Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes Mellitus, Type 2, Metformin XR, Metformin IR
Brief summary
This is a Phase 4, prospective, open label, randomized, parallel controlled multicenter trial in which metformin extended release (XR) will be compared with metformin immediate release (IR) for the gastrointestinal tolerability and efficacy in the newly diagnosed subjects with Type 2 diabetes who have glycosylated hemoglobin (HbA1c) value between 7.0 to 10.0 percent (%).
Interventions
DRUGMetformin IR
Subjects will receive Metformin Immediate Release (IR) tablets, orally once daily at a dose of 500 milligram (mg) for 1 week, and then dose will increase with increments of 500 mg every week in first 2 weeks to 1500 mg. After that dose will increase up to maximum dose of 2000 mg for the next 2 weeks and will be maintained at 2000 mg until Week 16.
DRUGMetformin XR
Subjects will receive Metformin Extended Release (XR) tablets, orally once daily at a dose of 500 mg for 1 week, and then dose will increase with increments of 500 mg every week in first 2 weeks to 1500 mg. After that dose will increase up to maximum dose of 2000 mg for the next 2 weeks and will be maintained at 2000 mg until Week 16.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Type 2 diabetes mellitus before the screening visit based on the World Health Organization (WHO) diagnostic and classification criteria * HbA1c value of 7.0-10.0%, inclusive * Age ranging from 18 to 79 years, inclusive * Treatment-naive for oral antidiabetic agents (that is, had not received antidiabetic medication previously, or had received antidiabetic medication for at least 14 days and not within 1 month of enrolment) * Male, or non-pregnant, non-breastfeeding females * Body mass index (BMI) greater than or equal to (\>=) 18.5 and less than (\<) 35 kilogram per square meter (kg/m\^2) * In the opinion of the investigator, subjects are well-motivated, capable and willing to continue the study treatment as required during the whole study period, maintain a study dietary, as required for this protocol, attend scheduled visits and be willing to receive phone calls between visits, avoid pregnancy by using an adequate method of contraception throughout the duration of the study for the female subjects of child bearing potential (and if appropriate male subjects with female partners of childbearing potential) * Written informed consent given before any trial-related activities are carried out
Exclusion criteria
* Type 1 diabetes * Previous treatment with insulin or other antidiabetics (including Chinese traditional medicine) for more than 14 days continuously or within 1 month of enrolment * Any of the protocol-specified cardiovascular conditions within 3 months prior to the screening visit * Impaired liver function as defined in the protocol * Serum creatinine values as specified in the protocol * Known proliferative retinopathy or maculopathy requiring acute treatment, or recurrent major hypoglycemia or hypoglycemic unawareness as judged by the investigator * Persistent uncontrolled hypertension * Severe chronic gastrointestinal disease * Previous history of 1 or more episodes of ketoacidosis or hyperosmolar state/coma * Currently receiving chronic (\>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, inhaled or intranasal preparations) or have received such therapy within 4 weeks of the screening visit * Current use of beta-blockers, thiazide diuretic, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, nifedipine and isoniazid and cannot be replaced by any other treatment * Have any hematologic condition that may interfere with HbA1c measurement (for example, hemolytic anemia, sickle-cell disease) * Have any other condition (such as, known drug or alcohol abuse or a psychiatric disorder) that may prevent the subject from following and completing the protocol * Known hypersensitivity to Metformin Hydrochloride * Currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Any contraindications to Metformin according to local package insert
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 16 | Baseline, Week 16 | — |
| Overall Gastrointestinal (GI) Tolerability Assessed as Percentage of Subjects With Gastrointestinal Adverse Events During Treatment Period | Baseline up to Week 16 | An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) Level at Weeks 8 and 16 | Baseline, Week 8 and 16 | The 2-hour Postprandial plasma glucose (PPG) level refers to the plasma glucose concentrations after 2 hours of eating. |
| Percentage of Subjects With Hypoglycemia | Baseline up to Week 16 | Hypoglycemia, also called as low blood glucose or low blood sugar, is defined as the blood glucose level of less than normal (that is less than 3.9 millimole per liter \[mmol/L\]). |
| Percentage of Subjects With Marked Hyperglycemia | Baseline up to Week 16 | Marked hyperglycemia was defined as the FPG level of greater than or equal to 11.1 mmol/L. |
| Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Baseline up to Week 16 | An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. Number of subjects with pre-specified gastrointestinal adverse events (diarrhea, nausea, abdominal pain, bloating, constipation, dyspepsia and flatulence) were reported. |
| Percentage of Subjects Who Are Totally Intolerant to the Treatment | Baseline up to Week 16 | Subjects were considered to be totally intolerant if they experienced a Grade 3 or higher toxicity considered at least possibly related to the treatment. |
| Percentage of Subjects With HbA1c Less Than (<) 7% and With no Severe Gastrointestinal (GI) and Other Adverse Events (AEs) | Baseline up to Week 16 | Percentage of subjects with HbA1c \<7% and with no severe GI and other AEs were reported. Severe adverse events were based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 and were defined as those events which were medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living (ADL). Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. |
| Percentage of Subjects Who Are Compliant to Treatment | Baseline up to Week 16 | Compliance was defined as not skipping or forgetting dosing or not delaying the dosing time. Subjects who never missed a dose of medication were considered compliant. |
| Percentage of Subjects With HbA1c Less Than (<) 7% | Baseline up to Week 16 | — |
| Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Baseline, Week 1, 2, 4, 8, 12,16 | — |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin IR Subjects received Metformin IR tablets, orally QD at a dose of 500 milligram (mg) for 1 week, and then the dose was increased with increments of 500 mg every week in the first 2 weeks to 1500 mg. After that, the dose was increased up to a maximum dose of 2000 mg for the next two weeks and maintained at 2000 mg until Week 16. | 267 |
| Metformin XR Subjects received Metformin XR tablets, orally QD at a dose of 500 mg for 1 week, and then the dose was increased with increments of 500 mg every week in the first 2 weeks to 1500 mg. After that, the dose was increased up to a maximum dose of 2000 mg for next 2 weeks and maintained at 2000 mg until Week 16. | 265 |
| Total | 532 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 14 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 16 | 8 |
| Overall Study | Other | 4 | 5 |
| Overall Study | Protocol Violation | 4 | 5 |
| Overall Study | Withdrawal by Subject | 7 | 9 |
Baseline characteristics
| Characteristic | Metformin IR | Metformin XR | Total |
|---|---|---|---|
| Age, Continuous | 54.4 years STANDARD_DEVIATION 10.21 | 53.1 years STANDARD_DEVIATION 9.72 | 53.8 years STANDARD_DEVIATION 9.98 |
| Gender Female | 112 Participants | 108 Participants | 220 Participants |
| Gender Male | 155 Participants | 157 Participants | 312 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 96 / 249 | 136 / 264 | 12 / 12 |
| serious Total, serious adverse events | 6 / 249 | 2 / 264 | 0 / 12 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 16
Time frame: Baseline, Week 16
Population: Per-protocol (PP) population included all subjects who were randomly allocated to a treatment based on intent to treat and were compliant with protocol (absence of any major protocol violations). Here Number of Participants Analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Metformin IR | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 16 | -1.61 Percentage of HbA1c | Standard Error 0.05 |
| Metformin XR | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 16 | -1.58 Percentage of HbA1c | Standard Error 0.05 |
95% CI: [-0.1, 0.17]
Primary
Overall Gastrointestinal (GI) Tolerability Assessed as Percentage of Subjects With Gastrointestinal Adverse Events During Treatment Period
An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product.
Time frame: Baseline up to Week 16
Population: The safety population included all subjects who received at least 1 dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin IR | Overall Gastrointestinal (GI) Tolerability Assessed as Percentage of Subjects With Gastrointestinal Adverse Events During Treatment Period | 23.8 percentage of subjects |
| Metformin XR | Overall Gastrointestinal (GI) Tolerability Assessed as Percentage of Subjects With Gastrointestinal Adverse Events During Treatment Period | 22.3 percentage of subjects |
p-value: 0.67495% CI: [-8.6, 5.56]Mantel Haenszel
Secondary
Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) Level at Weeks 8 and 16
The 2-hour Postprandial plasma glucose (PPG) level refers to the plasma glucose concentrations after 2 hours of eating.
Time frame: Baseline, Week 8 and 16
Population: ITT population included all subjects who were randomly allocated to a treatment based on the intention to treat. Here Number of Participants Analyzed signifies those subjects who were evaluable for this outcome measure. Here n signifies those subjects who were evaluable for the specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin IR | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) Level at Weeks 8 and 16 | Baseline (n= 223, 231) | 14.604 mmol/L | Standard Deviation 3.4334 |
| Metformin IR | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) Level at Weeks 8 and 16 | Change at Week 8 (n= 215, 229) | -3.608 mmol/L | Standard Deviation 3.6964 |
| Metformin IR | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) Level at Weeks 8 and 16 | Change at Week 16 (n= 213, 215) | -3.642 mmol/L | Standard Deviation 3.7261 |
| Metformin XR | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) Level at Weeks 8 and 16 | Baseline (n= 223, 231) | 14.764 mmol/L | Standard Deviation 3.7705 |
| Metformin XR | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) Level at Weeks 8 and 16 | Change at Week 8 (n= 215, 229) | -3.264 mmol/L | Standard Deviation 5.9134 |
| Metformin XR | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) Level at Weeks 8 and 16 | Change at Week 16 (n= 213, 215) | -3.693 mmol/L | Standard Deviation 3.5414 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16
Time frame: Baseline, Week 1, 2, 4, 8, 12,16
Population: ITT population included all subjects who were randomly allocated to a treatment based on the intention to treat. Here Number of Participants Analyzed signifies those subjects who were evaluable for this outcome measure. Here n signifies those subjects who were evaluable for the specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin IR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 2 (n= 243, 244) | -1.324 Millimole Per Liter (mmol/L) | Standard Deviation 1.4426 |
| Metformin IR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 8 (n= 219, 230) | -2.075 Millimole Per Liter (mmol/L) | Standard Deviation 1.7359 |
| Metformin IR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 1 (n= 249, 248) | -0.647 Millimole Per Liter (mmol/L) | Standard Deviation 1.5615 |
| Metformin IR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 12 (n= 216, 221) | -2.053 Millimole Per Liter (mmol/L) | Standard Deviation 1.7599 |
| Metformin IR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 4 (n= 240, 239) | -1.558 Millimole Per Liter (mmol/L) | Standard Deviation 1.6245 |
| Metformin IR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 16 (n= 214, 218) | -1.976 Millimole Per Liter (mmol/L) | Standard Deviation 1.7529 |
| Metformin IR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Baseline (n=251, 254) | 8.464 Millimole Per Liter (mmol/L) | Standard Deviation 1.747 |
| Metformin XR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 16 (n= 214, 218) | -2.183 Millimole Per Liter (mmol/L) | Standard Deviation 1.8481 |
| Metformin XR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Baseline (n=251, 254) | 8.690 Millimole Per Liter (mmol/L) | Standard Deviation 2.0977 |
| Metformin XR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 1 (n= 249, 248) | -0.736 Millimole Per Liter (mmol/L) | Standard Deviation 1.4305 |
| Metformin XR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 2 (n= 243, 244) | -1.267 Millimole Per Liter (mmol/L) | Standard Deviation 1.9346 |
| Metformin XR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 4 (n= 240, 239) | -1.604 Millimole Per Liter (mmol/L) | Standard Deviation 1.7971 |
| Metformin XR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 8 (n= 219, 230) | -1.999 Millimole Per Liter (mmol/L) | Standard Deviation 2.0192 |
| Metformin XR | Change From Baseline in Fasting Plasma Glucose (FPG) Level at Week 1, 2, 4, 8, 12 and 16 | Change at Week 12 (n= 216, 221) | -2.048 Millimole Per Liter (mmol/L) | Standard Deviation 1.8532 |
Secondary
Percentage of Subjects Who Are Compliant to Treatment
Compliance was defined as not skipping or forgetting dosing or not delaying the dosing time. Subjects who never missed a dose of medication were considered compliant.
Time frame: Baseline up to Week 16
Population: The safety population included all subjects who received at least 1 dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin IR | Percentage of Subjects Who Are Compliant to Treatment | 99.2 percentage of subjects |
| Metformin XR | Percentage of Subjects Who Are Compliant to Treatment | 99.2 percentage of subjects |
Secondary
Percentage of Subjects Who Are Totally Intolerant to the Treatment
Subjects were considered to be totally intolerant if they experienced a Grade 3 or higher toxicity considered at least possibly related to the treatment.
Time frame: Baseline up to Week 16
Population: The safety population included all subjects who received at least 1 dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin IR | Percentage of Subjects Who Are Totally Intolerant to the Treatment | 7.3 percentage of subjects |
| Metformin XR | Percentage of Subjects Who Are Totally Intolerant to the Treatment | 5.7 percentage of subjects |
Secondary
Percentage of Subjects With HbA1c Less Than (<) 7%
Time frame: Baseline up to Week 16
Population: ITT population included all subjects who were randomly allocated to a treatment based on the intention to treat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin IR | Percentage of Subjects With HbA1c Less Than (<) 7% | 68.5 percentage of subjects |
| Metformin XR | Percentage of Subjects With HbA1c Less Than (<) 7% | 69.8 percentage of subjects |
Secondary
Percentage of Subjects With HbA1c Less Than (<) 7% and With no Severe Gastrointestinal (GI) and Other Adverse Events (AEs)
Percentage of subjects with HbA1c \<7% and with no severe GI and other AEs were reported. Severe adverse events were based on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 and were defined as those events which were medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living (ADL). Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
Time frame: Baseline up to Week 16
Population: ITT population included all subjects who were randomly allocated to a treatment based on the intention to treat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin IR | Percentage of Subjects With HbA1c Less Than (<) 7% and With no Severe Gastrointestinal (GI) and Other Adverse Events (AEs) | 68.2 percentage of subjects |
| Metformin XR | Percentage of Subjects With HbA1c Less Than (<) 7% and With no Severe Gastrointestinal (GI) and Other Adverse Events (AEs) | 69.8 percentage of subjects |
Secondary
Percentage of Subjects With Hypoglycemia
Hypoglycemia, also called as low blood glucose or low blood sugar, is defined as the blood glucose level of less than normal (that is less than 3.9 millimole per liter \[mmol/L\]).
Time frame: Baseline up to Week 16
Population: The safety population included all subjects who received at least 1 dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin IR | Percentage of Subjects With Hypoglycemia | 1.1 percentage of subjects |
| Metformin XR | Percentage of Subjects With Hypoglycemia | 3.0 percentage of subjects |
Secondary
Percentage of Subjects With Marked Hyperglycemia
Marked hyperglycemia was defined as the FPG level of greater than or equal to 11.1 mmol/L.
Time frame: Baseline up to Week 16
Population: ITT population included all subjects who were randomly allocated to a treatment based on the intention to treat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin IR | Percentage of Subjects With Marked Hyperglycemia | 0.7 percentage of subjects |
| Metformin XR | Percentage of Subjects With Marked Hyperglycemia | 2.3 percentage of subjects |
Secondary
Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period
An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. Number of subjects with pre-specified gastrointestinal adverse events (diarrhea, nausea, abdominal pain, bloating, constipation, dyspepsia and flatulence) were reported.
Time frame: Baseline up to Week 16
Population: The safety population included all subjects who received at least 1 dose of trial treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metformin IR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Nausea | 6.1 percentage of subjects |
| Metformin IR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Constipation | 1.9 percentage of subjects |
| Metformin IR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Abdominal Distension | 6.1 percentage of subjects |
| Metformin IR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Dyspepsia | 1.1 percentage of subjects |
| Metformin IR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Abdominal Pain | 2.3 percentage of subjects |
| Metformin IR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Flatulence | 0.4 percentage of subjects |
| Metformin IR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Diarrhoea | 16.5 percentage of subjects |
| Metformin XR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Flatulence | 0 percentage of subjects |
| Metformin XR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Diarrhoea | 12.5 percentage of subjects |
| Metformin XR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Abdominal Distension | 6.4 percentage of subjects |
| Metformin XR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Nausea | 4.5 percentage of subjects |
| Metformin XR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Abdominal Pain | 1.9 percentage of subjects |
| Metformin XR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Constipation | 1.9 percentage of subjects |
| Metformin XR | Percentage of Subjects With Pre-specified Gastrointestinal Adverse Events During Treatment Period | Dyspepsia | 0.8 percentage of subjects |