-
University of MinnesotaRecruiting
-
Northwell HealthRecruitingSystemic Lupus ErythematosusUnited States
-
University Hospital Inselspital, BerneLudwig-Maximilians - University of Munich; Idiap Research Institute; CSEM Centre...Completed
-
Memorial Sloan Kettering Cancer CenterActive, not recruitingHistiocytosisUnited States
-
Daniel BenjaminEunice Kennedy Shriver National Institute of Child Health and Human Development... and other collaboratorsCompletedHeart Failure | Epilepsy | Pain | Pneumonia | Sepsis | Inflammation | Hypertension | Chronic Kidney Diseases | Hemophilia | Schizophrenia | Central Nervous System Infections | Nosocomial Pneumonia | Insomnia | Anxiety | Bipolar Disorder | Neutropenia | Staphylococcal Infections | Bradycardia | Seizures | Urinary Tract Infections | Pulmonary... and other conditionsUnited States, Canada, United Kingdom, Israel, Singapore