scholarly journals Daprodustat Compared with Epoetin Beta Pegol for Anemia in Japanese Patients Not on Dialysis: A 52-Week Randomized Open-Label Phase 3 Trial

2021 ◽  
pp. 1-10 ◽  
Author(s):  
Masaomi Nangaku ◽  
Takayuki Hamano ◽  
Tadao Akizawa ◽  
Yoshiharu Tsubakihara ◽  
Reiko Nagai ◽  
...  
Keyword(s):  
Transferrin Saturation ◽  
Japanese Patients ◽  
Hemoglobin Level ◽  
Target Range ◽  
Open Label ◽  
Once Daily ◽  
Epoetin Beta Pegol ◽  
Epoetin Beta ◽  
Starting Dose ◽  
The Difference

<b><i>Background:</i></b> Daprodustat is an oral agent that stimulates erythropoiesis by inhibiting the prolyl hydroxylases which mark hypoxia-inducible factor for degradation through hydroxylation. Its safety and efficacy (noninferiority) were assessed in this 52-week, open-label study. <b><i>Methods:</i></b> Japanese patients not on dialysis (ND) (<i>N</i> = 299) with anemia of CKD (stages G3, G4, and G5) with iron parameters of ferritin &#x3e;100 ng/mL or transferrin saturation &#x3e;20% at screening were randomized to daprodustat or epoetin beta pegol (continuous erythropoietin receptor activator [CERA], also known as methoxy polyethylene glycol-epoetin beta). After initiation of the study, the daprodustat starting dose for erythropoiesis-stimulating agent (ESA)-naïve participants was revised, and daprodustat was started at 2 or 4 mg once daily depending on baseline hemoglobin. ESA users switched to daprodustat 4 mg once daily. CERA was started at 25 μg every 2 weeks for ESA-naïve patients and 25–250 μg every 4 weeks for ESA users based on previous ESA dose. In both treatment groups, dose was adjusted every 4 weeks based on hemoglobin level and changed according to a prespecified algorithm. The primary endpoint was mean hemoglobin level during weeks 40–52 in the intention-to-treat (ITT) population. ESA-naïve patients who entered before the protocol amendment revising the daprodustat starting dose were excluded from the ITT population. <b><i>Results:</i></b> Mean hemoglobin levels during weeks 40–52 were 12.0 g/dL in the daprodustat group (<i>n</i> = 108; 95% confidence interval [CI], 11.8–12.1) and 11.9 g/dL for CERA (<i>n</i> = 109; 95% CI 11.7–12.0); the difference between the groups was 0.1 g/dL (95% CI −0.1 to 0.3 g/dL). The lower limit of the 95% CI of the difference was greater than the prespecified margin of −1.0 g/dL. The mean hemoglobin level was within the target range (11.0–13.0 g/dL) during weeks 40–52 for 92% of participants in both groups. There was no meaningful difference in the frequencies of adverse events. <b><i>Conclusions:</i></b> Oral daprodustat was noninferior to CERA in achieving and maintaining target hemoglobin levels in Japanese ND patients. Daprodustat was well tolerated, with no new safety concerns identified.

MO542MOLIDUSTAT FOR ANAEMIA IN JAPANESE PATIENTS UNDERGOING PERITONEAL DIALYSIS: A SINGLE ARM, OPEN-LABEL, PHASE 3 STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Tadao Akizawa ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Kentaro Taki ◽  
Yasuhiro Hayashi ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Japanese Patients ◽  
Target Range ◽  
Renal Anaemia ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Evaluation Period ◽  
Maintenance Haemodialysis ◽  
Rescue Treatment

Abstract Background and Aims Erythropoiesis-stimulating agents (ESA) are the standard of care for anaemia due to chronic kidney disease (renal anaemia). Molidustat, a novel hypoxia-inducible factor prolyl hydroxylase (HIF–PH) inhibitor for the treatment of renal anaemia, could offer an alternative to ESAs. Molidustat was evaluated in the “molidustat once daily improves renal anaemia by inducing erythropoietin (MIYABI) program”, comprising five phase 3 studies. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anaemia undergoing peritoneal dialysis (PD) and previously treated with ESAs or not. Method This was a 36-week, open-label, single-arm, phase 3 study in Japanese patients ≥20 years with renal anaemia undergoing PD and not expected to start maintenance haemodialysis. Molidustat was administered once daily at a starting dose of 75 mg. Doses were titrated every 4 weeks based on the patient’s haemoglobin (Hb) response to the previous dose during visits to maintain the Hb level within the target range of ≥ 11.0 g/dL to &lt; 13.0 g/dL (Japanese guidelines). The primary efficacy outcome was the responder rate, defined as the proportion of patients who meet all of the following criteria: (1) mean Hb level during the evaluation period in the target range from week 30 to week 36; (2) ≥50% of Hb values within the target range during the evaluation period; (3) no rescue treatment before the end of the evaluation period. Other outcomes included mean Hb level during the evaluation period and its change from baseline, Hb level at each visit and the number of treatment-emergent adverse events (TEAEs). Results Overall, 51 patients received molidustat (49 ESA-treated; 2 ESA-untreated) and 36 (70.6%) completed treatment. Mean age was 63.3 years, mean body weight was 62.4 kg and 62.7% were male. Mean baseline Hb level was 11.19 g/dL and mean duration of peritoneal dialysis was 2.8 years. Over the study period, mean treatment duration was 200.8 days with a mean dosage of 93.8 mg/day. The responder rate (95% confidence interval [CI]) during the evaluation period was 54.9% (40.3, 68.9). The proportions of patients meeting criterion (1), (2) or (3) were 54.9%, 58.8% and 92.2%, respectively. The mean (95% CI) for mean Hb level during the evaluation period was 11.18 (10.83, 11.54) g/dL and the mean (95% CI) for the change in mean Hb level during the evaluation period from baseline was 0.00 (–0.41, 0.41) g/dL. Mean Hb level stayed in the target range from week 12–36. Of the 15 patients who did not complete treatment, 9 discontinued because of a TEAE, 4 initiated rescue treatment and 2 progressed to maintenance haemodialysis. Overall, 98.0% of patients experienced ≥1 TEAE during the study; most TEAEs were mild (49.0%) or moderate (37.3%) in intensity. The most common TEAEs were nasopharyngitis (35.3%), constipation and medical device site infection (11.8% each). No deaths were reported, and major adverse cardiovascular events occurred in 2.0% of patients. Conclusion In this phase 3, single-arm, open-label study, over 70% of patients completed the study and more than half of the patients met the responder criteria. Molidustat maintained Hb in the prespecified range (≥ 11.0 g/dL to &lt; 13.0 g/dL) and was well-tolerated over the 36 weeks of treatment. Molidustat offers a potential alternative to ESAs in patients with renal anaemia undergoing PD.

scholarly journals Efficacy and Safety of Molidustat for Anemia in ESA-Naive Nondialysis Patients: A Randomized, Phase 3 Trial

2021 ◽  
pp. 1-13
Author(s):  
Hiroyasu Yamamoto ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Yasuhiro Hayashi ◽  
Takanori Hayasaki ◽  
...  
Keyword(s):  
Japanese Patients ◽  
Renal Anemia ◽  
Target Range ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Evaluation Period ◽  
The Mean ◽  
Change In Mean

<b><i>Introduction:</i></b> Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated for the treatment of anemia associated with chronic kidney disease (CKD) in the “Molidustat Once Daily Improves Renal Anemia by Inducing EPO” (MIYABI) program, which comprises 5 phase 3 clinical trials. The present MIYABI Non-Dialysis Correction (ND-C) study investigated the efficacy and safety of molidustat in Japanese patients with renal anemia who were not undergoing dialysis and were not receiving erythropoiesis-stimulating agent (ESA) treatment. <b><i>Methods:</i></b> This was a 52-week, randomized (1:1), open-label, active-control, parallel-group, multicenter, phase 3 study in Japanese patients with renal anemia associated with CKD (stages 3–5). Molidustat or the ESA darbepoetin alfa (hereinafter referred to as darbepoetin) were initiated at 25 mg once daily or 30 μg every 2 weeks, respectively, and doses were regularly titrated to correct and to maintain hemoglobin (Hb) levels in the target range of ≥11.0 g/dL and &#x3c;13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30–36). The safety outcomes included evaluation of all adverse events. <b><i>Results:</i></b> In total, 162 patients were randomized to receive molidustat (<i>n</i> = 82) or darbepoetin (<i>n</i> = 80). Baseline characteristics were generally well balanced between treatment groups. The mean (standard deviation) Hb levels at baseline were 9.84 (0.64) g/dL for molidustat and 10.00 (0.61) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.28 [11.07, 11.50] g/dL) and darbepoetin (11.70 [11.50, 11.90] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin in the change in mean Hb level during the evaluation period from baseline; the least-squares mean (95% CI) difference (molidustat-darbepoetin) was −0.38 (−0.67, −0.08) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 93.9% for molidustat and 93.7% for darbepoetin. Most TEAEs were mild (54.9% for molidustat and 63.3% for darbepoetin) or moderate (22.0% for molidustat and 22.8% for darbepoetin) in intensity. There were 3 deaths in the molidustat group and 1 in the darbepoetin group. <b><i>Discussion/Conclusion:</i></b> In the MIYABI ND-C study, molidustat appeared to be an efficacious and generally well-tolerated alternative to darbepoetin for the treatment of renal anemia in Japanese patients who were not undergoing dialysis and were not receiving ESA treatment.

scholarly journals Molidustat for Renal Anemia in Nondialysis Patients Previously Treated with Erythropoiesis-Stimulating Agents: A Randomized, Open-Label, Phase 3 Study

2021 ◽  
pp. 1-10
Author(s):  
Hiroyasu Yamamoto ◽  
Kiyoshi Nobori ◽  
Yoshimi Matsuda ◽  
Yasuhiro Hayashi ◽  
Takanori Hayasaki ◽  
...  
Keyword(s):  
Japanese Patients ◽  
Renal Anemia ◽  
Target Range ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Evaluation Period ◽  
Erythropoiesis Stimulating Agents ◽  
Previously Treated ◽  
The Mean

<b><i>Introduction:</i></b> Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs. <b><i>Methods:</i></b> This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3–5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0–13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30–36). The safety outcomes included evaluation of all adverse events. <b><i>Results:</i></b> In total, 164 patients were randomized to receive molidustat (<i>n</i> = 82) or darbepoetin (<i>n</i> = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48–11.85] g/dL) and darbepoetin (11.53 [11.31–11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (−0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively. <b><i>Discussion/Conclusion:</i></b> Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.

scholarly journals A Randomized Open-Label Trial To Evaluate The Efficacy And Safety Of Triple Therapy With Aspirin, Atorvastatin, And Nicorandil In Hospitalised Patients With SARS Cov-2 Infection: A Structured Summary Of A Study Protocol For A Randomized Controlled Trial

2021 ◽  
Author(s):  
Ambudhar Sharma ◽  
Charu Sharma ◽  
Sujeet Raina ◽  
Balraj singh ◽  
Devendra Singh Dadhwal ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Hospital Discharge ◽  
Intervention Group ◽  
Control Group ◽  
Open Label ◽  
Once Daily ◽  
Starting Dose ◽  
Full Protocol ◽  
Open Label Trial ◽  
And Control

Abstract ObjectivesThe pathophysiology of SARS-Cov-2 is characterized by inflammation, immune dysregulation, coagulopathy, and endothelial dysfunction. No single therapeutic agent can target all these pathophysiologic substrates. Moreover, the current therapies are not fully effective in reducing mortality in moderate and severe disease. Hence, we aim to evaluate the combination of drugs (aspirin, atorvastatin, and nicorandil) with anti-inflammatory, antithrombotic, immunomodulatory, and vasodilator properties as adjuvant therapy in covid- 19.Trial designSingle-centre, prospective, two-arm parallel design, open-label randomized control superiority trial. ParticipantsThe study will be conducted at the covid centre of Dr. Rajendra Prasad Government Medical College Tanda Kangra, Himachal Pradesh, India. All SARS-CoV-2 infected patients requiring admission to the study centre will be screened for the trial. All patients >18years who are RT-PCR/RAT positive for SARS-CoV-2 infection with pneumonia but without ARDS at presentation (presence of clinical features of dyspnoea hypoxia, fever, cough, spo2 <94% on room air and respiratory rate >24/minute) requiring hospital admission and consenting to participate in the trial will be included.Patients with documented significant liver disease/dysfunction (AST/ALT > 240), myopathy and rhabdomyolysis (CPK > 5x normal), allergy or intolerance to statins, allergy or intolerance to aspirin, patients taking medications with significant interaction with statins, prior statin use (within 30 days), prior aspirin use (within 30 days), history of active GI bleeding in past three months, coagulopathy, thrombocytopenia (platelet count < 100000/ dl), pregnancy, active breastfeeding, patient unable to take oral or nasogastric medications, patients in altered mental status, shock, acute renal failure, acute coronary syndrome, sepsis and ARDS at presentation will be excluded. Intervention and comparatorAfter randomization, participants in the intervention group will receive aspirin, atorvastatin, and nicorandil. Atorvastatin will be prescribed as 40 mg starting dose followed by 40 mg oral tablets once daily for ten days or till hospital discharge whichever is later. Aspirin dose will be 325 starting dose followed by 75 mg once daily for ten days or till hospital discharge whichever is later. Nicorandil will be given as 10 mg starting dose followed by 5mg twice daily ten days or till hospital discharge whichever is later. All patients in the intervention and control group will receive a standard of care for covid management as per national guidelines. All patients will receive symptomatic treatment with antipyretics, adequate hydration, anticoagulation with low molecular weight heparin, intravenous remdesivir, corticosteroids (intravenous dexamethasone for 5 days or more duration if oxygen requirement increasing or inflammatory markers are raised), and oxygen support. Patients will receive treatment for comorbid conditions as per guidelines.Main outcomesThe patients will be followed up for outcomes during the hospital stay or for ten days whichever is longer. The primary outcome will be in-hospital mortality. Any progression to ARDS, shock, acute kidney injury, impaired consciousness, length of hospital stay, length of mechanical ventilation (invasive plus non-invasive) will be secondary outcomes. Changes in serum markers (CRP, D –dimer, S ferritin) will be other secondary outcomes. The safety endpoints will be hepatotoxicity (ALT/AST > 3x ULN; hyperbilirubinemia), myalgia—muscle ache, or weakness without creatine kinase (CK) elevation, myositis—muscle symptoms with increased CK levels (3-10) ULN, rhabdomyolysis—muscle symptoms with marked CK elevation (typically substantially greater than 10 times the upper limit of normal [ULN]) and with creatinine elevation (usually with brown urine and urinary myoglobin) observed during the hospital stay. RandomizationComputer-generated block randomization will be used to randomize the participants in a 1:1 ratio to the active intervention group A (Aspirin, Atorvastatin, Nicorandil) plus conventional therapy and control group B conventional therapy only. Blinding (masking)The study will be an open-label trial. Numbers to be randomized (sample size)A total of 396 patients will participate in this study, which is randomly divided with 198 participants in each group.Trial statusThe first version of the protocol was approved by the institutional ethical committee on 1st February 2021, IEC /006/2021. The recruitment started on 8/4/2021 and will continue until 08/07/2021. A total of 281 patients have been enrolled till 21/5/2021.Trial registrationThe trial has been prospectively registered in Clinical Trial Registry – India (ICMR- NIMS): CTRI/2021/04/032648 [Registered on: 08/04/2021].Full protocolThe full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported under the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

scholarly journals Effects of Molidustat in the Treatment of Anemia in CKD

2018 ◽  
Vol 14 (1) ◽  
pp. 28-39 ◽  
Author(s):  
Iain C. Macdougall ◽  
Tadao Akizawa ◽  
Jeffrey S. Berns ◽  
Thomas Bernhardt ◽  
Thilo Krueger
Keyword(s):  
Oral Treatment ◽  
Hypoxia Inducible Factor ◽  
Mean Value ◽  
Fixed Dose ◽  
Target Range ◽  
Efficacy And Safety ◽  
Open Label ◽  
Once Daily ◽  
Endogenous Erythropoietin ◽  
Dose Trial

Background and objectivesThe efficacy and safety of molidustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, have been evaluated in three 16-week, phase 2b studies in patients with CKD and anemia who are not on dialysis (DaIly orAL treatment increasing endOGenoUs Erythropoietin [DIALOGUE] 1 and 2) and in those who are on dialysis (DIALOGUE 4).Design, setting, participants, & measurementsDIALOGUE 1 was a placebo-controlled, fixed-dose trial (25, 50, and 75 mg once daily; 25 and 50 mg twice daily). DIALOGUE 2 and 4 were open-label, variable-dose trials, in which treatment was switched from darbepoetin (DIAGLOGUE 2) or epoetin (DIALOGUE 4) to molidustat or continued with the original agents. Starting molidustat ranged between 25–75 and 25–150 mg daily in DIAGLOGUE 2 and 4, respectively, and could be titrated to maintain hemoglobin levels within predefined target ranges. The primary end point was the change in hemoglobin level between baseline and the mean value from the last 4 weeks of the treatment period.ResultsIn DIAGLOGUE 1 (n=121), molidustat treatment was associated with estimated increases in mean hemoglobin levels of 1.4–2.0 g/dl. In DIAGLOGUE 2 (n=124), hemoglobin levels were maintained within the target range after switching to molidustat, with an estimated difference in mean change in hemoglobin levels between molidustat and darbepoetin treatments of up to 0.6 g/dl. In DIAGLOGUE 4 (n=199), hemoglobin levels were maintained within the target range after switching to molidustat 75 and 150 mg, with estimated differences in mean change between molidustat and epoetin treatment of −0.1 and 0.4 g/dl. Molidustat was generally well tolerated, and most adverse events were mild or moderate in severity.ConclusionsThe overall phase 2 efficacy and safety profile of molidustat in patients with CKD and anemia enables the progression of its development into phase 3.

Phase 3 Randomized Study Comparing Vadadustat with Darbepoetin Alfa for Anemia in Japanese Patients with Nondialysis-Dependent CKD

2021 ◽  
pp. ASN.2020091311
Author(s):  
Masaomi Nangaku ◽  
Kazuoki Kondo ◽  
Yoshimasa Kokado ◽  
Kiichiro Ueta ◽  
Genki Kaneko ◽  
...  
Keyword(s):  
Darbepoetin Alfa ◽  
Randomized Study ◽  
Hypoxia Inducible Factor ◽  
Safety Data ◽  
Japanese Patients ◽  
Open Label ◽  
Phase 3 ◽  
Cardiovascular Morbidity And Mortality ◽  
The Difference ◽  
Average Hemoglobin

BackgroundStandard care for treating anemia in patients with CKD includes use of erythropoiesis-stimulating agents, which sometimes involves increased risks of cardiovascular morbidity and mortality. Previous studies in patients with anemia and nondialysis-dependent CKD (NDD-CKD) found significantly elevated hemoglobin levels with use of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, compared with placebo.MethodsIn this phase 3, open-label, active-controlled noninferiority trial, we randomized 304 Japanese adults with anemia in NDD-CKD (including erythropoiesis-stimulating agent users and nonusers) to oral vadadustat or subcutaneous darbepoetin alfa for 52 weeks. The primary efficacy end point was average hemoglobin at weeks 20 and 24. Safety data included adverse events (AEs) and serious AEs.ResultsA total of 151 participants received vadadustat and 153 received darbepoetin alfa. Least squares mean of the average hemoglobin at weeks 20 and 24 was 11.66 (95% confidence interval [95% CI], 11.49 to 11.84) g/dl for vadadustat and 11.93 (95% CI, 11.76 to 12.10) g/dl for darbepoetin alfa. The 95% CIs for both treatments were within the target hemoglobin range (11.0–13.0 g/dl), and the lower 95% confidence limit for the difference between groups (−0.50 g/dl) was above the predefined noninferiority margin (−0.75 g/dl), demonstrating noninferiority of vadadustat to darbepoetin alfa. Similar proportions of patients in each group reported AEs and serious AEs. The most frequent AEs with vadadustat were nasopharyngitis, diarrhea, and constipation.ConclusionsIn Japanese patients with NDD-CKD, vadadustat was noninferior to darbepoetin alfa, was effective up to week 52 in terms of average hemoglobin, and was generally well tolerated. These results suggest that vadadustat may be a potential treatment for anemia in this patient population.

Epoetin Delta, Erythropoietin Produced in a Human Cell Line, Is as Effective as Epoetin Alfa in the Treatment of Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1296-1296
Author(s):  
Michael Smyth ◽  
Raymond D. Pratt
Keyword(s):  
Adverse Events ◽  
Hematological Parameters ◽  
Human Cell Line ◽  
Target Range ◽  
Epoetin Alfa ◽  
Open Label ◽  
Double Blind ◽  
Open Label Phase ◽  
The Difference ◽  
Average Hemoglobin

Abstract Epoetin therapy for anemia in patients with chronic kidney disease (CKD) is widespread and effective. Currently available erythropoietins are produced in Chinese hamster ovary (CHO) cell lines. Epoetin delta (Dynepo®, Shire plc) is the only erythropoietin synthesized in a human cell line. We report data from a 24-week, double-blind, active-comparator study, followed by a 28 week open-label phase, designed to test whether epoetin delta was as effective as epoetin alfa in the treatment of anemia in patients receiving hemodialysis. Patients with hemoglobin levels of 9.6–12.4 g/dL who had been receiving epoetin therapy for at least 90 days were eligible for entry to the study. Patients were randomized to epoetin delta or epoetin alfa in a 3:1 ratio with the first dose of study medication identical to the last dose the patient received before entering the study. Subsequent dosing was adjusted according to a predefined algorithm to maintain hemoglobin within the target range of 10–12 g/dL. Efficacy was evaluated on the basis of weekly determinations of hematological parameters (hemoglobin, hematocrit, red blood cell [RBC] and reticulocyte count). The primary efficacy endpoint was average hemoglobin over Weeks 12, 16, 20 and 24 and to demonstrate that the difference in hemoglobin levels between the two groups was less than 1g/dL (90% CI contained within the range -1 to 1). Other key efficacy measures included the percentage of hemoglobin levels > 10g/dL and hematocrit levels > 30% and profiles of hematological parameters from baseline to Week 52. From the randomized population, 555 patients received epoetin delta and 191 received epoetin alfa. 583 finished the 24-week double-blind phase and all these patients passed into the open-label phase to be treated with epoetin delta. Adjusted average hemoglobin over Weeks 12–24 was 11.57 g/dL for the epoetin delta group and 11.56 g/dL for the epoetin alfa group. The difference between the groups was 0.01g/dL with both 90% CI (-0.13; 0.15) and 95% CI (-0.16; 0.17) within the predefined acceptable range of -1 to 1 g/dL demonstrating equivalence between the agents. 89.5 % of patients receiving epoetin delta had hemoglobin levels > 10 g/dL compared with 91.5% of patients receiving epoetin alfa. Average hemoglobin levels were maintained in the target range until the end of the study with no need to increase mean dose. Overall, treatment with epoetin delta at a mean dose of 63.7 IU/kg maintained hemoglobin levels at an average value of 11.31 g/dL over Weeks 12 through to the end of the study. In the double-blind phase the overall incidence of adverse events was similar between the study groups and at levels expected given the baseline characteristics of the study population. Hypotension, upper respiratory infection, muscle cramps and headache were the most commonly reported events overall and the levels were similar between the groups. Adverse events considered possibly related to treatment occurred in 11.6% of patients receiving epoetin delta compared with 8.4% of patients receiving epoetin alfa. No patient in this study developed neutralizing anti-erythropoietin antibodies to either epoetin alfa or epoetin delta. Epoetin delta was demonstrated to be as effective as epoetin alfa for maintenance of hemoglobin levels in CKD patients requiring hemodialysis. Control of hemoglobin level was maintained over 52 weeks without the need to increase average dose and epoetin delta was well tolerated for up to one year of exposure.

scholarly journals A randomized open-label trial to evaluate the efficacy and safety of triple therapy with aspirin, atorvastatin, and nicorandil in hospitalised patients with SARS Cov-2 infection: A structured summary of a study protocol for a randomized controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ambudhar Sharma ◽  
Charu Sharma ◽  
Sujeet Raina ◽  
Balraj Singh ◽  
Devendra Singh Dadhwal ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Hospital Discharge ◽  
Intervention Group ◽  
Control Group ◽  
Open Label ◽  
Once Daily ◽  
Starting Dose ◽  
Full Protocol ◽  
Open Label Trial ◽  
And Control

Abstract Objectives The pathophysiology of SARS-Cov-2 is characterized by inflammation, immune dysregulation, coagulopathy, and endothelial dysfunction. No single therapeutic agent can target all these pathophysiologic substrates. Moreover, the current therapies are not fully effective in reducing mortality in moderate and severe disease. Hence, we aim to evaluate the combination of drugs (aspirin, atorvastatin, and nicorandil) with anti-inflammatory, antithrombotic, immunomodulatory, and vasodilator properties as adjuvant therapy in covid- 19. Trial design Single-centre, prospective, two-arm parallel design, open-label randomized control superiority trial. Participants The study will be conducted at the covid centre of Dr. Rajendra Prasad Government Medical College Tanda Kangra, Himachal Pradesh, India. All SARS-CoV-2 infected patients requiring admission to the study centre will be screened for the trial. All patients >18years who are RT-PCR/RAT positive for SARS-CoV-2 infection with pneumonia but without ARDS at presentation (presence of clinical features of dyspnoea hypoxia, fever, cough, spo2 <94% on room air and respiratory rate >24/minute) requiring hospital admission and consenting to participate in the trial will be included. Patients with documented significant liver disease/dysfunction (AST/ALT > 240), myopathy and rhabdomyolysis (CPK > 5x normal), allergy or intolerance to statins, allergy or intolerance to aspirin, patients taking medications with significant interaction with statins, prior statin use (within 30 days), prior aspirin use (within 30 days), history of active GI bleeding in past three months, coagulopathy, thrombocytopenia (platelet count < 100000/ dl), pregnancy, active breastfeeding, patient unable to take oral or nasogastric medications, patients in altered mental status, shock, acute renal failure, acute coronary syndrome, sepsis and ARDS at presentation will be excluded. Intervention and comparator After randomization, participants in the intervention group will receive aspirin, atorvastatin, and nicorandil (Fig. 1). Atorvastatin will be prescribed as 40 mg starting dose followed by 40 mg oral tablets once daily for ten days or till hospital discharge whichever is later. Aspirin dose will be 325 starting dose followed by 75 mg once daily for ten days or till hospital discharge whichever is later. Nicorandil will be given as 10 mg starting dose followed by 5mg twice daily ten days or till hospital discharge whichever is later. All patients in the intervention and control group will receive a standard of care for covid management as per national guidelines. All patients will receive symptomatic treatment with antipyretics, adequate hydration, anticoagulation with low molecular weight heparin, intravenous remdesivir, corticosteroids (intravenous dexamethasone for 5 days or more duration if oxygen requirement increasing or inflammatory markers are raised), and oxygen support. Patients will receive treatment for comorbid conditions as per guidelines. Main outcomes The patients will be followed up for outcomes during the hospital stay or for ten days whichever is longer. The primary outcome will be in-hospital mortality. Any progression to ARDS, shock, acute kidney injury, impaired consciousness, length of hospital stay, length of mechanical ventilation (invasive plus non-invasive) will be secondary outcomes. Changes in serum markers (CRP, D –dimer, S ferritin) will be other secondary outcomes. The safety endpoints will be hepatotoxicity (ALT/AST > 3x ULN; hyperbilirubinemia), myalgia—muscle ache, or weakness without creatine kinase (CK) elevation, myositis—muscle symptoms with increased CK levels (3-10) ULN, rhabdomyolysis—muscle symptoms with marked CK elevation (typically substantially greater than 10 times the upper limit of normal [ULN]) and with creatinine elevation (usually with brown urine and urinary myoglobin) observed during the hospital stay. Randomization Computer-generated block randomization will be used to randomize the participants in a 1:1 ratio to the active intervention group A (Aspirin, Atorvastatin, Nicorandil) plus conventional therapy and control group B conventional therapy only. Blinding (masking) The study will be an open-label trial. Numbers to be randomized (sample size) A total of 396 patients will participate in this study, which is randomly divided with 198 participants in each group. Trial status The first version of the protocol was approved by the institutional ethical committee on 1st February 2021, IEC /006/2021. The recruitment started on 8/4/2021 and will continue until 08/07/2021. A total of 281 patients have been enrolled till 21/5/2021. Trial registration The trial has been prospectively registered in Clinical Trial Registry – India (ICMR- NIMS): CTRI/2021/04/032648 [Registered on: 8 April 2021]. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported under the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.

Sign in / Sign up

Export Citation Format

Share Document