Diabetes Mellitus Arising in Pregnancy, Insulin-RequiringNCT04907708
Comparative Effects of Metformin and Insulin on Stereological Studies and Immunohistochemistry of Placenta
A study testing Metformin and Insulin in people with Diabetes Mellitus Arising in Pregnancy, Insulin-Requiring and Diabetes Mellitus in Pregnancy, run by University of Karachi at 1 site in Pakistan.
Trial summary
Diabetes mellitus is a group of metabolic disorder characterized by high blood glucose level mainly due to defect in insulin secretion or resistance. In pregnancy, insulin resistance increases as the pregnancy advances, due to the placental hormones predisposing the female to gestational diabetes mellitus (GDM). Read more about this study
- Who is it for?
- Ages 18 to 40 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus Arising in Pregnancy, Insulin-Requiring, Diabetes Mellitus in Pregnancy
- What is being tested?
- Metformin and Insulin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 156 participants
- Where
- 1 sitePakistan
- Study dates
- 1 Jan 2018to 7 Aug 2019
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- For this study placentae were collected from:
- Patients who were diagnosed as GDM during second trimester screening for FBS and RBS, confirmed further by OGCT and OGTT.
- GDM patients who signed the written informed consent.
- GDM patients who were in ages between 18 years and 40 years and had no other comorbid such hypertension, CVD etc
- Full term GDM patients with singleton pregnancy (37 weeks and above)
- GDM patients whose placenta were preserved within 30-40 minutes of delivery.
Who cannot join
- Placentae were not collected from:
- GDM Patients with ages less than 18 or more than 40 years
- GDM females with some co-morbid and complications (e.g. hypertension, CVD, diabetes type 1 or diabetes type 2 before gestation, abnormal Urea Creatinine Electrolyte (UCE) and Liver function test (LFTs).
- GDM Patients who delivered pre-termed (< 37 weeks of gestation) or post termed (>42 weeks of gestation)
- GDM patients with twin pregnancy.
- GDM Patients if not preserved in the formalin properly within 30-40 minutes of delivery.
- GDM females who were given combined (Metformin and insulin) therapy.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Comparative Studies of Metformin and Insulin on Stereological Studies and Immunohistochemistry of Placenta
Diabetes mellitus is a group of metabolic disorder characterized by high blood glucose level mainly due to defect in insulin secretion or resistance. In pregnancy, insulin resistance increases as the pregnancy advances, due to the placental hormones predisposing the female to gestational diabetes mellitus (GDM). Placenta is a vital organ as it provides nutrition to the fetus. It shows morphological changes in patients with GDM leading to feto-maternal complications. Insulin, a traditional treatment given for GDM is also known to cause intra uterine deaths, stillbirths and hypoglycemia in mothers and newborns. Insulin being anabolic hormone makes placenta larger in size and causes hypoxic changes with vascular insufficiency, infarctions and hemorrhages. In contrast to this, oral insulin sensitizing drug Metformin, is euglycemic in nature. It has been proven now that Metformin is a vasculo-protective agent, with better patient compliance and beneficial micro-vascular effects in type 2 diabetics. This study was designed to clearly visualize in detail if there are any unrevealed beneficial vascular effects of Metformin on placental tissues and also to compare these effects with Insulin and diet restriction therapy, by doing placental light microscopy, morphometric studies and immunohistochemistry.
Read the detailed description
Diabetes mellitus is a group of metabolic disorder with relative or absolute deficiency of insulin. Pregnancy is a potentially glucose intolerant condition as insulin sensitivity decreases with the progress of pregnancy leading to the development of gestational diabetes mellitus (GDM). It is diagnosed in approximately 3-9% of pregnancies and is growing in prevalence. In Pakistan the recent prevalence of GDM is reported to be 3-3.45% but the complications are much higher due to poor glycemic control, lack of awareness and inadequate medical facilities. Placenta is an important feto-maternal organ which is responsible for nutrition of the fetus. It also provides the retrospective information regarding infant's prenatal development. Structurally, human placenta is a complex vascular organ that allows exchange of nutrients and chemicals between fetal and maternal blood. Proper development and maturity of placenta are strongly connected with fetal growth and survival.
GDM produces anatomical and physiological alterations in placenta. This can be related to altered levels of fetal insulin and multiple growth factors such as placental vascular endothelial growth factor (VEGF), Insulin like growth factors (IGF and IGF binding proteins) which regulate the fetal and placental development. Morphologically, diabetic placentae are larger in size and volume. Microscopically, diabetic placenta shows degenerative alternations such as villous fibrinoid necrosis, chorangiosis, villous immaturity, calcification and syncytial knots formation which show intense hypoxia of the placental tissues.
Nutritional therapy (diet control) is foremost important for achieving target glucose values during pregnancy but in uncontrolled cases pharmacological intervention is required. Parental Insulin is the traditional therapy in such circumstances, but is an expensive medication and is associated with high incidence of neonatal and maternal hypoglycemia, still births, neonatal morbidity and mortality. It is documented to produce many placental alterations such as immature villi, hemorrhages, edema, cystic changes and fibrinoid necrosis. It has been postulated that the reason behind all these hypoxic changes are the variation in the blood glucose level that occur in the maternal blood as sugar level suddenly dropped soon after Insulin injection and are at highest just before the next dose of Insulin.
The use of oral anti-diabetic medications such as Metformin in the management of gestational diabetes has increased over the past several years. Recent studies has established that Metformin can be a better option for GDM as it well controls glycemia (produces euglycemic) with good pregnancy outcomes. Metformin is an oral anti-diabetic drug from biguanide group; work by improving insulin sensitivity, reducing hepatic gluconeogenesis and also by increasing peripheral glucose uptake and utilization. It is now been upgraded to category B drug as is not associated with teratogenic effects. But what are the effects of Metformin on stereological morphometric study and immunochemistry of placental tissues were left to be evaluated. Stereology provides practical measurements and significant approach for obtaining quantitative estimates of small structures on histological slides. In placental tissue it is performed to obtain unbiased quantitative estimates of placental components that inform about development and also estimate of structural parameters that have direct influence on placental functional capacity. Immunohistochemistry or immunofluorescence of tissue sections also provide valuable insight to placental structure and protein expression with three-dimensional spatial information, including morphology that cannot be obtained on microscopy.
With this background knowledge, study was designed with the following objectives:
- To evaluate the placental gross and microscopic changes in normal, diet control, Metformin and Insulin treated in newly enrolled GDM females
- To evaluate stereological morphometric details of placenta in normal, diet control, Metformin and Insulin all enrolled females
- To evaluate immunohistochemistry of placental tissues in normal, diet control, Metformin and Insulin in all enrolled females
- To compare the placental morphology, stereology and immunohistochemistry with in the groups.
- To evaluate the fetal and maternal outcome in normal, diet control, Metformin and Insulin treated gestational diabetics.
- To correlate the placental morphology with the fetal and maternal outcome in Metformin and Insulin treated gestational diabetics
- Keywords
- placenta, metformin, insulin, stereology, immunohistochemistry, morphometry
- Medical subject headings
- Diabetes, Gestational, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Normal healthy controls | No intervention | females in second trimester with normal glucose levels |
| Diet controlled | No intervention | females in second trimester with blood sugar levels below 129mg/dl |
| Metformin | Experimental | females in second trimester with blood sugar levels above 130mg/dl treated with Metformin Receives: Drug: Metformin |
| Insulin | Experimental | females in second trimester with blood sugar levels above 130mg/dl being treated with Insulin Receives: Drug: Insulin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean morphometric diffusion capacity for oxygen (MMDC) in placental tissues
With detailed stereological assessment MMDC can be calculated for the placenta to visualize which group placenta allows better diffusion of oxygen
Measured: 15 months
Secondary outcomes (1)
Percentage of immuno-antigens present in placental tissue
The percentage of immuno-antigens on the placental tissue is related to the hypoxic and vascular changes in the placenta.
Measured: 15 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jun 2021
- Study start1 Jan 2018
- Primary completion10 Feb 2019
- Study completion7 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus Arising in Pregnancy, Insulin-RequiringStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 156 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Karachi
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr Rabia Arshad, University of Karachi
- Investigators
- KAUSER AAMIR, Ph.D, Study director, BMSI, JPMC,KARACHI
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04907708
- Sponsor's protocol ID
- UKarachi
- Status last verified
- May 2021
- First submitted
- 17 May 2021
- Last updated
- 1 Jun 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Liang HL, Ma SJ, Xiao YN, Tan HZ. Comparative efficacy and safety of oral antidiabetic drugs and insulin in treating gestational diabetes mellitus: An updated PRISMA-compliant network meta-analysis. Medicine (Baltimore). 2017 Sep;96(38):e7939. doi: 10.1097/MD.0000000000007939.
PubMed 28930827
Study at a glance
From the registry record, last updated by the sponsor on 1 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparative Studies of Metformin and Insulin on Stereological Studies and Immunohistochemistry of Placenta
- ClinicalTrials.gov ID
- NCT04907708
- Acronym / sponsor ID
- UKarachi
- Keywords
- placenta, metformin, insulin, stereology, immunohistochemistry, morphometry
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 156 participants (actual)
- Lead sponsor
- University of KarachiUniversity, hospital or other
- Study start
- 1 Jan 2018 (actual)
- Primary completion
- 10 Feb 2019 (actual)
- Study completion
- 7 Aug 2019 (actual)
- First posted
- 1 Jun 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Diabetes mellitus is a group of metabolic disorder characterized by high blood glucose level mainly due to defect in insulin secretion or resistance. In pregnancy, insulin resistance increases as the pregnancy advances, due to the placental hormones predisposing the female to gestational diabetes mellitus (GDM). Placenta is a vital organ as it provides nutrition to the fetus. It shows morphological changes in patients with GDM leading to feto-maternal complications. Insulin, a traditional treatment given for GDM is also known to cause intra uterine deaths, stillbirths and hypoglycemia in mothers and newborns. Insulin being anabolic hormone makes placenta larger in size and causes hypoxic changes with vascular insufficiency, infarctions and hemorrhages. In contrast to this, oral insulin sensitizing drug Metformin, is euglycemic in nature. It has been proven now that Metformin is a vasculo-protective agent, with better patient compliance and beneficial micro-vascular effects in type 2 diabetics. This study was designed to clearly visualize in detail if there are any unrevealed beneficial vascular effects of Metformin on placental tissues and also to compare these effects with Insulin and diet restriction therapy, by doing placental light microscopy, morphometric studies and immunohistochemistry.
Detailed description
Diabetes mellitus is a group of metabolic disorder with relative or absolute deficiency of insulin. Pregnancy is a potentially glucose intolerant condition as insulin sensitivity decreases with the progress of pregnancy leading to the development of gestational diabetes mellitus (GDM). It is diagnosed in approximately 3-9% of pregnancies and is growing in prevalence. In Pakistan the recent prevalence of GDM is reported to be 3-3.45% but the complications are much higher due to poor glycemic control, lack of awareness and inadequate medical facilities. Placenta is an important feto-maternal organ which is responsible for nutrition of the fetus. It also provides the retrospective information regarding infant's prenatal development. Structurally, human placenta is a complex vascular organ that allows exchange of nutrients and chemicals between fetal and maternal blood. Proper development and maturity of placenta are strongly connected with fetal growth and survival.
GDM produces anatomical and physiological alterations in placenta. This can be related to altered levels of fetal insulin and multiple growth factors such as placental vascular endothelial growth factor (VEGF), Insulin like growth factors (IGF and IGF binding proteins) which regulate the fetal and placental development. Morphologically, diabetic placentae are larger in size and volume. Microscopically, diabetic placenta shows degenerative alternations such as villous fibrinoid necrosis, chorangiosis, villous immaturity, calcification and syncytial knots formation which show intense hypoxia of the placental tissues.
Nutritional therapy (diet control) is foremost important for achieving target glucose values during pregnancy but in uncontrolled cases pharmacological intervention is required. Parental Insulin is the traditional therapy in such circumstances, but is an expensive medication and is associated with high incidence of neonatal and maternal hypoglycemia, still births, neonatal morbidity and mortality. It is documented to produce many placental alterations such as immature villi, hemorrhages, edema, cystic changes and fibrinoid necrosis. It has been postulated that the reason behind all these hypoxic changes are the variation in the blood glucose level that occur in the maternal blood as sugar level suddenly dropped soon after Insulin injection and are at highest just before the next dose of Insulin.
The use of oral anti-diabetic medications such as Metformin in the management of gestational diabetes has increased over the past several years. Recent studies has established that Metformin can be a better option for GDM as it well controls glycemia (produces euglycemic) with good pregnancy outcomes. Metformin is an oral anti-diabetic drug from biguanide group; work by improving insulin sensitivity, reducing hepatic gluconeogenesis and also by increasing peripheral glucose uptake and utilization. It is now been upgraded to category B drug as is not associated with teratogenic effects. But what are the effects of Metformin on stereological morphometric study and immunochemistry of placental tissues were left to be evaluated. Stereology provides practical measurements and significant approach for obtaining quantitative estimates of small structures on histological slides. In placental tissue it is performed to obtain unbiased quantitative estimates of placental components that inform about development and also estimate of structural parameters that have direct influence on placental functional capacity. Immunohistochemistry or immunofluorescence of tissue sections also provide valuable insight to placental structure and protein expression with three-dimensional spatial information, including morphology that cannot be obtained on microscopy.
With this background knowledge, study was designed with the following objectives:
- To evaluate the placental gross and microscopic changes in normal, diet control, Metformin and Insulin treated in newly enrolled GDM females
- To evaluate stereological morphometric details of placenta in normal, diet control, Metformin and Insulin all enrolled females
- To evaluate immunohistochemistry of placental tissues in normal, diet control, Metformin and Insulin in all enrolled females
- To compare the placental morphology, stereology and immunohistochemistry with in the groups.
- To evaluate the fetal and maternal outcome in normal, diet control, Metformin and Insulin treated gestational diabetics.
- To correlate the placental morphology with the fetal and maternal outcome in Metformin and Insulin treated gestational diabetics
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Normal healthy controls | No intervention | –females in second trimester with normal glucose levels |
| Diet controlled | No intervention | –females in second trimester with blood sugar levels below 129mg/dl |
| Metformin | Experimental | Drug: Metforminfemales in second trimester with blood sugar levels above 130mg/dl treated with Metformin |
| Insulin | Experimental | Drug: Insulinfemales in second trimester with blood sugar levels above 130mg/dl being treated with Insulin |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Patients who were diagnosed as GDM during second trimester screening for FBS and RBS, confirmed further by OGCT and OGTT.
- GDM patients who signed the written informed consent.
- GDM patients who were in ages between 18 years and 40 years and had no other comorbid such hypertension, CVD etc
- Full term GDM patients with singleton pregnancy (37 weeks and above)
- GDM patients whose placenta were preserved within 30-40 minutes of delivery.
Key exclusion criteria (7 listed)
- GDM Patients with ages less than 18 or more than 40 years
- GDM females with some co-morbid and complications (e.g. hypertension, CVD, diabetes type 1 or diabetes type 2 before gestation, abnormal Urea Creatinine Electrolyte (UCE) and Liver function test (LFTs).
- GDM Patients who delivered pre-termed (< 37 weeks of gestation) or post termed (>42 weeks of gestation)
- GDM patients with twin pregnancy.
- GDM Patients if not preserved in the formalin properly within 30-40 minutes of delivery.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminEuglycemic agent | Drug | Metformin |
| InsulinHypoglycemic agent | Drug | Insulin |
Primary outcome
Mean morphometric diffusion capacity for oxygen (MMDC) in placental tissues
Time frame: 15 months
With detailed stereological assessment MMDC can be calculated for the placenta to visualize which group placenta allows better diffusion of oxygen
1 secondary outcome
Percentage of immuno-antigens present in placental tissue
Time frame: 15 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jun 2021.
- Background: PubMed 28930827Liang HL, Ma SJ, Xiao YN, Tan HZ. Comparative efficacy and safety of oral antidiabetic drugs and insulin in treating gestational diabetes mellitus: An updated PRISMA-compliant network meta-analysis. Medicine (Baltimore). 2017 Sep;96(38):e7939. doi: 10.1097/MD.0000000000007939.
- Belkacemi, L., Kjos, S., Nelson, D. M., \& Desai, M. (2013). Reduced apoptosis in term placentas from gestational diabetic pregnancies. Journal of Developmental Origins of Health and Disease, 4 (3), 256-265.Link provided by the sponsor.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
KAUSER AAMIR, Ph.D study director
BMSI, JPMC,KARACHI
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Metformin and Insulin in people with Diabetes Mellitus Arising in Pregnancy, Insulin-Requiring and Diabetes Mellitus in Pregnancy, run by University of Karachi at 1 site in Pakistan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Pakistan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean morphometric diffusion capacity for oxygen (MMDC) in placental tissues (time frame: 15 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04907708, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jun 2021.