Optimal Anemia Treatment in End Stage Renal Disease (ERSD)

Hyperparathyroidism, Secondary Clinical Trial

— OPTIMAL  

Official title:

Single-center, Open-label, Randomized Study of Anemia Management Improvement in End Stage Renal Disease (ESRD) Patients With Secondary Hyperparathyroidism

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02273570
• Other study ID #: AOSantAnna
• Status: Recruiting
• Phase: N/A
• First received: June 27, 2014
• Last updated: September 12, 2015
• Start date: March 2015
• Est. completion date: March 2017

Study information

• Verified date: September 2015
• Source: Azienda Ospedaliera Sant'Anna
• Contact: Antonio Bellasi, MD
• Email: antonio.bellasi[@]hsacomo.org
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Clinical study aimed at improving anemia management in End Stage Renal Disease Patient (ESRD) on maintenance Hemodialysis with evidence of Chronic Kidney disease Mineral Bone Disorder (CKD-MBD)

Description:

Anemia is one of the most worrisome complications of Chronic Kidney Disease (CKD). Numerous prospective studies have repeatedly documented an increase risk of morbidity and mortality associated with lower levels of hemoglobin (Hb). Hence the international guidelines on patient care suggest the use of Erythropoietin Stimulating Agents (ESA), iron, folates supplementation for anemia correction.

However, recent randomized controlled trials (RCT) have demonstrated that hemoglobin correction to normal levels increases the risk of major cardiovascular (CV) events. Though, the reasons are still unclear, the cumulative ESA dose may at least partly explain these findings suggesting limiting ESA to the minimal dose allowed to achieve the suggested Hb targets in ESRD patients.

Among other factors, CKD-MBD has been repeatedly associated with poor more severe anemia and higher dose of ESA. However, the latest Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on CKD-MBD management suggest a higher reference target for intact parathyroid hormone (iPTH) (2-9 fold the upper level of the normal range) when compared to the National Kidney Foundation (NKF) guidelines published in 2003 (150-300 pg/ml).

A few observational studies suggest a linear inverse association between intact iPTH and ESA dose even for iPTH value within the iPTH target level proposed by the KDIGO working group. Similarly, a large body of evidence supports the notion that the higher the iPTH the faster the CV system deterioration in ESRD.

Aim of the study is to test whether a tighter iPTH control to achieve a iPTH level lower than 300 pg/ml vs iPTH levels between 300-540 pg/ml is associated with a ESA dose reduction and a slower CV system deterioration in ESRD patients receiving dialysis.

STUDY DESIGN Pilot, single center, open label with blinded end point (PROBE-Prospective Randomized Open Blinded End-Point) aimed at improving patient care.

Eligible patients will be randomized (1:1) to either:

(A) Control group: standard care. The iPTH target in this group is 300-540 pg/ml (B) Optimal CKD-MBD control: in this group the iPTH target is150-300 pg/ml to be achieved with a therapeutic algorithm.

TREATMENTS

All patients will be randomized (1:1) to either:

(A) Control group: standard care. The iPTH target in this group is 300-540 pg/ml.

(B) Optimal CKD-MBD control:: in this group the iPTH target is 150-300 pg/ml to be achieved with a therapeutic algorithm:

I. iPTH control: in order to achieve the iPTH target (150-300 pg/ml), all patients will receive 400 IU/day of vitamin-25-OH-D (25OHD) and a flexible dose of any active vitamin D available in Italy (calcitriol and paricalcitol-"Zemplar®") at the maximum dose of 6 mcg/week of paricalcitol("Zemplar®")of equivalent (see existing conversion table). Patients will also receive a flexible dose of cinacalcet("Mimpara®") to a maximum dose of 90 mg/day.

II. Phosphorous control: all patients need to achieve a serum phosphorous level lower than 5.5 mg/dl. All available phosphate binders are allowed [sevelamer("Renvela®"), calcium carbonate, calcium acetate("Phoslo®"), calcium acetate/magnesium carbonate ("Osvaren®"), lanthanum carbonate "Foznol®"). A rescue therapy with aluminum("Maalox®") is allowed for no more than 30 days.

III. Serum calcium control: the suggested target is less than 9.5 mg/dl. In case of serum calcium greater than 9.5 mg/dl the calcium and vitamin D dose should be lowered in order to lower the risk of vascular calcification deposition and progression

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: March 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

INCLUSION CRITERIA.

• Men and women

• Age >18 years

• Maintenance dialysis via Artero-Venous fistula

• ESA use

• iPTH between 300-600 pg/ml

• Hb between 10.0-11.5

• Kt/V greater/equal than 1.2

• Signed informed consent prior to the initiation of the study

EXCLUSION CRITERIA: None.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Hyperparathyroidism
• Hyperparathyroidism, Secondary
• Kidney Failure, Chronic
• Neoplasm Metastasis

Intervention

Drug:
• standard care
Standard care. Patients allocated to this study arm will be treated with all drugs available for PTH control (at the investigator discretion) to obtain a iPTH of 300-540 pg/ml.
• Optimal (I. iPTH control: Zemplar®,Mimpara®; phosphorous control: Renvela®, Phoslo®, Osvaren®, Foznol®,Maalox®; calcium control: calcium and vitamin D
Optimal care. Patients allocated to this study arm will be treated with all drugs available for PTH control (at the investigator discretion - see therapeutic algorithm) to obtain a iPTH of less than 300 pg/ml.

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Sant'Anna	San Fermo della battaglia (CO)

Sponsors (2)

Lead Sponsor	Collaborator
Azienda Ospedaliera Sant'Anna	Amgen

Country where clinical trial is conducted

Italy, 

References & Publications (8)

Capuano A, Serio V, Pota A, Memoli B, Andreucci VE. Beneficial effects of better control of secondary hyperparathyroidism with paricalcitol in chronic dialysis patients. J Nephrol. 2009 Jan-Feb;22(1):59-68. — View Citation

Ebben JP, Gilbertson DT, Foley RN, Collins AJ. Hemoglobin level variability: associations with comorbidity, intercurrent events, and hospitalizations. Clin J Am Soc Nephrol. 2006 Nov;1(6):1205-10. Epub 2006 Sep 6. — View Citation

Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int. 2005 Sep;68(3):1337-43. — View Citation

Gilbertson DT, Ebben JP, Foley RN, Weinhandl ED, Bradbury BD, Collins AJ. Hemoglobin level variability: associations with mortality. Clin J Am Soc Nephrol. 2008 Jan;3(1):133-8. Epub 2007 Nov 28. — View Citation

Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009 Aug;(113):S1-130. doi: 10.1038/ki.2009.188. — View Citation

Lacson E Jr, Ofsthun N, Lazarus JM. Effect of variability in anemia management on hemoglobin outcomes in ESRD. Am J Kidney Dis. 2003 Jan;41(1):111-24. — View Citation

National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003 Oct;42(4 Suppl 3):S1-201. — View Citation

Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, Bommer J, Cruz JM, Kerr PG, Mendelssohn DC, Held PJ, Port FK. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004 Jul;44(1):94-111. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	percent reduction in weekly ESA consumption to maintain Hb levels within the recommended range 10.0-11.5 g/dl	Primary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with a lower ESA dose use to achieve the target Hb of 10.0-11.5 g/dl	baseline and after 12 months of followup	No
Secondary	Change in iron status and storage.	Secondary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with a better iron storage and mobilization.	baseline and after 12 months of followup	No
Secondary	Difference in prevalence of cardiac valvular calcification progression detected by echocardiography between groups.	Secondary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with cardiac valves deposition and progression attenuation.	baseline and after 12 months of followup	No
Secondary	Difference in pulse wave velocity assessed by applanation tonometry between groups.	Secondary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with arterial stiffness increase attenuation	baseline and after 12 months of followup	No
Secondary	CKD-MBD control	Secondary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with a better CKD-MBD control	baseline and after 12 months of followup	No