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| ID | Type | Description | Link |
|---|---|---|---|
| 2004-004061-15 | EudraCT Number |
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Essential thrombocythaemia is a disorder of bone marrow, which causes too many platelets to be produced. Platelets are small cells carried around in the blood, which help form blood clots. When patients have too many platelets, there is a risk of blood clots forming unnecessarily and excessive bleeding. The aim of this study is to gain additional information on the safety profile of Anagrelide (Xagrid(r)) and Hydroxyurea (also known as hydroxycarbamide).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| A | Experimental |
| |
| B | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Anagrelide | Drug | Anagrelide hydrochloride 0.5mg capsules;initial dose administered will be 1.0mg/day administered as 0.5mg bid. The dose will be titrated such that the total daily dose is incremented by no more than 0.5mg per week as required depending on platelet reduction versus adverse event profile. |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | The LVEF was measured by echocardiography and considered a sufficiently sensitive measure to evaluate any changes in cardiac function. | Baseline and Month 1, 2, 3, 6, 9, 12, 18, 24, 30 and 36 |
| Platelet Count at Month 6 | Platelet count was evaluated. | Month 6 |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Platelet Counts at Month 3 and 36 | Platelet count was evaluated throughout the study. | Baseline and Month 3 and 36 |
| Percentage of Participants With Complete Response | A complete response was defined as a platelet count of less than (<) 400x10^9/Liter which was confirmed over 2 consecutive visits at least 28 days apart. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Takeda | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Multiprofile Hospital for Active Treatment ''Dr Georgi Stranski'' - Pleven | Pleven | 5800 | Bulgaria | |||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30368038 | Result | Birgegard G, Folkvaljon F, Garmo H, Holmberg L, Besses C, Griesshammer M, Gugliotta L, Wu J, Achenbach H, Kiladjian JJ, Harrison CN. Leukemic transformation and second cancers in 3649 patients with high-risk essential thrombocythemia in the EXELS study. Leuk Res. 2018 Nov;74:105-109. doi: 10.1016/j.leukres.2018.10.006. Epub 2018 Oct 11. | |
| 33123978 |
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A total of 183 participants were screened, 149 participants were randomized at 29 sites across 10 countries. Four (4) participants randomized but withdrawn prior to treatment and 1 participant not randomized but treated.
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| ID | Title | Description |
|---|---|---|
| FG000 | Anagrelide | Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years. |
| FG001 | Hydroxyurea | Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The safety population was defined as all participants who received at least 1 dose of study medication.
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| ID | Title | Description |
|---|---|---|
| BG000 | Anagrelide | Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | The LVEF was measured by echocardiography and considered a sufficiently sensitive measure to evaluate any changes in cardiac function. | The Full Analysis Set (FAS) population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, n = Number of participants analysed for specified category at the specified time points in each arm respectively. | Posted | Mean | Standard Deviation | percentage of ejection fraction | Baseline and Month 1, 2, 3, 6, 9, 12, 18, 24, 30 and 36 |
|
From the signing of informed consent until the last study-related visit (Month 36)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Anagrelide | Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | 17.0 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | 17.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Shire | +1 866 842 5335 | ClinicalTransparency@shire.com |
| ID | Term |
|---|---|
| D013920 | Thrombocythemia, Essential |
| ID | Term |
|---|---|
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D013922 | Thrombocytosis |
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| ID | Term |
|---|---|
| C021139 | anagrelide |
| D006918 | Hydroxyurea |
| ID | Term |
|---|---|
| D014508 | Urea |
| D000577 | Amides |
| D009930 | Organic Chemicals |
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|
| Hydroxyurea | Drug | Hydroxyurea is 500mg hydroxycarbamide capsules; initial dose is 1000mg/day, administered in two divided doses (500mg/dose). Dose titrated to effect to achieve a response. |
|
| Baseline up to Month 36 |
| Percentage of Participants With Partial Response | A partial response is defined as a platelet count of 400-600 x 10^9/Liter and a reduction in platelet count of at least 200 x 10^9/Liter from baseline which was confirmed over 2 consecutive visits at least 28 days apart. | Baseline up to Month 36 |
| Time to Complete Response | Time in days from the date of the first dose of study medication to the date of the first visit at which response was classified. If a participant did not achieve response then they were censored at their last visit in the study (Month 36 or withdrawal). | Baseline up to Month 36 |
| Time to Partial Response | Time in days from the date of the first dose of study medication to the date of the first visit at which response was classified. If a participant did not achieve response then they were censored at their last visit in the study (Month 36 or withdrawal). | Baseline up to Month 36 |
| Number of Participants With Thrombotic and Haemorrhagic Events | Thrombohaemorrhagic events are a well-known complication of the underlying essential thrombocythemia (ET) and disease progression. Events such as arterial and venous thrombosis, serious haemorrhage (including gastrointestinal haemorrhage), and death from vascular causes have been reported in participants who received cytoreductive treatment. | From the signing of informed consent until the last study-related visit (Month 36) |
| Change From Baseline in White Blood Cell Count Over Time | White blood cell count was evaluated throughout the study. | Baseline and Month 6, 12, 18, 24, 30 and 36 |
| Change From Baseline in Red Blood Cell Count Over Time | Red blood cell count was evaluated throughout the study. | Baseline and Month 6, 12, 18, 24, 30 and 36 |
| University Multiprofile Hospital for active Treatment ''Alexandrovska'' Clinic of Haematology |
| Sofia |
| 1303 |
| Bulgaria |
| University Multiprofile Hospital for Active Treament ''Sv. Marina'' - Varna Haematology Clinic | Varna | 9010 | Bulgaria |
| CHU Angers Services des Maladies du Sang | Angers | Cedex 09 | 49933 | France |
| Hopital Saint Louis - Centre d'Investigation Clinique | Paris | France |
| University of Debrecen Medical and Health Science Centre | Debrecen | 4012 | Hungary |
| Petz Aladar County Teaching Hospital | Győr | 9024 | Hungary |
| Pandy Kalman Hospital of Bekes County | Gyula | 5700 | Hungary |
| Kaposi Mor Teaching Hospital | Kaposvár | 7400 | Hungary |
| Uniwersyteckie Centrum Kliniczne Katedra i Klinika Hematologii i Transplantologii | Gdansk | 80-952 | Poland |
| Samodzielny Publiczny Szpital Kliniczny Nr 1 | Lublin | 21-081 | Poland |
| Katedra i Klinika Onkologii i Chorob Wewnetrznych Akademii Medycznej | Warsaw | 02-097 | Poland |
| Klinika Hematologii Instytut Hematologii i Transfuzjologi | Warsaw | 02-776 | Poland |
| Hospitals da Universidade de Coimbra | Coimbra | 3000-076 | Portugal |
| Institute for Haematology of Clinical Centre of Serbia | Belgrade | 11000 | Serbia |
| Gotic M, Egyed M, Gercheva L, Warzocha K, Kvasnicka HM, Achenbach H, Wu J. Cardiovascular Safety of Anagrelide Hydrochloride versus Hydroxyurea in Essential Thrombocythaemia. Cardiovasc Toxicol. 2021 Mar;21(3):236-247. doi: 10.1007/s12012-020-09615-0. Epub 2020 Oct 29. |
| Lack of Efficacy |
|
| Lost to Follow-up |
|
| Other |
|
| BG001 | Hydroxyurea | Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | Hydroxyurea | Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years. |
|
|
| Primary | Platelet Count at Month 6 | Platelet count was evaluated. | The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, N = Number of participants analysed in each arm for this outcome measure. | Posted | Mean | Standard Deviation | 10^9 platelets per liter | Month 6 |
|
|
|
|
| Secondary | Change From Baseline in Platelet Counts at Month 3 and 36 | Platelet count was evaluated throughout the study. | The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded with last observation carried forward (LOCF). Here, n=number of participants analysed for specified category at specified time points in each arm respectively. | Posted | Mean | Standard Deviation | 10^9 platelets per liter | Baseline and Month 3 and 36 |
|
|
|
|
| Secondary | Percentage of Participants With Complete Response | A complete response was defined as a platelet count of less than (<) 400x10^9/Liter which was confirmed over 2 consecutive visits at least 28 days apart. | The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. | Posted | Number | percenatge of participants | Baseline up to Month 36 |
|
|
|
| Secondary | Percentage of Participants With Partial Response | A partial response is defined as a platelet count of 400-600 x 10^9/Liter and a reduction in platelet count of at least 200 x 10^9/Liter from baseline which was confirmed over 2 consecutive visits at least 28 days apart. | The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. | Posted | Number | percentage of participants | Baseline up to Month 36 |
|
|
|
| Secondary | Time to Complete Response | Time in days from the date of the first dose of study medication to the date of the first visit at which response was classified. If a participant did not achieve response then they were censored at their last visit in the study (Month 36 or withdrawal). | The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. | Posted | Median | 95% Confidence Interval | days | Baseline up to Month 36 |
|
|
|
| Secondary | Time to Partial Response | Time in days from the date of the first dose of study medication to the date of the first visit at which response was classified. If a participant did not achieve response then they were censored at their last visit in the study (Month 36 or withdrawal). | The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. | Posted | Median | 95% Confidence Interval | days | Baseline up to Month 36 |
|
|
|
| Secondary | Number of Participants With Thrombotic and Haemorrhagic Events | Thrombohaemorrhagic events are a well-known complication of the underlying essential thrombocythemia (ET) and disease progression. Events such as arterial and venous thrombosis, serious haemorrhage (including gastrointestinal haemorrhage), and death from vascular causes have been reported in participants who received cytoreductive treatment. | The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. | Posted | Number | participants | From the signing of informed consent until the last study-related visit (Month 36) |
|
|
|
| Secondary | Change From Baseline in White Blood Cell Count Over Time | White blood cell count was evaluated throughout the study. | The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, n = Number of participants analysed for specified category at the specified time points in each arm respectively. | Posted | Mean | Standard Deviation | 10^9 cells per liter | Baseline and Month 6, 12, 18, 24, 30 and 36 |
|
|
|
| Secondary | Change From Baseline in Red Blood Cell Count Over Time | Red blood cell count was evaluated throughout the study. | The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, n = Number of participants analysed for specified category at the specified time points in each arm respectively. | Posted | Mean | Standard Deviation | 10^12 cells per liter | Baseline and Month 6, 12, 18, 24, 30 and 36 |
|
|
|
| 17 |
| 76 |
| 46 |
| 76 |
| EG001 | Hydroxyurea | Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years. | 13 | 70 | 27 | 70 |
| Iron deficiency anaemia | Blood and lymphatic system disorders | 17.0 | Non-systematic Assessment |
|
| Pancytopenia | Blood and lymphatic system disorders | 17.0 | Non-systematic Assessment |
|
| Angina unstable | Cardiac disorders | 17.0 | Non-systematic Assessment |
|
| Left ventricular failure | Cardiac disorders | 17.0 | Non-systematic Assessment |
|
| Tachycardia | Cardiac disorders | 17.0 | Non-systematic Assessment |
|
| Anal fistula | Gastrointestinal disorders | 17.0 | Non-systematic Assessment |
|
| Crohn's disease | Gastrointestinal disorders | 17.0 | Non-systematic Assessment |
|
| Gastrointestinal haemorrhage | Gastrointestinal disorders | 17.0 | Non-systematic Assessment |
|
| Inguinal hernia | Gastrointestinal disorders | 17.0 | Non-systematic Assessment |
|
| Upper gastrointestinal haemorrhage | Gastrointestinal disorders | 17.0 | Non-systematic Assessment |
|
| Asthenia | General disorders | 17.0 | Non-systematic Assessment |
|
| Sudden death | General disorders | 17.0 | Non-systematic Assessment |
|
| Ear infection | Infections and infestations | 17.0 | Non-systematic Assessment |
|
| Laryngitis | Infections and infestations | 17.0 | Non-systematic Assessment |
|
| Sepsis | Infections and infestations | 17.0 | Non-systematic Assessment |
|
| Foot fracture | Injury, poisoning and procedural complications | 17.0 | Non-systematic Assessment |
|
| Traumatic amputation | Injury, poisoning and procedural complications | 17.0 | Non-systematic Assessment |
|
| Traumatic haematoma | Injury, poisoning and procedural complications | 17.0 | Non-systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | 17.0 | Non-systematic Assessment |
|
| Type 2 diabetes mellitus | Metabolism and nutrition disorders | 17.0 | Non-systematic Assessment |
|
| Scleroderma | Musculoskeletal and connective tissue disorders | 17.0 | Non-systematic Assessment |
|
| Tendon calcification | Musculoskeletal and connective tissue disorders | 17.0 | Non-systematic Assessment |
|
| Adenoid cystic carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 17.0 | Non-systematic Assessment |
|
| Bladder cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 17.0 | Non-systematic Assessment |
|
| Breast cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 17.0 | Non-systematic Assessment |
|
| Malignant melanoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 17.0 | Non-systematic Assessment |
|
| Peripheral nerve sheath tumour malignant | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 17.0 | Non-systematic Assessment |
|
| Aphasia | Nervous system disorders | 17.0 | Non-systematic Assessment |
|
| Cerebral infarction | Nervous system disorders | 17.0 | Non-systematic Assessment |
|
| Ischaemic stroke | Nervous system disorders | 17.0 | Non-systematic Assessment |
|
| Neurological decompensation | Nervous system disorders | 17.0 | Non-systematic Assessment |
|
| Vasculitis cerebral | Nervous system disorders | 17.0 | Non-systematic Assessment |
|
| Ovarian cyst | Reproductive system and breast disorders | 17.0 | Non-systematic Assessment |
|
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | 17.0 | Non-systematic Assessment |
|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | 17.0 | Non-systematic Assessment |
|
| Deep vein thrombosis | Vascular disorders | 17.0 | Non-systematic Assessment |
|
| Hypertensive crisis | Vascular disorders | 17.0 | Non-systematic Assessment |
|
| Peripheral artery thrombosis | Vascular disorders | 17.0 | Non-systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | 17.0 | Non-systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | 17.0 | Non-systematic Assessment |
|
| Palpitations | Cardiac disorders | 17.0 | Non-systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | 17.0 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | 17.0 | Non-systematic Assessment |
|
| Asthenia | General disorders | 17.0 | Non-systematic Assessment |
|
| Chest pain | General disorders | 17.0 | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | 17.0 | Non-systematic Assessment |
|
| Pharyngitis | Infections and infestations | 17.0 | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | 17.0 | Non-systematic Assessment |
|
| Urinary tract infection | Infections and infestations | 17.0 | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | 17.0 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | 17.0 | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | 17.0 | Non-systematic Assessment |
|
| Hypertension | Vascular disorders | 17.0 | Non-systematic Assessment |
|
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.
| D001791 | Blood Platelet Disorders |
| D009196 | Myeloproliferative Disorders |
| D001855 | Bone Marrow Diseases |
| D006474 | Hemorrhagic Disorders |
Month 36 |
| Least Square Mean |
| -68.3 |
| Standard Error of the Mean |
| 43.83 |
| 2-Sided |
| 95 |
| -154.95 |
| 18.43 |
| Non-Inferiority or Equivalence (legacy) |
Noninferiority of anagrelide could be concluded if lower limit of 95% Confidence Interval for the difference between treatment groups (Hydroxyurea - Anagrelide) was > -100 x 10^9/Liter. |
| Change from baseline at Month 6 |
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| Change from baseline at Month 12 |
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| Change from baseline at Month 18 |
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| Change from baseline at Month 24 |
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| Change from baseline at Month 30 |
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| Change from baseline at Month 36 |
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| Change from baseline at Month 6 |
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| Change from baseline at Month 12 |
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| Change from baseline at Month 18 |
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| Change from baseline at Month 24 |
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| Change from baseline at Month 30 |
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| Change from baseline at Month 36 |
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