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This study compared the pharmacokinetics (PK) and assessed the safety of delayed-release metformin (Met DR, EFB0027) at two dosage levels, immediate-release metformin (Met IR, ETB0015), and extended-release metformin (Met XR, ETB0014) in healthy subjects.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 500 mg Met DR BID | Experimental | Two doses of 500 mg metformin delayed-release |
|
| 1000 mg Met DR BID | Experimental | Two doses of 1000 mg metformin delayed-release |
|
| 1000 mg Met IR BID | Active Comparator | Two doses of 1000 mg metformin immediate-release |
|
| 2000 mg Met XR QD | Active Comparator | Single dose of 2000 mg metformin extended-release |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Met DR | Drug | metformin delayed-release tablets |
| |
| Measure | Description | Time Frame |
|---|---|---|
| AUC (0-t) of Plasma Metformin | AUC (0-t) = Area under the curve from the time of dosing (0 h) to the time of the last quantifiable concentration after the standardized dinner. Doses were administered 1 min prior to 0 h (standardized dinner) for once daily in the evening (qPM) and twice daily (BID) dosing and 1 min prior to 12 h (standardized breakfast) for once daily in the morning (qAM) and BID dosing. | Time points to create AUC (0-t) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. |
| Cmax of Plasma Metformin | Cmax = Maximum concentration from the first dose of study medication administration (0 h) to the time of the last quantifiable concentration following dose administration. Doses were administered 1 min prior to 0 h (standardized dinner) for qPM and BID dosing and 1 min prior to 12 h (standardized breakfast) for qAM and BID dosing. | Time points to create Cmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. |
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Inclusion Criteria:
19 to 65 (inclusive) years old at Visit 1 (Screening)
Male, or if female and met all of the following criteria:
Body mass index (BMI) of 25.0 to 35.0 kg/m² (inclusive) at Visit 1 (Screening)
Had a physical examination with no clinically significant abnormalities as judged by the investigator
Had normal renal function with an estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m² based on the Modification of Diet in Renal Disease (MDRD) equation
Ability to understand and willingness to adhere to protocol requirements
Exclusion Criteria:
Had a clinically significant medical condition as judged by the investigator that could potentially affect study participation and/or personal well-being, including but not limited to the following conditions:
Had any chronic disease requiring medication that was adjusted in the past 90 days (subjects could take acute intermittent over-the-counter medications such as Tylenol, if needed)
Had major surgery of any kind within 6 months of Visit 1 (Screening)
Had a history of >6 kg weight change within 3 months of Visit 1 (Screening)
Had clinical laboratory test (clinical chemistry, hematology, or urinalysis) abnormalities judged by the investigator to be clinically significant at Visit 1 (Screening)
Had a physical, psychological, or historical finding that, in the investigator's opinion, would make the subject unsuitable for the study
Had any drug treatment that affects gastric pH (prescription or over-the-counter), including any antacids or medications such as Rolaids or Pepcid within 2 days of Visit 1 (Screening)
Currently abused drugs or alcohol or had a history of abuse that in the investigator's opinion would cause the individual to be noncompliant with study procedures
Smoked more than 10 cigarettes per day, 3 cigars per day, 3 pipes per day, used more than 1 can of smokeless tobacco per week, or used a combination of tobacco products that approximate nicotine doses equivalent to 10 cigarettes per day
Had donated blood within 3 months of the date of the first dose of randomized study medication, or was planning to donate blood during the study
Had received any investigational drug within 2 months (or five half-lives of the investigational drug, whichever was greater) of the date of the first dose of randomized study medication
Had known allergies or hypersensitivity to any component of study treatment
Was employed by Elcelyx Therapeutics, Inc (that is an employee, temporary contract worker, or designee of the company)
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| Name | Affiliation | Role |
|---|---|---|
| Scott Rasmussen, MD | Celerion | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | DeFronzo RA, Buse JB, Kim T, Skare S, Baron A, Fineman M, editors. Dissociation between Metformin Plasma Exposure and its Glucose-Lowering Effect: A Novel Gut-Mediated Mechanism of Action. 73rd Annual Scientific Meeting of The American Diabetes Association; 2013 June 21-25th; Chicago, Il. | ||
| 26285584 | Background | Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M. The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation: Results From Short-term Pharmacokinetic and 12-Week Dose-Ranging Studies. Diabetes Care. 2016 Feb;39(2):198-205. doi: 10.2337/dc15-0488. Epub 2015 Aug 18. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Sequence 1: ABDC | Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD |
| FG001 | Sequence 2: BCAD | Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD |
| FG002 | Sequence 3: CDBA | Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD |
| FG003 | Sequence 4: DACB | Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Randomized (ITT) Population
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| ID | Title | Description |
|---|---|---|
| BG000 | Sequence 1: ABDC | Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD |
| BG001 | Sequence 2: BCAD | Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD |
| 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 | AUC (0-t) of Plasma Metformin | AUC (0-t) = Area under the curve from the time of dosing (0 h) to the time of the last quantifiable concentration after the standardized dinner. Doses were administered 1 min prior to 0 h (standardized dinner) for once daily in the evening (qPM) and twice daily (BID) dosing and 1 min prior to 12 h (standardized breakfast) for once daily in the morning (qAM) and BID dosing. | Evaluable Population | Posted | Mean | Standard Error | ng*h/mL | Time points to create AUC (0-t) were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. |
|
Approximately 18 to 57 days depending on the number of days between the start of Visit 1 and Visit 2 and the number of washout days between the treatment visits
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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 | 500 mg Met DR BID | Two doses of 500 mg Metformin Delayed-Release Met DR: metformin delayed-release tablets |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Director, Development | Elcelyx Therapeutics, Inc | 858-876-1814 | info@elcelyx.com |
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| Met XR |
| Drug |
metformin extended-release tablets |
|
| Met IR | Drug | metformin immediate-release tablets |
|
| BG002 | Sequence 3: CDBA | Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD |
| BG003 | Sequence 4: DACB | Treatment A = 1000 mg Met IR BID Treatment B = 500 mg Met DR BID Treatment C = 1000 mg Met DR BID Treatment D = 2000 mg Met XR QD |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m^2 |
|
| OG001 |
| 1000 mg Met DR BID |
Two doses of 1000 mg Metformin Delayed-Release Met DR: metformin delayed-release tablets |
| OG002 | 1000 mg Met IR BID | Two doses of 1000 mg Metformin Immediate-Release Met IR: metformin immediate-release tablets |
| OG003 | 2000 mg Met XR QD | Single dose of 2000 mg Metformin Extended-Release Met XR: metformin extended-release tablets |
|
|
|
| Primary | Cmax of Plasma Metformin | Cmax = Maximum concentration from the first dose of study medication administration (0 h) to the time of the last quantifiable concentration following dose administration. Doses were administered 1 min prior to 0 h (standardized dinner) for qPM and BID dosing and 1 min prior to 12 h (standardized breakfast) for qAM and BID dosing. | Evaluable Population | Posted | Mean | Standard Error | ng/mL | Time points to create Cmax were: t = -0.08, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 11.92, 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24 hours relative to the start time of the standardized dinner. |
|
|
|
|
| 0 |
| 19 |
| 6 |
| 19 |
| EG001 | 1000 mg Met DR BID | Two doses of 1000 mg Metformin Delayed-Release Met DR: metformin delayed-release tablets | 0 | 19 | 3 | 19 |
| EG002 | 1000 mg Met IR BID | Two doses of 1000 mg Metformin Immediate-Release Met IR: metformin immediate-release tablets | 0 | 20 | 5 | 20 |
| EG003 | 2000 mg Met XR QD | Single dose of 2000 mg Metformin Extended-Release Met XR: metformin extended-release tablets | 0 | 20 | 10 | 20 |
| Nausea | Gastrointestinal disorders |
|
| Vomiting | Gastrointestinal disorders |
|
| Headache | Nervous system disorders |
|
| Dyspepsia | Gastrointestinal disorders |
|
| Catheter Site Pain | General disorders |
|
| Catheter Site Related Reaction | General disorders |
|
| Fatigue | General disorders |
|
| Vessel Puncture Site Haematoma | General disorders |
|
| Vessel Puncture Site Pain | General disorders |
|
| Anxiety | Psychiatric disorders |
|
| Insomnia | Psychiatric disorders |
|
| Cough | Respiratory, thoracic and mediastinal disorders |
|
| Dry Throat | Respiratory, thoracic and mediastinal disorders |
|
| Nasal Congestion | Respiratory, thoracic and mediastinal disorders |
|
| Oropharyngeal Pain | Respiratory, thoracic and mediastinal disorders |
|
The results of the Study may be published by INSTITUTE, however the publication shall not disclose any SPONSOR Confidential Information, the INSTITUTE shall send the SPONSOR a copy of any such proposed publication 90 days prior to submission for publication, the INSTITUTE, on request of the SPONSOR, shall delete any SPONSOR Confidential Information in the proposed publication, and the INSTITUTE shall, on the SPONSOR's request, delay submission while the SPONSOR files applications for patents.
2000 mg Met XR QD is the denominator for the % ratio of LS means and the comparator for the p-values. |
| ANOVA |
Included treatment, sequence, and period and as fixed effects and subject nested within sequence as a random effect. |
| <0.001 |
| % Ratio of LS Means |
| 53.0 |
| 2-Sided |
| 90 |
| 47.88 |
| 58.71 |
| No |
| Superiority or Other |
| 1000 mg Met IR BID is the denominator for the % ratio of LS means and the comparator for the p-values. | ANOVA | Included treatment, sequence, and period and as fixed effects and subject nested within sequence as a random effect. | <0.001 | % Ratio of LS Means | 45.3 | 2-Sided | 90 | 40.88 | 50.13 | No | Superiority or Other |
| 1000 mg Met IR BID is the denominator for the % ratio of LS means and the comparator for the p-values. | ANOVA | Included treatment, sequence, and period and as fixed effects and subject nested within sequence as a random effect. | <0.001 | % Ratio of LS Means | 66.8 | 2-Sided | 90 | 60.34 | 74.00 | No | Superiority or Other |
| 2000 mg Met XR QD is the denominator for the % ratio of LS means and the comparator for the p-values. | ANOVA | Included treatment, sequence, and period and as fixed effects and subject nested within sequence as a random effect. | 0.0004 | % Ratio of LS Means | 79.3 | 2-Sided | 90 | 71.65 | 87.86 | No | Superiority or Other |