PRIMS: Surveillance Study to Estimate the Incidence of Pure Red Blood Cell Aplasia Among Patients With Chronic Kidney Failure

Sponsor

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)

Overall Status

Completed

CT.gov ID

NCT00391287

Collaborator

Janssen-Cilag International NV (Industry)

15,334

Enrollment

391

Locations

Duration (Months)

39.2

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to estimate the incidence rate of pure red cell aplasia (PRCA; aplastic anemia) mediated by erythropoietin (EPO) antibodies in patients who are receiving subcutaneous (s.c.) epoetin alfa (polysorbate 80 formulation) for the treatment of anemia associated with chronic renal failure (CRF), and to compare this incidence rate to the incidence rate with s.c. exposure to other currently marketed recombinant erythropoietin products (epoetin alfa, epoetin beta, darbepoetin alfa), with adjustment of duration for which the drug is given to the patient. The study will also examine the impact of the pattern of using mixed s.c. exposure to multiple erythropoietin products occurring in this patients, and the impact of the time from which the treatment is started to the onset of PRCA.

Condition or Disease	Intervention/Treatment	Phase
Pure Red-Cell Aplasia Chronic Kidney Failure

Detailed Description

In 1998, prompted by concern that human serum albumin (HAS- the stabilizer in the epoetin alfa formulation) could theoretically transmit Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, an alternative epoetin alfa formulation using polysorbate 80 as a stabilizer was introduced. The polysorbate 80 epoetin alfa formulation became available in a variety of product presentations (i.e., single-use vials and prefilled syringes with both coated and uncoated stoppers) to provide for prescribing flexibility, patient convenience, and choice of route of administration. Soon after the introduction of the polysorbate 80 epoetin alfa formulation in prefilled syringes, an increasing number of cases of EPO antibody-mediated pure red cell aplasia (PRCA) were reported in patients with chronic renal failure (CRF) exposed to epoetin alfa by the s.c. route. This led to contraindication of the s.c. route for epoetin alfa in the European Union (E.U.) and Switzerland in December 2002. It was subsequently shown that the increased risk for PRCA was associated with one specific polysorbate 80 epoetin alfa presentation - prefilled syringes with uncoated rubber stoppers. It appeared that uncoated rubber stoppers, when exposed to polysorbate 80, released organic compounds (leachates) into the epoetin alfa formulation, and that these leachates were the most probable product-specific cause for the increase in EPO antibody-mediated PRCA. A worldwide recall of the polysorbate 80 epoetin formulation in prefilled syringes with uncoated stoppers was completed in March 2004. FluroTec-coated stoppers are now used in all prefilled syringes containing the polysorbate 80 epoetin alfa formulation, to prevent leachates from entering the formulation. Following these actions, the incidence rate of EPO antibody-mediated PRCA in CRF patients receiving s.c. epoetin alfa fell to a level similar to that for the HSA-containing epoetin formulation, which has a long-standing and well-characterized safety profile. As of 30 November 2005, s.c. exposure in CRF patients to the polysorbate 80 epoetin alfa formulation in prefilled syringes with coated stoppers was 71,880 patient-years, with 4 cases of EPO antibody-mediated PRCA reported. In 2006, E.U. Health Authorities reauthorized s.c. epoetin alfa use in CRF patients for whom intravenous access is not readily available. As part of the reauthorization, the sponsor agreed to conduct this registry in order to demonstrate that the polysorbate 80 epoetin alfa formulation using a coated stopper has an acceptable immunogenic safety profile and to define the incidence of EPO antibody-mediated PRCA associated with recombinant erythropoietin use among patients with anemia associated with CRF. This is a multicenter, multinational, immunogenicity surveillance registry using a prospective cohort design (patients identified by a common characteristic), with enrollment of parallel groups that are exposed to the polysorbate 80 formulation of epeotin alfa or other marketed erythropoietin products administered by the s.c. route of administration for the treatment of anemia associated with CRF. The registry is designed to address the following question: Is the current rate of PRCA with the s.c. polysorbate 80 epoetin alfa formulation using coated stoppers similar to the current rate with other marketed erythropoietin products administered by the s.c. route, adjusted for duration of exposure? Each patient will be observed for development of PRCA for up to 3 years. Information on exposure to erythropoietin products, stage of CRF, treatment modality for CRF, erythropoietin handling and storage information, and most recent hemoglobin level will be collected quarterly. Cases of unexplained loss or lack of effect (LOE) with an administered erythropoietin product, including cases of suspected PRCA, will be reported to the sponsor as serious adverse events. Cases of EPO antibody-mediated PRCA will be determined by the clinical presence of suspected PRCA, an unexplained LOE with administered erythropoietin product, and the presence of EPO antibody. An Independent Case Adjudication Committee will review blinded case data for patients with unexplained LOE and identify cases of EPO antibody-mediated PRCA. A separate Independent Safety Advisory Committee will be responsible for periodically reviewing unblinded patient data and summary data and will make recommendations related to the incidence rate of PRCA associated with s.c. epoetin alfa use. The sponsor will actively monitor registry enrollment and erythropoietin brand usage to ensure that the registry accrues 20,000 person-years of s.c. exposure to epoetin alfa and 20,000 person-years of s.c. exposure to all other erythropoietin products combined. If it appears that one registry arm will meet this accrual goal before the other, the sponsor may elect to selectively close those investigational sites with predominant use of the erythropoietin product(s) in the arm approaching full accrual. The registry will provide no inducement to change therapy and will be non-interventional.

Study Design

Study Type:

Observational

Actual Enrollment :

15334 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

A Prospective, Immunogenicity Surveillance Registry (PRIMS) to Estimate the Incidence of Erythropoietin Antibody-Mediated Pure Red Cell Aplasia Among Subjects With Chronic Renal Failure and Subcutaneous Exposure to Recombinant Erythropoietin Products

Study Start Date :

Jun 1, 2006

Actual Primary Completion Date :

Dec 1, 2010

Actual Study Completion Date :

Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
erythropoietin treatment in CRF Patients exposed to EPREX or other marketed erythropoietin products administered by the subcutaneous route of administration for the treatment of anemia of Chronic Renal Failure

Outcome Measures

Primary Outcome Measures

estimate the incidence rate of EPO antibody-mediated Pure Red Cell Aplasia (PRCA) [Unexplained Loss of Effect (LOE) follow-up]
estimate the incidence rate of EPO antibody-mediated PRCA with s.c. exposure to the polysorbate 80 formulation of epoetin alfa and to compare this incidence rate to the incidence rate with s.c. exposure to other currently marketed recombinant erythropoietin products (epoetin alfa, epoetin beta, darbepoetin alfa) with adjustment for duration of exposure.

Secondary Outcome Measures

sensitivity analyses [Unexplained Loss of Effect (LOE) follow-up]
to examine, in sensitivity analyses of the incidence rates of EPO antibody-mediated Pure Red Cell Aplasia (PRCA) and their rate ratios, the impact of the patterns of mixed s.c. exposure to multiple erythropoietin products occurring in this subject population and of varying the assumption of 1 to 12 months for latency from exposure to the onset of PRCA

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with established CRF as an indication for the treatment of anemia
Patients who are receiving or are about to receive (within 1 month) a marketed erythropoietin (i.e., epoetin alfa [EPREX/ERYPO/GLOBUREN], epoetin beta [NEORECORMON®], or darbepoetin alfa [ARANESP®]) by the s.c. route of administration
Patients who are likely to continue to receive s.c. erythropoietin product(s) for at least 1 year.

Exclusion Criteria:

Patients with a history of pure red cell aplasia or aplastic anemia
Patients who are experiencing unexplained loss or lack of effect to a recombinant erythropoietin product ongoing at the time of enrollment
Patients who have had prior recombinant erythropoietin treatment whose anemia had never responded (primary lack of efficacy)
Patients with a history of EPO antibodies prior to enrollment
Subjects who are currently receiving immunosuppressive medication (e.g., cyclosporine, tacrolimus, sirolimus, mycophenolic mofetil, azathioprine, or monoclonal antibodies) or corticosteroids at a dose corresponding to >15 mg/day prednisolone
Subjects whose first s.c. exposure to any erythropoietin product was >1 year prior to enrollment.

Contacts and Locations

Locations

	City	Country
1	Adelaide	Australia
2	Central Queensland M C	Australia
3	Fremantle	Australia
4	Hobart	Australia
5	Launceston	Australia
6	Liverpool	Australia
7	Newcastle	Australia
8	Parkville	Australia
9	Perth	Australia
10	Randwick	Australia
11	Wollongong	Australia
12	Woodville	Australia
13	Aalst	Belgium
14	Antwerpen	Belgium
15	Arlon	Belgium
16	Assebroek	Belgium
17	Ath	Belgium
18	Bonheiden	Belgium
19	Brugge	Belgium
20	Brussels	Belgium
21	Brussel	Belgium
22	Charleroi	Belgium
23	Deinze	Belgium
24	Doornik	Belgium
25	Edegem	Belgium
26	Eeklo	Belgium
27	Frameries	Belgium
28	Genk	Belgium
29	Gent	Belgium
30	Gilly	Belgium
31	Huy	Belgium
32	Ieper	Belgium
33	La Louviere	Belgium
34	Leuven	Belgium
35	Liege	Belgium
36	Liège	Belgium
37	Mons	Belgium
38	Namur	Belgium
39	Roeselare	Belgium
40	Sint-Gillis-Dendermonde	Belgium
41	Sint-Niklaas	Belgium
42	St-Truiden	Belgium
43	Turnhout	Belgium
44	Westmalle	Belgium
45	Wilrijk	Belgium
46	Holstebro N/A	Denmark
47	Sønderborg	Denmark
48	Viborg	Denmark
49	Århus N N/A	Denmark
50	Helsinki	Finland
51	Tampere	Finland
52	Turku	Finland
53	Aachen	Germany
54	Aalen	Germany
55	Altötting	Germany
56	Alzey	Germany
57	Annaberg-Buchholz	Germany
58	Ansbach	Germany
59	Arnstadt	Germany
60	Aschersleben	Germany
61	Augsburg	Germany
62	Aurich	Germany
63	Bad Bevensen	Germany
64	Bad Ems	Germany
65	Bad Homburg	Germany
66	Bad Krozingen	Germany
67	Bad König	Germany
68	Bad Mergentheim	Germany
69	Bad Nenndorf	Germany
70	Bad Oeynhausen	Germany
71	Bad Tölz	Germany
72	Bassum	Germany
73	Bergisch Gladbach	Germany
74	Berlin	Germany
75	Bernburg	Germany
76	Betzdorf	Germany
77	Biberach	Germany
78	Bielefeld	Germany
79	Bischofswerda	Germany
80	Bonn	Germany
81	Braunschweig	Germany
82	Bremen	Germany
83	Bremerhaven	Germany
84	Coburg	Germany
85	Cochem	Germany
86	Coesfeld	Germany
87	Cottbus	Germany
88	Darmstadt	Germany
89	Deggendorf	Germany
90	Dillingen	Germany
91	Dinkelsbühl	Germany
92	Dormagen	Germany
93	Düsseldorf	Germany
94	Eberswalde	Germany
95	Eisenach	Germany
96	Elmshorn	Germany
97	Elsenfeld	Germany
98	Emmering	Germany
99	Emsdetten	Germany
100	Erftstadt	Germany
101	Erfurt	Germany
102	Erkelenz	Germany
103	Essen	Germany
104	Finsterwalde	Germany
105	Flensburg	Germany
106	Frankfurt	Germany
107	Freiberg	Germany
108	Freiburg	Germany
109	Fürstenwalde	Germany
110	Fürstenzell	Germany
111	Fürth	Germany
112	Gera	Germany
113	Greifswald	Germany
114	Göppingen	Germany
115	Gütersloh	Germany
116	Hagenow	Germany
117	Halberstadt	Germany
118	Hamburg	Germany
119	Hameln	Germany
120	Hannover	Germany
121	Haßfurt	Germany
122	Heidenau	Germany
123	Heilbronn	Germany
124	Helmstedt	Germany
125	Herford	Germany
126	Herzberg	Germany
127	Hilden	Germany
128	Hildesheim	Germany
129	Hoyerswerda	Germany
130	Hürth	Germany
131	Ibbenbüren	Germany
132	Immenstadt	Germany
133	Ingolstadt	Germany
134	Jena	Germany
135	Kaiserslautern	Germany
136	Kamen	Germany
137	Kelheim	Germany
138	Kempten	Germany
139	Kerpen	Germany
140	Kiel	Germany
141	Kleve	Germany
142	Kronach	Germany
143	Kulmbach	Germany
144	Köln	Germany
145	Lahr	Germany
146	Landshut	Germany
147	Landstuhl	Germany
148	Langenfeld	Germany
149	Langenhagen	Germany
150	Langenselbold	Germany
151	Lehrte	Germany
152	Leipzig	Germany
153	Leverkusen	Germany
154	Lichtenfels	Germany
155	Lindau	Germany
156	Linnich	Germany
157	Lohr	Germany
158	Lutherstadt Wittenberg	Germany
159	Lübeck	Germany
160	Lüdenscheid	Germany
161	Lüneburg	Germany
162	Magdeburg	Germany
163	Malente	Germany
164	Mannheim	Germany
165	Marburg	Germany
166	Markkleeberg	Germany
167	Marl	Germany
168	Mayen	Germany
169	Meiningen	Germany
170	Moers	Germany
171	Mönchengladbach	Germany
172	Mühlhausen	Germany
173	München	Germany
174	Münster	Germany
175	Neubrandenburg	Germany
176	Neunkirchen	Germany
177	Neuruppin	Germany
178	Nürnberg	Germany
179	Nürtingen	Germany
180	Oberschleißheim	Germany
181	Offenburg	Germany
182	Olpe	Germany
183	Passau	Germany
184	Peine	Germany
185	Pfaffenhofen	Germany
186	Pforzheim	Germany
187	Potsdam	Germany
188	Quedlinburg	Germany
189	Regensburg	Germany
190	Remagen	Germany
191	Rosenheim	Germany
192	Rostock	Germany
193	Rüsselsheim	Germany
194	Saarlouis	Germany
195	Sachsen	Germany
196	Salzgitter	Germany
197	Schwabach	Germany
198	Schwedt	Germany
199	Schweinfurt	Germany
200	Schwerin	Germany
201	Schönebeck	Germany
202	Seehausen	Germany
203	Seelow	Germany
204	Siegen	Germany
205	Sigmaringen	Germany
206	Sindelfingen	Germany
207	Singen	Germany
208	Sinsheim	Germany
209	Sonneberg	Germany
210	Spremberg	Germany
211	St Martin	Germany
212	St Wendel	Germany
213	Stade	Germany
214	Straubing	Germany
215	Stuttgart	Germany
216	Suhl	Germany
217	Tangermünde	Germany
218	Traunstein	Germany
219	Uelzen	Germany
220	Viersen	Germany
221	Villingen-Schwenningen	Germany
222	Waiblingen	Germany
223	Waldshut-Tiengen	Germany
224	Weinheim	Germany
225	Weißenburg	Germany
226	Weißenfels	Germany
227	Weißwasser	Germany
228	Wesseling	Germany
229	Weyhausen	Germany
230	Wiesbaden	Germany
231	Wolfenbüttel	Germany
232	Worms	Germany
233	Wuppertal	Germany
234	Würzburg	Germany
235	Zirndorf	Germany
236	Zwickau	Germany
237	Alexandroupolis	Greece
238	Athens	Greece
239	Chalkida	Greece
240	Didimoteicho	Greece
241	Edessa	Greece
242	Grevena	Greece
243	Ioannina	Greece
244	Iraklio	Greece
245	Larisa	Greece
246	Piraias	Greece
247	Rodos	Greece
248	Serres	Greece
249	Thessalonikis	Greece
250	Thessaloniki	Greece
251	Veroia	Greece
252	Cork	Ireland
253	Galway	Ireland
254	'S-Hertogenbosch	Netherlands
255	Apeldoorn	Netherlands
256	Rotterdam	Netherlands
257	Weert	Netherlands
258	Oslo	Norway
259	Trondheim N/A	Norway
260	Tvnsberg	Norway
261	Bialystok	Poland
262	Bytom	Poland
263	Chojnice	Poland
264	Ciechanow	Poland
265	Dzialdowo	Poland
266	Gdansk-Zaspa	Poland
267	Gdansk	Poland
268	Koszalin	Poland
269	Lodz	Poland
270	Lomza N/A	Poland
271	Lublin	Poland
272	Olawa	Poland
273	Poznan	Poland
274	Proszowice	Poland
275	Radomsko	Poland
276	Rybnik	Poland
277	Stalowa Wola N/A	Poland
278	Torun	Poland
279	Warszawa	Poland
280	Wroclaw	Poland
281	Aveiro	Portugal
282	Barcelos	Portugal
283	Braga	Portugal
284	Coimbra	Portugal
285	Evora N/A	Portugal
286	Faro	Portugal
287	Leiria	Portugal
288	P-1100 Lisboa N/A	Portugal
289	Portalegre	Portugal
290	Porto	Portugal
291	S. Joao Da Madeira	Portugal
292	Setubal N/A	Portugal
293	Viana Do Castelo	Portugal
294	Vila Nova De Gaia	Portugal
295	Alcorcon	Spain
296	Barcelona	Spain
297	Burgos	Spain
298	Castellón	Spain
299	Girona	Spain
300	Leganés	Spain
301	León	Spain
302	Madrid	Spain
303	Manresa	Spain
304	Maranon	Spain
305	Mollet Del Valles	Spain
306	Oviedo	Spain
307	Palma De Mallorca	Spain
308	Sabadell	Spain
309	Santa Cruz De Tenerife	Spain
310	Santander	Spain
311	Teruel	Spain
312	Valencia N/A	Spain
313	Valencia	Spain
314	Valladolid	Spain
315	Zaragoza	Spain
316	Avesta	Sweden
317	Bollnäs	Sweden
318	Borås	Sweden
319	Eksjö	Sweden
320	Eskilstuna	Sweden
321	Gällivare	Sweden
322	Gävle	Sweden
323	Göteborg	Sweden
324	Halmstad	Sweden
325	Karlshamn	Sweden
326	Karlskoga	Sweden
327	Karlskrona	Sweden
328	Köping	Sweden
329	Linköping	Sweden
330	Lulea	Sweden
331	Malmö	Sweden
332	Norrköping	Sweden
333	Nyköping	Sweden
334	Skellefteå	Sweden
335	Skene	Sweden
336	Skövde	Sweden
337	Stockholm N/A	Sweden
338	Stockholm	Sweden
339	Sundsvall	Sweden
340	Trollhättan	Sweden
341	Umeå	Sweden
342	Uppsala	Sweden
343	Varberg N/A	Sweden
344	Värnamo	Sweden
345	Västervik	Sweden
346	Västerås	Sweden
347	Örebro	Sweden
348	Örnsköldsvik N/A	Sweden
349	Östersund	Sweden
350	Aarau	Switzerland
351	Baden	Switzerland
352	Bellinzona	Switzerland
353	Chur	Switzerland
354	Lausanne	Switzerland
355	Nyon	Switzerland
356	Schwyz	Switzerland
357	Sierre	Switzerland
358	Sion	Switzerland
359	Wil Sg	Switzerland
360	Zurich	Switzerland
361	Antrim	United Kingdom
362	Basildon	United Kingdom
363	Bradford	United Kingdom
364	Brighton	United Kingdom
365	Cambridge	United Kingdom
366	Cardiff	United Kingdom
367	Carshalton	United Kingdom
368	Derby	United Kingdom
369	Doncaster N/A	United Kingdom
370	Dundee	United Kingdom
371	Edinburgh	United Kingdom
372	Exeter	United Kingdom
373	Great Yarmouth	United Kingdom
374	Inverness	United Kingdom
375	Kilmarnock	United Kingdom
376	Leicester	United Kingdom
377	Londonderry	United Kingdom
378	London	United Kingdom
379	Manchester	United Kingdom
380	Merseyside	United Kingdom
381	Merthyr Tydfil	United Kingdom
382	Norwich	United Kingdom
383	Nottingham	United Kingdom
384	Oxford	United Kingdom
385	Plymouth	United Kingdom
386	Portsmouth	United Kingdom
387	Reading	United Kingdom
388	Sheffield	United Kingdom
389	Shrewsbury	United Kingdom
390	Stevenage N/A	United Kingdom
391	Suffolk	United Kingdom

Sponsors and Collaborators

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Janssen-Cilag International NV

Investigators

Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.