Hydroxyurea to Prevent Organ Damage in Children With Sickle Cell Anemia

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00006400
• Collaborator: (none)
• Enrollment: 193
• Locations: 14
• Arms: 2
• Duration (Months): 109
• Patients Per Site: 13.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if hydroxyurea therapy is effective in the prevention of chronic end organ damage in pediatric patients with sickle cell anemia.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Diseases; Anemia, Sickle Cell	Drug: Hydroxyurea; Drug: Placebo	Phase 3

Detailed Description

BACKGROUND:

In 1995, the Multicenter Study of Hydroxyurea (MSH) demonstrated that hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The recently completed phase II study of hydroxyurea in children (PED HUG) demonstrated that children have a response to hydroxyurea similar to that seen in adults in terms of increasing fetal hemoglobin levels and total hemoglobin, and decreasing complications associated with sickle cell anemia. In addition, this study demonstrated that the drug does not adversely affect growth and development between the ages of 5 and 15. A recently completed pilot study of hydroxyurea given to children between the ages of 6 months and 24 months demonstrated that the drug is tolerated well by small infant, and that the fetal hemoglobin switch can be forced to remain in the "on position" by hydroxyurea administration.

A Special Emphasis Panel (SEP) met on April 12, 1996 to review the results of the MSH trial and the progress to date of the PED HUG study. The SEP recommended that NHLBI undertake the BABY HUG trial.

DESIGN NARRATIVE:

BABY HUG is a randomized, double-blind, placebo-controlled study to determine if hydroxyurea can prevent the onset of chronic end organ damage in young children with sickle cell anemia. Approximately 200 children with sickle cell disease will be recruited to receive either hydroxyurea or placebo. The children will be screened at study entry for signs of abnormal brain, kidney, pulmonary, and splenic function, and developmental milestones. They will then be randomly assigned to receive either hydroxyurea or placebo and followed yearly to assess chronic end organ damage of the major organ systems. The primary endpoint will be a 50% reduction in rates of damage to the major organs with surrogate markers of organ function during follow-up in Phase II of the trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 193 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG)
• Study Start Date: Aug 1, 2000
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Hydroxyurea Participants will receive hydroxyurea.	Drug: Hydroxyurea; Participants will receive hydroxyurea.
Placebo Comparator: Placebo Participants will receive placebo.	Drug: Placebo; Participants will receive placebo.

Outcome Measures

Primary Outcome Measures

1. Treatment Differences of the Change in Qualitative Splenic Function From Baseline [Before initiation of treatment and at 2 years]

   Primary Endpoint: Spleen function was assessed by uptake of 99mTc sulfur colloid on liver-spleen scan before initiation of treatment (baseline) and 2 years later (exit). The results of each of the two scans were categorized as normal, functional but abnormal, or not functional by a panel of nuclear medicine specialists blinded to treatment assignment. The proportion of patients whose paired scans demonstrated a decline in splenic function was compared in the hydroxyurea versus placebo groups. The change in splenic function from baseline to 2 years was defined as worse if it changed from normal to decreased or absent, or decreased to absent; and not worse if it changed from decreased to decreased, normal to normal, or decreased to normal.

Secondary Outcome Measures

1. Change From Baseline in the Renal Function That Was Measured by Diethylenetriaminepentaacetic Acid (DTPA) Glomerular Filtration Rate (GFR) [Before initiation of treatment and at 2 years]

   DTPA GFR was originally a co-primary efficacy outcome for the study. Later in May 29, 2009, this measurement was discontinued because of statistical futility (an extremely small chance that the difference between treatment groups would be statistically significant for this outcome) and the small risk posed by the radiation exposure involved with performing the DTPA GFR test. Subjects who had missing data at baseline or 2 years measurement were excluded from the analysis (29 subjects from the hydroxurea, and 31 subjects from the placebo group excluded).

2. Change From Baseline in the Renal Function That Was Measured by Glomerular Filtration Rate (GFR) (Calculated Using Schwartz Formula) [Before initiation of treatment and at 2 years]

   Schwartz formula used to calculate GFR is: 0.55× height (cm)/serum creatinine (mg/dL). Where height is in cm and serum creatinine is in mg/dL. Children with missing baseline or 2 years GFR were excluded from the analysis.

3. Change From Baseline in the Renal Function That Was Measured by GFR (Calculated Using New Schwartz Formula) [Before initiation of treatment and at 2 years]

   GFR was calculated using new Schwartz formula: 39.1× [height (cm)/serum creatinine (mg/dL)]0.516 × [1.8/cystatin C]0.294 × [30/blood urea nitrogen]0.169 × [1.099]if male × [height(m)/1.4]0.188. Children with missing baseline or 2 years GFR were excluded from the analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 9 Months to 18 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Majority fetal and sickle (FS or SF) hemoglobin pattern confirmed centrally by electrophoresis (screening may begin at 7 months of age)

Exclusion Criteria:

• Chronic transfusion therapy

• Cancer

• Less than 5th percentile (10th percentile for the pilot study) height, weight, or head circumference for age

• Severe developmental delay (e.g., cerebral palsy or other mental retardation, Grade III/IV intraventricular hemorrhage)

• Stroke with neurological deficit

• Surgical splenectomy

• Participating in other clinical intervention trials

• Probable or known diagnosis of Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin

• Known hemoglobin S-beta plus thalassemia (hemoglobin A present)

• Any condition or chronic illness, which in the opinion of the principal investigator, makes participation unadvised or unsafe

• Inability or unwillingness to complete baseline (pre-enrollment) studies, including blood or urine specimen collection, liver-spleen scan, abdominal sonogram, neurological examination, neuropsychological testing, or transcranial Doppler ultrasound (interpretable study not required, but confirmed velocity greater than 200 cm/sec results in ineligibility)

• Previous or current treatment with hydroxyurea (HU) or another anti-sickling drug

• The following exclusion criteria are transient; patients can be re-evaluated for eligibility:

1. Hemoglobin less than 6.0 gm/dL

2. Reticulocyte count less than 80,000/cu mm if hemoglobin is less than 9 gm/dL

3. Neutrophil count less than 2,000/cu mm

4. Platelet count less than 130,000/cu mm

5. Blood transfusion in the 2 months prior to study entry unless HbA is less than 10%

6. ALT greater than twice the upper limit of normal

7. Ferritin less than 10 ng/ml

8. Serum creatinine greater than twice the upper limit of normal for age

9. Bayley standardized mental score below 70

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Children's National Medical Center	Washington	District of Columbia	United States	20010
3	Howard University	Washington	District of Columbia	United States	20060
4	University of Miami	Miami	Florida	United States	33136
5	Emory University School of Medicine	Atlanta	Georgia	United States	30342
6	Johns Hopkins University	Baltimore	Maryland	United States	21287
7	Children's Hospital of Michigan/Wayne State Univ.	Detroit	Michigan	United States	48201
8	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
9	SUNY Health Science Center, Brooklyn	Brooklyn	New York	United States	11203
10	Duke University Medical Center	Durham	North Carolina	United States	27710
11	Drexel University	Philadelphia	Pennsylvania	United States	19134
12	Medical University of South Carolina	Charleston	South Carolina	United States	29425
13	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
14	University of Texas SW Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Sherron Jackson, MD, Medical University of South Carolina
• Principal Investigator: James F. Casella, MD, Johns Hopkins University
• Principal Investigator: Lori Luchtman-Jones, MD, Children's National Research Institute
• Principal Investigator: Rathi V. Iyer, MD, University of Mississippi Medical Center
• Principal Investigator: Scott T. Miller, MD, SUNY Health Science Center, Brooklyn
• Principal Investigator: Sohail R. Rana, MD, Howard University
• Principal Investigator: Zora R. Rogers, MD, University of Texas SW Medical Center
• Principal Investigator: Bruce W Thompson, Ph.D., Clinical Trials and Surveys Corp
• Principal Investigator: Julio Barredo, MD, University of Miami Medical Center
• Study Chair: Winfred C. Wang, MD, St. Jude Children's Research Hospital
• Principal Investigator: Courtney Thornburg, MD, Duke University
• Principal Investigator: Thomas Howard, MD, University of Alabama at Birmingham
• Principal Investigator: Lori Luck, MD, Drexel University
• Principal Investigator: R. Clark Brown, MD, PhD, Emory University
• Principal Investigator: Sharada Sarnaik, MD, Wayne State University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 9, 2009
• Informed Consent Form - Oct 16, 2006

More Information

Publications

• Heeney MM, Whorton MR, Howard TA, Johnson CA, Ware RE. Chemical and functional analysis of hydroxyurea oral solutions. J Pediatr Hematol Oncol. 2004 Mar;26(3):179-84.
• Thompson BW, Miller ST, Rogers ZR, Rees RC, Ware RE, Waclawiw MA, Iyer RV, Casella JF, Luchtman-Jones L, Rana S, Thornburg CD, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik S, Howard TH, Luck L, Wang WC. The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design. Pediatr Blood Cancer. 2010 Feb;54(2):250-5. doi: 10.1002/pbc.22269.

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT00006400
• Other Study ID Numbers: 89; N01 HB07150; N01 HB07151; N01 HB07152; N01 HB07153; N01 HB07154; N01 HB07155; N01 HB07156; N01 HB07157; N01 HB07158; N01 HB07159; N01 HB07160
• First Posted: Oct 13, 2000
• Last Update Posted: Aug 19, 2020
• Last Verified: Apr 1, 2011

• Keywords provided by National Heart, Lung, and Blood Institute (NHLBI): Blood Diseases; Sickle Cell Anemia
• Additional relevant MeSH terms: Anemia; Anemia, Sickle Cell; Hematologic Diseases; Hydroxyurea

Study Results

Participant Flow

Recruitment Details	200 patients planned; 233 patients screened; 197 patients eligible for study participation; 193 patients randomized to study treatment; 191 patients initiated study treatment

Arm/Group Title	Hydroxyurea	Placebo
Arm/Group Description	Participants will receive hydroxyurea.	Participants will receive placebo.
Period Title: Overall Study
STARTED	96	97
COMPLETED	83	84
NOT COMPLETED	13	13

Baseline Characteristics

Arm/Group Title	Hydroxyurea	Placebo	Total
Arm/Group Description	Participants will receive hydroxyurea.	Participants will receive placebo.	Total of all reporting groups
Overall Participants	96	97	193
Age (Count of Participants)
<=18 years	96 100%	97 100%	193 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	13.57 (2.60)	13.56 (2.74)	13.56 (2.66)
Sex: Female, Male (Count of Participants)
Female	52 54.2%	57 58.8%	109 56.5%
Male	44 45.8%	40 41.2%	84 43.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	94 97.9%	87 89.7%	181 93.8%
White	0 0%	1 1%	1 0.5%
More than one race	0 0%	5 5.2%	5 2.6%
Unknown or Not Reported	2 2.1%	4 4.1%	6 3.1%
Region of Enrollment (participants) [Number]
United States	96 100%	97 100%	193 100%

Outcome Measures

1. Primary Outcome

Title	Treatment Differences of the Change in Qualitative Splenic Function From Baseline
Description	Primary Endpoint: Spleen function was assessed by uptake of 99mTc sulfur colloid on liver-spleen scan before initiation of treatment (baseline) and 2 years later (exit). The results of each of the two scans were categorized as normal, functional but abnormal, or not functional by a panel of nuclear medicine specialists blinded to treatment assignment. The proportion of patients whose paired scans demonstrated a decline in splenic function was compared in the hydroxyurea versus placebo groups. The change in splenic function from baseline to 2 years was defined as worse if it changed from normal to decreased or absent, or decreased to absent; and not worse if it changed from decreased to decreased, normal to normal, or decreased to normal.
Time Frame	Before initiation of treatment and at 2 years

Outcome Measure Data

Analysis Population Description

Subjects who had baseline and 2 years splenic function measurements, and had baseline measurement different from absent splenic function. A total of 26 hydroxyurea and 23 placebo subjects had missing data or had absent splenic function at baseline.

Arm/Group Title	Hydroxyurea	Placebo
Arm/Group Description	Participants will receive hydroxyurea. Hydroxyurea: Participants will receive hydroxyurea.	Participants will receive placebo. Placebo: Participants will receive placebo.
Measure Participants	70	74
Worse	19 19.8%	28 28.9%
Not worse	51 53.1%	46 47.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxyurea, Placebo
	Comments	The primary analysis compared the frequency of worsening spleen function (from normal to decreased or absent, or decreased to absent) and not worsening (from decreased to decreased, normal to normal, or decreased to normal) as measured by splenic uptake on a technetium-99m (99mTc) sulfur colloid liver-spleen scan. Children with missing data or absent spleen function at baseline were excluded from the analysis (26 subjects from hydroxyurea and 23 subjects from placebo group were excluded).
	Type of Statistical Test	Superiority
	Comments	The primary analysis was done using an intention-to-treat principle.
Statistical Test of Hypothesis	p-Value	0.21
	Comments	The spleen endpoint was to be tested at an overall alpha = 0.04. Originally there was a second primary outcome to be tested at alpha = 0.01, but this outcome was dropped.
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Change From Baseline in the Renal Function That Was Measured by Diethylenetriaminepentaacetic Acid (DTPA) Glomerular Filtration Rate (GFR)
Description	DTPA GFR was originally a co-primary efficacy outcome for the study. Later in May 29, 2009, this measurement was discontinued because of statistical futility (an extremely small chance that the difference between treatment groups would be statistically significant for this outcome) and the small risk posed by the radiation exposure involved with performing the DTPA GFR test. Subjects who had missing data at baseline or 2 years measurement were excluded from the analysis (29 subjects from the hydroxurea, and 31 subjects from the placebo group excluded).
Time Frame	Before initiation of treatment and at 2 years

Outcome Measure Data

Analysis Population Description

Subjects who had baseline and 2 years measurements

Arm/Group Title	Hydroxyurea	Placebo
Arm/Group Description	Participants will receive hydroxyurea. Hydroxyurea: Participants will receive hydroxyurea.	Participants will receive placebo. Placebo: Participants will receive placebo.
Measure Participants	67	66
Mean (Standard Deviation) [mL/min/1.73m^2]	22.56 (54.67)	20.74 (51.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxyurea, Placebo
	Comments	The change from baseline to exit as measured by DTPA GFR were compared between treatment groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments	This was originally a second primary outcome to be tested at alpha = 0.01, but was later dropped from the protocol. We analyzed the available data.
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Change From Baseline in the Renal Function That Was Measured by Glomerular Filtration Rate (GFR) (Calculated Using Schwartz Formula)
Description	Schwartz formula used to calculate GFR is: 0.55× height (cm)/serum creatinine (mg/dL). Where height is in cm and serum creatinine is in mg/dL. Children with missing baseline or 2 years GFR were excluded from the analysis.
Time Frame	Before initiation of treatment and at 2 years

Outcome Measure Data

Analysis Population Description

All subjects who had baseline and 2 years GFR calculated using Schwartz formula (0.55× height (cm)/serum creatinine (mg/dL)).

Arm/Group Title	Hydroxyurea	Placebo
Arm/Group Description	Participants will receive hydroxyurea. Hydroxyurea: Participants will receive hydroxyurea.	Participants will receive placebo. Placebo: Participants will receive placebo.
Measure Participants	70	76
Mean (Standard Deviation) [mL/min/1.73m^2]	28.65 (76.46)	33.36 (95.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxyurea, Placebo
	Comments	The change from baseline to exit as measured by GFR (calculated using Shwartz formula) were compared between treatment groups.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments	All secondary outcomes were tested at alpha=0.01
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Change From Baseline in the Renal Function That Was Measured by GFR (Calculated Using New Schwartz Formula)
Description	GFR was calculated using new Schwartz formula: 39.1× [height (cm)/serum creatinine (mg/dL)]0.516 × [1.8/cystatin C]0.294 × [30/blood urea nitrogen]0.169 × [1.099]if male × [height(m)/1.4]0.188. Children with missing baseline or 2 years GFR were excluded from the analysis.
Time Frame	Before initiation of treatment and at 2 years

Outcome Measure Data

Analysis Population Description

All subjects who had baseline and 2 years GFR calculated using the new Schwartz formula (39.1× [height (cm)/serum creatinine (mg/dL)]0.516 × [1.8/cystatin C]0.294 × [30/blood urea nitrogen]0.169 × [1.099]if male × [height(m)/1.4]0.188).

Arm/Group Title	Hydroxyurea	Placebo
Arm/Group Description	Participants will receive hydroxyurea. Hydroxyurea: Participants will receive hydroxyurea.	Participants will receive placebo. Placebo: Participants will receive placebo.
Measure Participants	34	47
Mean (Standard Deviation) [mL/min/1.73m^2]	10.57 (20.78)	14.33 (24.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxyurea, Placebo
	Comments	The change in GFR from baseline to exit were compared between treatment groups. GFR was calculated using new Schwartz formula.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments	All secondary outcomes were to be tested at alpha = 0.01
	Method	ANOVA
	Comments

Adverse Events

Time Frame	From randomization through study completion, an average of 1.93 years.
Adverse Event Reporting Description	The CC, NHLBI, and the DSMB continuously monitored the safety of study treatments. A serious adverse event(SAE) was defined as an untoward medical event that is fatal, life threatening, causes/prolongs a hospitalization, or poses a risk of permanent disability, i.e. SAE was defined as one or more of the following: Death Life-threatening events Prolonged hospitalization (greater than 7 days) Splenic sequestration crisis Stroke, TIA Acute chest syndrome ICU admissions
Arm/Group Title	Hydroxyurea		Placebo
Arm/Group Description	Participants were to receive hydroxyurea.		Participants were to receive placebo.
All Cause Mortality
	Hydroxyurea		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/96 (0%)		0/97 (0%)
Serious Adverse Events
	Hydroxyurea		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/96 (19.8%)		35/97 (36.1%)
Blood and lymphatic system disorders
Splenic Sequestration	11/96 (11.5%)	16	12/97 (12.4%)	17
Acute chest syndrome	1/96 (1%)	1	0/97 (0%)	0
APLASTIC CRISIS	0/96 (0%)	0	2/97 (2.1%)	2
anemia (Hgb 6.3 - given PRBC transfusion)	0/96 (0%)	0	1/97 (1%)	1
General disorders
Pain	1/96 (1%)	1	0/97 (0%)	0
FEVER > 101.5°F(38.4°C)	1/96 (1%)	1	0/97 (0%)	0
Infections and infestations
ACUTE OSTEOMYELITIS	0/96 (0%)	0	1/97 (1%)	1
SEPSIS OR MENINGITIS	0/96 (0%)	0	2/97 (2.1%)	2
Bacteremia	0/96 (0%)	0	1/97 (1%)	1
Streptococcus pneumonieae	0/96 (0%)	0	1/97 (1%)	1
Acute chest syndrome	1/96 (1%)	1	0/97 (0%)	0
Injury, poisoning and procedural complications
Possible Accidental Hydroxyurea overdose	1/96 (1%)	1	0/97 (0%)	0
Investigations
ABNORMAL TCD	1/96 (1%)	1	3/97 (3.1%)	3
Metabolism and nutrition disorders
dehydration	0/96 (0%)	0	1/97 (1%)	1
Nervous system disorders
STROKE, WITH NEUROLOGIC DEFICIT	0/96 (0%)	0	1/97 (1%)	1
encephalopathy (indeterminate etiology)	0/96 (0%)	0	1/97 (1%)	1
severe obstructive sleep apnea	0/96 (0%)	0	1/97 (1%)	1
Respiratory, thoracic and mediastinal disorders
Acute Chest Syndrome	6/96 (6.3%)	7	19/97 (19.6%)	28
Vascular disorders
DVT	1/96 (1%)	1	0/97 (0%)	0
Other (Not Including Serious) Adverse Events
	Hydroxyurea		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	95/96 (99%)		95/97 (97.9%)
Blood and lymphatic system disorders
SPLENOMEGALY	32/96 (33.3%)	105	35/97 (36.1%)	84
Ear and labyrinth disorders
Otitis Media	11/96 (11.5%)	12	10/97 (10.3%)	13
Gastrointestinal disorders
Pain	10/96 (10.4%)	13	15/97 (15.5%)	35
GASTROENTERITIS	7/96 (7.3%)	10	3/97 (3.1%)	3
CONSTIPATION	16/96 (16.7%)	23	33/97 (34%)	65
Diarrhea	12/96 (12.5%)	15	14/97 (14.4%)	14
Emesis	7/96 (7.3%)	9	9/97 (9.3%)	11
Vomiting	11/96 (11.5%)	13	14/97 (14.4%)	15
General disorders
FEVER >101.5 F (38.4 C)	75/96 (78.1%)	231	82/97 (84.5%)	272
Pain	50/96 (52.1%)	131	62/97 (63.9%)	268
Low Grade Fever (<101.5)	9/96 (9.4%)	12	14/97 (14.4%)	18
Infections and infestations
UPPER RESPIRATORY INFECTION	83/96 (86.5%)	298	77/97 (79.4%)	326
Viral Syndrome	46/96 (47.9%)	69	46/97 (47.4%)	80
Otitis Media	38/96 (39.6%)	80	48/97 (49.5%)	103
GASTROENTERITIS	33/96 (34.4%)	45	31/97 (32%)	47
SKIN INFECTION, FUNGAL	15/96 (15.6%)	21	13/97 (13.4%)	14
SKIN INFECTION, BACTERIAL	5/96 (5.2%)	5	9/97 (9.3%)	14
Pneumonia	11/96 (11.5%)	14	21/97 (21.6%)	28
CONJUNCTIVITIS	16/96 (16.7%)	18	13/97 (13.4%)	16
URI	2/96 (2.1%)	3	6/97 (6.2%)	9
Bronchitis	4/96 (4.2%)	7	6/97 (6.2%)	7
Urinary Tract Infection	5/96 (5.2%)	7	11/97 (11.3%)	13
PHARYNGITIS	7/96 (7.3%)	7	5/97 (5.2%)	6
SINUSITIS	3/96 (3.1%)	3	6/97 (6.2%)	6
Injury, poisoning and procedural complications
Insect Bites	12/96 (12.5%)	15	15/97 (15.5%)	22
Musculoskeletal and connective tissue disorders
Pain	15/96 (15.6%)	20	27/97 (27.8%)	49
DACTYLITIS	14/96 (14.6%)	23	43/97 (44.3%)	123
Respiratory, thoracic and mediastinal disorders
UPPER RESPIRATORY INFECTION	8/96 (8.3%)	12	14/97 (14.4%)	16
Viral Syndrome	4/96 (4.2%)	4	5/97 (5.2%)	6
Cough	3/96 (3.1%)	3	11/97 (11.3%)	12
Allergic Rhinitis	10/96 (10.4%)	12	15/97 (15.5%)	21
Wheezing	8/96 (8.3%)	11	3/97 (3.1%)	4
Reactive Airway Disease	5/96 (5.2%)	9	9/97 (9.3%)	13
RHINORRHEA	5/96 (5.2%)	5	11/97 (11.3%)	15
Asthma	8/96 (8.3%)	13	6/97 (6.2%)	9
Skin and subcutaneous tissue disorders
SKIN INFECTION, FUNGAL	1/96 (1%)	1	6/97 (6.2%)	7
Eczema	11/96 (11.5%)	15	12/97 (12.4%)	18
Rash	21/96 (21.9%)	25	29/97 (29.9%)	43
Diaper DERMATITIS	7/96 (7.3%)	7	4/97 (4.1%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.