An Open-label Safety Study of Lusutrombopag (S-888711) in Adults With Chronic Immune Thrombocytopenia (ITP)

• Sponsor: Shionogi (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01129024
• Collaborator: (none)
• Enrollment: 19
• Locations: 19
• Arm: 1
• Actual Duration (Months): 14
• Patient Per Site: 1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this study was to assess the long-term safety of lusutrombopag in the treatment of adults with relapsed persistent or chronic ITP with or without prior splenectomy.

Condition or Disease	Intervention/Treatment	Phase
Immune Thrombocytopenia	Drug: Lusutrombopag	Phase 2

Detailed Description

This was an open-label, long-term safety study of lusutrombopag in the treatment of adults with relapsed persistent or chronic ITP with or without prior splenectomy. Patients who participate in this study must have completed the Phase 2 study 0913M0621 (NCT01054443), a double-blind, placebo controlled, parallel group study that evaluated the efficacy and safety lusutrombopag during which they either completed treatment or discontinued treatment due to a platelet count > 400,000/μL.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Safety Study of S-888711 in Adult Subjects With Relapsed Persistent or Chronic Immune Thrombocytopenia With or Without Prior Splenectomy
• Actual Study Start Date: Apr 29, 2010
• Actual Primary Completion Date: Jun 30, 2011
• Actual Study Completion Date: Jun 30, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lusutrombopag Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts. If a subject's platelet count remained < 50,000/μL, the dose could have been increased by 0.25 mg up to a maximum dose of 2.0 mg.	Drug: Lusutrombopag; tablet; Other Names: MULPLETA® S-888711

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [From first dose of study drug in the extension study up to 6 weeks after last dose; median (range) time on study treatment was 148 (10-387) days.]

   An AE is defined as any untoward medical occurrence in a subject administered a pharmaceutical product during the course of a clinical investigation, including any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product (IP), whether or not thought to be related to the IP. AEs reported after initial study drug administration were considered treatment-emergent. A serious adverse event is defined as any AE that resulted in death, was life-threatening, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect or an important medical event that, based upon medical judgment, may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above. A treatment-related AE is any AE determined by the investigator to be possibly related, probably related, or definitely related to study drug.

Secondary Outcome Measures

1. Duration of Response [From first dose of study drug in the extension study up to 6 weeks after last dose; median (range) time on treatment was 148 (10 - 387) days.]

   Duration of response was defined as the percentage of the cumulative time a platelet count was ≥ 50,000 cells/µL during the extension study.

2. Number of Participants With Worst Severity of Bleeding Associated With ITP During the Treatment Period [Bleeding assessments were performed at Weeks 1, 2, 3, 4, 5, and 6, Months 1, 2, 3, 6, 9, and 12, and every 3 months thereafter until end of treatment; median (range) time on treatment was 148 (10-387) days.]

   Bleeding assessments were performed by the Investigator according to the World Health Organization (WHO) criteria bleeding scale: Grade 0: no bleeding; Grade 1: petechial bleeding; Grade 2: mild blood loss (clinically significant); Grade 3: gross blood loss, requires transfusion (severe); Grade 4: debilitating blood loss, retinal or cerebral associated with fatality. For each participant, the most severe WHO bleeding grade observed during the treatment period is reported.

3. Percentage of Participants Who Achieved a Platelet Count of < 50,000 Cells/μL, Between 50,000 to 400,000 Cells/μL, and ≥ 400,000 Cells/μL [Platelets were assessed at Weeks 1, 2, 3, 4, 5, and 6, Months 1, 2, 3, 6, 9, and 12, and every 3 months thereafter, until end of treatment; median (range) time on treatment was 148 (10-387) days.]

   This analysis includes platelet counts measured during the treatment period, including while participants were taking rescue medications.

4. Percentage of Participants Who Achieved a Platelet Count of < 50,000 Cells/μL, Between 50,000 to 400,000 Cells/μL, and ≥ 400,000 Cells/μL Without Rescue Medication [Platelets were assessed at Weeks 1, 2, 3, 4, 5, and 6, Months 1, 2, 3, 6, 9, and 12, and every 3 months thereafter, until end of treatment; median (range) time on treatment was 148 (10-387) days.]

   This analysis excludes platelet counts measured while the participant was taking rescue medications and during the 4 weeks after rescue medication.

5. Change From Baseline in Platelet Counts at the Final Visit [Baseline and the final visit (If a subject had multiple platelet count measurements for the specific dose level due to dose adjustments, the final platelet count was used)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects who previously participated in Study 0913M0621 (NCT01054443) and who completed treatment or discontinued treatment due to a platelet count > 400,000/μL and continued to meet all inclusion criteria of the previous study, listed below, including platelet counts < 50,000/μL were eligible for study participation. For the purpose of this study, initial screening visit and all prestudy time period refer to Study 0913M0621.

• A signed and dated written informed consent

• Males and females ≥ 18 years of age

• All subjects must agree to use barrier contraception

• Diagnosis of ITP

• Subjects > 60 years must have had a diagnostic bone marrow aspiration

• Relapsed persistent or chronic ITP status, with or without prior splenectomy

• Subjects receiving steroid therapy must be on a stable dose for at least 2 weeks prior to Screening

• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) within 20% of the upper limit of normal (ULN) at Screening

• Subjects receiving stable dosages of cyclosporine A, mycophenolate mofetil, azathioprine, or danazol are allowed

Exclusion Criteria:

• History of clinically important hemorrhagic clotting disorder

• Females who are pregnant, lactating, or taking oral contraceptives

• History of alcohol/drug abuse or dependence within 1 year

• Use of the following drugs or treatment prior to Visit 1 (Day 1):

• Within 1 week - Rho(D) immune globulin or intravenous immunoglobulin;

• Within 2 weeks - plasmaphoresis treatment;

• Within 4 weeks - use of anti-platelet or anti-coagulant drugs;

• Within 8 weeks - rituximab;

• Within 12 weeks - alemtuzumab, multi-drug systemic chemotherapy, stem cell therapy;

• History of clinically significant cardiovascular or thromboembolic disease within 26 weeks prior to Initial Screening

• Splenectomy within 4 weeks prior to Initial Screening

• Clinically significant laboratory abnormalities

• Hemoglobin < 10.0 g/dL for men or women, not clearly related to ITP

• Absolute neutrophil count < 1000/mm3

• Abnormal peripheral blood smear with evidence of fibrosis confirmed by bonemarrow biopsy

• Total bilirubin > 1.5 x upper limit of normal

• Alanine aminotransferase (ALT) > 1.5 x upper limit of normal

• Aspartate aminotransferase (AST) > 1.5 x upper limit of normal

• Creatinine > 1.5 x upper limit of normal

• Human immunodeficiency virus positive

• Hepatitis A IgM antibody positive, hepatitis B surface antigen or hepatitis C antibody positive

• Exposure to previous thrombopoietin (TPO) mimetics/agonists (e.g., eltrombopag,romiplostim, E5501 [AKR-501] or LGD-4665) within 4 weeks prior to Initial Screening

• Subjects unresponsive to previous TPO mimetics/agonists (e.g., eltrombopag, romiplostim, E5501 [AKR-501] or LGD-4665)

• Exposure to an investigative medication within 4 weeks prior to the initial Screening Visit

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigator	Anaheim	California	United States	92801
2	Investigator	Los Angeles	California	United States	90272
3	Investigator	Washington	District of Columbia	United States	20007
4	Investigator	Boynton Beach	Florida	United States	33426
5	Investigator	Jacksonville	Florida	United States	32207
6	Investigator	Atlanta	Georgia	United States	30341
7	Investigator	Riverdale	Georgia	United States	30274
8	Investigator	Metairie	Louisiana	United States	70006
9	Investigator	Bethesda	Maryland	United States	20817
10	Investigator	Boston	Massachusetts	United States	02114
11	Investigator	Jefferson City	Missouri	United States	65109
12	Investigator	Kansas City	Missouri	United States	64131
13	Investigator	New Brunswick	New Jersey	United States	08903
14	Investigator	New York	New York	United States	10021
15	Investigator	New York	New York	United States	10029
16	Investigator	Cleveland	Ohio	United States	44106
17	Investigator	San Antonio	Texas	United States	78229
18	Investigator	Salt Lake City	Utah	United States	84132
19	Investigator	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Shionogi

Investigators

• Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line, Shionogi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shionogi
• ClinicalTrials.gov Identifier: NCT01129024
• Other Study ID Numbers: 0914M0622
• First Posted: May 24, 2010
• Last Update Posted: Feb 26, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Shionogi: Splenectomy; Low Platelet Count; Thrombopoiesis; Thrombocytopaenia; Idiopathic Thrombocytopenic Purpura; Immune Thrombocytopenia (ITP); Thrombotic Thrombocytopenic Purpura (ITP); Hematologic Disease; Auto-immune Thrombocytopenic Purpura; S-888711; Blood Platelet Disorders; Relapsed Persistent or Chronic ITP; ITP
• Additional relevant MeSH terms: Thrombocytopenia; Purpura, Thrombocytopenic, Idiopathic

Study Results

Participant Flow

Recruitment Details	Eligible participants who previously participated in Study 0913M0621 (NCT01054443) and who completed treatment or discontinued treatment due to a platelet count > 400,000 cells/μL were rolled over into this open-label extension study.

Arm/Group Title	Lusutrombopag
Arm/Group Description	Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts.
Period Title: Overall Study
STARTED	19
COMPLETED	0
NOT COMPLETED	19

Baseline Characteristics

Arm/Group Title	Lusutrombopag
Arm/Group Description	Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts.
Overall Participants	19
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.7 (20.98)
Sex: Female, Male (Count of Participants)
Female	11 57.9%
Male	8 42.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 10.5%
Not Hispanic or Latino	17 89.5%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	18 94.7%
Black or African American	1 5.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	An AE is defined as any untoward medical occurrence in a subject administered a pharmaceutical product during the course of a clinical investigation, including any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product (IP), whether or not thought to be related to the IP. AEs reported after initial study drug administration were considered treatment-emergent. A serious adverse event is defined as any AE that resulted in death, was life-threatening, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect or an important medical event that, based upon medical judgment, may jeopardize the participant or require medical or surgical intervention to prevent one of the outcomes listed above. A treatment-related AE is any AE determined by the investigator to be possibly related, probably related, or definitely related to study drug.
Time Frame	From first dose of study drug in the extension study up to 6 weeks after last dose; median (range) time on study treatment was 148 (10-387) days.

Outcome Measure Data

Analysis Population Description

All enrolled and treated participants

Arm/Group Title	Lusutrombopag
Arm/Group Description	Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts.
Measure Participants	19
Any treatment-emergent adverse event (TEAE)	19 100%
Serious TEAEs	1 5.3%
Treatment-related TEAEs	3 15.8%
Treatment-related serious TEAEs	0 0%
TEAEs leading to study discontinuation	2 10.5%

2. Secondary Outcome

Title	Duration of Response
Description	Duration of response was defined as the percentage of the cumulative time a platelet count was ≥ 50,000 cells/µL during the extension study.
Time Frame	From first dose of study drug in the extension study up to 6 weeks after last dose; median (range) time on treatment was 148 (10 - 387) days.

Outcome Measure Data

Analysis Population Description

All enrolled and treated participants

Arm/Group Title	Lusutrombopag
Arm/Group Description	Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts.
Measure Participants	19
Median (Full Range) [percentage of days]	0.200

3. Secondary Outcome

Title	Number of Participants With Worst Severity of Bleeding Associated With ITP During the Treatment Period
Description	Bleeding assessments were performed by the Investigator according to the World Health Organization (WHO) criteria bleeding scale: Grade 0: no bleeding; Grade 1: petechial bleeding; Grade 2: mild blood loss (clinically significant); Grade 3: gross blood loss, requires transfusion (severe); Grade 4: debilitating blood loss, retinal or cerebral associated with fatality. For each participant, the most severe WHO bleeding grade observed during the treatment period is reported.
Time Frame	Bleeding assessments were performed at Weeks 1, 2, 3, 4, 5, and 6, Months 1, 2, 3, 6, 9, and 12, and every 3 months thereafter until end of treatment; median (range) time on treatment was 148 (10-387) days.

Outcome Measure Data

Analysis Population Description

All enrolled and treated participants

Arm/Group Title	Lusutrombopag
Arm/Group Description	Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts.
Measure Participants	19
Grade 0	3 15.8%
Grade 1	11 57.9%
Grade 2	5 26.3%
Grade 3	0 0%
Grade 4	0 0%

4. Secondary Outcome

Title	Percentage of Participants Who Achieved a Platelet Count of < 50,000 Cells/μL, Between 50,000 to 400,000 Cells/μL, and ≥ 400,000 Cells/μL
Description	This analysis includes platelet counts measured during the treatment period, including while participants were taking rescue medications.
Time Frame	Platelets were assessed at Weeks 1, 2, 3, 4, 5, and 6, Months 1, 2, 3, 6, 9, and 12, and every 3 months thereafter, until end of treatment; median (range) time on treatment was 148 (10-387) days.

Outcome Measure Data

Analysis Population Description

All enrolled and treated participants

Arm/Group Title	Lusutrombopag
Arm/Group Description	Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts.
Measure Participants	19
Platelet count < 50,000 cells/μL	31.6 166.3%
Platelet count ≥ 50,000 and < 400 cells/μL	68.4 360%
Platelet count ≥ 400,000 cells/μL	0.0 0%

5. Secondary Outcome

Title	Percentage of Participants Who Achieved a Platelet Count of < 50,000 Cells/μL, Between 50,000 to 400,000 Cells/μL, and ≥ 400,000 Cells/μL Without Rescue Medication
Description	This analysis excludes platelet counts measured while the participant was taking rescue medications and during the 4 weeks after rescue medication.
Time Frame	Platelets were assessed at Weeks 1, 2, 3, 4, 5, and 6, Months 1, 2, 3, 6, 9, and 12, and every 3 months thereafter, until end of treatment; median (range) time on treatment was 148 (10-387) days.

Outcome Measure Data

Analysis Population Description

All enrolled and treated participants

Arm/Group Title	Lusutrombopag
Arm/Group Description	Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts.
Measure Participants	19
Platelet count < 50,000 cells/μL	42.1 221.6%
Platelet count ≥ 50,000 and < 400,000 cells/μL	57.9 304.7%
Platelet count ≥ 400,000 cells/μL	0.0 0%

6. Secondary Outcome

Title	Change From Baseline in Platelet Counts at the Final Visit
Time Frame	Baseline and the final visit (If a subject had multiple platelet count measurements for the specific dose level due to dose adjustments, the final platelet count was used)

Outcome Measure Data

Analysis Population Description

All enrolled and treated participants

Arm/Group Title	Lusutrombopag
Arm/Group Description	Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts.
Measure Participants	19
Baseline	23000.00
Final visit	23000.00
Change from Baseline	3000.00

Adverse Events

Time Frame	From first dose of study drug in the extension study up to 6 weeks after last dose; median (range) time on study treatment was 148 (10-387) days.
Arm/Group Title	Lusutrombopag
Arm/Group Description	Participants received lusutrombopag 0.5 mg administered orally once a day for up to 3 years or until study termination. The dose was adjusted based on platelet counts.
All Cause Mortality
	Lusutrombopag
	Affected / at Risk (%)	# Events
Total	0/19 (0%)
Serious Adverse Events
	Lusutrombopag
	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)
Blood and lymphatic system disorders
Thrombocytopenia	1/19 (5.3%)
Injury, poisoning and procedural complications
Overdose	1/19 (5.3%)
Psychiatric disorders
Suicidal ideation	1/19 (5.3%)
Other (Not Including Serious) Adverse Events
	Lusutrombopag
	Affected / at Risk (%)	# Events
Total	19/19 (100%)
Blood and lymphatic system disorders
Idiopathic thrombocytopenic purpura	1/19 (5.3%)
Anaemia	1/19 (5.3%)
Bone marrow failure	1/19 (5.3%)
Bone marrow reticulin fibrosis	1/19 (5.3%)
Iron deficiency anaemia	1/19 (5.3%)
Leukocytosis	1/19 (5.3%)
Cardiac disorders
Atrial fibrillation	1/19 (5.3%)
Ear and labyrinth disorders
Ear pain	1/19 (5.3%)
Ear discomfort	1/19 (5.3%)
Eye disorders
Myodesopsia	1/19 (5.3%)
Eye pruritus	1/19 (5.3%)
Vision blurred	1/19 (5.3%)
Visual impairment	1/19 (5.3%)
Gastrointestinal disorders
Nausea	3/19 (15.8%)
Vomiting	3/19 (15.8%)
Mouth haemorrhage	2/19 (10.5%)
Abdominal distension	1/19 (5.3%)
Aphthous stomatitis	1/19 (5.3%)
Dental caries	1/19 (5.3%)
Diarrhoea	1/19 (5.3%)
Flatulence	1/19 (5.3%)
Gingival bleeding	1/19 (5.3%)
Gingival pain	1/19 (5.3%)
Salivary gland disorder	1/19 (5.3%)
General disorders
Fatigue	6/19 (31.6%)
Oedema peripheral	2/19 (10.5%)
Cyst	1/19 (5.3%)
Pain	1/19 (5.3%)
Infections and infestations
Nasopharyngitis	8/19 (42.1%)
Upper respiratory tract infection	3/19 (15.8%)
Urinary tract infection	2/19 (10.5%)
Fungal infection	1/19 (5.3%)
Pharyngitis	1/19 (5.3%)
Burn infection	1/19 (5.3%)
Ear infection	1/19 (5.3%)
Folliculitis	1/19 (5.3%)
Influenza	1/19 (5.3%)
Sinusitis	1/19 (5.3%)
Staphylococcal infection	1/19 (5.3%)
Tonsillitis	1/19 (5.3%)
Injury, poisoning and procedural complications
Contusion	3/19 (15.8%)
Facial bones fracture	1/19 (5.3%)
Mouth injury	1/19 (5.3%)
Muscle strain	1/19 (5.3%)
Road traffic accident	1/19 (5.3%)
Thermal burn	1/19 (5.3%)
Investigations
Blood potassium decreased	2/19 (10.5%)
C-reactive protein increased	2/19 (10.5%)
Platelet count decreased	1/19 (5.3%)
Transaminases increased	1/19 (5.3%)
Metabolism and nutrition disorders
Decreased appetite	1/19 (5.3%)
Hyperglycaemia	1/19 (5.3%)
Vitamin D deficiency	1/19 (5.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/19 (26.3%)
Pain in extremity	2/19 (10.5%)
Back pain	2/19 (10.5%)
Myositis	2/19 (10.5%)
Joint swelling	1/19 (5.3%)
Muscle spasms	1/19 (5.3%)
Musculoskeletal pain	1/19 (5.3%)
Osteopenia	1/19 (5.3%)
Nervous system disorders
Balance disorder	1/19 (5.3%)
Carotid artery disease	1/19 (5.3%)
Migraine	1/19 (5.3%)
Somnolence	1/19 (5.3%)
Psychiatric disorders
Insomnia	2/19 (10.5%)
Affective disorder	1/19 (5.3%)
Alcoholism	1/19 (5.3%)
Bipolar disorder	1/19 (5.3%)
Depression	1/19 (5.3%)
Middle insomnia	1/19 (5.3%)
Mood disorder due to a general medical condition	1/19 (5.3%)
Personality disorder	1/19 (5.3%)
Polysubstance dependence	1/19 (5.3%)
Tachyphrenia	1/19 (5.3%)
Renal and urinary disorders
Dysuria	1/19 (5.3%)
Pollakiuria	1/19 (5.3%)
Reproductive system and breast disorders
Amenorrhoea	1/19 (5.3%)
Breast fibrosis	1/19 (5.3%)
Breast pain	1/19 (5.3%)
Breast tenderness	1/19 (5.3%)
Vulvovaginal pruritus	1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	5/19 (26.3%)
Oropharyngeal pain	3/19 (15.8%)
Haemoptysis	1/19 (5.3%)
Nasal congestion	2/19 (10.5%)
Dysphonia	1/19 (5.3%)
Epistaxis	1/19 (5.3%)
Oropharyngeal blistering	1/19 (5.3%)
Postnasal drip	1/19 (5.3%)
Rhinorrhoea	1/19 (5.3%)
Skin and subcutaneous tissue disorders
Ecchymosis	3/19 (15.8%)
Blood blister	1/19 (5.3%)
Dermatitis contact	1/19 (5.3%)
Dry skin	1/19 (5.3%)
Erythema	1/19 (5.3%)
Pruritus	1/19 (5.3%)
Rash erythematous	1/19 (5.3%)
Urticaria	1/19 (5.3%)
Vascular disorders
Haematoma	1/19 (5.3%)
Hot flush	1/19 (5.3%)
Phlebitis superficial	1/19 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.