Rapid Antidepressant Effects of Ketamine in Major Depression

• Sponsor: National Institute of Mental Health (NIMH) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00088699
• Collaborator: (none)
• Enrollment: 67
• Location: 1
• Arms: 2
• Duration (Months): 156.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Depressive disorders may be severe, chronic and often life-threatening illnesses. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Recent preclinical and clinical studies suggest that the glutamatergic system is involved in the mechanism of action of antidepressants.

This study examines whether ketamine can cause a rapid-next day antidepressant effect in patients with Major Depressive Disorder.

This study was designed to address the questions:

Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant major depression? What are the neurobiological correlates of antidepressant response (examining multi-modal MRI, MEG, polysomnography and serum markers) Patients, ages 18 to 65 years with treatment-resistant major (unipolar) depression will in a double-blind crossover study receive either intravenous ketamine or saline solution.

Condition or Disease	Intervention/Treatment	Phase
Depression; Mood Disorders; Major Depresssion	Drug: Ketamine; Drug: Placebo	Phase 1/Phase 2

Detailed Description

This study will test whether a single dose of ketamine - a drug that blocks a brain receptor called NMDA - can cause a rapid (next day) antidepressant effect in patients with major depression. Several medications are effective for treating depression; however, they take weeks or months to achieve their full effects. A more rapidly acting antidepressant would have a significant impact on the treatment of depression. In a previous study, ketamine produced a rapid antidepressant effect within hours, but the effect lasted less than 1 week. Understanding how ketamine works may lead to a better understanding of the causes of depression and the design of a longer lasting rapidly acting antidepressant.

Patients between 18 and 65 years of age who are currently experiencing an episode of major depression of at least 4 weeks duration and have not responded to two treatment trials may be eligible for this study. Candidates are screened with a medical and psychiatric history, physical examination, and blood and urine tests.

Participants undergo the following tests and procedures:

Medication tapering: Patients who are taking medications for depression are tapered off the drugs over a 1- to 2-week period.

Ketamine/placebo trial: Patients are given a single dose of either ketamine or placebo (an inactive substance), administered intravenously (through a vein) over 40 minutes. After 7 days, patients are given another dose of study drug in crossover fashion; that is, those who previously took ketamine are switched to receive placebo, and those who took placebo are switched to ketamine. Oximetry (measurement of blood oxygen), pulse, and blood pressure are measured continuously for 1 hour before and 4 hours after each ketamine or placebo dose to monitor safety.

Interviews and rating scales: Patients complete a series of psychiatric rating scales to assess the effects of the study drug on mood and thinking. The rating scales are repeated up to 18 times during the study, with each time taking about 15 to 20 minutes.

Physical examination and laboratory tests: Patients have a physical examination, blood tests, weight measure, and electrocardiogram (ECG) at the beginning and end of the study. They will also have multi-modal MRI, MEG, polysomnography and serum marker studies.

The primary endpoint will be the change in clinical ratings of depression. Secondary endpoints will examine neurobiological correlates (i.e., multi-modal MRI, MEG, polysomnography and serum markers) of antidepressant response to ketamine (compared to placebo).

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Investigation of the Rapid (Next Day) Antidepressant Effects of an NMDA Antagonist
• Study Start Date: Jul 26, 2004
• Actual Primary Completion Date: Jul 31, 2017
• Actual Study Completion Date: Jul 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine, Then Placebo Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg.	Drug: Ketamine; Drug: Placebo
Experimental: Placebo, Then Ketamine Placebo and Ketamine infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg	Drug: Ketamine; Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. MADRS Score - Baseline [Baseline]

   Antidepressant effects were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). It is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60.

2. MADRS Score - Day 1 Following Intervention [Day 1]

   Antidepressant effects were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). It is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

• INCLUSION CRITERIA:

General patient inclusion criteria

1. Male or female subjects, 18 to 65 years of age.

2. Each subject must have a level of understanding sufficient to agree to all required tests and examinations and sign an informed consent document.

3. Subjects must fulfill DSM-IV criteria for Major Depressive Disorder (MDD) without psychotic features, based on clinical assessment and confirmed by a structured diagnostic interview, SCID-P.

4. Subjects must have an initial score of at least 20 on the MADRS at screen and at baseline of study phase I.

5. Subjects must have failed to respond in the past to an adequate dose and duration of at least one antidepressant (SSRI, bupropion, or venlafaxine) during a depressive episode

6. Current depressive episode of at least 4 weeks duration.

Additional inclusion criteria for substudy 4 (patients with MDD)

1. Age of onset less than 40 years of age.

2. Subjects with MDD must fulfill DSM-IV criteria for Major Depression single episode or recurrent without psychotic features based on clinical assessment and confirmed by a structured diagnostic interview (SCID-P).

3. A failed adequate trial of ECT would count as an adequate antidepressant trial.

4. In women of childbearing age, a negative pregnancy test within 24 hours of MRI.

Inclusion criteria for healthy control subjects (Substudy 4 only)

1. Age 18-65 years.

2. Written informed consent completed.

EXCLUSION CRITERIA:

General patient exclusion criteria

1. Current or past diagnosis of Schizophrenia or any other psychotic disorder as defined in the DSM-IV.

2. Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for nicotine or caffeine) within the preceding 3 months.

3. Female subjects who are either pregnant or nursing.

4. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.

5. Subjects with uncorrected hypothyroidism or hyperthyroidism.

6. Subjects with one or more seizures without a clear and resolved etiology.

7. Treatment with a reversible MAOI within 4 weeks prior to study phase I.

8. Treatment with fluoxetine within 5 weeks prior to study phase I.

9. Treatment with any other concomitant medication not allowed (Appendix A for Substudy 2; Appendix G for Substudy 4) 14 days prior to study phase I.

10. No structured psychotherapy will be permitted during the study.

11. Current NIMH employee/staff or their immediate family member.

Additional Exclusion Criteria for substudy 2 (patients with MDD)

1. Previous treatment with ketamine or hypersensitivity to amantadine.

Additional Exclusion Criteria for Substudy 4 (patients with MDD)

1. Subjects who currently are using drugs (except for caffeine or nicotine), must not have used illicit substances in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines) urine test at screening.

2. Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.

3. Clinically significant abnormal laboratory tests.

4. For imaging procedures, Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip).

5. Subjects who, in the investigator's judgment, pose a current serious suicidal or homicidal risk, or who have a MADRS item 10 score of >4.

Exclusion Criteria for healthy control subjects (Substudy 4 only)

1. Current or past Axis I diagnosis

2. Presence of metallic (ferromagnetic) implants (e.g., heart pacemaker, aneurysm clips).

3. Presence of medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.

4. Treatment with any of the exclusionary medications detailed in Appendix G 14 days prior to Phase 1 of the Substudy 4.

5. Current or past alcohol or substance abuse or dependence diagnosis (except for nicotine or caffeine).

6. Presence of psychiatric disorders in first-degree relatives.

7. Female subjects who are either pregnant or nursing.

7.8.Current NIMH employee/staff or their immediate family member.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Carlos A Zarate, M.D., National Institute of Mental Health (NIMH)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 8, 2016

More Information

Publications

None provided.

• Responsible Party: National Institute of Mental Health (NIMH)
• ClinicalTrials.gov Identifier: NCT00088699
• Other Study ID Numbers: 040222; 04-M-0222
• First Posted: Aug 2, 2004
• Last Update Posted: Oct 12, 2018
• Last Verified: Jul 31, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Institute of Mental Health (NIMH): Depression; NMDA Antagonist; Treatment Resistant; Glutamatergic System; Major Depression
• Additional relevant MeSH terms: Depression; Depressive Disorder; Mood Disorders; Ketamine

Study Results

Participant Flow

Arm/Group Title	MDD: Ketamine, Then Placebo	MDD: Placebo, Then Ketamine	Healthy Volunteers: Ketamine, Then Placebo	Healthy Volunteers:Placebo, Then Ketamine
Arm/Group Description	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg.	Placebo and Ketamine infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg	Placebo and Ketamine infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg	Placebo and Ketamine infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg
Period Title: Infusion 1
STARTED	23	19	13	12
COMPLETED	22	19	12	10
NOT COMPLETED	1	0	1	2
Period Title: Infusion 1
STARTED	19	18	11	11
COMPLETED	19	18	11	10
NOT COMPLETED	0	0	0	1

Baseline Characteristics

Arm/Group Title	Healthy Volunteer	Major Depressive Disorder (MDD)	Total
Arm/Group Description	Healthy volunteer patients	Patients diagnosed with Major Depressive Disorder (MDD)	Total of all reporting groups
Overall Participants	25	42	67
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	25 100%	41 97.6%	66 98.5%
>=65 years	0 0%	1 2.4%	1 1.5%
Sex: Female, Male (Count of Participants)
Female	16 64%	25 59.5%	41 61.2%
Male	9 36%	17 40.5%	26 38.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 16%	3 7.1%	7 10.4%
Not Hispanic or Latino	21 84%	39 92.9%	60 89.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 4%	1 2.4%	2 3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 24%	3 7.1%	9 13.4%
White	16 64%	36 85.7%	52 77.6%
More than one race	1 4%	2 4.8%	3 4.5%
Unknown or Not Reported	1 4%	0 0%	1 1.5%

Outcome Measures

1. Primary Outcome

Title	MADRS Score - Baseline
Description	Antidepressant effects were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). It is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The analyses included subjects who were given Ketamine or Placebo.

Arm/Group Title	Ketamine - Healthy Volunteers	Placebo - Healthy Volunteers	Ketamine - MDD Patients	Placebo - MDD Patients
Arm/Group Description	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg to healthy volunteer patients	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg to healthy volunteer patients	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg to patients with Major Depressive Disorders (MDD)	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg to patients with Major Depressive Disorders (MDD)
Measure Participants	24	23	41	38
Mean (Standard Deviation) [units on a scale]	1.17 (1.37)	1.48 (1.78)	33.83 (4.23)	31.82 (5.84)

2. Primary Outcome

Title	MADRS Score - Day 1 Following Intervention
Description	Antidepressant effects were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). It is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

The analyses included subjects who were given Ketamine or Placebo.

Arm/Group Title	Ketamine - Healthy Volunteers	Placebo - Healthy Volunteers	Ketamine - MDD Patients	Placebo - MDD Patients
Arm/Group Description	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg to healthy volunteer patients	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg to healthy volunteer patients	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg to patients with Major Depressive Disorders (MDD)	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg to patients with Major Depressive Disorders (MDD)
Measure Participants	22	21	40	38
Mean (Standard Deviation) [units on a scale]	2.45 (3.79)	0.67 (1.15)	23.73 (10.32)	30.68 (5.50)

Adverse Events

Time Frame	28 days
Arm/Group Title	Healthy Volunteer: Ketamine		MDD: Ketamine		Healthy Volunteer: Placebo		MDD: Placebo
Arm/Group Description	Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg.		Ketamine and placebo infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg.		Placebo and Ketamine infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg		Placebo and Ketamine infusions were administered two weeks apart, with Ketamine's dose being 0.5 mg/kg
All Cause Mortality
	Healthy Volunteer: Ketamine		MDD: Ketamine		Healthy Volunteer: Placebo		MDD: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/41 (0%)		0/23 (0%)		0/38 (0%)
Serious Adverse Events
	Healthy Volunteer: Ketamine		MDD: Ketamine		Healthy Volunteer: Placebo		MDD: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/41 (0%)		0/23 (0%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	Healthy Volunteer: Ketamine		MDD: Ketamine		Healthy Volunteer: Placebo		MDD: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/24 (100%)		36/41 (87.8%)		8/23 (34.8%)		16/38 (42.1%)
Cardiac disorders
Dizziness	19/24 (79.2%)		27/41 (65.9%)		1/23 (4.3%)		0/38 (0%)
Dyspnoea	0/24 (0%)		2/41 (4.9%)		0/23 (0%)		0/38 (0%)
Ear and labyrinth disorders
Auditory disorder	6/24 (25%)		7/41 (17.1%)		0/23 (0%)		0/38 (0%)
Ear pain	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		0/38 (0%)
Motion sickness	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		0/38 (0%)
Tinnitus	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		0/38 (0%)
Vertigo	1/24 (4.2%)		0/41 (0%)		0/23 (0%)		0/38 (0%)
Eye disorders
Diplopia	1/24 (4.2%)		4/41 (9.8%)		0/23 (0%)		0/38 (0%)
Vision blurred	5/24 (20.8%)		11/41 (26.8%)		0/23 (0%)		0/38 (0%)
Visual impairment	14/24 (58.3%)		20/41 (48.8%)		0/23 (0%)		0/38 (0%)
Gastrointestinal disorders
Abdominal discomfort	2/24 (8.3%)		2/41 (4.9%)		0/23 (0%)		0/38 (0%)
Constipation	0/24 (0%)		0/41 (0%)		0/23 (0%)		1/38 (2.6%)
Diarrhoea	1/24 (4.2%)		0/41 (0%)		0/23 (0%)		0/38 (0%)
Dry mouth	6/24 (25%)		5/41 (12.2%)		0/23 (0%)		0/38 (0%)
Dysgeusia	1/24 (4.2%)		2/41 (4.9%)		0/23 (0%)		0/38 (0%)
Flatulence	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		0/38 (0%)
Mouth ulceration	0/24 (0%)		0/41 (0%)		0/23 (0%)		1/38 (2.6%)
Nausea	5/24 (20.8%)		4/41 (9.8%)		0/23 (0%)		0/38 (0%)
Oropharyngeal pain	0/24 (0%)		0/41 (0%)		0/23 (0%)		1/38 (2.6%)
Vomiting	3/24 (12.5%)		1/41 (2.4%)		0/23 (0%)		0/38 (0%)
General disorders
Decreased appetite	4/24 (16.7%)		5/41 (12.2%)		0/23 (0%)		1/38 (2.6%)
Energy increased	2/24 (8.3%)		3/41 (7.3%)		0/23 (0%)		0/38 (0%)
Fatigue	7/24 (29.2%)		2/41 (4.9%)		1/23 (4.3%)		0/38 (0%)
Feeling abnormal	20/24 (83.3%)		32/41 (78%)		1/23 (4.3%)		0/38 (0%)
Flushing	2/24 (8.3%)		7/41 (17.1%)		0/23 (0%)		0/38 (0%)
Hyperhidrosis	1/24 (4.2%)		3/41 (7.3%)		0/23 (0%)		0/38 (0%)
Increased appetite	0/24 (0%)		2/41 (4.9%)		0/23 (0%)		1/38 (2.6%)
Irritability	0/24 (0%)		2/41 (4.9%)		0/23 (0%)		1/38 (2.6%)
Oedema	0/24 (0%)		0/41 (0%)		1/23 (4.3%)		0/38 (0%)
Thirst	1/24 (4.2%)		0/41 (0%)		0/23 (0%)		0/38 (0%)
Investigations
Body temperature decreased	2/24 (8.3%)		6/41 (14.6%)		0/23 (0%)		1/38 (2.6%)
Body temperature increased	4/24 (16.7%)		7/41 (17.1%)		0/23 (0%)		0/38 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	0/24 (0%)		3/41 (7.3%)		2/23 (8.7%)		1/38 (2.6%)
Nervous system disorders
Abnormal dreams	1/24 (4.2%)		2/41 (4.9%)		0/23 (0%)		0/38 (0%)
Amnesia	3/24 (12.5%)		5/41 (12.2%)		0/23 (0%)		1/38 (2.6%)
Balance disorder	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		0/38 (0%)
Confusional state	6/24 (25%)		17/41 (41.5%)		0/23 (0%)		0/38 (0%)
Disturbance in attention	15/24 (62.5%)		3/41 (7.3%)		1/23 (4.3%)		0/38 (0%)
Dysarthria	3/24 (12.5%)		4/41 (9.8%)		0/23 (0%)		0/38 (0%)
Headache	2/24 (8.3%)		4/41 (9.8%)		1/23 (4.3%)		1/38 (2.6%)
Hypoaesthesia	14/24 (58.3%)		24/41 (58.5%)		1/23 (4.3%)		0/38 (0%)
Hypokinesia	6/24 (25%)		2/41 (4.9%)		0/23 (0%)		1/38 (2.6%)
Insomnia	5/24 (20.8%)		7/41 (17.1%)		2/23 (8.7%)		5/38 (13.2%)
Paraesthesia	6/24 (25%)		9/41 (22%)		1/23 (4.3%)		0/38 (0%)
Parosmia	0/24 (0%)		2/41 (4.9%)		0/23 (0%)		0/38 (0%)
Psychomotor hyperactivity	1/24 (4.2%)		0/41 (0%)		0/23 (0%)		0/38 (0%)
Sedation	8/24 (33.3%)		7/41 (17.1%)		0/23 (0%)		3/38 (7.9%)
Slow speech	6/24 (25%)		17/41 (41.5%)		0/23 (0%)		0/38 (0%)
Speech disorder	11/24 (45.8%)		20/41 (48.8%)		0/23 (0%)		0/38 (0%)
Terminal insomnia	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		2/38 (5.3%)
Tremor	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		0/38 (0%)
Vibratory sense increased	1/24 (4.2%)		5/41 (12.2%)		0/23 (0%)		0/38 (0%)
Psychiatric disorders
Anxiety	2/24 (8.3%)		0/41 (0%)		0/23 (0%)		0/38 (0%)
Depression	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		0/38 (0%)
Dissociation	12/24 (50%)		19/41 (46.3%)		0/23 (0%)		0/38 (0%)
Euphoric mood	4/24 (16.7%)		7/41 (17.1%)		0/23 (0%)		0/38 (0%)
Fear	1/24 (4.2%)		5/41 (12.2%)		0/23 (0%)		0/38 (0%)
Hallucination	0/24 (0%)		2/41 (4.9%)		0/23 (0%)		0/38 (0%)
Libido decreased	1/24 (4.2%)		0/41 (0%)		0/23 (0%)		0/38 (0%)
Premenstrual syndrome	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		1/38 (2.6%)
Suicidal ideation	0/24 (0%)		2/41 (4.9%)		0/23 (0%)		0/38 (0%)
Renal and urinary disorders
Dysuria	0/24 (0%)		2/41 (4.9%)		0/23 (0%)		0/38 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/24 (0%)		0/41 (0%)		0/23 (0%)		1/38 (2.6%)
Nasal congestion	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		1/38 (2.6%)
Skin and subcutaneous tissue disorders
Alopecia	0/24 (0%)		0/41 (0%)		1/23 (4.3%)		0/38 (0%)
Skin irritation	0/24 (0%)		0/41 (0%)		0/23 (0%)		1/38 (2.6%)
Vascular disorders
Hypertension	3/24 (12.5%)		6/41 (14.6%)		0/23 (0%)		0/38 (0%)
Hypotension	0/24 (0%)		1/41 (2.4%)		0/23 (0%)		0/38 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.