Double-blind, multicenter, randomized trial to compare the effect of two doses of adrenocorticotropic hormone versus placebo in controlling delayed emesis after high-dose cisplatin in adult patients with cancer.

1997 ◽  
Vol 15 (6) ◽  
pp. 2467-2473 ◽  
Author(s):  
R Passalacqua ◽  
G Cocconi ◽  
C Caminiti ◽  
V Silingardi ◽  
M A Bella ◽  
...  
Keyword(s):  
Randomized Trial ◽  
Adrenocorticotropic Hormone ◽  
Serum Cortisol ◽  
High Dose ◽  
Delayed Emesis ◽  
Double Blind ◽  
Acute Emesis ◽  
Patients With Cancer ◽  
To Receive ◽  
Different Doses

PURPOSE To compare, in a double-blind, placebo-controlled, randomized trial, the efficacy of two different doses of the depot formulation of adrenocorticotropic hormone (ACTH) in controlling delayed emesis after cisplatin. PATIENTS AND METHODS One hundred fifty-two patients were enrolled onto the study. On day 1, all patients received cisplatin (60 to 120 mg/m2) and a combination of dexamethasone 20 mg plus ondansetron or metoclopramide to prevent acute emesis. On day 2 (24 hours after cisplatin administration), patients were randomized to receive placebo, or ACTH 1 mg intramuscularly (I.M.), or ACTH 2 mg I.M. plus one additional dose of 1 mg on day 4. Details of vomiting, nausea, and adverse effects were recorded daily for every 24-hour period from day 2 to day 6. In a subset of patients, serum cortisol levels were measured between 20 and 72 hours after cisplatin administration. RESULTS One hundred fifty patients were assessable. Over the 5 days of the study, delayed vomiting occurred less frequently in the patients treated with ACTH 2 mg plus 1 mg than in those treated with ACTH 1 mg or placebo (28%, 38%, and 65%, respectively; P = .001). The greatest observed differences were seen on days 2 (24 to 48 hours; P = .01) and 3 (48 to 72 hours; P = .01). On days 4, 5, and 6 (96 to 144 hours), no significant differences were observed among the three arms. The severity of delayed emesis expressed as the mean number of emetic episodes per day was 0.48, 0.70, and 0.80, respectively (P = .002). Patients treated with the higher dose of ACTH had the least nausea on day 3 (P = .02) and day 4 (P = .03). Adrenal cortisol secretion rapidly increased after ACTH injection, but was suppressed for approximately 44 hours in the placebo group. Toxicity was mild and transient in all groups. CONCLUSION ACTH reduces the incidence and severity of delayed vomiting and nausea after cisplatin. A dose of 2 mg 24 hours after cisplatin is better than one of 1 mg. Whether the activity of ACTH is mediated only by adrenal corticosteroids needs to be verified.

Solumedrol Treatment for Severe Sepsis in Humans with a Blunted Adrenocorticotropic Hormone-Cortisol Response: A Prospective Randomized Double-Blind Placebo-Controlled Pilot Clinical Trial

2021 ◽  
pp. 088506662110388
Author(s):  
Divya Birudaraju ◽  
Sajad Hamal ◽  
John A. Tayek
Keyword(s):  
Blood Pressure ◽  
Clinical Trial ◽  
Adrenocorticotropic Hormone ◽  
Serum Cortisol ◽  
High Dose ◽  
Cortisol Response ◽  
Acth Stimulation ◽  
Double Blind ◽  
Significant Difference ◽  
To Receive

Purpose To test the benefits of Solumedrol treatment in sepsis patients with a blunted adrenocorticotropic hormone (ACTH)-cortisol response (delta <13 µg/dL) with regard to the number of days on ventilator, days on intravenous blood pressure support, length of time in an intensive care unit (ICU), 14-day mortality, and 28-day mortality. The trial was prospective, randomized, and double-blind. As part of a larger sepsis trial, 54 patients with sepsis had an intravenous ACTH stimulation test using 250 µg of ACTH, and serum cortisol was measured at times 0, 30, and 60 min. Eleven patients failed to increase their cortisol concentration above 19.9 µg/dL and were excluded from the clinical trial as they were considered to have adrenal insufficiency. The remaining 43 patients had a baseline cortisol of 32 ± 1 µg/dL increased to 38 ± 3 µg/dL at 30 min and 40 ± 3 at 60 min. All cortisol responses were <12.9 µg/dL between time 0 and time 60, which is defined as a blunted cortisol response to intravenous ACTH administration. Twenty-one were randomized to receive 20 mg of intravenous Solumedrol and 22 were randomized to receive a matching placebo every 8 h for 7-days. There was no significant difference between the two randomized groups. Data analysis was carried out bya two-tailed test and P < .05 as significant. Results Results: The mean age was 51 ± 2 (mean ± SEM) with 61% female. Groups were well matched with regard to APACHE III score in Solumedrol versus placebo (59 ± 6 vs 59 ± 6), white blood cell count (18.8 ± 2.2 vs 18.6 ± 2.6), and incidence of bacteremia (29 vs 39%). The 28-day mortality rate was reduced in the Solumedrol treated arm (43 ± 11 vs 73 ± 10%; P < .05). There was no change in days in ICU, days on blood pressure agents, or days on ventilator. Seven days of high-dose intravenous Solumedrol treatment (20 mg every 8 h) in patients with a blunted cortisol response to ACTH was associated with an improved 28-day survival. This small study suggests that an inability to increase endogenous cortisol production in patients with sepsis who are then provided steroid treatment could improve survival.

Randomized, Double-Blind, Dose-Finding Study of Dexamethasone in Preventing Acute Emesis Induced by Anthracyclines, Carboplatin, or Cyclophosphamide:

2004 ◽  
Vol 22 (4) ◽  
pp. 725-729 ◽  
Author(s):  
Keyword(s):  
Single Dose ◽  
Dose Finding ◽  
Complete Protection ◽  
Double Blind ◽  
Acute Emesis ◽  
Intention To Treat ◽  
Finding Study ◽  
Dose Finding Study ◽  
To Receive ◽  
Different Doses

Purpose Different doses and schedules of dexamethasone, combined with a 5-HT3 antagonist, are used to prevent acute emesis induced by anthracyclines, carboplatin, or cyclophosphamide. Therefore, we planned a randomized, double-blind, dose finding study aimed to identify the preferred dose and schedule of dexamethasone. Patients and Methods All consecutive chemotherapy-naive patients enrolled onto study were randomly assigned to receive for the prevention of acute emesis, during the first 24 hours, one of the following dexamethasone regimens, in combination with ondansetron 8 mg intravenously (IV): for arm A, 8 mg IV before chemotherapy plus 4 mg orally every 6 hours for four doses, starting at the same time of the chemotherapy; for arm B, 24 mg IV single dose before chemotherapy; and for arm C, 8 mg IV single dose before chemotherapy. All patients received from day 2 to 5 oral dexamethasone 4 mg bid. Results A total of 587 patients were enrolled, and 585 were assessed according to the intention-to-treat principle (195 patients in each arm). The rate of complete protection from acute vomiting and nausea, respectively, was not significantly different among the three groups (arm A, 84.6% and 66.7%; arm B, 83.6% and 56.9%; arm C, 89.2% and 61.0%), nor was the rate of complete protection from delayed vomiting and nausea, respectively (arm A, 81.0% and 46.7%; arm B, 81.3% and 45.1%; arm C, 79.8% and 46.1%). The incidence of delayed vomiting and nausea was strictly dependent on the presence of acute vomiting and nausea. Adverse events were mild and not significantly different among the three groups. Conclusion Dexamethasone 8 mg single dose IV before chemotherapy, in combination with a 5-HT3 antagonist, should be considered the preferred dose to prevent acute emesis induced by anthracyclines, carboplatin, or cyclophosphamide.

Prevention of Cisplatin-Induced Emesis by the Oral Neurokinin-1 Antagonist, MK-869, in Combination With Granisetron and Dexamethasone or With Dexamethasone Alone

2001 ◽  
Vol 19 (6) ◽  
pp. 1759-1767 ◽  
Author(s):  
Daniel Campos ◽  
Jose Rodrigues Pereira ◽  
Rick R. Reinhardt ◽  
Carlos Carracedo ◽  
Sergio Poli ◽  
...  
Keyword(s):  
High Dose ◽  
Delayed Emesis ◽  
Double Blind ◽  
Acute Emesis ◽  
Group Iii ◽  
Group I ◽  
Efficacy Parameter ◽  
Group Ii ◽  
Neurokinin 1 ◽  
Present Trial

PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT3 antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT3 antagonist plus dexamethasone was more effective than just the 5HT3 antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (≥70 mg/m2). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 μg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P < .01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P < .01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P < .05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT3 antagonist, MK-869, and dexamethasone provided the best control of acute emesis.

Difference in persistence of efficacy of two antiemetic regimens on acute emesis during cisplatin chemotherapy. The Italian Group for Antiemetic Research.

1993 ◽  
Vol 11 (12) ◽  
pp. 2396-2404 ◽  
Keyword(s):  
Prognostic Factor ◽  
Adverse Events ◽  
Nausea And Vomiting ◽  
High Dose ◽  
Complete Protection ◽  
Double Blind ◽  
Acute Emesis ◽  
The Third ◽  
First Time ◽  
To Receive

PURPOSE AND METHODS We conducted a prospective, double-blind, multicenter study of 287 cancer patients treated for the first time with high-dose cisplatin chemotherapy who were randomly assigned to receive three consecutive cycles of the same antiemetic treatment consisting of ondansetron plus dexamethasone, or metoclopramide plus dexamethasone and diphenhydramine. RESULTS Patients who received the ondansetron combination achieved significantly greater complete protection from vomiting, but not from nausea, in all three cycles of chemotherapy than did patients treated with metoclopramide (78.7% v 59.6%, P < .002 during the first cycle; 73.4% v 51.0%, P < .002 during the second cycle; 73.7% v 47.5%, P < .001 during the third cycle). The ability of ondansetron treatment to protect patients from vomiting during the first cycle did not change in subsequent cycles, but decreased significantly as far as complete protection from nausea and from both nausea and vomiting are concerned. With the metoclopramide combination, a significantly greater reduction of complete protection from vomiting, nausea, and both nausea and vomiting was detected. Protection obtained in previous cycles of chemotherapy was the most important prognostic factor. Adverse events were significantly less frequent with ondansetron treatment during the three cycles of chemotherapy and no cumulative toxic effects were found with either treatment. CONCLUSION Ondansetron plus dexamethasone was significantly more efficacious and better tolerated than metoclopramide plus dexamethasone and diphenhydramine during three cycles of chemotherapy and, in contrast to the metoclopramide regimen, the efficacy of ondansetron plus dexamethasone, at least for vomiting, is maintained in subsequent cycles.

Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatin-induced acute emesis. Italian Group for Antiemetic Research.

1998 ◽  
Vol 16 (9) ◽  
pp. 2937-2942 ◽  
Keyword(s):  
Dose Finding ◽  
Complete Protection ◽  
Double Blind ◽  
Acute Emesis ◽  
Intention To Treat ◽  
Significant Difference ◽  
Finding Study ◽  
Dose Finding Study ◽  
To Receive ◽  
Different Doses

PURPOSE A 5-hydroxytryptamine 3 (5-HT3) receptor antagonist plus dexamethasone is the most efficacious antiemetic prophylactic treatment for the prevention of cisplatin-induced acute emesis, but the optimal intravenous (i.v.) dose of dexamethasone is unknown. This prompted us to perform a multicenter, randomized, double-blind, dose-finding study that compared four different doses of dexamethasone. PATIENTS AND METHODS Patients were randomized to receive dexamethasone, either 4, 8, 12, or 20 mg, administered by 15-minute i.v. infusion 45 minutes before cisplatin. Ondansetron 8 mg was added to dexamethasone and was administered i.v. 30 minutes before cisplatin. From March 1996 to July 1997, 531 patients were enrolled onto the study and 530 were assessable according to the intention-to-treat principle (133 patients received 4 mg; 136 patients, 8 mg; 130 patients, 12 mg; and 131 patients, 20 mg of dexamethasone). RESULTS Complete protection from acute vomiting and nausea was achieved by 69.2% and 60.9% of patients, respectively, who received 4 mg of dexamethasone, by 69.1% and 61.0% of those who received 8 mg, by 78.5% and 66.9% of those who received 12 mg, and by 83.2% and 71.0% of those who received 20 mg of dexamethasone. Complete protection from vomiting was significantly superior in patients who received 20 mg compared with those who received 4 and 8 mg of dexamethasone (P < .005) and was superior, but not significantly, compared with those who received 12 mg. Complete protection from nausea was superior, but not significantly, in patients who received 20 mg of dexamethasone. Multifactorial analysis confirmed these results. Antiemetic treatment was well tolerated, and no significant difference was found among the four groups in the incidence of adverse events. CONCLUSION A 20-mg single i.v. dose of dexamethasone should be considered the most efficacious prophylactic dose for the prevention of cisplatin-induced acute emesis.

scholarly journals Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

2016 ◽  
Vol 60 (10) ◽  
pp. 6326-6332 ◽  
Author(s):  
David C. Griffith ◽  
Jeffery S. Loutit ◽  
Elizabeth E. Morgan ◽  
Stephanie Durso ◽  
Michael N. Dudley
Keyword(s):  
Plasma Clearance ◽  
Healthy Adult ◽  
Phase 1 ◽  
High Dose ◽  
Double Blind ◽  
Time Curve ◽  
Content Type ◽  
Multiple Doses ◽  
To Receive ◽  
Lactamase Inhibitor

ABSTRACTVaborbactam (formerly RPX7009) is a member of a new class of β-lactamase inhibitor with pharmacokinetic properties similar to those of many β-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single- and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort. Maximum concentrations for vaborbactam were achieved at the end of the 3-h infusion. Vaborbactam exposure (Cmaxand area under the concentration-time curve [AUC]) increased in a dose-proportional manner following multiple doses. There was no evidence of accumulation with multiple doses, consistent with the terminal half-life of ∼2 h. Both the volume of distribution (Vss) and plasma clearance were independent of dose. For the 2,000-mg dose, the plasma clearance was 0.17 ± 0.03 liters/h, the AUC from 0 h to infinity (AUC0–∞) was 144.00 ± 13.90 mg · h/liter, and theVsswas 21.80 ± 2.26 mg · h/liter. Urinary recovery was 80% or greater over 48 h across all dose groups. No subjects discontinued the study due to adverse events (AEs), and no serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among the vaborbactam- and placebo-treated subjects, with mild lethargy as the only unique AE reported with the high dose of vaborbactam. Overall, this study revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and formed the basis for advancement into patient studies in combination with meropenem, including treatment of patients with carbapenem-resistantEnterobacteriaceae(CRE) infections. (This study is registered at ClinicalTrials.gov under identifier NCT01751269.)

scholarly journals High-Dose Adrenaline in Adult In-Hospital Asystolic Cardiopulmonary Resuscitation: A Double-Blind Randomised Trial

1993 ◽  
Vol 21 (2) ◽  
pp. 192-196 ◽  
Author(s):  
J. Lipman ◽  
W. Wilson ◽  
S. Kobilski ◽  
J. Scribante ◽  
C. Lee ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Cardiac Arrest ◽  
Intensive Care ◽  
Side Effects ◽  
Cardiopulmonary Resuscitation ◽  
Standard Dose ◽  
Randomised Trial ◽  
High Dose ◽  
Double Blind ◽  
To Receive

Forty intensive care unit patients requiring cardiopulmonary resuscitation were randomised to receive either the standard dose of adrenaline (1 mg every five minutes) or high-dose adrenaline (10 mg every five minutes). In the majority of patients, overwhelming sepsis was the major contributing factor leading to cardiac arrest. In this group of patients no difference could be detected in response to high-dose adrenaline compared with the standard dose. Although no side-effects were noted with this high dose of adrenaline, more investigation is required prior to its routine use in cardiopulmonary resuscitation.

scholarly journals Analysis of cumulative probabilities shows that the efficacy of 5HT3 antagonist prophylaxis is not maintained.

1996 ◽  
Vol 14 (2) ◽  
pp. 644-651 ◽  
Author(s):  
R de Wit ◽  
P I Schmitz ◽  
J Verweij ◽  
M de Boer-Dennert ◽  
P H de Mulder ◽  
...  
Keyword(s):  
Statistical Approach ◽  
High Dose ◽  
Conditional Probabilities ◽  
Delayed Emesis ◽  
Acute Emesis ◽  
Kaplan Meier ◽  
Three State Model ◽  
5Ht3 Antagonists ◽  
Transitional Probabilities ◽  
Cumulative Probabilities

PURPOSE Several investigators have reported that the efficacy of 5HT3 receptor antagonists is maintained over repeated cycles of chemotherapy. These investigators presented conditional probabilities of protection. Because conditional analyses by definition only include patients with protection in previous cycles, the results are flattered. PATIENTS AND METHODS We applied a novel statistical approach to investigate whether the efficacy of the 5HT3 receptor antagonist ICS 205-930 (tropisetron) is maintained over repeated cycles of weekly high-dose cisplatin. Overall protection was determined based on cumulative probabilities with the Kaplan-Meier method. Complete protection was calculated with a three state model for transitional probabilities. Eighty-three patients were studied. RESULTS Over six consecutive cycles, protection against both acute and delayed emesis decreased significantly. The initial complete and overall protection rates against acute emesis of 71% and 95%, respectively, decreased to 43% and 72% in the sixth cycle of chemotherapy. Similarly, the protection rates of 31% and 68% against delayed emesis decreased to 6% and 40%, respectively. CONCLUSION We conclude that overall and complete long-term protection is more accurately measured by cumulative probabilities than with a method that is based on conditional probabilities. Our statistical approach shows that the efficacy of 5HT3 antagonists is not maintained.

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