Ignite Creation Date:
2024-05-06 @ 6:24 PM
Last Modification Date:
2024-10-26 @ 2:47 PM
Study NCT ID:
NCT05651347
Status:
RECRUITING
Last Update Posted:
2022-12-15
First Post:
2022-08-23
Brief Title:
Antenatal Melatonin Supplementation for Neuroprotection in Fetal Growth Restriction
Sponsor:
Monash University
Organization:
Monash University
Study Overview
Official Title:
A Triple-blinded Randomized Parallel-group Placebo-controlled Trial to Assess the Impact of Maternal Antenatal Melatonin Supplementation on Early Childhood Neurodevelopmental Outcomes in the Setting of Severe Preterm Fetal Growth Restriction
Status:
RECRUITING
Status Verified Date:
2022-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PROTECTMe
Brief Summary:
Fetal growth restriction FGR is a significant health care issue affecting 20000 Australian pregnancies every year Undetected FGR is one of the key risk factors for stillbirth but FGR can also cause significant impairments in short and long-term health outcomes for the child
It is a major risk factor for preterm birth and is a recognised causal pathway to the neurodevelopmental injury underlying cognitive and behavioural impairment and cerebral palsy Current obstetric care is focused on the detection of the growth restricted fetus and then ultrasound assessment of fetal wellbeing to guide timing of delivery This approach seeks to maximize the gestational age of the fetus at delivery to minimise the risks of prematurity while delivering the fetus in time to reduce the likelihood of stillbirth Currently no therapies exist that can maximize fetal wellbeing in the setting of growth restriction and minimise the frequency of antenatally acquired brain injury due to in-utero hypoxia
This triple-blind randomized parallel group placebo-controlled trial will administer maternal melatonin or placebo supplementation antenatally in the setting of early-onset severe FGR to determine whether melatonin can PROTECT the fetal brain and lead to improved neurodevelopmental outcomes
It is a major risk factor for preterm birth and is a recognised causal pathway to the neurodevelopmental injury underlying cognitive and behavioural impairment and cerebral palsy Current obstetric care is focused on the detection of the growth restricted fetus and then ultrasound assessment of fetal wellbeing to guide timing of delivery This approach seeks to maximize the gestational age of the fetus at delivery to minimise the risks of prematurity while delivering the fetus in time to reduce the likelihood of stillbirth Currently no therapies exist that can maximize fetal wellbeing in the setting of growth restriction and minimise the frequency of antenatally acquired brain injury due to in-utero hypoxia
This triple-blind randomized parallel group placebo-controlled trial will administer maternal melatonin or placebo supplementation antenatally in the setting of early-onset severe FGR to determine whether melatonin can PROTECT the fetal brain and lead to improved neurodevelopmental outcomes
Detailed Description:
Following detection of FGR current goals in clinical care center on assessment of fetal wellbeing and evidence of a physiological adaption to placental insufficiency This information guides the timing of steroids if indicated and planning of delivery to minimise the likelihood of stillbirth Magnesium sulphate is the only available therapy shown to improve fetal brain development in the setting of placental insufficiency and hypoxia Magnesium sulphate works through reducing glutamate release in a hypoxic environment likely minimising hypoxic brain injury It appears to reduce the risk of subsequent cerebral palsy by approximately 30 However magnesium sulphate is only used in the hours immediately before birth while a significant proportion of underlying brain injury in FGR probably occurs over the preceding days to weeks The use of a safe maternally administered supplement commenced in the weeks prior to birth could provide further significant benefits in reducing the complications faced by premature infants in the setting of placental insufficiency
Melatonin 5-methoxy-N-acetyltryptamine is an endogenous lipid-soluble hormone produced primarily by the pineal gland in humans It provides circadian and seasonal timing cues due to neuroendocrine control in response to daylight As such melatonin secretion is relatively low during the daytime with an exponential increase in synthesis and secretion occurring from mid-afternoon and peaking at midnight
In addition to timing cues melatonin is a powerful antioxidant acting both as a direct scavenger of oxygen free radicals especially the highly damaging hydroxyl radical and indirectly via up-regulation of antioxidant enzymes including glutathione peroxidase glutathione-reductase superoxide dismutase and catalase The metabolites of melatonin provide further anti-oxidant effect
Melatonin is an appealing treatment for use as a fetal neuroprotectant in pregnancy as it freely crosses the placenta and blood-brain barrier It also has an excellent safety profile with no known adverse effects Placentae express receptors for melatonin and thus melatonin may protect against oxidative stress generated by ischaemia-reperfusion injury of the placenta
Melatonin has been studied in several clinical trials related to human reproduction and for different purposes However no randomized trial assessing the role of melatonin in fetal neuroprotection has been completed Melatonin has been evaluated in assisted reproductive technology where the quality of oocytes is vital for the success of in-vitro fertilization IVF Melatonin and myo-inositol are two compounds found in the follicular fluid that are important for oocyte maturation and quality Tamura et al in 2008 and Rizzo et al in 2010 conducted clinical studies where they co-treated patients with 2milligram mg and 3mg melatonin respectively The patients in the Tamura et al study were given melatonin from the fifth day of the previous menstrual cycle until the day of oocyte retrieval Both studies revealed improved oocyte quality but the tendency to increase pregnancy rates failed to reach statistical significance A study conducted by Unfer et al in 2011 administered 2g myo-inositol 200µg folic acid plus 3mg melatonin per day for 3-months to women who failed to become pregnant in previous IVF cycles at the commencement of a new IVF cycle This treatment resulted in a total of 13 pregnancies 9 of which were confirmed ultrasonographically and 4 undergoing spontaneous abortion Treatment continued after completion of the IVF cycle throughout pregnancy until delivery Treatment was associated with better quality oocytes and more successful pregnancies All babies that were born from melatonin-treated pregnancies were in healthy condition with no abnormalities
To evaluate the maternal-fetal transfer of melatonin a study by Okatani et al in 1998 administered a single oral dose of 3mg melatonin to 33 women at term 37-40 weeks gestation 1- to 4-hours before a planned caesarean section Levels of melatonin were evaluated in maternal venous blood and umbilical venous and arterial blood A total of 12 healthy pregnant women delivered by vaginal birth served as controls Administration of melatonin led to a rapid 120 minutes and marked 20-fold increase in the fetal serum levels There were no differences between maternal and fetal serum levels of melatonin suggesting a rapid and unrestricted transfer of melatonin from mother to fetus
The same investigators tested whether melatonin could up-regulate antioxidant enzymes No longer than 12 hours before voluntary termination of pregnancy between 7- and 9-weeks gestation an oral dose of 6mg melatonin was administered to 47 pregnant women A significant increase of the antioxidant enzyme glutathione peroxidase was observed in chorionic homogenates derived after the procedure leading to the conclusion that melatonin might provide an indirect protection against injury caused by reactive oxygen species as seen in preeclampsia FGR and fetal hypoxia
The dose used in this trial is based on data from a clinical trial of melatonin for preeclampsia showing that 30mg per day was safe for mother and baby without any apparent adverse effects Venous cord blood concentrations of melatonin achieved were unchanged between a mother receiving 8mg and 30mg per day of melatonin melatonin concentration 2100pgmL This cord blood concentration would appear sufficient for neuroprotection according to information in sheep models However the degree of oxidative stress reduction achieved within the placental bed was less in mothers receiving 8mg melatonin per day As such it was felt that the higher dose of 30mg per day was more likely to achieve a clinically significant result
The investigating team has shown that melatonin supplementation exerts multiple anti-oxidant and anti-inflammatory effects leading to a significant reduction in oxidative stress and lipid peroxidation within the fetal brain in an ovine model of FGR In the absence of melatonin this study showed that lipid peroxidation within the fetal brain led to significant white matter hypomyelination and axonal injury causing impaired neurological performance in the lambs Injury was ameliorated entirely in those exposed to melatonin supplementation with no structural brain injury seen and neurodevelopmental outcomes normalised
As a result a small n12 phase 1 trial was conducted at Monash Health supplementing pregnancies affected by severe FGR with 8mg of melatonin per day Melatonin use was well tolerated with no adverse effects seen A reduction in the degree of placental lipid peroxidation was seen n6
Early-onset FGR carries significant fetal risks of premature birth Following diagnosis those babies requiring delivery 32 weeks gestation carry approximately an 8 risk of stillbirth or neonatal death with those born 28 weeks gestation having a significantly higher perinatal mortality rate Around 30 of survivors will suffer serious neonatal morbidity Furthermore 8 are found to have neurodevelopmental impairment at two years of life These numbers are likely to be an underrepresentation as they are from a trial population which was closely surveyed compared to the general population
With approximately 97 of FGR infants born 32 weeks delivered by caesarean section the mother of a preterm FGR fetus faces the risks associated with morbidity and mortality relating to caesarean birth Furthermore the mother also faces a significant risk of morbidity and mortality from pre-eclampsia which develops among 15 - 40 of women who have a growth-restricted fetus
The most common side effects of melatonin are headache dizziness nausea and sleepiness Melatonin does not have any acute pharmacological effects on the nervous or vascular systems apart from its benign but active impact on sleep mechanisms Extremely high doses of up to 800mgkg of melatonin were safely administered to animals without deaths meaning a median lethal dose could not be established In humans long-term treatment with high daily doses of up to 10g melatonin did not cause any toxicity except for isolated cases of cutaneous flushing abdominal cramps diarrhoea scotoma lucidum and migraine
Prolonged ingestion of 1g melatonin per day caused only subjective drowsiness but did not provoke any toxicity in the eyes liver kidneys and bone marrow In a phase II clinical trial conducted in the Netherlands 1400 women were given 75mg melatonin nightly over 4-years with no side effects reported
The safety of melatonin use in pregnancy was explored in early pregnant Sprague-Dawley rats at doses ranging from 1 to 200mgkgday and did not affect antenatal mortality fetal body weight or other measures of fetal wellbeing Maternal adverse effects seen at high doses included mild sedation reduced maternal weight gain and reduced food intake This study sought to determine the maternal and fetal no adverse effect level NOAEL The NOAEL is the exposure level where a particular substance does not statistically or biologically significantly increase the frequency or severity of adverse effects in an exposed population compared to a suitable control population The maternal NOAEL in this study was found to be 100mgkgday the fetal NOAEL was established at 200mgkgday when administered to the mother The maternal lowest observed adverse effect level toxicity was 200mgkgday With the above information taken in context the Australian Therapeutic Goods Administration TGA has assigned melatonin a Pregnancy Category B3 classification
The investigators have recently completed a phase 1 trial NCT01695070 using melatonin supplementation in pregnancy as well as a clinical trial in women with pre-eclampsia ACTRN12613000476730 using the same dose as proposed for this trial and to date no adverse effects have been identified in the mother fetus or neonate
PROTECT Me aims to be a multicentre triple-blinded randomized parallel group placebo controlled trial This trial will be undertaken and co-ordinated by Monash Health
Other perinatal hospitals across Australia and New Zealand have agreed to join the trial so far Each centre will nominate a local investigator - a researcher to oversee local recruitment
The required sample size has been calculated to detect if melatonin supplementation affords a clinically relevant difference in neurodevelopmental outcomes among survivors An increase of 4-5 quotient points in the Bayley-IV Cognitive scale has been deemed sufficiently clinically meaningful to drive changes in health policy previously Power analysis shows that 69 participants per group will allow the detection of a difference in the Bayley-IV cognitive score of 5 points between the two groups with a power of 90 and an alpha level of 005 using 2 sided T test for comparison This assumes a standard deviation of 9 and that on average the growth restricted infant has been shown to have a cognitive score 5 points lower than the healthy preterm infant and 8 points lower than the healthy term infant Typically the Bayley IV score has a standard deviation of 15 however reduced variability has been seen in the FGR population and this has informed the standard deviation used here Among pregnancies complicated by early onset FGR a perinatal loss rate of 15 is commonly observed Allowing for a perinatal loss rate of 15 an extra 44 women will be recruited Assuming an additional 5 loss to follow-up rate the investigators will aim to recruit an extra 14 participants
This trial also aims to assess whether the impact of melatonin is different at different gestational ages Therefore a sub-analysis will be undertaken to compare those with early onset FGR identified 28 weeks gestation to those with late-onset FGR identified between 28-316 weeks gestation To ensure that this sub-analysis is adequately powered participants recruited will be randomized to either melatonin or placebo based on their gestational age at diagnosis Therefore recruiting 84 participants per group will see the overall trial aiming to recruit 336 participants
Melatonin 5-methoxy-N-acetyltryptamine is an endogenous lipid-soluble hormone produced primarily by the pineal gland in humans It provides circadian and seasonal timing cues due to neuroendocrine control in response to daylight As such melatonin secretion is relatively low during the daytime with an exponential increase in synthesis and secretion occurring from mid-afternoon and peaking at midnight
In addition to timing cues melatonin is a powerful antioxidant acting both as a direct scavenger of oxygen free radicals especially the highly damaging hydroxyl radical and indirectly via up-regulation of antioxidant enzymes including glutathione peroxidase glutathione-reductase superoxide dismutase and catalase The metabolites of melatonin provide further anti-oxidant effect
Melatonin is an appealing treatment for use as a fetal neuroprotectant in pregnancy as it freely crosses the placenta and blood-brain barrier It also has an excellent safety profile with no known adverse effects Placentae express receptors for melatonin and thus melatonin may protect against oxidative stress generated by ischaemia-reperfusion injury of the placenta
Melatonin has been studied in several clinical trials related to human reproduction and for different purposes However no randomized trial assessing the role of melatonin in fetal neuroprotection has been completed Melatonin has been evaluated in assisted reproductive technology where the quality of oocytes is vital for the success of in-vitro fertilization IVF Melatonin and myo-inositol are two compounds found in the follicular fluid that are important for oocyte maturation and quality Tamura et al in 2008 and Rizzo et al in 2010 conducted clinical studies where they co-treated patients with 2milligram mg and 3mg melatonin respectively The patients in the Tamura et al study were given melatonin from the fifth day of the previous menstrual cycle until the day of oocyte retrieval Both studies revealed improved oocyte quality but the tendency to increase pregnancy rates failed to reach statistical significance A study conducted by Unfer et al in 2011 administered 2g myo-inositol 200µg folic acid plus 3mg melatonin per day for 3-months to women who failed to become pregnant in previous IVF cycles at the commencement of a new IVF cycle This treatment resulted in a total of 13 pregnancies 9 of which were confirmed ultrasonographically and 4 undergoing spontaneous abortion Treatment continued after completion of the IVF cycle throughout pregnancy until delivery Treatment was associated with better quality oocytes and more successful pregnancies All babies that were born from melatonin-treated pregnancies were in healthy condition with no abnormalities
To evaluate the maternal-fetal transfer of melatonin a study by Okatani et al in 1998 administered a single oral dose of 3mg melatonin to 33 women at term 37-40 weeks gestation 1- to 4-hours before a planned caesarean section Levels of melatonin were evaluated in maternal venous blood and umbilical venous and arterial blood A total of 12 healthy pregnant women delivered by vaginal birth served as controls Administration of melatonin led to a rapid 120 minutes and marked 20-fold increase in the fetal serum levels There were no differences between maternal and fetal serum levels of melatonin suggesting a rapid and unrestricted transfer of melatonin from mother to fetus
The same investigators tested whether melatonin could up-regulate antioxidant enzymes No longer than 12 hours before voluntary termination of pregnancy between 7- and 9-weeks gestation an oral dose of 6mg melatonin was administered to 47 pregnant women A significant increase of the antioxidant enzyme glutathione peroxidase was observed in chorionic homogenates derived after the procedure leading to the conclusion that melatonin might provide an indirect protection against injury caused by reactive oxygen species as seen in preeclampsia FGR and fetal hypoxia
The dose used in this trial is based on data from a clinical trial of melatonin for preeclampsia showing that 30mg per day was safe for mother and baby without any apparent adverse effects Venous cord blood concentrations of melatonin achieved were unchanged between a mother receiving 8mg and 30mg per day of melatonin melatonin concentration 2100pgmL This cord blood concentration would appear sufficient for neuroprotection according to information in sheep models However the degree of oxidative stress reduction achieved within the placental bed was less in mothers receiving 8mg melatonin per day As such it was felt that the higher dose of 30mg per day was more likely to achieve a clinically significant result
The investigating team has shown that melatonin supplementation exerts multiple anti-oxidant and anti-inflammatory effects leading to a significant reduction in oxidative stress and lipid peroxidation within the fetal brain in an ovine model of FGR In the absence of melatonin this study showed that lipid peroxidation within the fetal brain led to significant white matter hypomyelination and axonal injury causing impaired neurological performance in the lambs Injury was ameliorated entirely in those exposed to melatonin supplementation with no structural brain injury seen and neurodevelopmental outcomes normalised
As a result a small n12 phase 1 trial was conducted at Monash Health supplementing pregnancies affected by severe FGR with 8mg of melatonin per day Melatonin use was well tolerated with no adverse effects seen A reduction in the degree of placental lipid peroxidation was seen n6
Early-onset FGR carries significant fetal risks of premature birth Following diagnosis those babies requiring delivery 32 weeks gestation carry approximately an 8 risk of stillbirth or neonatal death with those born 28 weeks gestation having a significantly higher perinatal mortality rate Around 30 of survivors will suffer serious neonatal morbidity Furthermore 8 are found to have neurodevelopmental impairment at two years of life These numbers are likely to be an underrepresentation as they are from a trial population which was closely surveyed compared to the general population
With approximately 97 of FGR infants born 32 weeks delivered by caesarean section the mother of a preterm FGR fetus faces the risks associated with morbidity and mortality relating to caesarean birth Furthermore the mother also faces a significant risk of morbidity and mortality from pre-eclampsia which develops among 15 - 40 of women who have a growth-restricted fetus
The most common side effects of melatonin are headache dizziness nausea and sleepiness Melatonin does not have any acute pharmacological effects on the nervous or vascular systems apart from its benign but active impact on sleep mechanisms Extremely high doses of up to 800mgkg of melatonin were safely administered to animals without deaths meaning a median lethal dose could not be established In humans long-term treatment with high daily doses of up to 10g melatonin did not cause any toxicity except for isolated cases of cutaneous flushing abdominal cramps diarrhoea scotoma lucidum and migraine
Prolonged ingestion of 1g melatonin per day caused only subjective drowsiness but did not provoke any toxicity in the eyes liver kidneys and bone marrow In a phase II clinical trial conducted in the Netherlands 1400 women were given 75mg melatonin nightly over 4-years with no side effects reported
The safety of melatonin use in pregnancy was explored in early pregnant Sprague-Dawley rats at doses ranging from 1 to 200mgkgday and did not affect antenatal mortality fetal body weight or other measures of fetal wellbeing Maternal adverse effects seen at high doses included mild sedation reduced maternal weight gain and reduced food intake This study sought to determine the maternal and fetal no adverse effect level NOAEL The NOAEL is the exposure level where a particular substance does not statistically or biologically significantly increase the frequency or severity of adverse effects in an exposed population compared to a suitable control population The maternal NOAEL in this study was found to be 100mgkgday the fetal NOAEL was established at 200mgkgday when administered to the mother The maternal lowest observed adverse effect level toxicity was 200mgkgday With the above information taken in context the Australian Therapeutic Goods Administration TGA has assigned melatonin a Pregnancy Category B3 classification
The investigators have recently completed a phase 1 trial NCT01695070 using melatonin supplementation in pregnancy as well as a clinical trial in women with pre-eclampsia ACTRN12613000476730 using the same dose as proposed for this trial and to date no adverse effects have been identified in the mother fetus or neonate
PROTECT Me aims to be a multicentre triple-blinded randomized parallel group placebo controlled trial This trial will be undertaken and co-ordinated by Monash Health
Other perinatal hospitals across Australia and New Zealand have agreed to join the trial so far Each centre will nominate a local investigator - a researcher to oversee local recruitment
The required sample size has been calculated to detect if melatonin supplementation affords a clinically relevant difference in neurodevelopmental outcomes among survivors An increase of 4-5 quotient points in the Bayley-IV Cognitive scale has been deemed sufficiently clinically meaningful to drive changes in health policy previously Power analysis shows that 69 participants per group will allow the detection of a difference in the Bayley-IV cognitive score of 5 points between the two groups with a power of 90 and an alpha level of 005 using 2 sided T test for comparison This assumes a standard deviation of 9 and that on average the growth restricted infant has been shown to have a cognitive score 5 points lower than the healthy preterm infant and 8 points lower than the healthy term infant Typically the Bayley IV score has a standard deviation of 15 however reduced variability has been seen in the FGR population and this has informed the standard deviation used here Among pregnancies complicated by early onset FGR a perinatal loss rate of 15 is commonly observed Allowing for a perinatal loss rate of 15 an extra 44 women will be recruited Assuming an additional 5 loss to follow-up rate the investigators will aim to recruit an extra 14 participants
This trial also aims to assess whether the impact of melatonin is different at different gestational ages Therefore a sub-analysis will be undertaken to compare those with early onset FGR identified 28 weeks gestation to those with late-onset FGR identified between 28-316 weeks gestation To ensure that this sub-analysis is adequately powered participants recruited will be randomized to either melatonin or placebo based on their gestational age at diagnosis Therefore recruiting 84 participants per group will see the overall trial aiming to recruit 336 participants
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None