Of these patients, 536 (43.19%) were male and 705 (56.81%) were female.
The median age was 69.0 years. The number of patients by age category is as follows: 7 patients (0.56%) were under 18 years; 443 patients (35.70%) were between 18 years and 64 years; 790 patients (63.66%) were 65 years or older; and the age of 1 patient (0.08%) was unknown. Of the patients between 18 years and 64 years, 127 patients (10.23%) were between 18 years and 44 years; 135 patients (10.88%) were between 45 years and 54 years; and 181 patients (14.59%) were between 55 years and 64 years. Of the patients aged 65 years or older, 386 patients (31.10%) were between 65 years and 74 years; 318 patients (25.62%) were between 75 years and 84 years; and 86 patients (6.93%) were 85 years or older.
Mean (SD) time since the ET diagnosis until the time of enrollment was 5.7 (6.10) years.
Mean (SD) platelet count at the time of enrollment was 97.7 (45.63) x 104/mcrL.
The JAK2 mutation test was performed to confirm the presence of JAK2 mutation: 374 patients (30.14%) had a positive test result; 276 patients (22.24%) had a negative test result; 584 patients (47.06%) did not undergo the test; and test results of 7 patients (0.56%) were unknown.
As prior medications for ET, 999 patients (80.50%) had received any treatment for ET. The number of patients who had received anti-platelet therapy was 998 patients (80.42%) and anti-coagulation therapy was 19 patients (1.53%). Of the 998 patients who had received anti-platelet therapy, 811 patients (65.35%) had received hydroxycarbamide. No patients had received thrombolytic agents as prior medications.
As a result of pregnancy test at the time of enrollment (the start of administration of Agrylin), no patient (0.00%) resulted in positive, 4 patients (0.57%) resulted in negative, and 701 patients (99.43%) did not undergo or were unknown whether or not to have undergone a pregnancy test; that is, this drug was not administered to any pregnant patients who had been confirmed to be pregnant after the pregnancy test.
A total of 796 patients (64.14%) had previous or concurrent disease(s) while 445 patients (35.86%) had no previous or concurrent disease(s). Of the patients with previous or concurrent disease(s), 81 patients (6.53%) had hepatic impairment (mild: 69 patients [5.56%], moderate: 9 patients [0.73%], severe: 1 patient [0.08%], severity unknown: 2 patients ); 108 patients (8.70%) had renal impairment (mild: 72 patients [5.80%], moderate: 30 patients [2.42%], severe: 5 patients [0.40%], severity unknown: 1 patient ); 137 patients (11.04%) had cardiac disorders; 2 patients (0.16%) had QT/QTc prolongation; 138 patients (11.12%) had thrombohemorrhagic events; and 7 patients (0.56%) had interstitial lung disease. In addition, 685 patients (55.20%) had previous or concurrent diseases other than the above.
Number of patient enrolled: 689 as all patients who had started treatment with anagrelide hydrochloride capsules by May 31, 2015; 1826 as overall
Number of patient included in the safety analysis set: 648 as all patients who had started treatment with anagrelide hydrochloride capsules by May 31, 2015; 1241 as overall
Adverse events for all patients who had started treatment with anagrelide hydrochloride capsules by May 31, 2015;
Adverse events were reported in 429 of 648 patients in the safety analysis set at an incidence of 66.20%. Adverse reactions were reported in 352 of 648 patients in the safety analysis set at the incidence of 54.32%.
Through the surveillance period, the most common adverse reactions (incidence) was headache reported in 100 patients (15.43%), followed by palpitations in 90 patients (13.89%), anaemia in 43 patients (6.64%), and diarrhoea in 38 patients (5.86%), and oedema peripheral in 23 patients (3.55%). These incidences of adverse reactions were low compared with those reported before the approval; however, the pattern in the occurrence of adverse reactions at a higher incidence was almost similar. Most of the adverse events occurred within 6 months after starting treatment with Agrylin, and no adverse events except hypertension occurred at a high incidence in patients who continued treatment with for 7 months or longer.
A total of 63 serious adverse reactions occurred in 53 patients at the incidence of 8.18% (53/648 patients). The most common serious adverse reaction was 6 events of cardiac failure, followed by 3 events each of atrial fibrillation, cerebral infarction, electrocardiogram QT prolonged, and renal impairment. All of the outcomes of serious adverse reactions were assessed as "Recovered/resolved" or "Recovering/resolving" except 3 events assessed as "Fatal", 2 events as "Recovered/resolved with sequelae", 7 events assessed as "Not recovered/not resolved", and 2 events as "Unknown". The outcome of each event was counted separately as 1 event, if a patient experienced more than one serious adverse reaction. The serious adverse reactions which resulted in death were 1 event each of cardiac failure, cerebral infarction, and cerebrovascular stenosis.
The proportion of patients who discontinued or terminated the treatment during the 1-year surveillance observation period was 38.12% (247/648 patients). The most common reason for discontinuation was "adverse events" in 117 patients, followed by "withdrawal by the patient" in 49 patients and "lack of efficacy" in 28 patients.
Of the factors which may potentially affect the safety of Agrylin, statistically significant differences were found in the presence of sex, previous or concurrent disease(s), other previous or concurrent disease(s), and average dose of Agrylin; however, there were no noteworthy trends in types of adverse reactions occurring at a high incidence.
Regarding the important items for investigation including hematological toxicity, data was compared between the results of clinical study and this survey. Incidence of adverse reactions in cardiac disorders, QT/QTc prolongation, hematological toxicity, interstitial lung disease and thrombohemorrhagic events did not overweigh the result of clinical studies, with using the definition of important items in the clinical studies. The reported QT/QTc prolongation were all serious; however, outcomes were all "recovered" or "recovering".
The median time to the initial onset of adverse reactions in important items was 55 days (122patients) for cardiac disorders, 100 days (17patients) for thrombohemorrhagic events, 110.5 days (2 patients) for interstitial lung disease, 113 days (53 patients) for hematotoxicity, and 160 days (3 patients) for QT/QTc prolongation.
AE in overall patients:
Throughout the surveillance period, the most common adverse reaction was headache reported in 174 patients (14.02%,) followed by palpitations in 151 patients (12.17%), anaemia in 73 patients (5.88%), diarrhoea in 62 patients (5.00%), and oedema peripheral in 35 patients (2.82%). The incidence of these adverse reactions was lower than those reported before the approval; however, the pattern in the occurrence of adverse reactions at a higher incidence was almost similar. Most of the adverse reactions occurred within 6 months after starting treatment with Agrylin. This pattern was also similar to that reported in the patients who started treatment with Agrylin by 31 May 2015.
A total of 115 serious adverse reactions occurred in 100 patients, an incidence of 8.06% (100/1241 patients). Overall, the most common serious adverse reaction was cardiac failure in 12 patients, followed by cardiac failure congestive in 7 patients, electrocardiogram QT prolonged in 6 patients, renal impairment in 5 patients, and atrial fibrillation and cerebral infarction in 4 patients each. All of the outcomes of serious adverse reactions were assessed as "Recovered/resolved" or "Recovering/resolving" except 4 events assessed as "Fatal", 5 events assessed as "Recovered/resolved with sequelae", 15 events assessed as "Not recovered/not resolved", and 5 events reported as "Unknown". The outcome of each event was counted separately as 1 event, if a patient experience more than one serious adverse reaction. The serious adverse reaction which resulted in fatal outcome was 1 event each of cardiac failure, cerebral infarction, cardiac failure acute, and cerebrovascular stenosis.
Of the 1241 patients in the safety analysis set, 429 patients (34.57%) discontinued or terminated the treatment with Agrylin. The most common reason for discontinuation was "adverse event" reported from 193 patients (15.55%), followed by "withdrawal by the patient" reported from 92 patients (7.41%), and "lack of efficacy" reported from 45 patients (3.63%).
Statistically significant differences were found in the incidence of adverse reactions for the following factors which were considered to potentially affect the safety of patients on treatment with Agrylin: "sex", "history of ET", "presence of previous or concurrent disease(s)", "presence of other previous or concurrent disease(s)", and "duration of exposure ".
The safety results for these two datasets were comparable, demonstrating reproducibility in the results of the survey
Outcome measures for all patients who had started treatment with anagrelide hydrochloride capsules by May 31, 2015;
The efficacy of Agrylin was assessed in terms of platelet reduction.
As the primary efficacy variable, the percentage of patients whose platelet count had decreased below 600,000/mcrL beyond 3 months after baseline was 64.68% (282/436 patients). As the secondary efficacy variables, the percentage of patients whose platelet count had decreased below 400,000/mcrL beyond 3 months after the start of administration was 32.96% (175/531 patients), and the percentage of patients whose platelet count had decreased by 50% from that at the baseline was 40.22% (251/624 patients).
The adverse reactions were reported in 352 patients and the incidence of adverse reactions was 54.32% (352/648 patients). The incidence of adverse reactions in this survey was generally low compared to that reported before the marketing approval (92.45%:49/53 patients).
The adverse reactions with high incidence were "headache" 15.43% (100/648 patients), "palpitations" 13.89% (90/648 patients), and "anaemia" 6.64% (43/684 patients) and so on. Of these, serious adverse reactions were reported in 53 patients at the incidence of 8.18% (53/648 patients). The most common serious adverse reaction was 6 events of cardiac failure, followed by 3 events each of atrial fibrillation, cerebral infarction, electrocardiogram QT prolonged, and renal impairment.
Of the factors which may potentially affect the safety of Agrylin, statistically significant differences were found in the presence of sex, previous or concurrent disease(s), other previous or concurrent disease(s), and average dose of Agrylin; however, there were no noteworthy trends in types of adverse reactions occurring at a high incidence.
Outcome measures in overall patients:
The percentage of patients whose platelet count had decreased below 600,000/mcrL beyond 3 months after baseline was 61.02% (537/880 patients). With regard to the secondary efficacy variables, the percentage of patients whose platelet count had decreased below 400,000/mcrL beyond 3 months after baseline was 28.97% (301/1039 patients) and the percentage of patients whose platelet count had decreased by 50% from that at the baseline was 38.90% (468/1203 patients).
Please refer to "Adverse events" for safety analysis.
The safety and efficacy results for these two datasets were comparable, demonstrating reproducibility in the results of the survey
Incidence and number, seriousness, and outcomes of adverse reactions, and factors which might influence their occurrence were investigated concerning the safety specification in the RMP for Agrylin and important items for investigation in this survey, but no noticeable trends were seen.
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
1. Number of Participants Who Had One or More Adverse Events
Time Frame: From start of study drug administration up to 12 months
An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
2. Number of Participants Who Had One or More Serious Adverse Event
Time Frame: From start of study drug administration up to 12 months
A serious AE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.
3. Number of Participants Who Had One or More Adverse Drug Reactions
Time Frame: From start of study drug administration up to 12 months
AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Adverse drug reaction refers to AE related to administered drug.
4. Number of Participants Who Had One or More Serious Adverse Drug Reactions
Time Frame: From start of study drug administration up to 12 months
A serious AE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. Serious adverse drug reaction refers to serious AE that are related to administered drug.
5. Percentage of Participants Who Responded in Platelet Count
Time Frame: Baseline, 1, 3, 6, 9 and 12 months after the start of study drug administration
Percentage of participants who responded in platelet count was assessed. A response was defined as platelet counts to <60x10^4/mcrL beyond 3 months after the start of study drug administration.
6. Percentage of Participants With Normalization in Platelet Count
Time Frame: Baseline, 1, 3, 6, 9 and 12 months after the start of study drug administration
Percentage of participants with normalization in platelet count was assessed. Normalization was defined as platelet counts to <40x10^4/mcrL beyond 3 months after the start of study drug administration.
1. Percentage of Participants With at Least 50% Reduction in Platelet Count
Time Frame: Baseline, 1, 3, 6, 9 and 12 months after the start of study drug administration
Participants who achieved at least 50% reduction in platelet count from their baseline during the 1-year observation period was assessed.