Ignite Creation Date:
2024-05-06 @ 8:09 AM
Last Modification Date:
2024-10-26 @ 11:56 AM
Study NCT ID:
NCT02677870
Status:
COMPLETED
Last Update Posted:
2022-04-27
First Post:
2016-01-26
Brief Title:
The Effectiveness of Kuvan in Amish PKU Patients
Sponsor:
University Hospitals Cleveland Medical Center
Organization:
University Hospitals Cleveland Medical Center
Study Overview
Official Title:
The Effectiveness of High-Dose Synthetic BH4 Saproterin Dihydrochloride or Kuvan in Amish PKU Patients
Status:
COMPLETED
Status Verified Date:
2022-04
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:
None
Brief Summary:
The purpose of this study is to determine if Amish patients with PKU show responsiveness after a high dose prolonged Saproterin trial The population of interest has a high frequency of a specific splice site mutation the 1066-11GA mutation This splice site mutation activates a cryptic splice site resulting in an in frame insertion of 9 nucleotides preceding exon 11 This leads to protein conformational changes and abrogation of function Previous studies of this genotype have indicated 1 residual activity of the PAH enzyme and an insignificant responsiveness to Saproterin However in this specific study Phe levels were evaluated only over 24 hours after a single-dose BH4 challenge at the standard dose of 20mgkg
Based on new clinical information the investigators hypothesize that if given a prolonged trial of Saproterin at a higher dose Amish patients with PKU specifically those homozygous for the c1066-11GA mutation will have a significant reduction in Phe levels or an increase in Phe tolerance andor improvement in executive functioning and quality of life
Based on new clinical information the investigators hypothesize that if given a prolonged trial of Saproterin at a higher dose Amish patients with PKU specifically those homozygous for the c1066-11GA mutation will have a significant reduction in Phe levels or an increase in Phe tolerance andor improvement in executive functioning and quality of life
Detailed Description:
Phenylketonuria PKU is caused by a deficiency of the enzyme phenylalanine hydroxylase PAH PAH is responsible for the rate limiting step in phenylalanine catabolism This reaction is dependent on tetrahydrobiopterin BH4 BH4 is a catalytic cofactor for the enzyme PAH Supplementation with synthetic BH4 saproterin dihydrochloride or KuvanTm has been shown to activate residual PAH activity and lower Phe levels in certain patients It may also have a chaperone effect by binding abnormal PAH protein and decreasing its degradation Saproterin is an approved oral drug developed to reduce blood Phenylalanine Phe levels and increase Phe tolerance in BH4 responsive patients with hyperphenylalaninemia
Certain genotypes have been found to be good predictors of Saproterin responsiveness however these correlations are imperfect Therefore the standard of care is to perform a trial of Saproterin therapy to assess responsiveness in every PAH patient regardless of genotype Currently this recommendation does not include patients with two null mutations
The purpose of this study is to determine if Amish patients with PKU show responsiveness after a high dose prolonged Saproterin trial The population of interest has a high frequency of a specific splice site mutation the 1066-11GA mutation This splice site mutation leads to protein conformational changes and abrogation of function Previous studies of this genotype have indicated 1 residual activity of the PAH enzyme and an insignificant responsiveness to Saproterin However in this specific study Phe levels were evaluated only over 24 hours after a single-dose BH4 challenge at the standard dose of 20mgkg
Recently observation in several Amish patients suggests some promise that these patients may be responsive to Saproterin after a longer trial of the medication Personal comment - Samuel Yang MD In addition studies evaluating PAH enzyme activity in these patients have found evidence that this genotype may need higher cofactor concentrations for optimal enzyme activity and therefore may require a higher dose of Saproterin then the currently recommended 20mgkg 9 To date no formal clinical trial has been done
To answer the question of whether this genotype is responsive to Saproterin at higher doses over a prolonged period the investigators propose a randomized clinical trial comparing blood Phe levels in patients treated with standard-dose Saproterin to those treated with high-dose Saproterin The results of this study could reveal a new population of Saproterin responsive PKU patients This could call into question other null mutations of the PAH gene and their responsiveness to Saproterin This may lead to the investigation of genotypes previously thought to be unresponsive to Saproterin Further diet treatment alone has proven to be difficult for the Amish population for cultural and economic reasons
This study will include patients from three local centers with the potential of a fourth out of state center participating All patients will be enrolled through University Hospitals Case Medical Center Consent will be obtained over the phone or in person
Amish patients from University Hospitals Case Western ReserveRainbow Babies and Childrens HospitalCenter for Human Genetics
Amish patients from Akron Childrens hospital in Akron Ohio
Amish patients from The Center for Children with Special Needs DDC clinic Middlefield Ohio
Patients from Shodair Childrens Hospital in Helena Montana These patients may be recruited if more patients are required to meet our enrollment goal
Study patients will present to their preferred clinic for 5 office visits Initial testingPart 1 length 4 weeks
Recruited patients will present to clinic for part 1 of the study After informed consent is obtained molecular genetic testing will be performed Testing will include sequence analysis of the PAH gene This testing is necessary to identify the specific genotypes present in each patient The investigators expect the majority of this population to be homozygous or heterozygous for the above described splice site mutation Any patients found to have one or no identifiable mutations after sequencing will not be included in the study Genotypes will be grouped and analyzed separately at the conclusion of the study Patients who do not wish to undergo genetic testing will not be included in the study
Each patient will also have an initial blood Phe level drawn in the form of a dried blood spot on filter paper card that will be supplied by the testing company All Phe testing will be performed in a Clinical Laboratory Improvement Amendment CLIA certified laboratory at The Clinic for Special Children in Strasburg PA
Baseline assessment tools BRIEF PKU-QOL will also be performed at this initial visit Patients will be given a unique study number by our investigational drug pharmacy and will begin part 1 of the study as described below
In part 1 of the study patients will not receive any medication Each patient will be treated with diet alone Patients will maintain a stable Phe restricted diet including formula that is consistent with their diet at the time of enrollment This will be monitored by food diaries kept for 3 days of each week Specifically patients will be expected to keep diaries for the 3 consecutive days leading up to blood draw Based on these diaries average weekly Phe intake and Phe tolerance will be calculated and recorded Patients will also complete a food frequency tool which will be reviewed at part 1 2 and 3s initial visit We will use all of the tools above plus allow patients regular access to our dietician in order to encourage the maintenance of a stable diet
Blood Phe concentration will be measured weekly each Monday by blood spot cards Patients will not require weekly clinic visits to have Phe levels drawn Blood spot cards will be performed at their home and then mailed to the reference laboratory In order to teach and enable patients to become comfortable performing their own blood spots at home nursing staff from the DDC clinic will travel to each patients house weekly for part 1 of the study total of 3 home blood spots For parts 2 and 3 of the study those patients and families who are able will perform their own blood spots at home Those families who remain uncomfortable performing their own blood spots will continue to have their blood spots collected by home nursing
Initial visit
Venous blood draw for PAH gene sequencing
Baseline Phe level by dried blood spot card in office
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Baseline diet information collected and recorded Average weekly Phe calculated Phe tolerance calculated
Food frequency tool completed and reviewed
Blood Phe values and Phe tolerance from part 1 of the study on diet treatment alone will be compared to blood Phe values and Phe tolerance from parts 2 and 3 on low-dose and high-dose treatment
Part 2 length - 4 weeks
Study numbers will be randomized into standard-dose Saproterin or high-dose Saproterin groups treatment group A or treatment group B The investigational drug pharmacy will provide study patients with their medication in kits at the beginning of each treatment period Goal high-dose Saproterin dosing will be 40mgkg rounded up to the nearest 500mg provided in the form of pre-packaged 500mg packets of powder Labeled dosing on these packets will be covered by the investigational drug pharmacy and unidentifiable to patients Standard-dose Saproterin will be 20mgkg rounded to the nearest 100mg provided in the form of 100mg tablets Dosing of the tablets will be unidentifiable to patients Medication will be given orally once daily
Initial part 2 visit after 4 week diet only period
Food diaries collected for the previous 4 weeks 3 per week Average weekly Phe calculated Phe tolerance calculated
Food frequency tool completed and reviewed
Baseline Phe level drawn by dried blood spot card in office
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Provided with medication kits high or standard-dose 4 week supply
Final part 2 visit after 4 weeks of treatment
Food diaries collected for the previous 4 weeks 3 per week Average weekly Phe calculated Phe tolerance calculated
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Empty medication bottlespacket kits collected from each patient to assess compliance
Review of any potential adverse events
This is the end of part 2 There will then be a 2 week wash out period where patients receive no treatment The length of this washout period was determined based on the mean elimination half-life of saproterin and previous clinical trials The mean elimination half-life of saproterin ranges from 39 to 17 hours In previous trials washout periods have consisted of 7 and 30 days No efficacy assessments have been performed to differentiate or support one washout period over the other BioMarin Pharmaceuticals Inc Data on file Based on the elimination range above we determined that a two week washout period is sufficient Patients should maintain their steady diet during this time
Part 3 length - 4 weeks The cross-over will occur between treatment groups A to B and B to A
Initial part 3 visit after 2 week washout period
Food diaries collected for the previous 2 weeks 3 per week Average weekly Phe calculated Phe tolerance calculated
Food frequency tool completed and reviewed
Baseline Phe level performed by dried blood spot card in office
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Provided with medication kits high or standard-dose 4 week supply
Review of any potential adverse events
Final part 3 visit after 4 weeks of treatment
Food diaries collected for the previous 4 weeks 3 per week
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Empty medication bottles kits collected from each patient to assess compliance
Review of any potential adverse events
During all parts patients will maintain a stable Phe restricted diet including formula same diet as in part 1 of the study All Phe levels will be blinded and researchers will not have access to them until the conclusion of the study At the conclusion of the study after all data have been analyzed a complete list of blood Phe levels obtained during the study both on high and low-dose treatment will be sent to each patients primary metabolic physician Physicians can then discuss long term Saproterin treatment with their patients based on their Phe levels
The study will conclude after all parts are complete and groups A and B have both received a trial of high and standard-dose Saproterin All medication will be discontinued at this time
Certain genotypes have been found to be good predictors of Saproterin responsiveness however these correlations are imperfect Therefore the standard of care is to perform a trial of Saproterin therapy to assess responsiveness in every PAH patient regardless of genotype Currently this recommendation does not include patients with two null mutations
The purpose of this study is to determine if Amish patients with PKU show responsiveness after a high dose prolonged Saproterin trial The population of interest has a high frequency of a specific splice site mutation the 1066-11GA mutation This splice site mutation leads to protein conformational changes and abrogation of function Previous studies of this genotype have indicated 1 residual activity of the PAH enzyme and an insignificant responsiveness to Saproterin However in this specific study Phe levels were evaluated only over 24 hours after a single-dose BH4 challenge at the standard dose of 20mgkg
Recently observation in several Amish patients suggests some promise that these patients may be responsive to Saproterin after a longer trial of the medication Personal comment - Samuel Yang MD In addition studies evaluating PAH enzyme activity in these patients have found evidence that this genotype may need higher cofactor concentrations for optimal enzyme activity and therefore may require a higher dose of Saproterin then the currently recommended 20mgkg 9 To date no formal clinical trial has been done
To answer the question of whether this genotype is responsive to Saproterin at higher doses over a prolonged period the investigators propose a randomized clinical trial comparing blood Phe levels in patients treated with standard-dose Saproterin to those treated with high-dose Saproterin The results of this study could reveal a new population of Saproterin responsive PKU patients This could call into question other null mutations of the PAH gene and their responsiveness to Saproterin This may lead to the investigation of genotypes previously thought to be unresponsive to Saproterin Further diet treatment alone has proven to be difficult for the Amish population for cultural and economic reasons
This study will include patients from three local centers with the potential of a fourth out of state center participating All patients will be enrolled through University Hospitals Case Medical Center Consent will be obtained over the phone or in person
Amish patients from University Hospitals Case Western ReserveRainbow Babies and Childrens HospitalCenter for Human Genetics
Amish patients from Akron Childrens hospital in Akron Ohio
Amish patients from The Center for Children with Special Needs DDC clinic Middlefield Ohio
Patients from Shodair Childrens Hospital in Helena Montana These patients may be recruited if more patients are required to meet our enrollment goal
Study patients will present to their preferred clinic for 5 office visits Initial testingPart 1 length 4 weeks
Recruited patients will present to clinic for part 1 of the study After informed consent is obtained molecular genetic testing will be performed Testing will include sequence analysis of the PAH gene This testing is necessary to identify the specific genotypes present in each patient The investigators expect the majority of this population to be homozygous or heterozygous for the above described splice site mutation Any patients found to have one or no identifiable mutations after sequencing will not be included in the study Genotypes will be grouped and analyzed separately at the conclusion of the study Patients who do not wish to undergo genetic testing will not be included in the study
Each patient will also have an initial blood Phe level drawn in the form of a dried blood spot on filter paper card that will be supplied by the testing company All Phe testing will be performed in a Clinical Laboratory Improvement Amendment CLIA certified laboratory at The Clinic for Special Children in Strasburg PA
Baseline assessment tools BRIEF PKU-QOL will also be performed at this initial visit Patients will be given a unique study number by our investigational drug pharmacy and will begin part 1 of the study as described below
In part 1 of the study patients will not receive any medication Each patient will be treated with diet alone Patients will maintain a stable Phe restricted diet including formula that is consistent with their diet at the time of enrollment This will be monitored by food diaries kept for 3 days of each week Specifically patients will be expected to keep diaries for the 3 consecutive days leading up to blood draw Based on these diaries average weekly Phe intake and Phe tolerance will be calculated and recorded Patients will also complete a food frequency tool which will be reviewed at part 1 2 and 3s initial visit We will use all of the tools above plus allow patients regular access to our dietician in order to encourage the maintenance of a stable diet
Blood Phe concentration will be measured weekly each Monday by blood spot cards Patients will not require weekly clinic visits to have Phe levels drawn Blood spot cards will be performed at their home and then mailed to the reference laboratory In order to teach and enable patients to become comfortable performing their own blood spots at home nursing staff from the DDC clinic will travel to each patients house weekly for part 1 of the study total of 3 home blood spots For parts 2 and 3 of the study those patients and families who are able will perform their own blood spots at home Those families who remain uncomfortable performing their own blood spots will continue to have their blood spots collected by home nursing
Initial visit
Venous blood draw for PAH gene sequencing
Baseline Phe level by dried blood spot card in office
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Baseline diet information collected and recorded Average weekly Phe calculated Phe tolerance calculated
Food frequency tool completed and reviewed
Blood Phe values and Phe tolerance from part 1 of the study on diet treatment alone will be compared to blood Phe values and Phe tolerance from parts 2 and 3 on low-dose and high-dose treatment
Part 2 length - 4 weeks
Study numbers will be randomized into standard-dose Saproterin or high-dose Saproterin groups treatment group A or treatment group B The investigational drug pharmacy will provide study patients with their medication in kits at the beginning of each treatment period Goal high-dose Saproterin dosing will be 40mgkg rounded up to the nearest 500mg provided in the form of pre-packaged 500mg packets of powder Labeled dosing on these packets will be covered by the investigational drug pharmacy and unidentifiable to patients Standard-dose Saproterin will be 20mgkg rounded to the nearest 100mg provided in the form of 100mg tablets Dosing of the tablets will be unidentifiable to patients Medication will be given orally once daily
Initial part 2 visit after 4 week diet only period
Food diaries collected for the previous 4 weeks 3 per week Average weekly Phe calculated Phe tolerance calculated
Food frequency tool completed and reviewed
Baseline Phe level drawn by dried blood spot card in office
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Provided with medication kits high or standard-dose 4 week supply
Final part 2 visit after 4 weeks of treatment
Food diaries collected for the previous 4 weeks 3 per week Average weekly Phe calculated Phe tolerance calculated
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Empty medication bottlespacket kits collected from each patient to assess compliance
Review of any potential adverse events
This is the end of part 2 There will then be a 2 week wash out period where patients receive no treatment The length of this washout period was determined based on the mean elimination half-life of saproterin and previous clinical trials The mean elimination half-life of saproterin ranges from 39 to 17 hours In previous trials washout periods have consisted of 7 and 30 days No efficacy assessments have been performed to differentiate or support one washout period over the other BioMarin Pharmaceuticals Inc Data on file Based on the elimination range above we determined that a two week washout period is sufficient Patients should maintain their steady diet during this time
Part 3 length - 4 weeks The cross-over will occur between treatment groups A to B and B to A
Initial part 3 visit after 2 week washout period
Food diaries collected for the previous 2 weeks 3 per week Average weekly Phe calculated Phe tolerance calculated
Food frequency tool completed and reviewed
Baseline Phe level performed by dried blood spot card in office
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Provided with medication kits high or standard-dose 4 week supply
Review of any potential adverse events
Final part 3 visit after 4 weeks of treatment
Food diaries collected for the previous 4 weeks 3 per week
Executive functioning and quality of life assessment tools BRIEF PKU-QOL given
Empty medication bottles kits collected from each patient to assess compliance
Review of any potential adverse events
During all parts patients will maintain a stable Phe restricted diet including formula same diet as in part 1 of the study All Phe levels will be blinded and researchers will not have access to them until the conclusion of the study At the conclusion of the study after all data have been analyzed a complete list of blood Phe levels obtained during the study both on high and low-dose treatment will be sent to each patients primary metabolic physician Physicians can then discuss long term Saproterin treatment with their patients based on their Phe levels
The study will conclude after all parts are complete and groups A and B have both received a trial of high and standard-dose Saproterin All medication will be discontinued at this time
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None