Study of Ibrutinib in Patients With Symptomatic, Previously Untreated Waldenstrom's Macroglobulinemia, and Impact on Tumor Genomic Evolution Using Whole Genome Sequencing

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02604511
• Collaborator: Pharmacyclics LLC. (Industry)
• Enrollment: 31
• Locations: 2
• Arm: 1
• Anticipated Duration (Months): 85
• Patients Per Site: 15.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This research study is studying a drug called ibrutinib as a possible treatment for untreated Waldenstrom's Macroglobulinemia (WM).

Condition or Disease	Intervention/Treatment	Phase
Waldenstrom's Macroglobulinemia	Drug: Ibrutinib	Phase 2

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has approved ibrutinib as a form of treatment for the patient specific disease.

Ibrutinib has been under investigation in research studies in participants with recurrent B-cell lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and prolymphocytic leukemia, and WM. In a study of ibrutinib in relapsed/refractory WM patients, response rates were high and the treatment was well tolerated.

The prior studies suggest that ibrutinib may be a useful treatment strategy for untreated WM patients. This study will test the safety and efficacy of ibrutinib as an option for untreated WM patients. The study will also conduct genomic sequencing of malignant WM cells before the start of treatment, and 6, 12, 24, 36 and 48 months afterwards. Genomic sequencing is the analysis of the entire DNA structure from tumor and normal cells. The purpose of this sequencing is to study which genetic changes effect how ibrutinib works. The results of these studies could also help in better understanding the course of WM disease, and be applicable to the development of other effective drug treatments.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Ibrutinib in Patients With Symptomatic, Previously Untreated Waldenstrom's Macroglobulinemia, and Impact on Tumor Genomic Evolution Using Whole Genome Sequencing
• Actual Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Feb 1, 2021
• Anticipated Study Completion Date: Feb 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ibrutinib This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration.	Drug: Ibrutinib; Other Names: Imbruvica PCI-32765

Outcome Measures

Primary Outcome Measures

1. Major Response Rate [4 years]

   To asses the proportion of participants with a PR (50% reduction or more in serum IgM) or better.

2. Best Overall Response Rate [4 years]

   To asses the proportion of participants with an MR (25% reduction or more in serum IgM) or better.

Secondary Outcome Measures

1. Duration of Response [4 years]

   The amount of time between attainment of at least a minor response and disease progression.

Other Outcome Measures

1. Time to Response [4 years]

   The amount of time between starting treatment and attaining at least a minor response to therapy

2. Progression Free Survival [4 years]

   The number of participants who have not experienced disease progression 4 years after therapy initiation

3. Overall Survival [4 years]

   The number of participants who are still living 4 years after initiation of ibrutinib

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Clinicopathological diagnosis of Waldenstrom's Macroglobulinemia and meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenstrom's macroglobulinemia (Kyle et al, 2003).

• Measurable disease, defined as presence of serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of normal is required.

• Age ≥ 18 years.

• ECOG performance status ≤2 (see Appendix A.).

• Participants must have normal organ and marrow function as defined below:

• Absolute neutrophil count ≥ 1,000/μL

• Platelets ≥ 50,000/μL

• Hemoglobin ≥ 8 g/dL

• Total bilirubin ≤ 2.0. mg/dL or < 2.5 mg/dL if attributable to hepatic infiltration by neoplastic disease or Gilbert's syndrome.

• AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional upper limit of normal

• Estimated Creatinine Clearance ≥30ml/min

• Not on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin.

• Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or have or will have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 28 days after discontinuation from the study. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. FCBP must be referred to a qualified provider of contraceptive methods if needed.

• Able to adhere to the study visit schedule and other protocol requirements.

• Ability to understand and the willingness to sign a written informed consent document.

• Both men and women of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

• Prior systemic therapy for WM

• Any serious medical condition, laboratory abnormality, uncontrolled intercurrent illness, or psychiatric illness/social condition that would prevent the participant from signing the informed consent form.

• Concurrent use of any other anti-cancer treatments or any other investigational agents.

• Concomitant use of warfarin or other Vitamin K antagonists.

• Concomitant treatment with strong CYP3A4/5 inhibitor.

• Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.

• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion could interfere with the absorption or metabolism of ibrutinib.

• Known CNS lymphoma.

• Concomitant use of medication known to cause QT prolongation.

• Currently active, clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction, unstable angina or acute coronary syndrome within 6 months of screening.

• Malabsorption, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

• Known history of Human Immunodeficiency Virus (HIV), active infection with Hepatitis B Virus (HBV), and/or Hepatitis C Virus (HCV). Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.

• Lactating or pregnant women.

• Inability to swallow capsules.

• History of non-compliance to medical regimens.

• Unwilling or unable to comply with the protocol.

• Major surgery within 4 weeks of first dose of study drug.

• No active infections requiring systemic therapy.

• Known bleeding disorders with the exception of acquired Von Willebrand Disorder suspected on the basis of WM.

• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massacusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Pharmacyclics LLC.

Investigators

• Principal Investigator: Steven P Treon, MD, PhD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 5, 2021

More Information

Publications

None provided.

• Responsible Party: Steven P. Treon, MD, PhD, Steven P. Treon, MD, PhD, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT02604511
• Other Study ID Numbers: 15-359
• First Posted: Nov 13, 2015
• Last Update Posted: Jan 12, 2022
• Last Verified: Dec 1, 2021

• Keywords provided by Steven P. Treon, MD, PhD, Steven P. Treon, MD, PhD, Dana-Farber Cancer Institute: Waldenstrom's Macroglobulinemia
• Additional relevant MeSH terms: Waldenstrom Macroglobulinemia

Study Results

Participant Flow

Arm/Group Title	Ibrutinib
Arm/Group Description	This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration. Ibrutinib
Period Title: Overall Study
STARTED	31
COMPLETED	19
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	Ibrutinib
Arm/Group Description	This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration. Ibrutinib
Overall Participants	31
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 35.5%
>=65 years	20 64.5%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	67
Sex: Female, Male (Count of Participants)
Female	23 74.2%
Male	8 25.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 6.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	28 90.3%
More than one race	0 0%
Unknown or Not Reported	1 3.2%
Region of Enrollment (participants) [Number]
United States	31 100%

Outcome Measures

1. Primary Outcome

Title	Major Response Rate
Description	To asses the proportion of participants with a PR (50% reduction or more in serum IgM) or better.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

All participants except one participant determined to be ineligible

Arm/Group Title	Ibrutinib
Arm/Group Description	This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration. Ibrutinib
Measure Participants	30
Count of Participants [Participants]	26 83.9%

2. Primary Outcome

Title	Best Overall Response Rate
Description	To asses the proportion of participants with an MR (25% reduction or more in serum IgM) or better.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

All participants except one participant determined to be ineligible

Arm/Group Title	Ibrutinib
Arm/Group Description	This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration. Ibrutinib
Measure Participants	30
Count of Participants [Participants]	30 96.8%

3. Secondary Outcome

Title	Duration of Response
Description	The amount of time between attainment of at least a minor response and disease progression.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Time to Response
Description	The amount of time between starting treatment and attaining at least a minor response to therapy
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

All participants except one determined to be ineligible

Arm/Group Title	Ibrutinib
Arm/Group Description	This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration. Ibrutinib
Measure Participants	30
Median (95% Confidence Interval) [months]	0.9

5. Other Pre-specified Outcome

Title	Progression Free Survival
Description	The number of participants who have not experienced disease progression 4 years after therapy initiation
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

All participants except for one determined to be ineligible

Arm/Group Title	Ibrutinib
Arm/Group Description	This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration. Ibrutinib
Measure Participants	30
Count of Participants [Participants]	24 77.4%

6. Other Pre-specified Outcome

Title	Overall Survival
Description	The number of participants who are still living 4 years after initiation of ibrutinib
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

All participants except one who was determined to be ineligible

Arm/Group Title	Ibrutinib
Arm/Group Description	This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration. Ibrutinib
Measure Participants	30
Count of Participants [Participants]	30 96.8%

Adverse Events

Time Frame	Adverse events were collected after ibrutinib initiation, through 30 days of last dose of ibrutinib (e.g. 49 months)
Arm/Group Title	Ibrutinib
Arm/Group Description	This is single arm, open label, Phase II, single center study designed to evaluate the safety and efficacy of ibrutinib in previously untreated WM patients. Treatment will be administered in 4-week cycles, and participants will receive treatment for up to 48 cycles. Treatment will be comprised of ibrutinib at 420 mg per day by oral administration. Ibrutinib
All Cause Mortality
	Ibrutinib
	Affected / at Risk (%)	# Events
Total	0/31 (0%)
Serious Adverse Events
	Ibrutinib
	Affected / at Risk (%)	# Events
Total	15/31 (48.4%)
Cardiac disorders
Atrial fibrillation	2/31 (6.5%)	2
Ventricular fibrillation	1/31 (3.2%)	1
Gastrointestinal disorders
Rectal bleeding	1/31 (3.2%)	1
General disorders
Non-Cardiac Chest pain	1/31 (3.2%)	1
Fever	1/31 (3.2%)	1
Drug-induced hepatitis	1/31 (3.2%)	1
Infections and infestations
Colitis	1/31 (3.2%)	1
Pneumonia	1/31 (3.2%)	1
Prostatitis	1/31 (3.2%)	1
Injury, poisoning and procedural complications
Head trauma	1/31 (3.2%)	1
Hip fracture	1/31 (3.2%)	1
Investigations
AST elevation	2/31 (6.5%)	2
ALT elevation	2/31 (6.5%)	2
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/31 (3.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	1/31 (3.2%)	1
Esophageal cancer	1/31 (3.2%)	1
Nervous system disorders
Stroke	1/31 (3.2%)	1
Psychiatric disorders
Mania	1/31 (3.2%)	1
Renal and urinary disorders
Kidney infection	1/31 (3.2%)	1
Kidney dysfunction	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/31 (3.2%)	1
Vascular disorders
Hematoma	1/31 (3.2%)	1
Other (Not Including Serious) Adverse Events
	Ibrutinib
	Affected / at Risk (%)	# Events
Total	31/31 (100%)
Blood and lymphatic system disorders
Anemia	7/31 (22.6%)	7
Coagulopathy	1/31 (3.2%)	1
Ecchymosis	1/31 (3.2%)	1
Leukocytosis	1/31 (3.2%)	1
Cardiac disorders
Atrial fibrillation	5/31 (16.1%)	5
Bradycardia	1/31 (3.2%)	1
Palpitations	5/31 (16.1%)	5
Pericarditis	1/31 (3.2%)	1
Sinus bradycardia	2/31 (6.5%)	2
Sinus tachycardia	2/31 (6.5%)	2
Ear and labyrinth disorders
Hearing impaired	1/31 (3.2%)	1
Tinnitus	2/31 (6.5%)	2
Vertigo	2/31 (6.5%)	2
Endocrine disorders
Hypothyroidism	1/31 (3.2%)	1
Eye disorders
Blurred vision	3/31 (9.7%)	3
Cataract	2/31 (6.5%)	2
Conjunctivitis	1/31 (3.2%)	1
Dry eye	3/31 (9.7%)	3
Eye pain	1/31 (3.2%)	1
Floaters	1/31 (3.2%)	1
Watering eyes	1/31 (3.2%)	1
Gastrointestinal disorders
Abdominal distension	1/31 (3.2%)	1
Abdominal pain	1/31 (3.2%)	1
Anal hemorrhage	1/31 (3.2%)	1
Bloating	3/31 (9.7%)	3
Constipation	7/31 (22.6%)	7
Diarrhea	24/31 (77.4%)	24
Dry mouth	2/31 (6.5%)	2
Dyspepsia	2/31 (6.5%)	2
Dysphagia	5/31 (16.1%)	5
Eructation	2/31 (6.5%)	2
Flatulence	2/31 (6.5%)	2
Gastroesophageal reflux disease	8/31 (25.8%)	8
Gastrointestinal pain	1/31 (3.2%)	1
Melena	2/31 (6.5%)	2
Mucositis oral	11/31 (35.5%)	11
Nausea	11/31 (35.5%)	11
Oral hemorrhage	3/31 (9.7%)	3
Oral pain	2/31 (6.5%)	2
Rectal hemorrhage	2/31 (6.5%)	2
Stomach flu	3/31 (9.7%)	3
Vomiting	7/31 (22.6%)	7
Diverticulitis	1/31 (3.2%)	1
General disorders
Blood blister	1/31 (3.2%)	1
Brain bleed	1/31 (3.2%)	1
Chills	10/31 (32.3%)	10
Dental implant	1/31 (3.2%)	1
Edema face	1/31 (3.2%)	1
Edema limbs	9/31 (29%)	9
Esophageal spasm	1/31 (3.2%)	1
Fatigue	22/31 (71%)	22
Fever	7/31 (22.6%)	7
Flu-like symptoms	3/31 (9.7%)	3
Hernia	1/31 (3.2%)	1
Irritability	1/31 (3.2%)	1
Localized edema	1/31 (3.2%)	1
Malaise	1/31 (3.2%)	1
Non-cardiac chest pain	1/31 (3.2%)	1
Pain	4/31 (12.9%)	4
Poison ivy	1/31 (3.2%)	1
Sunburn	1/31 (3.2%)	1
Teeth grinding	1/31 (3.2%)	1
Varicose veins	1/31 (3.2%)	1
Immune system disorders
Allergic reaction	1/31 (3.2%)	1
Infections and infestations
Bronchial infection	3/31 (9.7%)	3
Herpes zoster	4/31 (12.9%)	4
Influenza	1/31 (3.2%)	1
Lung infection	2/31 (6.5%)	2
Lyme disease	2/31 (6.5%)	2
Mucosal infection	2/31 (6.5%)	2
Otitis media	1/31 (3.2%)	1
Papulopustular rash	1/31 (3.2%)	1
Paronychia	2/31 (6.5%)	2
Rectum fungus	1/31 (3.2%)	1
Sinusitis	7/31 (22.6%)	7
Skin infection	9/31 (29%)	9
Soft tissue infection	1/31 (3.2%)	1
Tooth infection	1/31 (3.2%)	1
Upper respiratory infection	15/31 (48.4%)	15
Urinary tract infection	4/31 (12.9%)	4
Injury, poisoning and procedural complications
Ankle fracture	1/31 (3.2%)	1
Bone marrow procedure hemorrhage	1/31 (3.2%)	1
Bruising	13/31 (41.9%)	13
Calf injury	1/31 (3.2%)	1
Concussion	1/31 (3.2%)	1
Fall	6/31 (19.4%)	6
Foot laceration	1/31 (3.2%)	1
Fracture	1/31 (3.2%)	1
Knee injury	2/31 (6.5%)	2
Spinal fracture	1/31 (3.2%)	1
Wrist fracture	1/31 (3.2%)	1
Investigations
Alanine aminotransferase increased	2/31 (6.5%)	2
Blood bilirubin increased	2/31 (6.5%)	2
Creatinine increased	5/31 (16.1%)	5
Lymphocyte count decreased	1/31 (3.2%)	1
Neutrophil count decreased	3/31 (9.7%)	3
Platelet count decreased	7/31 (22.6%)	7
Urine output decreased	1/31 (3.2%)	1
Weight loss	4/31 (12.9%)	4
White blood cell decreased	1/31 (3.2%)	1
Metabolism and nutrition disorders
Anorexia	2/31 (6.5%)	2
Hyperglycemia	3/31 (9.7%)	3
Hyperuricemia	1/31 (3.2%)	1
Hypoglycemia	1/31 (3.2%)	1
Hypokalemia	1/31 (3.2%)	1
Hyponatremia	2/31 (6.5%)	2
Hypophosphatemia	1/31 (3.2%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	12/31 (38.7%)	12
Back pain	10/31 (32.3%)	10
Bone pain	2/31 (6.5%)	2
Flank pain	2/31 (6.5%)	2
Generalized muscle weakness	4/31 (12.9%)	4
Joint effusion	2/31 (6.5%)	2
Knee joint hyperflexion	1/31 (3.2%)	1
Myalgia	19/31 (61.3%)	19
Neck pain	2/31 (6.5%)	2
Osteoporosis	1/31 (3.2%)	1
Pain in extremity	1/31 (3.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	6/31 (19.4%)	6
Melanoma	1/31 (3.2%)	1
Mucoid cyst	1/31 (3.2%)	1
Sebaceous cyst	1/31 (3.2%)	1
Nervous system disorders
Ataxia	1/31 (3.2%)	1
Carpal tunnel	1/31 (3.2%)	1
Dizziness	5/31 (16.1%)	5
Headache	10/31 (32.3%)	10
Lethargy	2/31 (6.5%)	2
Memory impairment	1/31 (3.2%)	1
Paresthesia	1/31 (3.2%)	1
Peripheral sensory neuropathy	6/31 (19.4%)	6
Presyncope	1/31 (3.2%)	1
Syncope	2/31 (6.5%)	2
Transient ischemic attack	1/31 (3.2%)	1
Tremor	3/31 (9.7%)	3
Vasovagal reaction	1/31 (3.2%)	1
Psychiatric disorders
Anxiety	3/31 (9.7%)	3
Confusion	1/31 (3.2%)	1
Insomnia	2/31 (6.5%)	2
Renal and urinary disorders
Hematuria	4/31 (12.9%)	4
Renal calculi	2/31 (6.5%)	2
Urinary frequency	1/31 (3.2%)	1
Urinary tract obstruction	2/31 (6.5%)	2
Urinary tract pain	1/31 (3.2%)	1
Reproductive system and breast disorders
Irregular menstruation	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/31 (6.5%)	2
Cough	7/31 (22.6%)	7
Dyspnea	5/31 (16.1%)	5
Epistaxis	8/31 (25.8%)	8
Hiccups	1/31 (3.2%)	1
Pleuritic pain	1/31 (3.2%)	1
Postnasal drip	1/31 (3.2%)	1
Sore throat	5/31 (16.1%)	5
Wheezing	1/31 (3.2%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/31 (3.2%)	1
Bee sting	1/31 (3.2%)	1
Dry skin	2/31 (6.5%)	2
Eczematous Rash	1/31 (3.2%)	1
Hyperhidrosis	8/31 (25.8%)	8
Nail loss	1/31 (3.2%)	1
Nail ridging	5/31 (16.1%)	5
Onychoclasis	2/31 (6.5%)	2
Onychoschizia	2/31 (6.5%)	2
Petechiae	1/31 (3.2%)	1
Pruritus	3/31 (9.7%)	3
Purpura	1/31 (3.2%)	1
Rash maculo-papular	5/31 (16.1%)	5
Rash not otherwise specified	9/31 (29%)	9
Rosacea	1/31 (3.2%)	1
Seborrheic dermatitis	1/31 (3.2%)	1
Sensitive skin	2/31 (6.5%)	2
Skin atrophy	1/31 (3.2%)	1
Skin bleeding	1/31 (3.2%)	1
Skin induration	1/31 (3.2%)	1
Skin ulceration	3/31 (9.7%)	3
Urticaria	1/31 (3.2%)	1
Wart	1/31 (3.2%)	1
Surgical and medical procedures
Tooth extraction	2/31 (6.5%)	2
Vascular disorders
Hematoma	8/31 (25.8%)	8
Hypertension	6/31 (19.4%)	6
Phlebitis	1/31 (3.2%)	1
Vasculitis	1/31 (3.2%)	1

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.