Ignite Creation Date:
2024-05-06 @ 1:48 AM
Last Modification Date:
2024-10-26 @ 11:10 AM
Study NCT ID:
NCT01901666
Status:
UNKNOWN
Last Update Posted:
2013-07-17
First Post:
2013-06-29
Brief Title:
Assessment Of Gh-Igf-1 Axis In Children With Chronic Myelogenous Leukemia CML In Remission
Sponsor:
Post Graduate Institute of Medical Education and Research Chandigarh
Organization:
PIMERIndia
Study Overview
Official Title:
ASSESSMENT OF GH-IGF1 AXIS AND TO STUDY RESPONSE TO GH THERAPY IN CHILDREN WITH CML IN REMISSION HAVING GH DEFICIENCY
Status:
UNKNOWN
Status Verified Date:
2013-07
Last Known Status:
RECRUITING
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:
None
Brief Summary:
CML is a myeloproliferative disorder defined by the presence of the Philadelphia chromosome which arises from the reciprocal translocation of genes on chromosomes 9 and 22It is rare in childhood and accounts for 2-3 of all leukemias in childhood
BCR-ABL gene on Philadelphia chromosome results in a 210kd fused BCR-ABL protein with constitutive tyrosine kinase activity and subsequent activation of cytoplasmic and nuclear signal transduction pathways including STAT RAS JUN MYC and phosphatidylinositol-3 kinase The ultimate result of such activation is the myeloid proliferation and differentiation and suppressed apoptosis
Children present with a higher WBC count otherwise presentation is nearly identical to adults Current treatment include tyrosine kinase inhibitors TKI and allogeneic stem cell transplant SCTImatinibmesylate inhibits the tyrosine kinase TK activity of BCR-ABL1 and several related TKs including c-kit and the platelet-derived growth factor receptor PDGFR Development of tyrosine kinase inhibitor TKI therapy has revolutionizedtreatment of CML Imatinib or second generation TKIs dasatinib or nilotinib have become standard front-line therapy forchildren and adults with CML and are also important componentsof therapy for Ph acute lymphoblastic leukemia ALL
TKIs are administered orally and cause a number of side effects including fatigue hypertension rash impaired wound healing myelosuppression and diarrhea The overall toxicity of TKIs while less life-threatening than conventional cytotoxic chemotherapy nevertheless is common and may require dose reductionRecently proposed endocrine-related side effects of these agents include alterations in thyroid function bone metabolism linear growth gonadal function fetal development glucose metabolism and adrenal function
Growth impairment is one of the major adverse effect of long-term imatinib treatment in children with CML Multiple case reports have demonstrated growth retardation in children onimatinibImatinibmesylate inhibits the TK activity of BCR-ABL1 and several related TKs including c-kit and theplatelet-derived growth factor receptor PDGFR It isthe inhibition of TK activity at the non-BCR-ABL sites that couldbe the likely cause for the adverse effect on growth Severalstudies in adults have suggested that inhibition of c-kitc-fms and PDGF receptors results in modulation of bone metabolism Other reports are focusing on disturbance of the growth hormone GH axis as a mechanism for growth impairment Receptor and non receptor TK is expressed at multiple levels in GH-IGF-1 axis including GHRH-R GH-R and IGF-1R Inhibition of TKs with TKI at any one of these level might result in growth impairment
Various studies are available to show that Imainib therapy may cause short stature in children on prolonged treatment but exact mechanism by which this occurs is still not clear Further no treatment modality has been tried so far for short stature in these children
So the purpose of this study is to study GH-IGF1 axis in these children and to administer GH therapy to GH deficienct children in remission
BCR-ABL gene on Philadelphia chromosome results in a 210kd fused BCR-ABL protein with constitutive tyrosine kinase activity and subsequent activation of cytoplasmic and nuclear signal transduction pathways including STAT RAS JUN MYC and phosphatidylinositol-3 kinase The ultimate result of such activation is the myeloid proliferation and differentiation and suppressed apoptosis
Children present with a higher WBC count otherwise presentation is nearly identical to adults Current treatment include tyrosine kinase inhibitors TKI and allogeneic stem cell transplant SCTImatinibmesylate inhibits the tyrosine kinase TK activity of BCR-ABL1 and several related TKs including c-kit and the platelet-derived growth factor receptor PDGFR Development of tyrosine kinase inhibitor TKI therapy has revolutionizedtreatment of CML Imatinib or second generation TKIs dasatinib or nilotinib have become standard front-line therapy forchildren and adults with CML and are also important componentsof therapy for Ph acute lymphoblastic leukemia ALL
TKIs are administered orally and cause a number of side effects including fatigue hypertension rash impaired wound healing myelosuppression and diarrhea The overall toxicity of TKIs while less life-threatening than conventional cytotoxic chemotherapy nevertheless is common and may require dose reductionRecently proposed endocrine-related side effects of these agents include alterations in thyroid function bone metabolism linear growth gonadal function fetal development glucose metabolism and adrenal function
Growth impairment is one of the major adverse effect of long-term imatinib treatment in children with CML Multiple case reports have demonstrated growth retardation in children onimatinibImatinibmesylate inhibits the TK activity of BCR-ABL1 and several related TKs including c-kit and theplatelet-derived growth factor receptor PDGFR It isthe inhibition of TK activity at the non-BCR-ABL sites that couldbe the likely cause for the adverse effect on growth Severalstudies in adults have suggested that inhibition of c-kitc-fms and PDGF receptors results in modulation of bone metabolism Other reports are focusing on disturbance of the growth hormone GH axis as a mechanism for growth impairment Receptor and non receptor TK is expressed at multiple levels in GH-IGF-1 axis including GHRH-R GH-R and IGF-1R Inhibition of TKs with TKI at any one of these level might result in growth impairment
Various studies are available to show that Imainib therapy may cause short stature in children on prolonged treatment but exact mechanism by which this occurs is still not clear Further no treatment modality has been tried so far for short stature in these children
So the purpose of this study is to study GH-IGF1 axis in these children and to administer GH therapy to GH deficienct children in remission
Detailed Description:
AIMS AND OBJECTIVES
To study GH-IGF1 axis in children with CML having short stature following Imatinib therapy
To administer growth hormone therapy to children with CML on Imatinib in remission having GH deficiency
STUDY DESIGN It is an interventional non-randomized study STUDY GROUP one NUMBER OF PATIENTS 20
ELIGIBILITY CRITERIA
CML patients on Imatinib therapy for more than 6 months and in remission will be included in the study if there is
Severe short stature height SDS -3 SD
Severe growth deceleration height velocity SDS -2 SD over 12 months
Height -2 SD and height velocity -10 SD over 12 months
Height -15 SD and height velocity -15 SD over 2 years
EXCLUSION CRITERIA
Patients with coexisting systemic illness eg kidney disease liver disease celiac disease
Patients of CML not receiving Imatinib therapy as prescribed eg poor compliance
MATERIALS AND METHODS
Once eligibility criteria are confirmed after having written informed consent following parameters will be assessed
Chronological age
Height
Height for age
Height SDS
Target height
Body proportion
Weight
Weight for age
Following investigations will be done in all patients
Complete blood count with peripheral smear
Liver function tests
Renal function tests
Calcium phosphate ALP albumin
Fasting Blood glucose
Thyroid function tests T4 and TSH
Serum Cortisol
Serum Prolactin
Serum Follicular stimulating hormone FSH and Luteinizing hormone LH
Serum Testosterone
Serum Estrogen
Serum IgA anti-tTG antibodies
Serum IGF-1
Serum IGFBP-3
X-Ray of left hand and wrist
MRI Brain focussing pituitary hypothalamic region Two dynamic growth hormone provocationGHRH Arginine andGlucagon tests will be performed in all patients having no other cause for short statureMinimum gap of one week will be kept between the two GHstimulationtestsPriming will be done prior to each GH stimulation test IGF-1 generation test will be performed in all patientsMinimum gap of one week will be kept betweenGH stimulation and IGF-1 generation test
X-ray of left hand and wrist for bone age and sexual maturity rating SMR by Tanners scale will be performed for all patients All GH deficient patients with bone age 14 years will be treated with GH therapy for one year 03mgkgweek GH in seven divided doses will be given subcutaneously Serum IGF-1 will be measured 4weekly and GH dose will be titrated till SIGF-1 is in mid-normal range and then after every 3 months
Patients will be monitored for any side effects of GH therapy Growth parameters Serum T4 TSH and complete blood count will be assessed after every 3 monthsCytogenetic and molecular remission will be assessed before and after completion of GH therapy
To study GH-IGF1 axis in children with CML having short stature following Imatinib therapy
To administer growth hormone therapy to children with CML on Imatinib in remission having GH deficiency
STUDY DESIGN It is an interventional non-randomized study STUDY GROUP one NUMBER OF PATIENTS 20
ELIGIBILITY CRITERIA
CML patients on Imatinib therapy for more than 6 months and in remission will be included in the study if there is
Severe short stature height SDS -3 SD
Severe growth deceleration height velocity SDS -2 SD over 12 months
Height -2 SD and height velocity -10 SD over 12 months
Height -15 SD and height velocity -15 SD over 2 years
EXCLUSION CRITERIA
Patients with coexisting systemic illness eg kidney disease liver disease celiac disease
Patients of CML not receiving Imatinib therapy as prescribed eg poor compliance
MATERIALS AND METHODS
Once eligibility criteria are confirmed after having written informed consent following parameters will be assessed
Chronological age
Height
Height for age
Height SDS
Target height
Body proportion
Weight
Weight for age
Following investigations will be done in all patients
Complete blood count with peripheral smear
Liver function tests
Renal function tests
Calcium phosphate ALP albumin
Fasting Blood glucose
Thyroid function tests T4 and TSH
Serum Cortisol
Serum Prolactin
Serum Follicular stimulating hormone FSH and Luteinizing hormone LH
Serum Testosterone
Serum Estrogen
Serum IgA anti-tTG antibodies
Serum IGF-1
Serum IGFBP-3
X-Ray of left hand and wrist
MRI Brain focussing pituitary hypothalamic region Two dynamic growth hormone provocationGHRH Arginine andGlucagon tests will be performed in all patients having no other cause for short statureMinimum gap of one week will be kept between the two GHstimulationtestsPriming will be done prior to each GH stimulation test IGF-1 generation test will be performed in all patientsMinimum gap of one week will be kept betweenGH stimulation and IGF-1 generation test
X-ray of left hand and wrist for bone age and sexual maturity rating SMR by Tanners scale will be performed for all patients All GH deficient patients with bone age 14 years will be treated with GH therapy for one year 03mgkgweek GH in seven divided doses will be given subcutaneously Serum IGF-1 will be measured 4weekly and GH dose will be titrated till SIGF-1 is in mid-normal range and then after every 3 months
Patients will be monitored for any side effects of GH therapy Growth parameters Serum T4 TSH and complete blood count will be assessed after every 3 monthsCytogenetic and molecular remission will be assessed before and after completion of GH therapy
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None