Nicotinamide Versus Sevelamer Hydrochloride on Phosphatemia Control on Chronic Hemodialysed Patients

Hemodialysis Clinical Trial

— NICOREN  

Official title:

Comparison of Nicotinamide and Sevelamer Hydrochloride on Phosphatemia Control on Chronic Hemodialysed Patients

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01011699
• Other study ID #: PHRCIR08-PR-FOURNIER
• Secondary ID: Eudract N°2008-0
• Status: Terminated
• Phase: Phase 3
• First received: November 10, 2009
• Last updated: May 13, 2016
• Start date: January 2010
• Est. completion date: June 2013

Study information

• Verified date: May 2016
• Source: Centre Hospitalier Universitaire, Amiens
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

The comparison between nicotinamide and sevelamer aims to demonstrate, in chronic hemodialysed patients, the non-inferiority of nicotinamide in terms of control of the phosphatemia. Secondary objectives is to compare the two treatments in terms of efficiency in other biological parameters, vascular calcification and bone mass loss and on the clinical and biological tolerance and finally to explore the roles of metabolites of nicotinamide.

Description:

This is a multicenter randomized open study with 2 treatment arms (nicotinamide / Sevelamer).

Laboratories who will dose biochemical parameters and PTH, ignore which treatment is received by patients.

The team which will measure bone density and the radiologist or rheumatologist who will appreciate centrally calcification and deformity of the vertebrae, ignore which treatment is received by patients.

Therefore it's a Randomized Prospective Blinded Outcome Endpoint.

Pre-recruitment period (3 to 6 months) with basic medication

• Repletion of vitamin D (p 25 OHD between 30 and 50 ng / ml) (if required by supplementation Dedrogyl weekly by the dialysis nurse)

• Bath dialysis to 1.50 mmol / l calcium (1.75 mmol / l if hemodiafiltration), 32 mmol bicarbonate and 0.5 mmol / l magnesium - Support to provide a dietary protein intake with 1.2 g / kg / d and assessment of contributions of Ca and PO4

• Use of CaCO3 taken with meals rich in phosphorus (morning, noon and evening) without

• In case of hyperkalemia, Calcium Sorbisterit® will preferably be used instead of KAYEXALATE®. This process exposes the worsening effect of hyperphosphatemia increasing calcium malabsorption and therefore the negative calcium balance in renal failure.

• Statin therapy, fibrate or ezetimibe if necessary, but with stable dose

This treatment will be monitored on the following parameters:

• Biochemical weekly Predialytic (midweek): creatinine, urea, PO4, Ca, protein, Na, K, bicarbonate, glucose, uric acid

• Additional monthly balance: PTH intact, Mg, albumin, CRP

• Each 4 months update: lipid profile (fasting or not, but always at the same time, 25 OH D, complete blood count (CBC), AST-ALT, total alkaline phosphatase, gamma-GT, PKC, glycated hemoglobin (HbA1C) )

Recruitment (180 patients):

• Obtaining informed consent

• Perform a bone density by DXA third of the radius (cortical bone), radius ultradistal (trabecular bone), femoral neck bone (mixed), whole body and lumbar spine profile radiography.

• Lumbar and dorsal radiography (frontal and profile) for research and vertebral measurement of aortic calcification by the Framingham score) + pelvis radiography (frontal) and 2 hands radiography (frontal) searching vascular calcification, Looser's streaks and subperiosteal resorption.

• Freezing at -80 ° C (4 tubes of 1 ml of serum)for centralized analysis:PTH, 25 OHD, CTX, PAO. All samples will be sent for laboratory analysis of Biochemistry University Hospital of Amiens at the end of the study.

For this, 10 ml of blood will be collected with a dry tube then centrifuged 15 minutes, 4000-5000 rpm at room temperature within 30 minutes after collection. Then, aliquot 1ml into 4 polypropylene tubes being careful not to take the fibrin.

• Freezing at -80 ° C in a tube of 2.5 ml of plasma to be assayed later the metabolites of nicotinamide. These samples will only be achieved if patients accept and mark the second part of the consent. The tubes are then stored in the biological resource center, CHU Amiens for further research and for an indefinite period.

The nicotinamide metabolites measured in this study will annex the Met2PY (N-methyl-2-pyridone-5-carboxamide), the Met4PY (N-methyl-4-pyridone-3-carboxamide) and NAD (nicotinamide adenine dinucleotide).

6 ml of EDTA whole blood will be collected, then centrifuged 15 minutes, 4000-5000 rpm at room temperature within 30 minutes after collection. Then, 2.5 ml aliquot in 1 polypropylene tube.

• Then a heparinized blood sample of 2.5 ml will be frozen at -80 °C for determination of nicotinamide. All samples will be sent for analysis at CERBA at the end of the study.

Randomization will be done by the minimization technic with stratification factors: center, duration of dialysis and taking lipid lowering therapy. Randomization will be performed remotely via a website.

Follow-up of one year:

• Period titration nicotinamide or sevelamer to control serum phosphorus in 4 weeks, with stable doses of CaCO3

• Increased nicotinamide 500 mg up to 4 tablets: 0-1-0, 0-1-1, 1-1-1, 1-2-1

• Increased sevelamer 800 mg up to 12 tablets: 0-2-2 ; 2-4-4 ; 4-4-4 ; 2-5-5

• Maintenance period of 5 months with assessment of maintenance doses of Renagel (sevelamer) or Nicobion (nicotinamide) or during the last 3 months.

• After these 6 months:

• Freezing -80 ° C, 4 tubes of 1 ml of serum centralized reviews PTH, 25 OHD, CTX, PAO (as mentioned above).

• Freezing -80 ° C in a tube of 2.5 ml of plasma to be assayed later the metabolites of nicotinamide (as mentioned above).

• Freezing -80 ° C with a heparinized blood sample of 2.5 ml for determination of nicotinamide (as mentioned above).

• Second randomization via a website, patients with intact PTH> 300 pg / ml after 6 months of Nicobion ® and Renagel ®. Randomization 75-150 pg / ml or 150-300 mg / ml will be made by the minimization technic with stratification factors: the center and the type of Hypophosphatemia PTH will be reduced by introducing cinacalcet ® by increments of 30 mg every 3 weeks to 180 mg / day (given with meals 24 hours before the next dialysis). Increase of Cinacalcet ® will be stopped when PTH is <250 pg / ml for arm 150-300pg/ml or <125 per arm 75-150 pg / ml.

Once corrected calcemia <2.25 mmol / l, doses of CaCO3 will be increased; if the maximum tolerable of CaCO3 on the tract map does not prevent hypocalcemia (<2.10 mmol / l), the calcium bath will be increased to 1.75 mmol / l CaCO3 decreased and, if necessary adjustment of nicotinamide / Sevelamer to maintain PO4 between 1.30 and 1.60 mmol / l.

• During the first 6 months of administration of sevelamer, weekly, monthly and quarterly reports will be done. Regarding PTH assay will be performed, every 3 weeks during the titration of cinacalcet.

• A lumbar and dorsal radiography (frontal and profile), a pelvis radiography (face) and 2 hands radiography (front) will be conducted at the end of follow-up period.

• Bone densitometry will be performed at the end of the study (same camera - same site).

• Case report form: tolerance, serious adverse events, compliance, cardiovascular events (myocardial infarction, PAO, stroke, arteritis, vascular intervention),deaths and fractures during the follow-up study.

• Freezing -80 ° C to 4 tubes of 1 ml of serum centralized reviews PTH, 25 OHD, CTX, PAO at the end of the study (as mentioned above).

• Freezing -80 ° C in a tube of 2.5 ml of plasma to be assayed later the metabolites of nicotinamide at the end of the study (as mentioned above).

• Freezing at -80 ° C with a heparinized blood sample of 2.5 ml for determination of nicotinamide at the end of the study (as mentioned above).

Analytical Methodology

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 176
• Est. completion date: June 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Women or men over 18 years

• Chronic hemodialysis (since more than 3 months)

• Hyperphosphatemia controlled with only CaCO3

• PO4 > 1,60 mmol/l, PCa < 2,37 mmol/l

• patient able to understand and sign informed consent form

Exclusion Criteria:

• PTH < 60 ou > 800 pg/ml (PTX)

• Aluminium intoxication (aluminium level in blood > 0,5 µmol/l)

• Score of aortic calcifications = 20 (max 24)

• Characterized intolerance with Renagel and/or Nicobion

• Pregnant woman

• Autoimmune disease

• Patient known to have a bad drug compliance

• Blood tests abnormality (thrombopenia <150 000, serum albumin <30g)

• Hepatic tests abnormality

• Transplant probably within 6 months

• Patient who will need transplantation within 6 month

• Patients receiving chemotherapy

• Patients having a loss of dry weight of 3 kg in 3 months or 6 kg in 6 months.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Renal Failure
• Hemodialysis
• Kidney Failure, Chronic
• Renal Insufficiency, Chronic

Intervention

Drug:
• nicotinamide
Titration phase of nicotinamide (Nicobion) with the aim of phosphatemia control in 4 weeks with stable dose of calcic carbonate; Increase of nicotinamide dose of Nicobion 500mg (nicotinamide 500mg), up to 4 tablets daily, as follows: 0 morning, 1 noon, 0 evening (first week), then, 0 morning, 1 noon, 1 evening (second week), then, 1 morning, 1 noon, 1 evening (third week), then, 1 morning, 2 noon, 1 evening (fourth week).
• sevelamer
Titration phase with sevelamer (Renagel) with the aim of phosphatemia control before 4 weeks of treatment, with stable dose of calcic carbonate. Increase of sevelamer dose up to 12 tablets, as follows: 0 morning, 2 noon, 2 evening (first week), then, 0 morning, 4 noon, 4 evening (second week), then, 2 morning, 4 noon, 4 evening (third week), then, 4 morning, 4 noon, 4 evening (fourth week).
• cinacalcet
After 6 months of treatment, patient screening on PTH level: For patients with PTH > 300pg/ml, introduction of cinacalcet by level of 30 mg every 3 weeks, up to 180mg daily (administered during the meal and before next dialysis) Cinacalcet increase will be stopped once PTH < 250 pg/ml. Calcic carbonate dose will be increase once calcemia will be < 2.25 mmol/l. If maximum tolerated dose is not sufficient to prevent hypocalcemia < 2.10 mmol/l calcium of dialysis bath wille be increased up to 1.75 mmol/l and calcic carbonate will be decreased. A dose adjustment is possible with nicotinamide to obtain a phosphatemia between 1.10 and 1.60 mmol/l.

Locations

Country	Name	City	State
France	Centre Hospital-Universitaire d'Amiens	Amiens	Picardie
France	Centre Hospitalier Général	Beauvais	Oise
France	Clinique du Bois Bernard	Bois Bernard	Pas de calais
France	Centre Hospitalier	Boulogne sur mer	Pas de calais
France	Centre Hospitalier	Cambrai
France	Clinique Saint Côme	Compiegne	Oise
France	Centre Hospitalier Général	Creil	Oise
France	Association pour le Développement de l'Hémodialyse	Hénin-Beaumont	Nord-Pas de Calais
France	CHRU	Lille	Nord
France	Polyclinique de la Louvière	Lille	Nord
France	ALURAD	Limoges	Limousin
France	Centre Hospitalier	Lisieux	Calvados
France	Association Régionale Promotion Dialyse à domicile (ARPDD)	Reims	Marne
France	Centre Hospitalier Universitaire	Reims	Marne
France	Hôpital Victor Provo	Roubaix	Nord
France	Clinique de l'Europe	Rouen	Seine maritime
France	Centre Hospitalier Général	Soissons	Aisne
France	Centre Hospitalier Général	Valenciennes	Nord

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire, Amiens

Country where clinical trial is conducted

France, 

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* Note: There are 47 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The comparison between nicotinamide and Sevelamer was primarily to demonstrate the noninferiority of nicotinamide in terms of control of the phosphatemia observed during the 4th, 5th and 6th months before to introduce Cinacalcet ®.		6th months	Yes
Secondary	To demonstrate noninferiority of nicotinamide in terms of effect on dyslipidemia (evaluated by the ratio LDL / HDL cholesterol), the risk of hypercalcemia (PCa> 2.37 mmol / l) and increase of phospho-calcic product (> 3 , 79 mmol/l).		6 th months and one year	Yes
Secondary	To evaluate the difference between nicotinamide and sevelamer on vascular calcification		one year	Yes
Secondary	To evaluate the difference between nicotinamide and sevelamer on bone mass loss and fracture risk		one year	Yes
Secondary	Evaluate the percentage of population requiring use of cinacalcet® to control PTH (75-300 pg/ml). Evaluate his benefit on phosphatemia and calcemia control. Prevent the need for surgical PTX, and evaluate the additional cost of treatment by cinacalcet		6th months	Yes
Secondary	Evaluate roles of metabolites of nicotinamide (efficacy and side effects) through another study		6th months and one year	Yes
Secondary	Compare the cost-effectiveness ratio of these two treatments		one year	Yes