Trial Outcomes & Findings for Safety and Pregnancy Outcomes in Thrombocythemia Patients Exposed to XAGRID® (Anagrelide Hydrochloride) Compared to Other Treatments (NCT NCT00567502)

Last Updated: 2021-06-09

Results Overview

Pre-defined events (PDEs) were evaluated whenever an event occurred and was defined by a panel of independent qualified physicians, blinded to cytoreductive therapy, validated all PDEs prior to analysis (Event Validation Panel). Non-PDE death only included deaths not recorded as outcome of another PDE.

Recruitment status

COMPLETED

Target enrollment

3647 participants

Primary outcome timeframe

Up to 5 years

Results posted on

2021-06-09

Participant Flow

Participants who were newly diagnosed (received no treatment at the time of study registration) or previously diagnosed with essential thrombocythemia (ET), receiving or continuing previous cytoreductive therapy were recruited in the study

Due to the non-interventional nature of the study, participants could be receiving XAGRID, XAGRID+Other (Cytoreductives), other (cytoreductives) and no essential thrombocythemia (ET) therapy. During the study participants could change the treatments.

Participant milestones

Participant milestones
Measure	XAGRID Only Participants who received XAGRID at a dose and mode of administration managed as per investigator's discretion and the relevant Summary of Product Characteristics (SmPC) at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion	XAGRID+Other (Cytoreductives) Participants who received XAGRID+Other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	Other (Cytoreductives) Participants who received other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	No Essential Thrombocythemia (ET) Therapy Participants who were not receiving any cytoreductive treatment for at least 28 consecutive days at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.
Overall Study STARTED	804	141	2666	110
Overall Study Initiated Treatment	804	141	2666	38
Overall Study COMPLETED	563	108	1758	23
Overall Study NOT COMPLETED	241	33	908	87

Reasons for withdrawal

Reasons for withdrawal
Measure	XAGRID Only Participants who received XAGRID at a dose and mode of administration managed as per investigator's discretion and the relevant Summary of Product Characteristics (SmPC) at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion	XAGRID+Other (Cytoreductives) Participants who received XAGRID+Other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	Other (Cytoreductives) Participants who received other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	No Essential Thrombocythemia (ET) Therapy Participants who were not receiving any cytoreductive treatment for at least 28 consecutive days at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.
Overall Study Lost to Follow-up	91	14	351	2
Overall Study Death	65	16	360	5
Overall Study Other	64	2	134	6
Overall Study Participant request	12	1	33	1
Overall Study Sponsor request	9	0	30	1
Overall Study Never Initiated Treatment	0	0	0	72

Baseline Characteristics

Safety and Pregnancy Outcomes in Thrombocythemia Patients Exposed to XAGRID® (Anagrelide Hydrochloride) Compared to Other Treatments

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	XAGRID Only n=804 Participants Participants who received XAGRID at a dose and mode of administration managed as per investigator's discretion and the relevant Summary of Product Characteristics (SmPC) at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.	XAGRID+Other (Cytoreductives) n=141 Participants Participants who received XAGRID along with Other cytoreductives drugs at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	Other (Cytoreductives) n=2664 Participants Participants who received other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	No Essential Thrombocythemia (ET) Therapy n=38 Participants Participants who were not receiving any cytoreductive treatment for at least 28 consecutive days at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.	Total n=3647 Participants Total of all reporting groups
Age, Continuous	55.4 years STANDARD_DEVIATION 14.99 • n=99 Participants	59.9 years STANDARD_DEVIATION 13.74 • n=107 Participants	67.4 years STANDARD_DEVIATION 13.05 • n=206 Participants	64.3 years STANDARD_DEVIATION 14.26 • n=7 Participants	64.4 years STANDARD_DEVIATION 14.43 • n=31 Participants
Age, Customized Less than (<) 65 years	575 Participants n=99 Participants	89 Participants n=107 Participants	913 Participants n=206 Participants	14 Participants n=7 Participants	1591 Participants n=31 Participants
Age, Customized 65-<75 years	133 Participants n=99 Participants	30 Participants n=107 Participants	897 Participants n=206 Participants	13 Participants n=7 Participants	1073 Participants n=31 Participants
Age, Customized Greater than equal to (>=)75 years	96 Participants n=99 Participants	22 Participants n=107 Participants	854 Participants n=206 Participants	11 Participants n=7 Participants	983 Participants n=31 Participants
Sex: Female, Male Female	501 Participants n=99 Participants	80 Participants n=107 Participants	1632 Participants n=206 Participants	25 Participants n=7 Participants	2238 Participants n=31 Participants
Sex: Female, Male Male	303 Participants n=99 Participants	61 Participants n=107 Participants	1032 Participants n=206 Participants	13 Participants n=7 Participants	1409 Participants n=31 Participants

PRIMARY outcome

Timeframe: Up to 5 years

Population: First Treatment Safety Population included participants who received cytoreductive therapy at registration. All events/data were allocated to the treatment that a participant was receiving at the time of the event/assessment.

Outcome measures

Outcome measures
Measure	XAGRID Only n=804 Participants Participants who received XAGRID at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period.	XAGRID+Other (Cytoreductives) n=141 Participants Participants who received XAGRID+Other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	Other (Cytoreductives) n=2666 Participants Participants who received other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	No Essential Thrombocythemia (ET) Therapy Participants who were not receiving any cytoreductive treatment for at least 28 consecutive days at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.	Other (Cytoreductives)-Busulphan Participants who received other (Cytoreductives)-Busulphan at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Pipobroman Participants who received other (Cytoreductives)-Pipobroman at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Sodium Phosphate P32 Participants who received other (Cytoreductives)-Sodium Phosphate P32 at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Thromboreductin Participants who received other (Cytoreductives)-Thromboreductin at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other Participants who received other therapies at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Myocardial infarction	1.0 percentage of participants	0.0 percentage of participants	1.5 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Angina	0.7 percentage of participants	0.0 percentage of participants	0.7 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Congestive heart failure	1.2 percentage of participants	1.4 percentage of participants	1.2 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Cardiomyopathy	0.5 percentage of participants	0.0 percentage of participants	0.3 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Other cardiovascular symptoms	5.8 percentage of participants	8.5 percentage of participants	3.2 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Stroke	1.4 percentage of participants	1.4 percentage of participants	1.8 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Transient ischemic attack	1.1 percentage of participants	0.7 percentage of participants	1.3 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Severe Mucocutaneous Disorders	0.5 percentage of participants	1.4 percentage of participants	2.4 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Pulmonary hypertension	0.5 percentage of participants	0.0 percentage of participants	0.2 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Pulmonary fibrosis/ Interstitial pneumonia	0.1 percentage of participants	0.0 percentage of participants	0.3 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Venous thromboembolic events	0.5 percentage of participants	0.0 percentage of participants	1.9 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Pancreatitis	0.0 percentage of participants	0.0 percentage of participants	0.1 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Intermittent Claudication/ digital ischaemia	0.7 percentage of participants	0.7 percentage of participants	0.6 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Transformations	4.5 percentage of participants	6.4 percentage of participants	3.1 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Myelofibrosis	3.5 percentage of participants	5.0 percentage of participants	1.1 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Myelodysplasia	0.0 percentage of participants	0.0 percentage of participants	0.5 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Acute leukaemia	0.2 percentage of participants	1.4 percentage of participants	1.0 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Other leukaemia	0.6 percentage of participants	0.0 percentage of participants	0.5 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Other transformations	0.1 percentage of participants	0.0 percentage of participants	0.1 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Major haemorrhagic events	3.0 percentage of participants	0.7 percentage of participants	1.6 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Rhabdomyolysis/ myalgia	0.2 percentage of participants	0.0 percentage of participants	0.1 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Non-haematological malignancy	1.5 percentage of participants	1.4 percentage of participants	4.6 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Non-PDE death	2.2 percentage of participants	1.4 percentage of participants	3.9 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Pregnancy	0.5 percentage of participants	0.0 percentage of participants	0.5 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Thrombohaemorrhagic events	8.1 percentage of participants	3.5 percentage of participants	8.5 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Major thrombotic events	5.3 percentage of participants	2.8 percentage of participants	7.3 percentage of participants	—	—	—	—	—	—
Percentage of Participants With At Least One Pre-Defined Event (PDE), Deaths, Pregnancies Arterial events	4.9 percentage of participants	2.8 percentage of participants	5.5 percentage of participants	—	—	—	—	—	—

PRIMARY outcome

Timeframe: Up to 5 years

Population: Overall treatment safety population. All events/data were allocated to the treatment that a participant was receiving at the time of the event/assessment. Participants who had exposed to XAGRID (alone or in combination with other) was counted in Xagrid arm and those who had received other ET therapy in the "Other (Cytoreductives)".

SSAR: serious adverse event (SAE) that was considered related to cytoreductive therapy. SAE: any untoward medical occurrence that at any dose resulted in death, life-threatening (at the time of the event), in-patient hospitalization/prolongation of existing hospitalization (elective hospitalizations/procedures for pre-existing conditions that had not worsened were excluded), resulted in persistent or significant disability/incapacity or congenital abnormality/birth defect. Relatedness (suspected/not suspected) to XAGRID or other cytoreductive theraphy was determined by the investigator. As for SSARs, it was important to consider whether the events were related to XAGRID or other cytoreductive therapy. A participant was included in Xagrid or other treatment group based on treatment exposure, participants received Xagrid + Other was counted both in Xagrid and other treatment group.

Outcome measures

Outcome measures
Measure	XAGRID Only n=1300 Participants Participants who received XAGRID at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period.	XAGRID+Other (Cytoreductives) n=3069 Participants Participants who received XAGRID+Other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	Other (Cytoreductives) Participants who received other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	No Essential Thrombocythemia (ET) Therapy Participants who were not receiving any cytoreductive treatment for at least 28 consecutive days at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.	Other (Cytoreductives)-Busulphan Participants who received other (Cytoreductives)-Busulphan at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Pipobroman Participants who received other (Cytoreductives)-Pipobroman at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Sodium Phosphate P32 Participants who received other (Cytoreductives)-Sodium Phosphate P32 at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Thromboreductin Participants who received other (Cytoreductives)-Thromboreductin at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other Participants who received other therapies at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.
Number of Participants With Suspected Serious Adverse Reaction (SSAR) Events	37 participants	70 participants	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Up to 5 years

Population: Overall Treatment Safety Population. As participant could switch between therapies a participant with an event could be allocated to more than one therapy group. Participants analyzed included who were exposed to the specific treatment any time during the study.

Event Rate of Thrombohaemorrhagic Events was calculated by dividing number of participants with events by total patient-year exposure. The reporting unit is per 100 participant-years of treatment exposure. Thrombohaemorrhagic Events is a composite endpoint of the PDEs myocardial infarction, angina, stroke, transient ischaemic attack, venous thromboembolic events, intermittent claudication/digital ischaemia, and major haemorrhagic events.

Outcome measures

Outcome measures
Measure	XAGRID Only n=1127 Participants Participants who received XAGRID at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period.	XAGRID+Other (Cytoreductives) n=451 Participants Participants who received XAGRID+Other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	Other (Cytoreductives) n=2909 Participants Participants who received other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	No Essential Thrombocythemia (ET) Therapy n=645 Participants Participants who were not receiving any cytoreductive treatment for at least 28 consecutive days at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.	Other (Cytoreductives)-Busulphan Participants who received other (Cytoreductives)-Busulphan at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Pipobroman Participants who received other (Cytoreductives)-Pipobroman at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Sodium Phosphate P32 Participants who received other (Cytoreductives)-Sodium Phosphate P32 at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Thromboreductin Participants who received other (Cytoreductives)-Thromboreductin at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other Participants who received other therapies at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.
Event Rate of Thrombohaemorrhagic Events	2.75 participants/100 participant-years	2.86 participants/100 participant-years	2.60 participants/100 participant-years	4.91 participants/100 participant-years	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline, Month 6,12,18, 24, 30, 36, 42, 48, 54, 60

Population: Overall Treatment Safety population, Here n = participants evaluable at specified time-points. As participant could switch between therapies a participant with an event could be allocated to more than one therapy group. Participants analyzed included who were exposed to the specific treatment any time during the study.

Outcome measures

Outcome measures
Measure	XAGRID Only n=1127 Participants Participants who received XAGRID at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period.	XAGRID+Other (Cytoreductives) n=451 Participants Participants who received XAGRID+Other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	Other (Cytoreductives) n=2909 Participants Participants who received other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	No Essential Thrombocythemia (ET) Therapy n=645 Participants Participants who were not receiving any cytoreductive treatment for at least 28 consecutive days at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.	Other (Cytoreductives)-Busulphan Participants who received other (Cytoreductives)-Busulphan at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Pipobroman Participants who received other (Cytoreductives)-Pipobroman at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Sodium Phosphate P32 Participants who received other (Cytoreductives)-Sodium Phosphate P32 at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Thromboreductin Participants who received other (Cytoreductives)-Thromboreductin at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other Participants who received other therapies at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.
Platelet Count Baseline (n = 671, 120, 2279,136)	486.90 10^9 per Liter (10^9/L) Standard Deviation 210.106	542.77 10^9 per Liter (10^9/L) Standard Deviation 250.440	471.29 10^9 per Liter (10^9/L) Standard Deviation 201.620	837.23 10^9 per Liter (10^9/L) Standard Deviation 377.104	—	—	—	—	—
Platelet Count Month 6 (n = 777, 145, 2469, 60)	1093.73 10^9 per Liter (10^9/L) Standard Deviation 17634.779	521.44 10^9 per Liter (10^9/L) Standard Deviation 266.512	439.44 10^9 per Liter (10^9/L) Standard Deviation 153.766	545.30 10^9 per Liter (10^9/L) Standard Deviation 202.936	—	—	—	—	—
Platelet Count Month 12 (n= 739, 158, 2400, 81)	969.61 10^9 per Liter (10^9/L) Standard Deviation 14404.677	516.66 10^9 per Liter (10^9/L) Standard Deviation 245.789	436.64 10^9 per Liter (10^9/L) Standard Deviation 154.958	501.46 10^9 per Liter (10^9/L) Standard Deviation 275.880	—	—	—	—	—
Platelet Count Month 18 (n= 706, 170, 2231, 86)	1612.14 10^9 per Liter (10^9/L) Standard Deviation 22193.573	541.78 10^9 per Liter (10^9/L) Standard Deviation 706.564	432.99 10^9 per Liter (10^9/L) Standard Deviation 145.694	476.72 10^9 per Liter (10^9/L) Standard Deviation 245.450	—	—	—	—	—
Platelet Count Month 24 (n= 673, 181, 2106, 119)	865.09 10^9 per Liter (10^9/L) Standard Deviation 11047.483	492.67 10^9 per Liter (10^9/L) Standard Deviation 194.534	1025.11 10^9 per Liter (10^9/L) Standard Deviation 15888.471	499.29 10^9 per Liter (10^9/L) Standard Deviation 249.164	—	—	—	—	—
Platelet Count Month 30 (n= 642, 183, 2001, 116)	418.97 10^9 per Liter (10^9/L) Standard Deviation 159.129	467.37 10^9 per Liter (10^9/L) Standard Deviation 170.733	693.30 10^9 per Liter (10^9/L) Standard Deviation 8293.353	467.54 10^9 per Liter (10^9/L) Standard Deviation 255.641	—	—	—	—	—
Platelet Count Month 36 (n= 628, 167, 1917, 124)	423.10 10^9 per Liter (10^9/L) Standard Deviation 153.278	1138.81 10^9 per Liter (10^9/L) Standard Deviation 8787.658	1221.09 10^9 per Liter (10^9/L) Standard Deviation 20612.960	462.06 10^9 per Liter (10^9/L) Standard Deviation 256.357	—	—	—	—	—
Platelet Count Month 42 (n= 597, 161, 1799, 138)	831.62 10^9 per Liter (10^9/L) Standard Deviation 10257.081	466.83 10^9 per Liter (10^9/L) Standard Deviation 205.575	1898.48 10^9 per Liter (10^9/L) Standard Deviation 26724.419	463.52 10^9 per Liter (10^9/L) Standard Deviation 271.690	—	—	—	—	—
Platelet Count Month 48 (n= 581, 167, 1735, 131)	2461.07 10^9 per Liter (10^9/L) Standard Deviation 28879.771	443.91 10^9 per Liter (10^9/L) Standard Deviation 173.453	1360.17 10^9 per Liter (10^9/L) Standard Deviation 20669.182	457.44 10^9 per Liter (10^9/L) Standard Deviation 250.165	—	—	—	—	—
Platelet Count Month 54 (n= 557, 164, 1644, 132)	413.93 10^9 per Liter (10^9/L) Standard Deviation 145.601	447.17 10^9 per Liter (10^9/L) Standard Deviation 171.608	1771.77 10^9 per Liter (10^9/L) Standard Deviation 25187.992	408.41 10^9 per Liter (10^9/L) Standard Deviation 254.971	—	—	—	—	—
Platelet Count Month 60 (n = 523, 167, 1586, 144)	1174.87 10^9 per Liter (10^9/L) Standard Deviation 17473.437	466.31 10^9 per Liter (10^9/L) Standard Deviation 193.689	1362.94 10^9 per Liter (10^9/L) Standard Deviation 19098.693	425.22 10^9 per Liter (10^9/L) Standard Deviation 268.377	—	—	—	—	—

SECONDARY outcome

Timeframe: Up to 5 years

Total duration for each participant = sum of \[stop date - start date + 1\] across all periods of time where the specific treatment was taken during the study, where start date = registration/consent date for treatments started before registration/consent date and/or stop date withdrawal/final date for treatments ongoing at the time of withdrawal/end of study. Where a participant has multiple records of the same therapy on the same day, the therapy is counted once for that day.

Outcome measures

Outcome measures
Measure	XAGRID Only n=1300 Participants Participants who received XAGRID at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period.	XAGRID+Other (Cytoreductives) n=2742 Participants Participants who received XAGRID+Other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	Other (Cytoreductives) n=193 Participants Participants who received other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	No Essential Thrombocythemia (ET) Therapy n=144 Participants Participants who were not receiving any cytoreductive treatment for at least 28 consecutive days at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.	Other (Cytoreductives)-Busulphan n=105 Participants Participants who received other (Cytoreductives)-Busulphan at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Pipobroman n=159 Participants Participants who received other (Cytoreductives)-Pipobroman at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Sodium Phosphate P32 n=12 Participants Participants who received other (Cytoreductives)-Sodium Phosphate P32 at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Thromboreductin n=5 Participants Participants who received other (Cytoreductives)-Thromboreductin at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other n=91 Participants Participants who received other therapies at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.
Duration of Exposure for Each Essential Thrombocythemia (ET) Therapy	1213.7 days Standard Deviation 687.83	1382.3 days Standard Deviation 609.33	933.3 days Standard Deviation 748.09	744.0 days Standard Deviation 660.93	510.2 days Standard Deviation 560.28	992.8 days Standard Deviation 690.80	39.7 days Standard Deviation 96.73	979.0 days Standard Deviation 859.27	446.3 days Standard Deviation 561.46

SECONDARY outcome

Timeframe: Up to 5 years

Since the study is observational nature, interpreting the table is difficult due to inconsistencies in reporting the units of the dose.

Outcome measures

Outcome measures
Measure	XAGRID Only n=1162 Participants Participants who received XAGRID at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period.	XAGRID+Other (Cytoreductives) n=2168 Participants Participants who received XAGRID+Other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	Other (Cytoreductives) n=2 Participants Participants who received other (Cytoreductives) at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC at the time of registering into the study or after switching from another treatment any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.	No Essential Thrombocythemia (ET) Therapy n=9 Participants Participants who were not receiving any cytoreductive treatment for at least 28 consecutive days at the time of registering into the study for a 5 year observation period, during which participants were able to switch treatments per investigator's discretion.	Other (Cytoreductives)-Busulphan n=92 Participants Participants who received other (Cytoreductives)-Busulphan at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Pipobroman n=112 Participants Participants who received other (Cytoreductives)-Pipobroman at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Sodium Phosphate P32 n=1 Participants Participants who received other (Cytoreductives)-Sodium Phosphate P32 at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other (Cytoreductives)-Thromboreductin n=4 Participants Participants who received other (Cytoreductives)-Thromboreductin at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.	Other n=70 Participants Participants who received other therapies at a dose and mode of administration managed as per investigator's discretion and the relevant SmPC, was observed for 5 years.
Cumulative Dose for Each Essential Thrombocythemia (ET) Therapy	29096.2 milligram (mg) Standard Deviation 291472.25	957751.4 milligram (mg) Standard Deviation 883174.77	3592.2 milligram (mg) Standard Deviation 5076.77	5103.1 milligram (mg) Standard Deviation 10730.47	7749.6 milligram (mg) Standard Deviation 56031.79	28612.7 milligram (mg) Standard Deviation 67374.96	2745.0 milligram (mg)	2140.0 milligram (mg) Standard Deviation 835.26	111639.7 milligram (mg) Standard Deviation 190370.57

Adverse Events

XAGRID

Serious events: 37 serious events

Other events: 0 other events

Deaths: 0 deaths

Other (Cytoreductives)

Serious events: 70 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	XAGRID n=1300 participants at risk Participants who received XAGRID from "Xagrid only" or "Xagrid+other (cytoreductives)" arm groups (for serious adverse events) at a dose and mode of administration managed as per investigator's discretion and the relevant Summary of Product Characteristics (SmPC) at the time of registering into the study or after switching from another treatment (other adverse events) any time during the 5 year observation period.	Other (Cytoreductives) n=3069 participants at risk Participants who received other (cytoreductives) from " other (cytoreductives" or "Xagrid+other (cytoreductives)" arm groups (for serious adverse events) at a dose and mode of administration managed as per investigator's discretion and the relevant Summary of Product Characteristics (SmPC) at the time of registering into the study or after switching from another treatment (other adverse events) any time during the 5 year observation period. Other Cytoreductives included Hydroxyurea, Interferon- alpha, Pegylated interferon, Busulphan, Pipobroman, Sodium phosphate P32.
Cardiac disorders Cardiac failure	0.15% 2/1300 • Number of events 2 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Cardiac failure Congestive	0.23% 3/1300 • Number of events 3 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Cardiomyopathy	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Left ventricular failure	0.15% 2/1300 • Number of events 2 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Myocardial Infarction	0.15% 2/1300 • Number of events 2 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Palpitations	0.23% 3/1300 • Number of events 3 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Pericardial effusion	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Tachycardia	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Gastrointestinal disorders Diarrhoea	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Gastrointestinal disorders Enteritis	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Blood and lymphatic system disorders Anaemia	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.29% 9/3069 • Number of events 9 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Blood and lymphatic system disorders Leukopenia	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Blood and lymphatic system disorders Neutropenia	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.07% 2/3069 • Number of events 2 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Blood and lymphatic system disorders Splenic infarction	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.07% 2/3069 • Number of events 2 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Acute myocardial infarction	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Angina pectoris	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Cardiac disorders Atrial fibrillation	0.46% 6/1300 • Number of events 6 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.23% 3/1300 • Number of events 3 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.07% 2/3069 • Number of events 2 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Gastrointestinal disorders Haemorrhagic erosive gastritis	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Gastrointestinal disorders Melaena	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Gastrointestinal disorders Mouth ulceration	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
General disorders Asthenia	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
General disorders Pyrexia	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Immune system disorders Drug hypersensitivity	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Infections and infestations Cellulitis	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Infections and infestations Gastroenteritis	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Infections and infestations Klebsiella sepsis	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Infections and infestations Respiratory tract infection	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Injury, poisoning and procedural complications Overdose	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Injury, poisoning and procedural complications Skin injury	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Investigations Haemoglobin decreased	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Musculoskeletal and connective tissue disorders Muscle spasms	0.08% 1/1300 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.00% 0/3069 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute myeloid leukaemia	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.20% 6/3069 • Number of events 6 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.07% 2/3069 • Number of events 2 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/1300 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.	0.03% 1/3069 • Number of events 1 • Up to 5 years SSARs \[defined in outcome measure (OM) 2\]= SAEs considered related to cytoreductive drug and only "XAGRID" and "Other" treatment groups were to be reported. SAEs and non-SAEs was not planned to be reported separately, therefore, reported under OM 1.