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This Phase 1, open-label, single-sequence, non-randomized, multiple-dose, crossover pharmacokinetic study is a single site study in the United States and will be conducted to assess the effect of a CYP1A2 inducer (omeprazole 40 mg once daily [QD]) on the pharmacokinetics of anagrelide (1 mg) when administered concurrently in healthy participants.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| SPD422 + Omeprazole | Experimental | Participants will receive 1 milligram (mg) of SPD422 (Anagrelide hydrochloride) (2*0.5 mg) capsule orally on Day 1 in fasted state (10 hours prior to and until 4 hours following administration of anagrelide), followed by 40 mg of Omeprazole capsule orally once daily (prior to breakfast) on Days 2 to Day 7, followed by 1 mg of Anagrelide in fasted state in combination with Omeprazole 40 mg on Day 8. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| SPD422 | Drug | Participants will receive 1 mg of SPD422 (2*0.5 mg) capsule orally on Day 1 and 8 in fasted state. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Anagrelide (SPD422) | Cmax of Anagrelide (SPD422) on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
| Maximum Observed Plasma Concentration (Cmax) of 3-Hydroxy (OH)-Anagrelide (Active Metabolite of Anagrelide) | Cmax of 3-OH-Anagrelide (Active Metabolite of Anagrelide) on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
| Area Under the Concentration Versus Time Curve From Zero to Last Time Point (AUC[0-t]) of Anagrelide (SPD422) in Plasma | AUC(0-t) of Anagrelide (SPD422) in plasma on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
| Area Under the Concentration Versus Time Curve From Zero to Last Time Point (AUC[0-t]) of 3-Hydroxy (OH)-Anagrelide (Active Metabolite of Anagrelide) in Plasma | AUC(0-t) of 3-OH-Anagrelide (Active Metabolite of Anagrelide) in Plasma on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily had a causal relationship with this treatment. An AE was considered a TEAE if it started on or after dosing on Day 1 or if it started before dosing on Day 1 but increased in severity on or after dosing on Day 1 through the end of the study. Number of participants with TEAEs and TESAEs were reported. |
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Inclusion Criteria:
Exclusion Criteria:
Current or recurrent disease or conditions (example: cardiovascular, renal, liver, gastrointestinal, malignancy or other conditions) that could affect the absorption, action, or disposition of either omeprazole or anagrelide or its metabolites, or could affect clinical assessments or clinical laboratory evaluations.
Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment or make the participant unlikely to fully comply with the requirements of the study or complete the study, or any condition that presents undue risk from the investigational product or study procedures.
Significant illness, as judged by the investigator, within the 2 weeks of administration of the first dose of investigational product.
Use of any medication (including prescription, over-the-counter, herbal, multivitamin, oral contraceptives and other hormonal contraceptive treatments, or homeopathic preparations) within the 30 days prior to the first dose of study drug or during the study through Day 9 (occasional use of acetaminophen is allowed).
Treatment with any known hepatic and/or P450 enzyme-altering agents, including CYP1A2 inducers or inhibitors within 30 days prior to the first dose of investigational product. This includes: Strong inhibitor- ciprofloxacin, enoxacin, fluvoxamine, and zafirlukast; Moderate inhibitor- methoxsalen, mexiletine, and oral contraceptives; Moderate inducer- phenytoin, rifampin, ritonavir, smoking, teriflunomide; Inducer- lansoprazole
A history of any of the following medical conditions:
A participant's alcohol consumption that fulfils one of the following: (Note: One alcohol unit=1 beer [12 ounce {oz}]=1 wine [5 oz]=1 liquor [1.5 oz])
Positive screening test results for alcohol, drugs of abuse, or pregnancy (females of childbearing potential only) at the Screening Visit or Day -1.
A positive human immunodeficiency virus (HIV) antibody screen, hepatitis B surface antigen (HBsAG) or hepatitis C virus antibody (HCV) screen.
Use of tobacco in any form (smoking or chewing) or other nicotine-containing products in any form (gum, patch) within 30 days prior to the first dose of investigational product and during the in-house stay at the CRC.
A positive urine cotinine test that is >= 50 Nano grams per milliliter (ng/mL) at either the Screening Visit or on Day -1.
Routine consumption of more than 2 units of caffeine per day or participants who experience caffeine-withdrawal headaches or have a history of caffeine-withdrawal headaches. (One caffeine unit is contained in the following items: one 6-oz cup of coffee, two 12-oz cans of cola, one 12-oz cup of tea, and three 1-oz chocolate bars. Decaffeinated coffee, tea, or cola are not considered to contain caffeine.)
Consumption of grapefruit, Seville oranges, and/or products containing these items within 7 days prior to the first dose of investigational product.
Donation of blood or blood products (egg, plasma, or platelets) within 60 days prior to the first dose of investigational product.
Known or suspected intolerance or hypersensitivity to the investigational products (anagrelide or omeprazole) or closely related compounds, or any of the stated ingredients.
Within 30 days prior to the first dose of investigational product:
Prior screen failure, participation, or enrollment in this study.
History of sensitivity to heparin or heparin-induced thrombocytopenia.
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Takeda | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| New Orleans Center for Clinical Research | Knoxville | Tennessee | 37920 | United States |
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
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IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
A total of 20 participants were enrolled and completed the study.
This study was conducted at single site in United States of America from 26 February 2019 to 10 April 2019.
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| ID | Title | Description |
|---|---|---|
| FG000 | SPD422 + Omeprazole | Participants received 1 milligram (mg) of SPD422 (Anagrelide hydrochloride) (2*0.5 mg) capsule orally on Day 1 under fasted state (10 hours prior to and until 4 hours following administration of anagrelide), followed by 40 mg of Omeprazole capsule orally once daily (prior to breakfast) on Day 2 to Day 7, followed by 1 mg of Anagrelide under fasted state in combination with Omeprazole 40 mg on Day 8. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety set included all participants who had taken at least 1 dose of investigational product (anagrelide or omeprazole) and had at least 1 post dose safety assessment.
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| ID | Title | Description |
|---|---|---|
| BG000 | SPD422 + Omeprazole | Participants received 1 milligram (mg) of SPD422 (Anagrelide hydrochloride) (2*0.5 mg) capsule orally on Day 1 under fasted state (10 hours prior to and until 4 hours following administration of anagrelide), followed by 40 mg of Omeprazole capsule orally once daily (prior to breakfast) on Day 2 to Day 7, followed by 1 mg of Anagrelide under fasted state in combination with Omeprazole 40 mg on Day 8. |
| 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 | Maximum Observed Plasma Concentration (Cmax) of Anagrelide (SPD422) | Cmax of Anagrelide (SPD422) on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | Pharmacokinetic (PK) set included all participants who received at least 1 dose of investigational product (anagrelide or omeprazole) and had at least 1 measurable post dose plasma concentration. | Posted | Mean | Standard Deviation | nanogram per milliliter (ng/mL) | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
|
From start of study drug administration up to follow-up (up to Day 18)
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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 | SPD422 + Omeprazole | Participants received 1 milligram (mg) of SPD422 (Anagrelide hydrochloride) (2*0.5 mg) capsule orally on Day 1 under fasted state (10 hours prior to and until 4 hours following administration of anagrelide), followed by 40 mg of Omeprazole capsule orally once daily (prior to breakfast) on Day 2 to Day 7, followed by 1 mg of Anagrelide under fasted state in combination with Omeprazole 40 mg on Day 8. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 21.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Shire | +1 866 842 5335 | ClinicalTransparency@shire.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 4, 2018 | Apr 9, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 8, 2019 | Apr 9, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C021139 | anagrelide |
| D009853 | Omeprazole |
| ID | Term |
|---|---|
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
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Single sequence crossover drug-drug interaction study
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| Omeprazole | Drug | Participants will receive 40 mg of Omeprazole orally once daily on Days 2 - 8. |
|
| Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
| Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-infinity]) of Anagrelide (SPD422) in Plasma | AUC(0-infinity) of Anagrelide (SPD422) in plasma on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
| Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-infinity]) of 3-Hydroxy (OH)-Anagrelide (Active Metabolite of Anagrelide) in Plasma | AUC(0-infinity) of 3-OH-Anagrelide (Active Metabolite of Anagrelide) in Plasma on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
| From start of study drug administration up to follow-up (up to Day 18) |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | SPD422 + Omeprazole (Day 8) | Participants received 40 mg of Omeprazole capsule orally once daily (prior to breakfast) on Day 2 to Day 7, followed by received 1 mg of Anagrelide under fasted state in combination with Omeprazole 40 mg on Day 8. |
|
|
|
| Primary | Maximum Observed Plasma Concentration (Cmax) of 3-Hydroxy (OH)-Anagrelide (Active Metabolite of Anagrelide) | Cmax of 3-OH-Anagrelide (Active Metabolite of Anagrelide) on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | PK set included all participants who received at least 1 dose of investigational product (anagrelide or omeprazole) and had at least 1 measurable post dose plasma concentration. | Posted | Mean | Standard Deviation | ng/mL | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
|
|
|
|
| Primary | Area Under the Concentration Versus Time Curve From Zero to Last Time Point (AUC[0-t]) of Anagrelide (SPD422) in Plasma | AUC(0-t) of Anagrelide (SPD422) in plasma on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | PK set included all participants who received at least 1 dose of investigational product (anagrelide or omeprazole) and had at least 1 measurable post dose plasma concentration. | Posted | Mean | Standard Deviation | hour*nanogram per milliliter (h*ng/mL) | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
|
|
|
|
| Primary | Area Under the Concentration Versus Time Curve From Zero to Last Time Point (AUC[0-t]) of 3-Hydroxy (OH)-Anagrelide (Active Metabolite of Anagrelide) in Plasma | AUC(0-t) of 3-OH-Anagrelide (Active Metabolite of Anagrelide) in Plasma on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | PK set included all participants who received at least 1 dose of investigational product (anagrelide or omeprazole) and had at least 1 measurable post dose plasma concentration. | Posted | Mean | Standard Deviation | h*ng/mL | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
|
|
|
|
| Primary | Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-infinity]) of Anagrelide (SPD422) in Plasma | AUC(0-infinity) of Anagrelide (SPD422) in plasma on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | PK set included all participants who received at least 1 dose of investigational product (anagrelide or omeprazole) and had at least 1 measurable post dose plasma concentration. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure. | Posted | Mean | Standard Deviation | h*ng/mL | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
|
|
|
|
| Primary | Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC[0-infinity]) of 3-Hydroxy (OH)-Anagrelide (Active Metabolite of Anagrelide) in Plasma | AUC(0-infinity) of 3-OH-Anagrelide (Active Metabolite of Anagrelide) in Plasma on Day 1 and Day 8 was reported. For PK outcome measures the reporting groups were split based on administration of Anagrelide alone (Day 1) and Anagrelide in combination with Omeprazole (Day 8) to provide statistical comparison in this single arm study. | PK set included all participants who received at least 1 dose of investigational product (anagrelide or omeprazole) and had at least 1 measurable post dose plasma concentration. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure. | Posted | Mean | Standard Deviation | h*ng/mL | Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 hours on Day 1 and Day 8, 24 hours on Day 8 |
|
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|
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| Secondary | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily had a causal relationship with this treatment. An AE was considered a TEAE if it started on or after dosing on Day 1 or if it started before dosing on Day 1 but increased in severity on or after dosing on Day 1 through the end of the study. Number of participants with TEAEs and TESAEs were reported. | Safety set included all participants who had taken at least 1 dose of investigational product (anagrelide or omeprazole) and had at least 1 post dose safety assessment. | Posted | Count of Participants | Participants | From start of study drug administration up to follow-up (up to Day 18) |
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 9 |
| 20 |
| Vomiting | Gastrointestinal disorders | MedDRA 21.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 21.1 | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 21.1 | 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.
| D011725 |
| Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001562 | Benzimidazoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| Equivalence |
90% CIs of geometric mean ratios being within 80% to 125%. |
| Equivalence |
90% CIs of geometric mean ratios being within 80% to 125%. |
| Equivalence |
90% CIs of geometric mean ratios being within 80% to 125%. |
| Equivalence |
90% CIs of geometric mean ratios being within 80% to 125%. |
| Equivalence |
90% CIs of geometric mean ratios being within 80% to 125%. |