The Role of Vitamin D in Chronic Urticaria and Angioedema Treatment

• Sponsor: University of Nebraska (Other)
• Overall Status: Completed
• CT.gov ID: NCT01371877
• Collaborator: (none)
• Enrollment: 42
• Locations: 2
• Arms: 2
• Actual Duration (Months): 22
• Patients Per Site: 21
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This clinical study was designed based on our hypothesis that vitamin D plays an important role in chronic urticaria and that high dose supplementation with vitamin D in subjects with chronic urticaria will improve clinical response.

This clinical study will investigate our hypothesis in three Specific Aims:

1. Determine whether high dosing vitamin D supplementation (4000 IU/day) reduces medication usage (primary outcome) and urticaria severity score (secondary outcome) in subjects with chronic urticaria as compared to low dosing (600 IU/day).

2. Determine if high dosing of vitamin D (4000 IU/day) is safe and well-tolerated in subjects with chronic urticaria with or without baseline vitamin D deficiency.

3. Investigate whether there is an association with serum 25-hydroxyvitamin D levels, vitamin D receptor mRNA expression, and chronic urticaria severity.

Condition or Disease	Intervention/Treatment	Phase
Urticaria; Angioedema; Hives; Swelling	Drug: Vitamin D3; Drug: Vitamin D3	N/A

Detailed Description

The purpose of this pilot, 12 week, clinical research study is to determine if supplementation with Vitamin D will improve the clinical outcome in subjects with chronic urticaria and angioedema (CUA). Vitamin D is a key element in the regulation of immune system responses, and vitamin D could play an important role in the treatment of CUA. Recently, we published that there is an important association with CUA and serum 25-hydroxy vitamin D (25OHD). Namely, vitamin D levels in subjects with CUA were significantly lower as compared to subjects with an alternative allergic disorder, allergic rhinitis. There is now one other observational report that supplementation with vitamin D (50,000/wk) in subjects CUA resulted in clinical improvement; however, there was only one treatment arm and optimal serum 25OHD required to obtain benefit was not investigated.

This current study is a double-blinded, prospective, interventional study that seeks to recruit adult subjects with physician-diagnosed CUA and randomize subjects to either the recommended dietary allowance (Vitamin D 600 IU/day) or the recommended upper limit of intake (Vitamin D 4000 IU/day). Subjects will answer a questionnaire to collect information regarding demographics, previous diagnostic tests, medications, and complete an urticaria severity score (USS). Information from the medical record: weight, height, body mass index (BMI), thyroid stimulating hormone (TSH), free thyroxine (T4), thyroid autoantibodies, urticaria autoimmune testing (CD203c results), anti-nuclear antibody (ANA), urinalysis, and allergy skin prick testing, which are part of the CUA evaluation will be obtained. Subjects will have research blood draws for serum 25OHD level, iPTH, calcium, phosphorus, albumin, urine calcium, and vitamin D receptor (VDR) gene expression. All subjects will receive standard-of-care therapy according to the 2009 Third International Consensus Meeting on Urticaria position guidelines. Follow-up visits for medication usage, urticaria severity score, and serum and urine safety monitoring will be at 6 and 12 weeks.

The hypothesis of this study is that high dosing of vitamin D will result in clinical improvement in subjects with CUA. The primary clinical endpoint is medication usage, and the secondary outcomes are urticaria severity score and prednisone rescue use. We will explore if threshold serum 25OHD levels correlate and VDR expression correlate to clinical outcomes, and to determine power analysis to conduct a larger scale study. Finally, the study aims to determine if vitamin D supplementation is safe and well-tolerated in subjects with CUA.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: The Role of Vitamin D in Chronic Urticaria and Angioedema Treatment
• Actual Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vitamin D3 4000 IU Subjects will be randomized 1:1 to high dose vitamin D defined as 4000 IU per day for 3 months. Subjects will be given Vitamin D3 supplementation at 4000 IU daily.	Drug: Vitamin D3; Vitamin D 4000 IU per day for 3 months; Other Names: cholecalciferol
Active Comparator: Vitamin D3 600 IU Subjects will be randomized 1:1 to low dose vitamin D as defined as 600 IU per day for 3 months. Subjects will be given Vitamin D3 supplementation at 600 IU daily	Drug: Vitamin D3; Vitamin D 600 IU per day; Other Names: cholecalciferol

Outcome Measures

Primary Outcome Measures

1. Medication Usage [12 week intervention]

   The Unit of Measure is Efficacy. The primary outcome of this study is to determine if vitamin D supplementation reduces the medication usage in subjects with CUA. Thus, for the outcome of reduction in pills, at 12 weeks, subjects whose pill usage decreases by 2 or more pills per day will be classified as improved. Subjects whose pill consumption did not change or increased will be classified as unchanged.

Secondary Outcome Measures

1. Total Urticaria Severity Score at 3 Months [3 month intervention]

   The Unit of Measure is Efficacy. The Total Urticaria Severity Score (USS) ranges from 0 to 93, higher scores = worse symptoms. This secondary outcome of this study is to determine if high dose vitamin D supplementation improves the urticaria severity score (USS). The change in USS will be compared between the groups using the independent sample t-test (assuming the distribution is normal). Logistic regression and multiple linear regression will be used to adjust for possible confounders.

2. Number of Participants With Adverse Events [3 month study trial]

   Unit of Measure is Safety and Tolerability. The number of participants with adverse events will be compared between the groups using the independent sample t-test (assuming the distribution is normal).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects will be included if they have physician-diagnosed chronic urticaria and/or angioedema (CUA). CUA is defined by having urticarial wheals (hives) and/or angioedema (dermal swelling) on a daily or almost daily for more than 6 weeks. Patients with CUA also having signs of dermatographism and/or delayed-pressure urticaria will be included in the study. Subjects with history of intolerance to non-steroidal anti-inflammatory drugs will be included but warned not to take this drug class (acetaminophen will be allowed instead).

Exclusion Criteria:

• Subjects will be excluded if:

1. They are not capable of answering the questionnaire.

2. Subjects with a pure physical or allergic urticarias, and/or hereditary and acquired angioedema (C1 esterase inhibitor deficiency). These subjects will be excluded as the etiology of their disease is known.

3. Pregnant or lactating women. All child-bearing women will be asked (verbally and on the questionnaire) if they are pregnant or lactating. If they answer yes, they will be excluded. As there is no risk or harm to the pregnant or lactating woman, a urine pregnancy test will not be used.

4. Subjects with any clinically significant abnormality in biochemistry testing, and/or hypercalcemia (calcium > 10.3 mg/dl) or renal insufficiency (GFR< 50 ml/min).

5. Subjects with a history of primary hyperparathyroidism, renal tubular acidosis, sarcoidosis, granulomatous disease, or malignancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-5300
2	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198

Sponsors and Collaborators

• University of Nebraska

Investigators

• Principal Investigator: Jill A Poole, MD, University of Nebraska

Study Documents (Full-Text)

None provided.

More Information

Publications

• Thorp WA, Goldner W, Meza J, Poole JA. Reduced vitamin D levels in adult subjects with chronic urticaria. J Allergy Clin Immunol. 2010 Aug;126(2):413; author reply 413-4. doi: 10.1016/j.jaci.2010.04.040.

• Responsible Party: Jill Poole, MD, Associate Professor, University of Nebraska
• ClinicalTrials.gov Identifier: NCT01371877
• Other Study ID Numbers: 271-11-FB
• First Posted: Jun 13, 2011
• Last Update Posted: Sep 28, 2017
• Last Verified: Aug 1, 2017

• Keywords provided by Jill Poole, MD, Associate Professor, University of Nebraska: urticaria; angioedema; hive; swelling
• Additional relevant MeSH terms: Angioedema; Urticaria; Chronic Urticaria; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins

Study Results

Participant Flow

Arm/Group Title	High Dose Vitamin D	Low Dose Vitamin D
Arm/Group Description	Subjects will be randomized 1:1 to high dose vitamin D defined as 4000 IU per day for 3 months. Vitamin D: Vitamin D 4000 IU per day for 3 months	Subjects will be randomized 1:1 to low dose vitamin D as defined as 600 IU per day for 3 months. Vitamin D: Vitamin D 600 IU per day
Period Title: Overall Study
STARTED	21	21
COMPLETED	21	17
NOT COMPLETED	0	4

Baseline Characteristics

Arm/Group Title	High Dose Vitamin D	Low Dose Vitamin D	Total
Arm/Group Description	Subjects will be randomized 1:1 to high dose vitamin D defined as 4000 IU per day for 3 months. Vitamin D: Vitamin D 4000 IU per day for 3 months	Subjects will be randomized 1:1 to low dose vitamin D as defined as 600 IU per day for 3 months. Vitamin D: Vitamin D 600 IU per day	Total of all reporting groups
Overall Participants	21	21	42
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	43.9	43.1	43.5
Sex: Female, Male (Count of Participants)
Female	18 85.7%	15 71.4%	33 78.6%
Male	3 14.3%	6 28.6%	9 21.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 4.8%	1 2.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 4.8%	1 4.8%	2 4.8%
White	20 95.2%	19 90.5%	39 92.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	21 100%	21 100%	42 100%
Baseline vitamin D level (ng/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/mL]	28.86 (10.1)	37.2 (15.5)	33.0 (13.6)

Outcome Measures

1. Primary Outcome

Title	Medication Usage
Description	The Unit of Measure is Efficacy. The primary outcome of this study is to determine if vitamin D supplementation reduces the medication usage in subjects with CUA. Thus, for the outcome of reduction in pills, at 12 weeks, subjects whose pill usage decreases by 2 or more pills per day will be classified as improved. Subjects whose pill consumption did not change or increased will be classified as unchanged.
Time Frame	12 week intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D	Low Dose Vitamin D
Arm/Group Description	Subjects will be randomized 1:1 to high dose vitamin D defined as 4000 IU per day for 3 months. Vitamin D: Vitamin D 4000 IU per day for 3 months	Subjects will be randomized 1:1 to low dose vitamin D as defined as 600 IU per day for 3 months. Vitamin D: Vitamin D 600 IU per day
Measure Participants	21	17
Baseline medication usage	2.8 (2.6)	4.6 (3.2)
3 month medication usage	2.0 (2.9)	4.9 (2.8)

2. Secondary Outcome

Title	Total Urticaria Severity Score at 3 Months
Description	The Unit of Measure is Efficacy. The Total Urticaria Severity Score (USS) ranges from 0 to 93, higher scores = worse symptoms. This secondary outcome of this study is to determine if high dose vitamin D supplementation improves the urticaria severity score (USS). The change in USS will be compared between the groups using the independent sample t-test (assuming the distribution is normal). Logistic regression and multiple linear regression will be used to adjust for possible confounders.
Time Frame	3 month intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose Vitamin D	Low Dose Vitamin D
Arm/Group Description	Subjects will be randomized 1:1 to high dose vitamin D defined as 4000 IU per day for 3 months. Vitamin D: Vitamin D 4000 IU per day for 3 months	Subjects will be randomized 1:1 to low dose vitamin D as defined as 600 IU per day for 3 months. Vitamin D: Vitamin D 600 IU per day
Measure Participants	21	17
Baseline Total Urticaria Score	41.14 (2.36)	40.1 (3.4)
1 week Total Urticaria Score	25.48 (3.34)	29.24 (3.93)
3 month Total Urticaria Score	15.0 (2.9)	24.1 (2.9)

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Unit of Measure is Safety and Tolerability. The number of participants with adverse events will be compared between the groups using the independent sample t-test (assuming the distribution is normal).
Time Frame	3 month study trial

Outcome Measure Data

Analysis Population Description

No significant adverse events. All subjects in the high vitamin D3 group completed the study; 4 subjects in the low vitamin D3 600 IU/day withdrew from the study (1 for pregnancy and 3 unknown). There was no evidence of hypercalcemia.

Arm/Group Title	High Dose Vitamin D	Low Dose Vitamin D
Arm/Group Description	Subjects will be randomized 1:1 to high dose vitamin D defined as 4000 IU per day for 3 months. Vitamin D: Vitamin D 4000 IU per day for 3 months	Subjects will be randomized 1:1 to low dose vitamin D as defined as 600 IU per day for 3 months. Vitamin D: Vitamin D 600 IU per day
Measure Participants	21	21
Number [participants]	0 0%	0 0%

Adverse Events

Time Frame	Adverse event data were collected continuously and reported to data safety board every 3 months.
Arm/Group Title	High Dose Vitamin D		Low Dose Vitamin D
Arm/Group Description	Subjects will be randomized 1:1 to high dose vitamin D defined as 4000 IU per day for 3 months. Vitamin D: Vitamin D 4000 IU per day for 3 months		Subjects will be randomized 1:1 to low dose vitamin D as defined as 600 IU per day for 3 months. Vitamin D: Vitamin D 600 IU per day
All Cause Mortality
	High Dose Vitamin D		Low Dose Vitamin D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	High Dose Vitamin D		Low Dose Vitamin D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	High Dose Vitamin D		Low Dose Vitamin D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/21 (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.