EXTEND (Eltrombopag Extended Dosing Study)

EXTEND (Eltrombopag Extended Dosing Study): An Extension Study of Eltrombopag Olamine (SB-497115-GR) in Adults, With Idiopathic Thrombocytopenic Purpura (ITP), Previously Enrolled in an Eltrombopag Study.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00351468

Acronym

EXTEND

Enrollment

302

Registered

2006-07-12

Start date

2006-06-30

Completion date

2015-07-31

Last updated

2017-04-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Purpura, Thrombocytopaenic, Idiopathic

Keywords

eltrombopag olamine, SB-497115-GR, idiopathic thrombocytopenic purpura, thrombocytopenia, ITP, platelets

Brief summary

An open-label, dose-adjustment, extension study to evaluate the safety and efficacy of eltrombopag for the treatment of subjects with idiopathic thrombocytopenic purpura (ITP) who have previously been enrolled in an eltrombopag trial. This study will allow adjustment of the eltrombopag dose to achieve an individualized dose and schedule for each subject. In addition, the ability to reduce the dose of concomitant ITP medications in the presence of eltrombopag, while maintaining platelet counts = 50,000/μL will be investigated.

Interventions

DRUGeltrombopag olamine (SB-497115-GR)

Eltrombopag with starting dose of 50mg daily, max dose of 75mg daily and min dose of 25mg daily or less frequently. Modifications were given to maintain platelet count in range of 50 to 200 Gi/L.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Subject has signed and dated a written informed consent. * Adults (≥18 years) diagnosed with ITP according to the American Society for Hematology/British Committee for Standards in Haematology (ASH/BCSH) guidelines \[George, 1996; BCSH, 2003\]. In addition, a peripheral blood smear should support the diagnosis of ITP with no evidence of other disease causative of thrombocytopenia (e.g., pseudo thrombocytopenia, myelofibrosis). The physical examination should not suggest any disease which may cause thrombocytopenia other than ITP. * Prior completion of treatment and follow up periods in an ITP study of eltrombopag (e.g., TRA100773 or TRA102537/RAISE or TRA108057/REPEAT). * Subjects previously enrolled in Study TRA100773 must have completed the prescribed follow-up ophthalmic assessment at 6 months. * Subjects previously enrolled in TRA102537/RAISE or other studies that may lead into EXTEND (e.g., TRA108057/REPEAT) must have completed the treatment and follow-up periods as defined in that protocol. * Subject experienced no eltrombopag-related toxicity or other drug intolerance on prior eltrombopag study (e.g., TRA100773 or TRA102537/RAISE or TRA108057/REPEAT) even if resolved; subjects discontinued from previous study due to toxicity will not be eligible unless they received placebo. * Subject has no intercurrent medical event, including thrombosis. * Subjects must have either initially responded (platelet count \> 100,000/mL) to a previous ITP therapy or have had a bone marrow examination consistent with ITP within 3 years to rule out myelodysplastic syndromes or other causes of thrombocytopenia * Previous therapy for ITP with immunoglobulins (IVIg and anti-D) must have been completed at least 1 week prior to first dose of study medication and the platelet count must show a clear downward trend after the last treatment with immunoglobulins. Previous treatment for ITP with splenectomy, rituximab and cyclophosphamide must have been completed at least 4 weeks prior to randomization, or clearly be ineffective. * Subjects treated with concomitant ITP medication (e.g. corticosteroids or azathioprine) must be receiving a dose that has been stable for at least 4 weeks prior to randomization. Subjects treated with cyclosporine A, mycophenolate mofetil or danazol must be receiving a dose that has been stable for at least 3 months prior to the first dose of study medication. * Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) must be within 80 to 120% of the normal range with no history of hypercoagulable state. * A complete blood count (CBC), within the reference range (including WBC differential not indicative of a disorder other than ITP), with the following exceptions: * Hemoglobin: Subjects with hemoglobin levels between 10.0 g/dL and the lower limit of normal are eligible for inclusion, if anemia is clearly attributable to ITP (excessive blood loss). * ANC≥1500/mL (1.5 x 10\^9/L) is required for inclusion (elevated WBC/ANC due to steroid treatment is acceptable). * The following clinical chemistries MUST NOT exceed the upper limit of normal (ULN) reference range by more than 20%: creatinine, ALT, AST, total bilirubin, and alkaline phosphatase. In addition, total albumin must not be below the lower limit of normal (LLN) by more than 10%. * Subject is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must either be of non-childbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal \> 1 year), or of childbearing potential and use one of the following highly effective methods of contraception (i.e., Pearl Index \<1.0%) from two weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study: * Complete abstinence from intercourse; * Intrauterine device (IUD); * Two forms of barrier contraception (diaphragm plus spermicide, and for males condom plus spermicide); * Male partner is sterile prior to entry into the study and is the only partner of the female; * Systemic contraceptives (combined or progesterone only). * Subject is able to understand and comply with protocol requirements and instructions.

Exclusion criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply: * Any clinically relevant abnormality, other than ITP, identified on the screening examination, or any other medical condition or circumstance, which in the opinion of the investigator makes the subject unsuitable for participation in the study or suggests another diagnosis. * Concurrent malignant disease and/or history of cancer treatment with cytotoxic chemotherapy and/or radiotherapy. * Any prior history of arterial or venous thrombosis (stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism), AND≥two of the following risk factors: hormone replacement therapy, systemic contraception (containing estrogen), smoking, diabetes, hypercholesterolemia, medication for hypertension, cancer, hereditary thrombophilic disorders (e.g., Factor V Leiden, ATIII deficiency, etc), or any other family history of arterial or venous thrombosis * Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association \[NYHA\] Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTc \>450 msec. * Female subjects who are nursing or pregnant (positive serum or urine b-human chorionic gonadotrophin (b-hCG) pregnancy test) at screening or pre-dose on Day 1. * History of alcohol/drug abuse. * Treatment with an investigational drug within 30 days or five half-lives (whichever is longer) preceding the first dose of study medication. * Subject treated with drugs that affect platelet function (including but not limited to aspirin, clopidogrel and/or NSAIDs) or anti-coagulants for \> 3 consecutive days within 2 weeks of the study start and until the end of the study. * History of platelet agglutination abnormality that prevents reliable measurement of platelet counts. * All subjects with secondary immune thrombocytopenia, including those with laboratory or clinical evidence of HIV infection, antiphospholipid antibody syndrome, chronic hepatitis B infection, hepatitis C virus infection, or any evidence for active hepatitis at the time of subject screening. If a potential subject has no clinical history that would support HIV infection or hepatitis infection, no further laboratory screening is necessary; however, standard medical practice would suggest further evaluation of patients who have risk factors for these infections. * A subject is planning to have cataract surgery. * In France, a subject is neither affiliated with nor a beneficiary of a social security category. Other Eligibility Criteria Considerations: To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: CIB, SPM.

Design outcomes

Primary

Measure	Time frame	Description
Overall Summary of On-Therapy Adverse Events (Safety Population)	Start date was the first dose of investigational product and up to the day after the last dose . Post-therapy: start date was more than 1 day after the last dose and up to 30 days after last dose of investigational product up to week 364	All safety evaluation findings considered to be adverse events are reported in the Adverse Event section.

Secondary

Measure	Time frame	Description
Summary of Subjects Achieving Platelet Count Levels by Week, in the Absence of Rescue Medication	Baseline up to Year 7/Week 364	If a subject has more than 1 platelet count result within a week, the lowest value observed is used to determine response. All platelet counts after an on-study splenectomy are not classed as responses. Platelet counts within 7 days after a platelet transfusion are not classed as responses. Platelet counts while taking an increased ITP medication or within 6 weeks after the end of an increased ITP medication are not classed as responses.
Number of Subjects Who Responded to Eltrombopag in a Previous Study and Who Respond to Retreatment With a Rise in Platelet Count to Either ≥ 50,000/µL or ≥30,000/µL	Baseline up to 2 years	Responder in TRA100773: Platelet count 50 Gi/L and 2 x baseline (BL) at last on-treatment assessment. Responders in EXTEND: Platelet count 50 Gi/L and 2 x baseline (BL), 50 Gi/L, and 30 Gi/L at any time. Responder in RAISE: Platelet count 50GI/L and 2 x baseline at Week 6 assessment. Responders in EXTEND: Platelet count 50 Gi/L and 2 x baseline, 50 Gi/L, and 30 Gi/L at any time. Responder in REPEAT: Platelet count 50 GI/L and 2 x baseline (BL) at Week 6 assessment in Cycle 1. Responders in EXTEND: Platelet count 50 Gi/L and 2 x baseline (BL) 50 Gi/L, and 30 Gi/L at any time.
Number of Participants With Reduction and/or Sparing of Concomitant ITP Therapies, While Maintaining a Platelet Count ≥ 50,000/mL.	Baseline up to 2 years	Sustain reduct: Sustained reduction 1 Denominator is number of subjects taking an ITP medication at baseline. 2 Denominator is number of subjects with a sustained reduction. Note: Sustained reduction defined as reduction from baseline in dose and/or frequency which is maintained for at least 4 weeks. Excludes sustained reductions started more than 1 day after last dose.
Number of Subjects Who Required Rescue Therapy During Treatment With Eltrombopag.	Baseline up to 2 years	Rescue treatment is defined as a composite of: new ITP medication, increased dose of a concomitant ITP medication, platelet transfusion, and splenectomy. Subjects may have received more than 1 type of rescue therapy
Subjects Achieving Maximum Platelet Counts Greater Than or Equal to 30 Gi/L or 50 Gi/L in the Absence of Rescue Medication	Baseline up to 2 years	Subjects who achieved maximum platelet count at least once during treatment. All platelet counts after an on-study splenectomy are not classed as responses. Platelet counts within 7 days after a platelet transfusion are not classed as responses. Platelet counts while taking an increased ITP medication or within 6 weeks after the end of an increased ITP medication are not classed as responses.
Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years	The SF-36v2 assessment tool was used to obtain information about subjects' general health status and health-related quality of life. Until a formal assessment of minimal clinically important differences (MCID) is performed, changes from baseline of more than 0.5 standard deviations are suggested as clinically meaningful. Scores were transformed to a 0-100 point scale, with higher scores representing more positive answers. Scores were normalized to have a mean of 50 and SD of 10 to allow for comparison with outcomes from other chronic diseases. Recall period is the past week prior to administration. The change in scores was measured at the transitioning period and immediately prior to withdrawal/completion over 2 years, and the mean of these measurements was recorded to calculate the change from baseline and the best post baseline change score was reported for the entire group
Best Post-Baseline Change in the Short Form of the Motivation and Energy Scale (MEI-SF) From Any Time Point Compared With Baseline	Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years	The MEI-SF (18 questions) was used to measure the reductions in mental energy, physical energy, and social motivation, either as symptoms of chronic ITP or as a side effect of pharmacotherapy. Minimal clinically important differences are estimated as 0.5 standard deviations or 7.5 points. All items use either a 7-level (0 to 6) or 5-level (0 to 4) response scale; items with a 5-level response scale were rescaled to 7-levels, and items were reverse-scored as necessary such that higher scores represent higher HRQoL Total score ranges from 0 to 108 points. Recall period is past week prior to administration. The change in scores was measured at the transitioning period and immediately prior to withdrawal/completion over 2 years, and the mean of these measurements was recorded to calculate the change from baseline and the best post baseline change score was reported for the entire group
Best Post-Baseline Change in the FACIT-Fatigue 13 Item Subscale Score From Any Time Point Compared to Baseline	Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years	The FACIT-Fatigue consists of 13 questions in which patients rate the frequency (0-4) of symptoms of fatigue, in terms of tiredness, weakness, and fatigue Items were reverse-scored as necessary such that higher scores represent higher HRQoL Total score ranges from 0 to 52.Using anchor-based estimates, the minimally important difference in this subscale is 3.0 points. Recall period is past week prior to administration. The change in scores was measured at the transitioning period and immediately prior to withdrawal/completion over 2 years, and the mean of these measurements was recorded to calculate the change from baseline and the best post baseline change score was reported for the entire group
Best Post-Baseline Change in the FACT-TH6 at Any Time Point Compared to Baseline	Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years	The FACT-TH6 consists of 6 questions in which patients rate (0-4) their general degree of worry related to bleeding and bruising, and resulting activity impairment and frustration. Although the six items do not constitute a formal domain or subscale of the FACT-Th assessment tool, these items had been identified by focus groups of patients with chronic ITP as important indicators of their HRQoL. Items were reverse-scored as necessary such that higher scores represent higher HRQoL. Total scores ranged from 0 to 24. Recall period is not specified. The change in scores was measured at the transitioning period and immediately prior to withdrawal/completion over 2 years, and the mean of these measurements was recorded to calculate the change from baseline and the best post baseline change score was reported for the entire group
Maximum ITP Bleeding Score at Any Time During the Study During All Stages.	Baseline up to 2 years	The ITP bleeding score is a tool which has been designed specifically to assess the bruising and bleeding in patients with ITP across body sites, ranging from mild to severe. The WHO Grades were dichotomized into the following categories: - Grade 0, No bleeding -Grade 1 to 4, Any bleeding -Grade 0 to 1: No clinically significant bleeding -Grade 2 to 4 Clinically significant bleeding

Countries

Australia, Austria, Canada, China, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Italy, Netherlands, New Zealand, Pakistan, Peru, Poland, Romania, Russia, Slovakia, Slovenia, South Korea, Spain, Sweden, Taiwan, Thailand, Tunisia, Ukraine, United Kingdom, United States, Vietnam

Participant flow

Recruitment details

Subjects were previously enrolled in a study of eltrombopag: TRA100773A, TRA100773B, TRA102537/RAISE, or TRA108057/REPEAT. Eligibility of consenting subjects was assessed during the screening period of up to 28 days prior to Day 1 of treatment.

Participants by arm

Arm	Count
Eltrombopag Open-label eltrombopag was supplied in 25, 50, 75 mg tablets. All subjects started at 50mg once daily and dose was increased or decreased based on platelet count (target range 50-200Gi/L). Alternate days and interruption of dosing was permitted to maintain target range of platelet count. Doses could range from 25 to 75mg. Subjects could remain on treatment up to 2 years.	302
Total	302

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	42
Overall Study	Lack of Efficacy	32
Overall Study	Lost to Follow-up	4
Overall Study	Non-compliance	8
Overall Study	Protocol Violation	3
Overall Study	Various -follow up w clinical team	39
Overall Study	Withdrawal by Subject	39

Baseline characteristics

Characteristic	Eltrombopag
Age, Continuous	48.9 Years STANDARD_DEVIATION 15.61
Baseline Platelet Count 30 - 50 Gi/L	52 Participants
Baseline Platelet Count <30 Gi/L	211 Participants
Baseline Platelet Count > 50 Gi/L	39 Participants
Concomitant ITP Medication at Baseline No	201 Participant
Concomitant ITP Medication at Baseline Yes	101 Participant
Sex: Female, Male Female	201 Participants
Sex: Female, Male Male	101 Participants
Splenectomy Status at Baseline No	187 Participants
Splenectomy Status at Baseline Yes	115 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	253 / 302	28 / 302
serious Total, serious adverse events	96 / 302	10 / 302

Outcome results

Primary

Overall Summary of On-Therapy Adverse Events (Safety Population)

All safety evaluation findings considered to be adverse events are reported in the Adverse Event section.

Time frame: Start date was the first dose of investigational product and up to the day after the last dose . Post-therapy: start date was more than 1 day after the last dose and up to 30 days after last dose of investigational product up to week 364

Arm	Measure	Group	Value (NUMBER)
Eltrombopag	Overall Summary of On-Therapy Adverse Events (Safety Population)	Any adverse event	277 Participants
Eltrombopag	Overall Summary of On-Therapy Adverse Events (Safety Population)	Any serious adverse event	96 Participants
Eltrombopag	Overall Summary of On-Therapy Adverse Events (Safety Population)	Adverse events related to study medication	133 Participants
Eltrombopag	Overall Summary of On-Therapy Adverse Events (Safety Population)	Adverse events leading to withdrawal	41 Participants
Eltrombopag	Overall Summary of On-Therapy Adverse Events (Safety Population)	Serious adverse events leading withdrawal	28 Participants

Secondary

Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline

The SF-36v2 assessment tool was used to obtain information about subjects' general health status and health-related quality of life. Until a formal assessment of minimal clinically important differences (MCID) is performed, changes from baseline of more than 0.5 standard deviations are suggested as clinically meaningful. Scores were transformed to a 0-100 point scale, with higher scores representing more positive answers. Scores were normalized to have a mean of 50 and SD of 10 to allow for comparison with outcomes from other chronic diseases. Recall period is the past week prior to administration. The change in scores was measured at the transitioning period and immediately prior to withdrawal/completion over 2 years, and the mean of these measurements was recorded to calculate the change from baseline and the best post baseline change score was reported for the entire group

Time frame: Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years

Arm	Measure	Group	Value (MEAN)
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 Physical role (n=273)	14.2 Points on a scale
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 Bodily pain (n=273)	14.5 Points on a scale
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 Vitality (n=290)	13.9 Points on a scale
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 Emotional role (n=290)	11.4 Points on a scale
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 Social function (n=290)	12.6 Points on a scale
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 Mental health (n=290)	11.3 Points on a scale
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 Physical component summary (n=273)	5.3 Points on a scale
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 Mental component summary (n=290)	5.8 Points on a scale
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 Physical function (n=273	12.0 Points on a scale
Eltrombopag	Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline	SF-36v2 General health (n=273)	11.1 Points on a scale

Secondary

Best Post-Baseline Change in the FACIT-Fatigue 13 Item Subscale Score From Any Time Point Compared to Baseline

The FACIT-Fatigue consists of 13 questions in which patients rate the frequency (0-4) of symptoms of fatigue, in terms of tiredness, weakness, and fatigue Items were reverse-scored as necessary such that higher scores represent higher HRQoL Total score ranges from 0 to 52.Using anchor-based estimates, the minimally important difference in this subscale is 3.0 points. Recall period is past week prior to administration. The change in scores was measured at the transitioning period and immediately prior to withdrawal/completion over 2 years, and the mean of these measurements was recorded to calculate the change from baseline and the best post baseline change score was reported for the entire group

Time frame: Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years

Population: ITT

Arm	Measure	Value (MEAN)
Eltrombopag	Best Post-Baseline Change in the FACIT-Fatigue 13 Item Subscale Score From Any Time Point Compared to Baseline	6.9 Points on a scale

Secondary

Best Post-Baseline Change in the FACT-TH6 at Any Time Point Compared to Baseline

The FACT-TH6 consists of 6 questions in which patients rate (0-4) their general degree of worry related to bleeding and bruising, and resulting activity impairment and frustration. Although the six items do not constitute a formal domain or subscale of the FACT-Th assessment tool, these items had been identified by focus groups of patients with chronic ITP as important indicators of their HRQoL. Items were reverse-scored as necessary such that higher scores represent higher HRQoL. Total scores ranged from 0 to 24. Recall period is not specified. The change in scores was measured at the transitioning period and immediately prior to withdrawal/completion over 2 years, and the mean of these measurements was recorded to calculate the change from baseline and the best post baseline change score was reported for the entire group

Time frame: Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years

Arm	Measure	Value (MEAN)
Eltrombopag	Best Post-Baseline Change in the FACT-TH6 at Any Time Point Compared to Baseline	4.0 Points on a scale

Secondary

Best Post-Baseline Change in the Short Form of the Motivation and Energy Scale (MEI-SF) From Any Time Point Compared With Baseline

The MEI-SF (18 questions) was used to measure the reductions in mental energy, physical energy, and social motivation, either as symptoms of chronic ITP or as a side effect of pharmacotherapy. Minimal clinically important differences are estimated as 0.5 standard deviations or 7.5 points. All items use either a 7-level (0 to 6) or 5-level (0 to 4) response scale; items with a 5-level response scale were rescaled to 7-levels, and items were reverse-scored as necessary such that higher scores represent higher HRQoL Total score ranges from 0 to 108 points. Recall period is past week prior to administration. The change in scores was measured at the transitioning period and immediately prior to withdrawal/completion over 2 years, and the mean of these measurements was recorded to calculate the change from baseline and the best post baseline change score was reported for the entire group

Time frame: Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years

Arm	Measure	Value (MEAN)
Eltrombopag	Best Post-Baseline Change in the Short Form of the Motivation and Energy Scale (MEI-SF) From Any Time Point Compared With Baseline	11.3 Points on a scale

Secondary

Maximum ITP Bleeding Score at Any Time During the Study During All Stages.

The ITP bleeding score is a tool which has been designed specifically to assess the bruising and bleeding in patients with ITP across body sites, ranging from mild to severe. The WHO Grades were dichotomized into the following categories: - Grade 0, No bleeding -Grade 1 to 4, Any bleeding -Grade 0 to 1: No clinically significant bleeding -Grade 2 to 4 Clinically significant bleeding