APPLE: Paricalcitol in Reducing Parathyroid Hormone Levels and Ameliorating Markers of Bone Remodelling in Renal Transplant Recipients With Secondary Hyperparathyroidism

Sponsor

Mario Negri Institute for Pharmacological Research (Other)

Overall Status

Completed

CT.gov ID

NCT01220050

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The risk of fracture for kidney transplant recipients is 4 times higher that of the general population. The hyperparathyroidism plays a key role in the maintenance or development of post-transplant alterations of bone remodelling.

Renal transplant patients are at high risk of hyperparathyroidism, largely because of long-lasting renal insufficiency before transplant, and of progressive deterioration of kidney function because of chronic allograft nephropathy (a disease of proteinuria and progressive decline of the glomerular filtration rate).In hemodialysis patients, intravenous paricalcitol (19-nor-1,25-dihydroxyvitamin D2), a new vitamin D analogue, achieves a faster and more effective normalization of parathyroid hormone (PTH) levels than calcitriol (1,25-dihydroxyvitamin D3), an effect that is associated with smaller changes in serum calcium and phosphorus levels.

Whether oral paricalcitol may help achieving a prompt reduction in serum PTH levels and, secondarily, in urinary protein excretion in renal transplant recipients with secondary hyperparathyroidism is worth investigating.

Condition or Disease	Intervention/Treatment	Phase
Renal Transplant Secondary Hyperparathyroidism	Drug: Paricalcitol Drug: Standard therapy	Phase 2

Detailed Description

BACKGROUND The risk of fracture for kidney transplant recipients is 4 times higher that of the general population. The pathogenesis of post-transplant bone disease is multifactorial, but hyperparathyroidism plays a key role in the maintenance or development of post-transplant alterations of bone remodelling. Vitamin D and its analogues are key components of treatment aimed to prevent or ameliorate secondary hyperparathyroidism in patients with chronic kidney disease (CKD). In hemodialysis patients, intravenous paricalcitol (19-nor-1,25-dihydroxyvitamin D2), a new vitamin D analogue, achieves a faster and more effective normalization of parathyroid hormone (PTH) levels than calcitriol (1,25-dihydroxyvitamin D3), an effect that is associated with smaller changes in serum calcium and phosphorus levels. Preliminary evidence is also available that in pre-dialysis patients with CKD and secondary hyperparathyroidism, treatment with oral paricalcitol may also reduce urinary protein excretion, an effect that is independent of concomitant treatment with agents that block the renin-angiotensin system and that in the long-term might translate into slower progression to end stage kidney disease and need for renal replacement therapy.

Renal transplant patients are at high risk of hyperparathyroidism, largely because of long-lasting renal insufficiency before transplant, and of progressive deterioration of kidney function because of chronic allograft nephropathy (a disease of proteinuria and progressive decline of the glomerular filtration rate). Whether oral paricalcitol may help achieving a prompt reduction in serum PTH levels and, secondarily, in urinary protein excretion in renal transplant recipients with secondary hyperparathyroidism is worth investigating.

AIMS Primary To evaluate whether 6-months treatment with paricalcitol may achieve a prompt and effective reduction in PTH serum levels in stable renal transplant patients with secondary hyperparathyroidism.

DESIGN This will be a Prospective, Randomized, Open label, Cross-over study of 6-months with Paricalcitol or standard treatment for hyperparathyroidism.

After one month wash-out from any form of Vitamin D therapy, patients satisfying the inclusion/exclusion criteria will be randomized to two treatment arms:

Paricalcitol capsules 1- 2 mcg/day/pts for 26 weeks
Standard therapy for hyperparathyroidism for 26 weeks At the end of the first treatment period with Paricalcitol or Standard therapy each patient will cross-over to the other treatment.

After baseline evaluation eligible patients will enter a 6 months treatment period whit oral paricalcitol (1-2 mcg/day), or standard treatment for hyperparathyroidism, added-on background therapy whit calcium and phosphate supplementation as deemed clinically appropriate.

Study Design

Study Type:

Interventional

Actual Enrollment :

43 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A PROSPECTIVE, PILOT, CROSS-OVER STUDY TO ASSESS THE EFFICACY OF PARICALCITOL IN REDUCING PARATHYROID HORMONE LEVELS AND AMELIORATING MARKERS OF BONE REMODELLING IN RENAL TRANSPLANT RECIPIENTS WITH SECONDARY HYPERPARATHYROIDISM

Study Start Date :

Sep 1, 2009

Actual Primary Completion Date :

Jul 1, 2012

Actual Study Completion Date :

Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Paricalcitol	Drug: Paricalcitol Paricalcitol capsules 1- 2 mcg/day/pts for 26 weeks
Active Comparator: Standard therapy	Drug: Standard therapy Standard therapy for hyperparathyroidism for 26 weeks

Arm

Intervention/Treatment

Experimental: Paricalcitol

Drug: Paricalcitol

Paricalcitol capsules 1- 2 mcg/day/pts for 26 weeks

Active Comparator: Standard therapy

Drug: Standard therapy

Standard therapy for hyperparathyroidism for 26 weeks

Outcome Measures

Primary Outcome Measures

PTH reduction during the 6 months of paricalcitol therapy (during both treatment periods) compared to the change in PTH levels during the corresponding 6 months without paricalcitol therapy. [Every three months.]

Secondary Outcome Measures

Measurement of osteocalcin. [Baseline and then every three months.]
Measurement of bone alkaline phosphatase. [Baseline and then every three months.]
Measurement of urinary deoxypyridinoline. [Baseline and then every three months.]
Bone mineral density (by MOC). [At baseline and at the end of both treatment periods.]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Males and females >18 years old
Renal transplant recipients with persistent secondary hyperparathyroidism
PTH persistently >80 pg/mL up 2 month post transplant (stable or progressively increasing PTH levels)
No ongoing therapy with Vitamin D
Patients on maintenance therapy with calcineurin inhibitors and Mycophenolate Mofetil or Azathioprine
Serum creatinine < 2mg/dL
Patients legally able to give written informed consent to the trial (signed and dated by the patient)
Written informed consent.

Exclusion Criteria:

Concomitant administration of other forms of Vitamin D (different from paricalcitol)
PTH< 80 pg/ml
Serum Ca> 10,2 mg/dL
Clinically serious condition
History of malignancy
Evidence of active hepatitis C virus, hepatitis B virus or human acquired immunodeficiency virus infection
Specific contraindications or history of hypersensitivity to the study drugs;
Previous history of allergy or intolerance, or evidence of immunologically-mediated renal disease, systemic diseases, cancer
Drug or alcohol abuse
Any chronic clinical conditions that may affect completion of the trial or confound data interpretation
Pregnancy or lactating
Women of childbearing potential without following a scientifically accepted form of contraception
Legal incapacity
Evidence of an uncooperative attitude
Any evidence that patient will not be able to complete the trial follow-up.
Previous diagnosis of: intellectual disability/mental retardation, dementia, schizophrenia.