Efficacy of Eltrombopag to Improve Thrombocytopenia of MYH9-related Disease

• Sponsor: IRCCS Policlinico S. Matteo (Other)
• Overall Status: Completed
• CT.gov ID: NCT01133860
• Collaborator: University of Pavia (Other), GlaxoSmithKline (Industry), Azienda Ospedaliera di Padova (Other), Azienda Ospedaliera di Perugia (Other), Fondazione Telethon (Other)
• Enrollment: 12
• Locations: 3
• Arm: 1
• Duration (Months): 17
• Patients Per Site: 4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The term MYH9-related disease (MYH9RD) includes four genetic disorders: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome. All these disorders derive from mutation of a unique gene, named MYH9, and they have been recognized as different clinical presentations of a single illness that was named MYH9RD. All patients affected by MYH9RD present since birth with thrombocytopenia, which can result in a variable degree of bleeding diathesis; some of them subsequently develop additional clinical manifestations, such as renal damage, sensorineural hearing loss, and/or presenile cataracts. Eltrombopag is an oral thrombopoietin receptor agonist that stimulates proliferation and differentiation of megakaryocytes, the bone marrow cells that produce blood platelets. This drug is effective in increasing platelet count in healthy volunteers, as well as in patients affected by some acquired thrombocytopenias, such as idiopathic thrombocytopenic purpura and HCV related thrombocytopenia. The purpose of this study is to determine if eltrombopag, administered orally at the dose of 50 or 75 mg/daily for up to 6 weeks, is effective in increasing platelet count of patients affected by MYH9RD. Further aims of this study are to test if eltrombopag is effective in reducing bleeding tendency of MYH9RD patients; to evaluate safety and tolerability of eltrombopag in patients with MYH9RD; to evaluate in vitro function of platelets produced during therapy in patients responding to this drug.

Condition or Disease	Intervention/Treatment	Phase
Blood Platelet Disorders	Drug: eltrombopag	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Exploratory Phase II Dose Escalation Study of Eltrombopag in MYH9 Related Disease
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: eltrombopag

Drug: eltrombopag; Eltrombopag, administered orally, 50 mg/daily for 21 days. Patients with platelet counts between 100 and 150x10e9/L at day 21 will continue eltrombopag 50 mg/daily for 21 additional days. Patients with platelet count lower than 100x10e9/L at day 21 will receive eltrombopag 75 mg/daily for additional 21 days. Patients with more than 150x10e9 platelets/L at day 21 will stop therapy.; Other Names: Revolade Promacta

Outcome Measures

Primary Outcome Measures

1. Response to Drug Based on Platelet Count at the End of Therapy [21 days and/or 42 days of therapy, 15 and 30 days after the end of therapy]

   The primary endpoints were the achievement of a platelet count over 100 x10e9/L or at least 3 times the baseline value (major response), or at least twice the baseline value but less than major response (minor response). The overall response to therapy is reported. Platelet count was measured at the end of therapy (21 or 42 days, see study design) by phase-contrast microscopy.

Secondary Outcome Measures

1. Bleeding Tendency Assessed by WHO Bleeding Score [21 days and/or 42 days of therapy, 15 and 30 days after the end of therapy]

   The percentage of patients with bleeding diathesis (grade 1, i.e. cutaneous bleeding, or grade 2, i.e. mild blood loss, according to WHO bleeding score) was calculated at baseline and at the end of therapy. The results are expressed as the mean change in the percentage of patients with bleeding diathesis (95%CI).

2. All Types of Adverse Events [21 days and/or 42 days of therapy, 15 and 30 days after the end of therapy]

   All type of adverse events were registered.Results indicate the number of participants who experience a side effect of the drug.

3. in Vitro Function of Platelets Produced During Therapy in Responding Patients [21 days or 42 days of therapy]

   in vitro platelet function will be assessed in patients achieving a platelet count of 100 x10e9/L or more at the end of the therapy

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 16 years or more

• Confirmed diagnosis of MYH9-related disease

• Average platelet count for the previous year less than 50x10e9/L

• Written informed consent

Exclusion Criteria:

• Diseases known to involve the risk of thromboembolic events (e.g. atrial fibrillation)

• History of thrombosis within 1 year

• Use of drugs that affect platelet function (including but not limited to, aspirin, clopidogrel or NSAIDS) or anti-coagulants

• Females who are pregnant or nursing (a negative pregnancy test in required before enrollment of fertile women)

• Formal refusal of any recommendation of a safe contraception

• Alcohol or drug addiction

• Altered renal function as defined by creatinine of 20 mg/L or more

• Any other disease or condition that by the advise of the responsible physician would make the treatment dangerous for the patient or would make the patient ineligible for the study, including physical, psychiatric, social and behavioral problems. HCV positivity and liver diseases will not be considered an exclusion criterion since a phase II study showed that eltrombopag was effective and safe in this patient population.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Azienda Ospedaliero-Universitaria di Padova, Unità di Medicina Generale e Patologia Speciale	Padova		Italy	35128
2	Fondazione IRCCS Policlinico San Matteo, Unità di Medicina III	Pavia		Italy	27100
3	Policlinico Monteluce, Sezione di Medicina Interna e Cardiovascolare	Perugia		Italy	06122

Sponsors and Collaborators

• IRCCS Policlinico S. Matteo
• University of Pavia
• GlaxoSmithKline
• Azienda Ospedaliera di Padova
• Azienda Ospedaliera di Perugia
• Fondazione Telethon

Investigators

• Principal Investigator: Carlo Balduini, MD, IRCCS Policlinico San Matteo Foundation, Pavia, Italy

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47.
• McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, Berg T, Gordon SC, Campbell FM, Theodore D, Blackman N, Jenkins J, Afdhal NH; TPL102357 Study Group. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007 Nov 29;357(22):2227-36.
• Seri M, Cusano R, Gangarossa S, Caridi G, Bordo D, Lo Nigro C, Ghiggeri GM, Ravazzolo R, Savino M, Del Vecchio M, d'Apolito M, Iolascon A, Zelante LL, Savoia A, Balduini CL, Noris P, Magrini U, Belletti S, Heath KE, Babcock M, Glucksman MJ, Aliprandis E, Bizzaro N, Desnick RJ, Martignetti JA. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium. Nat Genet. 2000 Sep;26(1):103-5.
• Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, Nigro A, Noris P, Gangarossa S, Rocca B, Gresele P, Bizzaro N, Malatesta P, Koivisto PA, Longo I, Musso R, Pecoraro C, Iolascon A, Magrini U, Rodriguez Soriano J, Renieri A, Ghiggeri GM, Ravazzolo R, Balduini CL, Savoia A. MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore). 2003 May;82(3):203-15.
• Seri M, Savino M, Bordo D, Cusano R, Rocca B, Meloni I, Di Bari F, Koivisto PA, Bolognesi M, Ghiggeri GM, Landolfi R, Balduini CL, Zelante L, Ravazzolo R, Renieri A, Savoia A. Epstein syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene. Hum Genet. 2002 Feb;110(2):182-6. Epub 2001 Dec 14.

• ClinicalTrials.gov Identifier: NCT01133860
• Other Study ID Numbers: Eltrombopag-MYH9-2008
• First Posted: May 31, 2010
• Last Update Posted: Jul 26, 2011
• Last Verified: Jul 1, 2010

• Keywords provided by , ,: inherited thrombocytopenia; MYH9 mutations; eltrombopag
• Additional relevant MeSH terms: Thrombocytopenia; Blood Platelet Disorders

Study Results

Participant Flow

Recruitment Details	Patients enrolled between January 2009 and January 2010 as outpatients in medical clinic

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag, administered orally, 50 mg/daily for 21 days. Patients with platelet counts between 100 and 150x10e9/L at day 21 continued eltrombopag 50 mg/daily for 21 additional days. Patients with platelet count lower than 100x10e9/L at day 21 received eltrombopag 75 mg/daily for additional 21 days. Patients with more than 150x10e9 platelets/L at day 21 stopped therapy.
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag, administered orally, 50 mg/daily for 21 days. Patients with platelet counts between 100 and 150x10e9/L at day 21 continued eltrombopag 50 mg/daily for 21 additional days. Patients with platelet count lower than 100x10e9/L at day 21 received eltrombopag 75 mg/daily for additional 21 days. Patients with more than 150x10e9 platelets/L at day 21 stopped therapy.
Overall Participants	12
Age (Count of Participants)
<=18 years	1 8.3%
Between 18 and 65 years	11 91.7%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.0 (14.3)
Sex: Female, Male (Count of Participants)
Female	7 58.3%
Male	5 41.7%
Region of Enrollment (participants) [Number]
Italy	12 100%

Outcome Measures

1. Primary Outcome

Title	Response to Drug Based on Platelet Count at the End of Therapy
Description	The primary endpoints were the achievement of a platelet count over 100 x10e9/L or at least 3 times the baseline value (major response), or at least twice the baseline value but less than major response (minor response). The overall response to therapy is reported. Platelet count was measured at the end of therapy (21 or 42 days, see study design) by phase-contrast microscopy.
Time Frame	21 days and/or 42 days of therapy, 15 and 30 days after the end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag, administered orally, 50 mg/daily for 21 days. Patients with platelet counts between 100 and 150x10e9/L at day 21 continued eltrombopag 50 mg/daily for 21 additional days. Patients with platelet count lower than 100x10e9/L at day 21 received eltrombopag 75 mg/daily for additional 21 days. Patients with more than 150x10e9 platelets/L at day 21 stopped therapy.
Measure Participants	12
Number (95% Confidence Interval) [percentage of participants]	91.6 763.3%

2. Secondary Outcome

Title	Bleeding Tendency Assessed by WHO Bleeding Score
Description	The percentage of patients with bleeding diathesis (grade 1, i.e. cutaneous bleeding, or grade 2, i.e. mild blood loss, according to WHO bleeding score) was calculated at baseline and at the end of therapy. The results are expressed as the mean change in the percentage of patients with bleeding diathesis (95%CI).
Time Frame	21 days and/or 42 days of therapy, 15 and 30 days after the end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag, administered orally, 50 mg/daily for 21 days. Patients with platelet counts between 100 and 150x10e9/L at day 21 continued eltrombopag 50 mg/daily for 21 additional days. Patients with platelet count lower than 100x10e9/L at day 21 received eltrombopag 75 mg/daily for additional 21 days. Patients with more than 150x10e9 platelets/L at day 21 stopped therapy.
Measure Participants	12
Mean (95% Confidence Interval) [participants]	66.7 555.8%

3. Secondary Outcome

Title	All Types of Adverse Events
Description	All type of adverse events were registered.Results indicate the number of participants who experience a side effect of the drug.
Time Frame	21 days and/or 42 days of therapy, 15 and 30 days after the end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag, administered orally, 50 mg/daily for 21 days. Patients with platelet counts between 100 and 150x10e9/L at day 21 continued eltrombopag 50 mg/daily for 21 additional days. Patients with platelet count lower than 100x10e9/L at day 21 received eltrombopag 75 mg/daily for additional 21 days. Patients with more than 150x10e9 platelets/L at day 21 stopped therapy.
Measure Participants	12
Number [number of participants]	2 16.7%

4. Secondary Outcome

Title	in Vitro Function of Platelets Produced During Therapy in Responding Patients
Description	in vitro platelet function will be assessed in patients achieving a platelet count of 100 x10e9/L or more at the end of the therapy
Time Frame	21 days or 42 days of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eltrombopag
Arm/Group Description	In patients with more than 100 x10e9 platelets/L at the end of therapy, we evaluated also the in vitro platelet aggregation after stimulation with adenosine diphosphate (5 and 20 mcM), collagen (5 and 20 mg/mL) and ristocetin (3 mg/mL) by the densitometric method of Born in native platelet rich plasma. The extent of platelet aggregation was measured 5 minutes after the addition of stimulating agents and results obtained in patients were compared with the normal ranges in the laboratories where the assay was performed. Results are reported as the number of patients with normal platelet aggregation.
Measure Participants	7
Number [participants]	5 41.7%

Adverse Events

Time Frame	51 or 72 days, i.e. during the administration of Eltrombopag (21 or 42 days, see study design) and until 30 days after the end of treatment (see study design).
Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag, administered orally, 50 mg/daily for 21 days. Patients with platelet counts between 100 and 150x10e9/L at day 21 continued eltrombopag 50 mg/daily for 21 additional days. Patients with platelet count lower than 100x10e9/L at day 21 received eltrombopag 75 mg/daily for additional 21 days. Patients with more than 150x10e9 platelets/L at day 21 stopped therapy.
All Cause Mortality
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)
General disorders
headache	2/12 (16.7%)	2
dry mouth	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.