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Recombinant anti-D for prevention of maternal-foetal Rh(D) alloimmunization: a randomized multi-centre clinical trial
Mayekar RV, Paradkar GV, Bhosale AA, Sachan R, Beeram S, Anand AR, Mundle SR, Trivedi Y, Md R, Patole KP, et al
Obstet Gynecol Sci. 2020;63(3):315-322
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Abstract
Objective: To compare the efficacy and safety of recombinant anti-D (R-anti-D) with conventional polyclonal anti-D (Poly anti-D) in preventing maternal-fetal rhesus D (RhD) alloimmunization and to investigate the immunogenicity of R-anti-D. Methods: This was a randomized, open-label, multi-center clinical trial conducted in RhD-negative pregnant women who did not receive antenatal anti-D who delivered RhD-positive babies and showed negative indirect Coombs tests (ICTs) at baseline. The women were randomized in a 2:1 ratio to R-anti-D or Poly anti-D groups and were administered 300 mcg (IM) of the corresponding drug within 72 hours of delivery. ICT was performed 72 hours, 90 days, and 180 days after anti-D injection. Serum samples were collected to check for the development of antibodies against R-anti-D at days 90 and 180, using bridging enzyme-linked immunosorbent assay. The proportion of subjects who had positive ICT results at days 90 and 180 were compared between the groups using Fisher's exact test. Results: A total of 144 women were randomized to the R-anti-D group and 71 to the Poly anti-D group. Three women in the R-anti-D and none in the Poly anti-D group had a positive ICT result at day 90. No woman in either group had positive ICT result at day 180. Both drugs were well tolerated with only 4 reports of adverse events in each group-all were mild, non-serious, and resolved without sequelae. No subject developed antibodies against R-anti-D. Conclusion: The studied R-anti-D is comparable in efficacy to conventional Poly anti-D and is safe and non-immunogenic.Trial Registration: Clinical Trials Registry of India Identifier: Trial Registration: Clinical Trials Registry of India Identifier: CTRI/2017/03/008101.
PICO Summary
Population
RhD-negative pregnant women who did not receive antenatal anti-D and delivered RhD-positive babies and showed negative indirect Coombs tests (ICTs) at baseline (n= 215).
Intervention
Recombinant anti-D (300 mcg), (n= 144).
Comparison
Polyclonal anti-D (300 mcg), (n= 71).
Outcome
Three women in the Recombinant anti-D and none in the Polyclonal anti-D group had a positive ICT result at day 90. No woman in either group had positive ICT result at day 180. Both drugs were well tolerated with only 4 reports of adverse events in each group-all were mild, non-serious, and resolved without sequelae. No subject developed antibodies against Recombinant anti-D.
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Safety and efficacy of a single dose of anti-D (WinRho(R)) in severe thrombocytopenia secondary to dengue virus infection
Pannu AK, Bhalla A, Singhal M, Suri V, Shafiq N, Varma S
Indian Journal of Critical Care Medicine : Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine. 2017;21((2)):80-84.
Abstract
OBJECTIVE To evaluate the efficacy of a single intravenous (IV) dose of anti-D in severe thrombocytopenia (<20,000) due to dengue virus (DEV) infection. MATERIALS AND METHODS An open label, investigator-initiated, randomized interventional study was conducted that included thirty dengue patients (all positive for IgM enzyme-linked immunosorbent assay) with severe thrombocytopenia (<20,000/mm3). Patients were randomized to receive anti-D (50 mug/kg single IV dose) plus supportive therapy or supportive therapy alone. RESULTS The rate of rise in platelet count was significantly high in the intervention group at 24, 36, and 48 h. At the end of 48 h, 60% patients in the intervention group achieved a platelet count of ≥50,000/mm3 as compared to 6.7% in the control group (P = 0.0019). The requirement of the platelet concentrate infusion in the control group was significantly higher, i.e. 342 ml (+/-193) as compared to the intervention group requiring only 187 ml (+/-79). The intervention group showed a significant improvement in bleeding manifestations in all the patients by 24 h in Grade 2 bleed (P = 0.032) and by 48 h in Grade 1 bleed (P = 0.014). CONCLUSIONS Severe thrombocytopenia (≤20,000/mm3) secondary to DEV infection was rapidly and safely reversed by administration of a single dose of 50 mug/kg (250 IU/kg) anti-D IV.
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High dose intravenous anti-D immune globulin is more effective and safe in Indian paediatric patients of immune thrombocytopenic purpura
Swain TR, Jena RK, Swain KP
Journal of Clinical and Diagnostic Research : Jcdr. 2016;10((12)):FC12-FC15.
Abstract
INTRODUCTION Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. AIM: To compare the safety and efficacy of higher dose (75mug/kg) intravenous Anti-D immune globulin against the standard dose of 50mug/kg for the management of ITP in Indian patients. MATERIALS AND METHODS One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50mug/kg (standard dose) or 75mug /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. RESULTS Seventy one out of 84 patients treated with Anti-D at 75mug/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50mug/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. CONCLUSION A 75mug/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50mug dose for treatment of newly diagnosed Indian patients of ITP.
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Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa
Lentz SR, Ehrenforth S, Abdul Karim F, Matsushita T, Weldingh KN, Windyga J, Mahlangu JN, adept2 investigators
Journal of Thrombosis & Haemostasis. 2014;12((8):):1244-53.
Abstract
BACKGROUND Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. OBJECTIVES To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. PATIENTS AND METHODS In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept() 2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 mug kg(-1) ) or rFVIIa (one to three doses at 90 mug kg(-1) ). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. RESULTS In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. CONCLUSIONS This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa. 2014 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.
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Superior effect of intravenous anti-D compared with IV gammaglobulin in the treatment of HIV-thrombocytopenia: results of a small, randomized prospective comparison
Scaradavou A, Cunningham-Rundles S, Ho JL, Folman C, Doo H, Bussel JB
American Journal of Hematology. 2007;82((5):):335-41.
Abstract
This small, prospective, randomized study compared increases in platelet counts and duration of response after intravenous gammaglobulin (IVIG) and IV anti-D in patients with HIV-related thrombocytopenia (HIV-TP). Nine Rh+, nonsplenectomized HIV-positive patients with thrombocytopenia were treated sequentially, in random order, with IVIG and IV anti-D in a cross over design, receiving each therapy for 3 months. Peak platelet counts and duration of effect after each treatment were compared. In addition, viral load measurements and CD4 counts were followed serially, as well as thrombopoietin levels. IV anti-D resulted in a mean peak platelet count of 77 x 10(9)/L compared to only 29 x 10(9)/L after IVIG (P = 0. 07). The mean duration of response was significantly longer in patients treated with anti-D (41 days) compared to IVIG (19 days, P = 0. 01). No consistent changes were seen in the CD4 counts or viral load measurements as a result of either therapy. Thrombopoietin levels were normal in all patients despite often severe thrombocytopenia. Anti-D was more efficacious than IVIG for the treatment of HIV-TP, confirming and extending previous results. Anti-D should be the first line therapy in HIV-positive, Rh+ patients, when antiretroviral agents are not indicated, not effective, or there is an urgent need to increase the platelet count.
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Initial management of immune thrombocytopenic purpura in adults: a randomized controlled trial comparing intermittent anti-D with routine care
George JN, Raskob GE, Vesely SK, Moore D, Lyons RM, Cobos E, Towell BL, Klug P, Guthrie TH
American Journal of Hematology. 2003;74((3):):161-9.
Abstract
We conducted a randomized clinical trial in adults with a new diagnosis of ITP and a platelet count <30000/muL to test the hypothesis that initial intermittent treatment with anti-D may avoid or defer the need for splenectomy when compared to current routine care (glucocorticoid treatment, followed by splenectomy). Splenectomy was to be performed in the anti-D group if patients failed to respond to three consecutive anti-D treatments given within 10 days. The incidences of splenectomy were 14 of 37 (38%) in the routine care group and 14 of 33 (42%) in the anti-D group (absolute risk reduction = 4. 6% in favor of the routine care group, 95% CI, -18. 4 to 27. 6%). However, splenectomy was performed prematurely, not according to the protocol, in 11 of 14 patients in the anti-D group. The median time to splenectomy was 36 days (range, 9-78) in the routine care group and 112 days (range, 19-558) in the anti-D group (P = 0. 045 at 100 days after randomization, P = 0. 840 at 1 year after randomization, using log-rank analysis). Patients in the anti-D group were treated with prednisone for fewer days (70 days) compared to the routine care group (112 days, P = 0. 01). No major bleeding events occurred. In this study, initial treatment of patients with intermittent anti-D initially deferred splenectomy. Whether our aggressive regimen of anti-D could have prevented splenectomy if it had been adhered to in all patients remains uncertain. However, compliance with this anti-D regimen was not feasible for many patients and/or their physicians.
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Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy?
Cooper N, Woloski BM, Fodero EM, Novoa M, Leber M, Beer JH, Bussel JB
Blood. 2002;99((6):):1922-7.
Abstract
This study explored whether repeated infusions of intravenous anti-D could allow adults with recently diagnosed immune thrombocytopenic purpura (ITP) who had failed an initial steroid course to postpone and ultimately avoid splenectomy. Twenty-eight Rh(+), nonsplenectomized adults with ITP diagnosed within 1 to 11 months and platelet counts 30 x 10(9)/L (30 000/microL) or below were enrolled. Anti-D was infused whenever the platelet count decreased to 30 x 10(9)/L (30 000/microL) or below. Responsewas defined as a platelet increase of more than 20 x 10(9)/L (20 000/microL) to more than 30 x 10(9)/L (30 000/microL) within 7 days of treatment. Patients were a median 3.5 months from ITP diagnosis at enrollment and had received a median of 2 previous therapies, including prednisone in 26 of 28 cases. They were followed for a median 26 months. A total of 93% responded to their initial infusion of anti-D, and 68% repeatedly responded with counts maintained above 30 x 10(9)/L (30 000/microL) using anti-D alone. Currently, 12 (43%) of 28 patients have been off all treatment for more than 6 months without undergoing splenectomy, 6 maintaining counts above 100 x 10(9)/L (100 000/microL). Seven continue on treatment, 8 underwent splenectomy, and 1 was lost to follow-up at 10 months. One patient discontinued anti-D because of toxicity. Patients with platelet counts at least 14 x 10(9)/L (14 000/microL) at enrollment were more likely to discontinue treatment (P <.05). Anti-D was an effective maintenance treatment for two thirds of Rh(+), nonsplenectomized adults with ITP who had failed an initial steroid course. Intermittent infusions of intravenous anti-D allowed more than 40% of these adults to avoid splenectomy and to achieve stable platelet counts off all therapy, even after many months of treatment. Platelet count at study entry was the primary predictor of outcome.
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Anti-D (WinRho SD) treatment of children with chronic autoimmune thrombocytopenic purpura stimulates transient cytokine/chemokine production
Semple JW, Allen D, Rutherford M, Woloski M, David M, Wakefield C, Butchart S, Freedman J, Blanchette V, Canadian Children's Platelet Study Group
American Journal of Hematology. 2002;69((3):):225-7.
Abstract
Intravenous anti-D is often used in the treatment of autoimmune thrombocytopenic purpura (AITP), but little is known about its mechanisms of action. To investigate anti-D's potential in vivo mechanism(s) of action, a small group (N = 7) of children with chronic AITP was studied. The children initially received either 25 or 50 microg/kg of WinRho-SD in a four-cycle cross-over trial, and peripheral blood samples from the first and third cycles were assessed for cytokine levels at pre-treatment, 3 hr, 1 day, and 8 days post-treatment. Results showed that platelet counts significantly increased in all the children by day 8 post-treatment. Analysis of serum by ELISA showed that there was a significant but transient rise in both pro- and anti-inflammatory cytokine/chemokine levels (e.g., IL1RA, IL6, GM-CSF, MCP-1 alpha, TNF-alpha and MCP-1) by 3 hr post-treatment in both cycles which returned to baseline levels by 8 days post-treatment. These results suggest that anti-D administration may initially activate the RES in the form of cytokine/chemokine secretion, which is subsequently followed by an increase in platelet counts. It is possible that the induced cytokine/chemokine storm may have an effect on several physiological processes such as those mediating either adverse effects or potentially RES phagocytic activity.
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A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura
Newman GC, Novoa MV, Fodero EM, Lesser ML, Woloski BM, Bussel JB
British Journal of Haematology. 2001;112((4):):1076-8.
Abstract
Treatment with 75 microg/kg/d intravenous (i.v.) anti-D was compared with 50 microg/kg/d in a prospective randomized study of 27 RhD-positive, human immunodeficiency virus-negative, adult, acute, non-splenectomized patients with immune thrombocytopenic purpura (ITP) and platelet counts < or = 30 x 109/l. The higher dose resulted in greater median d 1 (43 x 109/l vs. 7.5 x 109/l; P = 0.012) and d 7 (153 x 109/l vs. 64.5 x 109/l; P = 0.001) platelet increases despite no greater haemoglobin decrease. Children with acute ITP receiving 75 microg/kg/d had overnight platelet increases in seven out of nine cases. The duration of effect at the 75 microg/kg/d dose was 46 d vs. 21 d (P = 0.03). Adverse events were mild to moderate and ameliorated with prednisone and acetaminophen premedication.
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Controlled trial of various anti-D dosages in suppression of Rh sensitization following pregnancy. Report to the Medical Research Council by the working party on the use of anti-D-immunoglobulin for the prevention of isoimmunization of Rh-negative women during pregnancy
Anonymous
British Medical Journal. 1974;2((5910):):75-80.
Abstract
In a controlled trial phials containing 200 mug, 100 mug, 50 mug, or 20 mug of IgG anti-D were given to nearly 2,000 D-negative primiparae whose infants were D-positive and ABO-compatible. Only mothers whose serum lacked anti-D were included and the dose of anti-D was always given within 36 hours of delivery. Each phial contained the same total volume of immunoglobulin and the particular dose given to any patient was not known to the clinician. The anti-D content of the phials was estimated three times during the course of the trials and remained fairly constant. Six months after delivery the incidence of a positive indirect antiglobulin test result, indicating the presence of anti-D, in the four dose groups (with about 450 women in each group) was as follows: 0.22%, 0.23%, 0.44%, and 1.35%. The trend towards an increase in the frequency of failures as the dose decreases was significant at the level of P=0.02.In each dose group about 200 women were followed to the end of a second pregnancy with a D-positive infant. The failure rates (in order of decreasing dosage) as judged by a positive indirect antiglobulin test result at the second delivery were as follows: 1.5%, 1.1%, 1.5% and 2.9%. The differences between the dose groups were not statistically significant. The overall failure rate (1.7%) was about one-tenth of that expected in an untreated series. Though the results failed to prove any differences in success rates between doses of 200, 100, 50, and 20 mug of anti-D, they do suggest, in conformity with other evidence, that a dose of 20 mug is suboptimal for routine use. The results support the belief that a dose of 100 mug is adequate.