Effectiveness of Paricalcitol in Reducing Parathyroid Hormone (PTH) Levels in X-linked Hypophosphatemic Rickets

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00417612
• Collaborator: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)
• Enrollment: 33
• Location: 1
• Arms: 2
• Duration (Months): 67
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effectiveness of paricalcitol, a form of synthetic vitamin D, in lowering parathyroid hormone (PTH) levels and reducing disease symptoms in children and adults with X-linked hypophosphatemic (XLH) rickets.

Condition or Disease	Intervention/Treatment	Phase
Hypophosphatemia, Familial; Hyperparathyroidism	Drug: Paricalcitol; Other: Placebo	Phase 3

Detailed Description

XLH rickets is a rare inherited disorder in which the bones become painfully soft and bend easily because of a phosphate deficiency. This genetic defect causes the kidneys to allow excretion of an inappropriately high amount of phosphate into the urine. The kidneys are also unable to convert vitamin D into a form usable by the body, resulting in inadequate amounts of active vitamin D. Because vitamin D is needed to absorb calcium and phosphate from the intestine, this deficiency further reduces phosphate levels. Without the sufficient phosphate needed for normal bone growth, individuals with XLH rickets typically develop skeletal malformations, bone pain, and abnormally bowed legs. Hyperparathyroidism, a condition in which the parathyroid glands excrete excess amounts of PTH, also occurs frequently in individuals with XLH rickets, and may play a significant role in the skeletal complications associated with XLH rickets. The purpose of this study is to determine the effectiveness of paricalcitol in lowering PTH levels and reducing disease symptoms in individuals with XLH rickets.

This study will last 12 months. Participants will be randomly assigned to receive either paricalcitol or placebo, taken in the form of two pills daily for the duration of the study. During a baseline 3-day inpatient hospital stay, participants will undergo a physical exam, a cardiac ultrasound, a bone scan, blood collection, and a radiographic skeletal survey. The skeletal survey will include x-rays of various body parts. Participants who are 18 years or younger will not undergo the radiographic skeletal survey. Study visits for all participants will occur every 2 months until the end of the study. These visits will include a physical exam, review of disease symptoms, blood and urine collection, and a check of medication compliance.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Role of Parathyroid Hormone in the Pathogenesis of Skeletal Disease in X-linked Hypophosphatemic Rickets (XLH)
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level	Drug: Paricalcitol; Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.; Other Names: Zemplar
Placebo Comparator: 2 Participants given placebo capsule to match for comparison	Other: Placebo; Placebo sugar pill

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve for Parathyroid Hormone (PTHauc) Measurement [Measured at baseline and Month 12]

   Mean area under the curve for parathyroid hormone levels (PTHauc) sampled during a 26 hour study period, for Paricalcitol (Active Drug) and Placebo groups at Baseline and Month 12 .

2. Area Under the Curve for Parathyroid Hormone (PTH; Percentage Decrease) [Measured at baseline and Month 12]

   Mean PTHauc (% decrease) for Paricalcitol (Active Drug) and Placebo from Baseline to Month 12.

3. Reduction of Parathyroid Hormone Area Under the Curve (PTHauc) of 20% or Greater [Measured at baseline and Month 12]

   Clinically significant reduction of Mean PTHauc (% decrease >/= 20) for Paricalcitol (Active Drug) and Placebo from Baseline to Month 12.

Secondary Outcome Measures

1. Static Parameters of Serum Alkaline Phosphatase at Baseline and 1 Year for Paricalcitol and Placebo Arms. [Measured at baseline and Month 12]

2. Serum Calcium [Measured at baseline and Month 12]

3. Bone Scan Severity Score [Measured at baseline and Month 12]

   99-Tc-methylenediphosphonate bone scans were completed and analyzed using the following scale*: Bone scan severity scale with minimum score of 0 and maximum score of 4 (0 is no disease and 4 is greatest severity of disease). Appearance of lumbar spine and the sacroiliac region were used as internal references to which all suspected lesions were compared, and scored as follows: grade 0, normal scan without suspicious lesions grade 1, lesion(s) less intense than normal lumbar spine grade 2, lesion(s) similar in intensity to normal lumbar spine grade 3, lesions more intense than normal lumbar spine but similar to the normal sacroiliac region grade 4, lesions more intense than the normal sacroiliac region. *devised by nuclear medicine radiologist at Yale New Haven Hospital

4. Percent Change in Urinary Calcium Excretion From Baseline to 1 Year [Measured at baseline and Month 12]

   Percent change in daily urinary calcium excretion, which is calculated the measurements of the calcium in the subject's 24-hr urine collections done at baseline and at the 1 year timepoints

5. Serum Intact Fibroblast Growth Factor 23 (FGF23) [Measured at baseline and Month 12]

6. Serum 1,25 (OH)2D [Measured at baseline and Month 12]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 9 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of XLH rickets

• Fasting serum calcium of 10.7 mg/dl or less

• Fasting PTH greater than 40 nleq/ml and less than 120 nleq/ml in the mid-molecule PTH assay at screening (upper limit of normal is 25 nleq/ml)

• Willing and able to participate in the trial

• Taking stable dose of standard therapy for XLH rickets for at least 2 months prior to study entry

• Concomitant therapy for XLH rickets will not be an exclusion criteria

• Parent or guardian willing to provide informed consent, if applicable

Exclusion Criteria:

• Concomitant kidney failure (estimated creatinine clearance less than 60 cc/min or serum creatinine greater than 1.5 mg/dl)

• Serum 25-hydroxy vitamin D less than 20 ng/ml. Participants meeting this criterion will receive vitamin D3 supplementation for 3 months and then be rescreened.

• Unable to comply with protocol and appropriate follow-up visits

• Treatment with agents that may affect skeletal metabolism, such as glucocorticoids and anticonvulsants

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University School of Medicine	New Haven	Connecticut	United States	06520

Sponsors and Collaborators

• Yale University
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

• Principal Investigator: Thomas O. Carpenter, MD, Yale University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Brown AJ, Dusso AS, Slatopolsky E. Vitamin D analogues for secondary hyperparathyroidism. Nephrol Dial Transplant. 2002;17 Suppl 10:10-9. Review.
• McElduff A, Posen S. Parathyroid hormone sensitivity in familial X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 1989 Aug;69(2):386-9.

• Responsible Party: Thomas Carpenter, Professor of Pediatrics, Yale University
• ClinicalTrials.gov Identifier: NCT00417612
• Other Study ID Numbers: 0607001636; P50AR054086; 1P50AR054086-01
• First Posted: Jan 1, 2007
• Last Update Posted: Mar 17, 2020
• Last Verified: Mar 1, 2020

• Keywords provided by Thomas Carpenter, Professor of Pediatrics, Yale University: Rickets, Hypophosphatemia; Rickets, Vitamin D-Resistant; Rickets, X-linked hypophosphatemic
• Additional relevant MeSH terms: Rickets; Rickets, Hypophosphatemic; Familial Hypophosphatemic Rickets; Hypophosphatemia, Familial; Hypophosphatemia; Hyperparathyroidism

Study Results

Participant Flow

Arm/Group Title	Paricalcitol (Active Drug)	Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce Parathyroid Hormone (PTH) level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
Period Title: Overall Study
STARTED	22	11
COMPLETED	19	8
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	Paricalcitol (Active Drug)	Placebo	Total
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill	Total of all reporting groups
Overall Participants	22	11	33
Age (Count of Participants)
<=18 years	2 9.1%	1 9.1%	3 9.1%
Between 18 and 65 years	19 86.4%	10 90.9%	29 87.9%
>=65 years	1 4.5%	0 0%	1 3%
Sex: Female, Male (Count of Participants)
Female	17 77.3%	9 81.8%	26 78.8%
Male	5 22.7%	2 18.2%	7 21.2%
Region of Enrollment (participants) [Number]
United States	22 100%	11 100%	33 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve for Parathyroid Hormone (PTHauc) Measurement
Description	Mean area under the curve for parathyroid hormone levels (PTHauc) sampled during a 26 hour study period, for Paricalcitol (Active Drug) and Placebo groups at Baseline and Month 12 .
Time Frame	Measured at baseline and Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paricalcitol (Active Drug)	Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
Measure Participants	19	8
Baseline	1223 (426)	1449 (865)
Month 12	987 (372)	1616 (945)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Paricalcitol (Active Drug), Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Static Parameters of Serum Alkaline Phosphatase at Baseline and 1 Year for Paricalcitol and Placebo Arms.
Time Frame	Measured at baseline and Month 12

Outcome Measure Data

Analysis Population Description

Alkaline phosphatase activity was analyzed separately for children (less than 18 years of age) and adults as values varied considerably between these two groups. In other outcome measure modules the paricalcitol group is comprised of 19 participants analyzed which includes adults and children. In this module, the children (2) are their own arm.

Arm/Group Title	Paricalcitol (Active Drug)	Placebo	Paricalcitol (Children Ages 9-17)
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill	Pediatric patients ages 9-17 given paricalcitol
Measure Participants	17	8	2
Serum Alkaline Phosphatase (Baseline)	141 (96)	96 (28)	354 (2)
Serum Alkaline Phosphatase (1 Year)	112 (70)	98 (34)	402 (211)

3. Secondary Outcome

Title	Serum Calcium
Time Frame	Measured at baseline and Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paricalcitol (Active Drug)	Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
Measure Participants	19	8
Serum Calcium (Baseline)	9.2 (0.5)	9.3 (0.5)
Serum Calcium (1 Year)	9.4 (0.5)	9.3 (0.5)

4. Secondary Outcome

Title	Bone Scan Severity Score
Description	99-Tc-methylenediphosphonate bone scans were completed and analyzed using the following scale*: Bone scan severity scale with minimum score of 0 and maximum score of 4 (0 is no disease and 4 is greatest severity of disease). Appearance of lumbar spine and the sacroiliac region were used as internal references to which all suspected lesions were compared, and scored as follows: grade 0, normal scan without suspicious lesions grade 1, lesion(s) less intense than normal lumbar spine grade 2, lesion(s) similar in intensity to normal lumbar spine grade 3, lesions more intense than normal lumbar spine but similar to the normal sacroiliac region grade 4, lesions more intense than the normal sacroiliac region. *devised by nuclear medicine radiologist at Yale New Haven Hospital
Time Frame	Measured at baseline and Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paricalcitol (Active Drug)	Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
Measure Participants	19	8
Baseline Scan Score	2.18 (1.19)	2.00 (1.51)
12 Month Scan Score	1.76 (1.25)	2.12 (1.55)

5. Secondary Outcome

Title	Percent Change in Urinary Calcium Excretion From Baseline to 1 Year
Description	Percent change in daily urinary calcium excretion, which is calculated the measurements of the calcium in the subject's 24-hr urine collections done at baseline and at the 1 year timepoints
Time Frame	Measured at baseline and Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paricalcitol (Active Drug)	Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
Measure Participants	19	8
Mean (Standard Deviation) [percent change]	253 (388)	9 (36)

6. Secondary Outcome

Title	Serum Intact Fibroblast Growth Factor 23 (FGF23)
Time Frame	Measured at baseline and Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paricalcitol (Active Drug)	Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
Measure Participants	19	8
Serum Intact FGF23 (Baseline)	120	93
Serum Intact FGF23 (1 Year)	244	104

7. Secondary Outcome

Title	Serum 1,25 (OH)2D
Time Frame	Measured at baseline and Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paricalcitol (Active Drug)	Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
Measure Participants	19	8
Serum 1,25(OH)2D (Baseline)	51 (18)	47 (9)
Serum 1,25 (OH)2D (1 Year)	52 (17)	46 (14)

8. Primary Outcome

Title	Area Under the Curve for Parathyroid Hormone (PTH; Percentage Decrease)
Description	Mean PTHauc (% decrease) for Paricalcitol (Active Drug) and Placebo from Baseline to Month 12.
Time Frame	Measured at baseline and Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paricalcitol (Active Drug)	Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce parathyroid hormone (PTH) level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
Measure Participants	19	8
20-29%	5 22.7%	1 9.1%
30-39%	1 4.5%	1 9.1%
>/= 40%	3 13.6%	0 0%

9. Primary Outcome

Title	Reduction of Parathyroid Hormone Area Under the Curve (PTHauc) of 20% or Greater
Description	Clinically significant reduction of Mean PTHauc (% decrease >/= 20) for Paricalcitol (Active Drug) and Placebo from Baseline to Month 12.
Time Frame	Measured at baseline and Month 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paricalcitol (Active Drug)	Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.	Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
Measure Participants	19	8
Number [percentage of participants]	53 240.9%	25 227.3%

Adverse Events

Arm/Group Title	Paricalcitol (Active Drug)		Placebo
Arm/Group Description	Participants given active drug, paricalcitol (Zemplar), in effort to reduce PTH level Paricalcitol: Paricalcitol given first as a dose of 2 capsules once per day. Dose titration as needed per biochemical results at outpatient visits.		Participants given placebo capsule to match for comparison Placebo: Placebo sugar pill
All Cause Mortality
	Paricalcitol (Active Drug)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Paricalcitol (Active Drug)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Paricalcitol (Active Drug)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/22 (9.1%)		0/11 (0%)
Blood and lymphatic system disorders
Hypercalcemia	1/22 (4.5%)	1	0/11 (0%)	0
Renal and urinary disorders
Elevated Serum Creatinine	1/22 (4.5%)	1	0/11 (0%)	0

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.