<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01676844</url>
  </required_header>
  <id_info>
    <org_study_id>UEC1112/65</org_study_id>
    <secondary_id>2012-003625-19</secondary_id>
    <nct_id>NCT01676844</nct_id>
  </id_info>
  <brief_title>Investigating a New Way of Giving Medicine to Newborn and Preterm Babies</brief_title>
  <official_title>Oral Potassium Acid Phosphate Supplementation for Preterm Neonates; a Comparison of Oral Thin Films and Standard Oral Therapy.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Strathclyde</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Strathclyde</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      There is a deficit in the number of 'age-appropriate' formulations available for the delivery&#xD;
      of medicines to children. Liquid preparations are considered the 'gold standard' for&#xD;
      delivering medicines to children however many of these are formulated using ingredients which&#xD;
      can be toxic to children (e.g. preservatives, alcohols), particularly to neonatal babies (&lt; 4&#xD;
      weeks old) who do not possess the metabolic processes and mature organ function of older&#xD;
      children or adults. Rapidly dissolving oral thin films (OTFs) dissolve quickly in the saliva,&#xD;
      releasing the active ingredient(s) without the need for chewing or water, making them ideally&#xD;
      suited to patients who find it difficult to swallow other oral dosage forms such as tablets&#xD;
      or capsules. The aim of this study is to demonstrate that OTFs can offer a safe and effective&#xD;
      alternative for oral administration of phosphate supplements to neonatal infants for the&#xD;
      treatment of hypophosphataemia and osteopenia of prematurity. It is hypothesised that this&#xD;
      treatment will be equal to standard therapy using an oral solution. Babies born before 32&#xD;
      weeks gestational age are routinely supplemented with oral phosphate as soon as they have&#xD;
      been established on oral feeds in order to prevent bone disorders such as osteopenia. Babies&#xD;
      recruited to this study will be given phosphate supplementation as per NHS Greater Glasgow&#xD;
      and Clyde guidelines. This single-centre cross-over study will take place in the intensive&#xD;
      care and special care baby units at the Princess Royal Maternity in Glasgow. The&#xD;
      investigators aim to recruit 20-30 babies and will use blood phosphate levels (obtained from&#xD;
      routine sampling only) to evaluate treatment effect. Babies will be randomised to receive&#xD;
      either OTFs or oral solution of potassium acid phosphate for 2 weeks followed by 2 weeks of&#xD;
      the other therapy. The investigators hypothesise that OTF treatment will be equivalent to&#xD;
      standard oral solution.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There is a lack of 'age-appropriate' formulations available for delivering medicines to&#xD;
      children. Liquid formulations are considered the 'gold standard' for delivering medicines to&#xD;
      children. However, many of these are formulated using ingredients which can be toxic to&#xD;
      children, and particularly to neonates (children &lt;4 weeks old), who do not possess the&#xD;
      metabolic processes and mature organ function of adults. For example, many liquid&#xD;
      formulations contain preservatives such as benzoic acid to improve the shelf-life of the&#xD;
      product, or include solvents such as propylene glycol or ethanol to improve solubility. Many&#xD;
      of these additional, functional ingredients can product toxic effects in children. For&#xD;
      example, neonates are unable to metabolise benzoic acid, resulting in the accumulation of&#xD;
      this ingredient and potentially serious neurological and respiratory effects known as&#xD;
      'gasping syndrome'. Additionally, the lack of suitable licensed formulations for children&#xD;
      leads to the routine prescribing of medicines outside the terms of their product license&#xD;
      and/or the manipulation of medicines to make them suitable for children e.g. grinding up&#xD;
      tablets. Further manipulation of products increases the risk of inaccurate dosages being&#xD;
      administered, and adds a risk of error where additional calculations are required. There are&#xD;
      also concerns over compatibility when medicines are, for example, mixed with foods or drinks&#xD;
      in an attempt to improve acceptability. Looking specifically at prescribing within neonatal&#xD;
      intensive care, up to 90% of medicines prescribed are unlicensed or off-label i.e. used in a&#xD;
      way not covered by the product licence. Therefore, there is a need for more age-appropriate&#xD;
      solid formulations suitable for delivering medicines to children. By formulating the medicine&#xD;
      in a solid dosage form, the need for excipients such as preservatives can be removed. Within&#xD;
      the last few years, rapidly dissolving oral thin films (OTFs) have been developed as a novel&#xD;
      solid dosage platform for drug delivery. They were first established as breath fresheners and&#xD;
      have since progressed towards delivery of active pharmaceutical ingredients (APIs).&#xD;
      Approximately the size of a postage stamp, OTFs dissolve quickly in the saliva, releasing the&#xD;
      drug(s) without the need for chewing or water. They are ideally suited to patients who find&#xD;
      it difficult to swallow other oral dosage forms such as tablets or capsules. Paediatric and&#xD;
      elderly patients are particularly suited to this dosage design. Flavourings and sweeteners&#xD;
      can be included in the films to mask a bitter tasting medicine if necessary. The films are&#xD;
      discreet, easy to use and convenient. They have a history of uses in oral hygiene products&#xD;
      and medical devices. Recent developments have seen their use in over-the-counter cough and&#xD;
      cold remedies and anti-allergy products. In 2010, Zuplenz® became the first FDA approved&#xD;
      prescription only medicine in an OTF formulation for the delivery of ondansetron in the&#xD;
      treatment of chemotherapy-induced nausea and vomiting. Most recently in February 2012,&#xD;
      Applied Pharma Research (APR) were successful in marketing a prescription only zolmitriptan&#xD;
      based OTF product for the treatment of migraine. A basic thin film formulation can contain&#xD;
      very few ingredients and since they are presented as a solid dosage form, they do not require&#xD;
      the addition of preservatives. In the USA, Novartis has already marketed several thin film&#xD;
      products under the brand Triaminic® which are aimed at children from as young as four for the&#xD;
      treatment of coughs, colds, and allergies. In order to investigate whether OTFs are a safe&#xD;
      alternative for drug delivery to neonates, an OTF containing potassium acid phosphate (KAP)&#xD;
      has been formulated. KAP was chosen for this study since it is a non-toxic mineral supplement&#xD;
      routinely given to preterm infants to improve bone health. The majority of fetal uptake of&#xD;
      calcium and phosphorus occurs during the third trimester of pregnancy and so preterm infants&#xD;
      are born with reduced body stores of these minerals. Hypophosphataemia (low blood phosphorus)&#xD;
      results in increased levels of calcitriol, the active form of vitamin D, and subsequent&#xD;
      demineralisation of bone (osteopenia). The association between low birth weight,&#xD;
      hypercalcaemia (high blood calcium) and hypophosphataemia was first identified in the early&#xD;
      1980s. It was identified that active demineralisation of bone was occurring in order to&#xD;
      maintain the blood levels of phosphate required for other cellular functions and tissue&#xD;
      growth. Reduced bone mineral density or metabolic bone disease in very low birth weight&#xD;
      premature infants can lead to complications such as fractures and reduced growth. Preterm&#xD;
      infant milk formulas and human breast milk fortifiers are supplemented with phosphate, and in&#xD;
      addition within NHS Greater Glasgow and Clyde it is routine clinical practice to provide all&#xD;
      preterm infants born before 32 weeks' gestational age with an oral phosphate supplement.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>February 2013</start_date>
  <completion_date type="Anticipated">November 2013</completion_date>
  <primary_completion_date type="Anticipated">November 2013</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Serum phosphate</measure>
    <time_frame>Participants will be followed from birth until the end of the study period, approximately 6 weeks on average</time_frame>
    <description>The aim of this research is to demonstrate that oral thin films (OTFs) containing potassium acid phosphate are equivalent to standard oral phosphate supplementation using an oral solution in the prevention of hypophosphataemia (low blood phosphorus). The primary outcome measure will be plasma phosphate. We will assume an equivalent therapeutic effect using OTFs if individual plasma levels for these babies are found to lie within an acceptable physiological range, and the difference between the means of the two groups (as determined by a statistical t-test) lies within 20% of the mean plasma level for the control group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Age-appropriateness</measure>
    <time_frame>Participants will be followed from birth until the end of the study period, approximately 6 weeks on average</time_frame>
    <description>Secondary objectives will be in terms of age-appropriateness and general acceptability. A lack of any observable adverse effects e.g. choking, vomiting, diarrhoea, will indicate the safety of oral thin films in this age group. Acceptability will be assessed in terms of observed discomfort/distress e.g. grimacing, crying, associated with treatment administration and will be assessed using visual analogue scales.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Hypophosphataemia</condition>
  <condition>Osteopenia of Prematurity</condition>
  <arm_group>
    <arm_group_label>Oral thin film therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One or more oral thin films (OTFs) containing potassium acid phosphate administered to the inside cheek, tongue or palate at a dose of 0.5 mmol/kg body weight twice daily. Dosages will be rounded to the nearest 0.1 mM/kg. Where more than one OTF is required to achieve a dosage of 0.5mmol/kg, strips will be administered consecutively with time allowed between doses to allow for complete dissolving of the previous strip. Treatment will continue until the participant has received OTF therapy for 14 consecutive days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard oral phosphate supplementation as per NHS Greater Glasgow and Clyde Guidelines. An oral solution containing potassium acid phosphate (1 mmol/mL) will be administered at a dosage of 0.5 mM/kg body weight twice daily. Dosages will be rounded to the nearest 0.1 mM/kg. Standard therapy will continue until the participant has received treatment for 14 consecutive days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oral thin film therapy (Potassium acid phosphate oral thin films)</intervention_name>
    <description>Orally dissolving thin film. White, square oral thin film. 15 mm x 15 mm surface area. 1-2 mm film thickness. No markings.&#xD;
Place a single OTF on the tongue, inside cheek or palate and allow to dissolve.</description>
    <arm_group_label>Oral thin film therapy</arm_group_label>
    <other_name>Potassium acid phosphate oral thin films 0.2, 0.3 and 0.4 mM</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard therapy (Potassium acid phosphate oral solution)</intervention_name>
    <description>Each millilitre contains approximately 136mg Monobasic Potassium Phosphate Ph.Eur. (KH2PO4) equivalent to 1mmol Potassium (39mg) and 1mmol Phosphate (31mg Phosphorus). Manufacturer: Specials Products Ltd., Surrey, UK.</description>
    <arm_group_label>Standard therapy</arm_group_label>
    <other_name>Potassium acid phosphate 1mmol in 1ml oral solution</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  GENDER Male or female&#xD;
&#xD;
          -  AGE Born &lt; 32 completed weeks' gestational age&#xD;
&#xD;
          -  CONSENT Parents/other caregivers demonstrate understanding of the study and&#xD;
             willingness to consent to their child's participation as evidenced by voluntary&#xD;
             written informed consent (signed and dated) obtained before any trial-related&#xD;
             activities. (Trial-related activities are any procedure that would not have been&#xD;
             performed during normal management of the subject.)&#xD;
&#xD;
          -  MEDICATIONS AND TREATMENTS Participants must have been established on oral feeds (as&#xD;
             defined by as &gt; 75% of predicted volume enterally for three consecutive days).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  MEDICATIONS Patients prescribed concomitant medication known to interact with&#xD;
             potassium phosphate or any of the other ingredients in the oral thin film.&#xD;
&#xD;
          -  CLINICAL STUDIES&#xD;
&#xD;
               -  Previous participation in this study.&#xD;
&#xD;
               -  Subject whose participation in this study will result in a participation in more&#xD;
                  than four studies over a twelve month period.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>26 Weeks</minimum_age>
    <maximum_age>40 Weeks</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alex Mullen</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Strathclyde</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Helen Mactier, MB ChB</last_name>
    <phone>011441412115249</phone>
    <email>Helen.Mactier@ggc.scot.nhs.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Stewart I Watts, MPharm</last_name>
    <phone>011441415483577</phone>
    <email>stewart.watts@strath.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Princess Royal Maternity</name>
      <address>
        <city>Glasgow</city>
        <state>Strathclyde</state>
        <zip>G31 2ER</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <contact>
      <last_name>Helen Mactier, MB ChB</last_name>
      <phone>011441412115249</phone>
      <email>Helen.Mactier@ggc.scot.nhs.uk</email>
    </contact>
    <contact_backup>
      <last_name>June Grant, MPharm</last_name>
      <phone>011441412115400</phone>
      <email>June.Grant@ggc.scot.nhs.uk</email>
    </contact_backup>
    <investigator>
      <last_name>Helen Mactier, MB ChB</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Conroy S, McIntyre J. The use of unlicensed and off-label medicines in the neonate. Semin Fetal Neonatal Med. 2005 Apr;10(2):115-22. doi: 10.1016/j.siny.2004.11.003. Epub 2005 Jan 25.</citation>
    <PMID>15701577</PMID>
  </reference>
  <reference>
    <citation>Lyon AJ, McIntosh N, Wheeler K, Brooke OG. Hypercalcaemia in extremely low birthweight infants. Arch Dis Child. 1984 Dec;59(12):1141-4. doi: 10.1136/adc.59.12.1141.</citation>
    <PMID>6441525</PMID>
  </reference>
  <reference>
    <citation>Mitchell SM, Rogers SP, Hicks PD, Hawthorne KM, Parker BR, Abrams SA. High frequencies of elevated alkaline phosphatase activity and rickets exist in extremely low birth weight infants despite current nutritional support. BMC Pediatr. 2009 Jul 29;9:47. doi: 10.1186/1471-2431-9-47.</citation>
    <PMID>19640269</PMID>
  </reference>
  <reference>
    <citation>Zhong B. How to calculate sample size in randomized controlled trial? J Thorac Dis. 2009 Dec;1(1):51-4.</citation>
    <PMID>22263004</PMID>
  </reference>
  <reference>
    <citation>Marks J, Srai SK, Biber J, Murer H, Unwin RJ, Debnam ES. Intestinal phosphate absorption and the effect of vitamin D: a comparison of rats with mice. Exp Physiol. 2006 May;91(3):531-7. doi: 10.1113/expphysiol.2005.032516. Epub 2006 Jan 23.</citation>
    <PMID>16431934</PMID>
  </reference>
  <reference>
    <citation>Walton J, Gray TK. Absorption of inorganic phosphate in the human small intestine. Clin Sci (Lond). 1979 May;56(5):407-12. doi: 10.1042/cs0560407.</citation>
    <PMID>477225</PMID>
  </reference>
  <reference>
    <citation>Chen TC, Castillo L, Korycka-Dahl M, DeLuca HF. Role of vitamin D metabolites in phosphate transport of rat intestine. J Nutr. 1974 Aug;104(8):1056-60. doi: 10.1093/jn/104.8.1056. No abstract available.</citation>
    <PMID>4854171</PMID>
  </reference>
  <reference>
    <citation>Uribarri J. Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake. Semin Dial. 2007 Jul-Aug;20(4):295-301. doi: 10.1111/j.1525-139X.2007.00309.x.</citation>
    <PMID>17635818</PMID>
  </reference>
  <reference>
    <citation>Borowitz SM, Ghishan FK. Phosphate transport in human jejunal brush-border membrane vesicles. Gastroenterology. 1989 Jan;96(1):4-10. doi: 10.1016/0016-5085(89)90757-9.</citation>
    <PMID>2909436</PMID>
  </reference>
  <verification_date>August 2012</verification_date>
  <study_first_submitted>August 23, 2012</study_first_submitted>
  <study_first_submitted_qc>August 30, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 31, 2012</study_first_posted>
  <last_update_submitted>August 30, 2012</last_update_submitted>
  <last_update_submitted_qc>August 30, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 31, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Strathclyde</investigator_affiliation>
    <investigator_full_name>Professor Alex Mullen</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Phosphorus</keyword>
  <keyword>Phosphate</keyword>
  <keyword>Hypophosphataemia</keyword>
  <keyword>Osteopenia</keyword>
  <keyword>Prematurity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bone Diseases, Metabolic</mesh_term>
    <mesh_term>Premature Birth</mesh_term>
    <mesh_term>Hypophosphatemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pharmaceutical Solutions</mesh_term>
    <mesh_term>Potassium phosphate</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01676844
org study id: UEC1112/65
secondary id: 2012-003625-19
nct id: NCT01676844
lead sponsor: 
has dmc: No
There is a deficit in the number of 'age-appropriate' formulations available for the delivery
      of medicines to children. Liquid preparations are considered the 'gold standard' for
      delivering medicines to children however many of these are formulated using ingredients which
      can be toxic to children (e.g. preservatives, alcohols), particularly to neonatal babies (< 4
      weeks old) who do not possess the metabolic processes and mature organ function of older
      children or adults. Rapidly dissolving oral thin films (OTFs) dissolve quickly in the saliva,
      releasing the active ingredient(s) without the need for chewing or water, making them ideally
      suited to patients who find it difficult to swallow other oral dosage forms such as tablets
      or capsules. The aim of this study is to demonstrate that OTFs can offer a safe and effective
      alternative for oral administration of phosphate supplements to neonatal infants for the
      treatment of hypophosphataemia and osteopenia of prematurity. It is hypothesised that this
      treatment will be equal to standard therapy using an oral solution. Babies born before 32
      weeks gestational age are routinely supplemented with oral phosphate as soon as they have
      been established on oral feeds in order to prevent bone disorders such as osteopenia. Babies
      recruited to this study will be given phosphate supplementation as per NHS Greater Glasgow
      and Clyde guidelines. This single-centre cross-over study will take place in the intensive
      care and special care baby units at the Princess Royal Maternity in Glasgow. The
      investigators aim to recruit 20-30 babies and will use blood phosphate levels (obtained from
      routine sampling only) to evaluate treatment effect. Babies will be randomised to receive
      either OTFs or oral solution of potassium acid phosphate for 2 weeks followed by 2 weeks of
      the other therapy. The investigators hypothesise that OTF treatment will be equivalent to
      standard oral solution.
There is a lack of 'age-appropriate' formulations available for delivering medicines to
      children. Liquid formulations are considered the 'gold standard' for delivering medicines to
      children. However, many of these are formulated using ingredients which can be toxic to
      children, and particularly to neonates (children <4 weeks old), who do not possess the
      metabolic processes and mature organ function of adults. For example, many liquid
      formulations contain preservatives such as benzoic acid to improve the shelf-life of the
      product, or include solvents such as propylene glycol or ethanol to improve solubility. Many
      of these additional, functional ingredients can product toxic effects in children. For
      example, neonates are unable to metabolise benzoic acid, resulting in the accumulation of
      this ingredient and potentially serious neurological and respiratory effects known as
      'gasping syndrome'. Additionally, the lack of suitable licensed formulations for children
      leads to the routine prescribing of medicines outside the terms of their product license
      and/or the manipulation of medicines to make them suitable for children e.g. grinding up
      tablets. Further manipulation of products increases the risk of inaccurate dosages being
      administered, and adds a risk of error where additional calculations are required. There are
      also concerns over compatibility when medicines are, for example, mixed with foods or drinks
      in an attempt to improve acceptability. Looking specifically at prescribing within neonatal
      intensive care, up to 90% of medicines prescribed are unlicensed or off-label i.e. used in a
      way not covered by the product licence. Therefore, there is a need for more age-appropriate
      solid formulations suitable for delivering medicines to children. By formulating the medicine
      in a solid dosage form, the need for excipients such as preservatives can be removed. Within
      the last few years, rapidly dissolving oral thin films (OTFs) have been developed as a novel
      solid dosage platform for drug delivery. They were first established as breath fresheners and
      have since progressed towards delivery of active pharmaceutical ingredients (APIs).
      Approximately the size of a postage stamp, OTFs dissolve quickly in the saliva, releasing the
      drug(s) without the need for chewing or water. They are ideally suited to patients who find
      it difficult to swallow other oral dosage forms such as tablets or capsules. Paediatric and
      elderly patients are particularly suited to this dosage design. Flavourings and sweeteners
      can be included in the films to mask a bitter tasting medicine if necessary. The films are
      discreet, easy to use and convenient. They have a history of uses in oral hygiene products
      and medical devices. Recent developments have seen their use in over-the-counter cough and
      cold remedies and anti-allergy products. In 2010, Zuplenz® became the first FDA approved
      prescription only medicine in an OTF formulation for the delivery of ondansetron in the
      treatment of chemotherapy-induced nausea and vomiting. Most recently in February 2012,
      Applied Pharma Research (APR) were successful in marketing a prescription only zolmitriptan
      based OTF product for the treatment of migraine. A basic thin film formulation can contain
      very few ingredients and since they are presented as a solid dosage form, they do not require
      the addition of preservatives. In the USA, Novartis has already marketed several thin film
      products under the brand Triaminic® which are aimed at children from as young as four for the
      treatment of coughs, colds, and allergies. In order to investigate whether OTFs are a safe
      alternative for drug delivery to neonates, an OTF containing potassium acid phosphate (KAP)
      has been formulated. KAP was chosen for this study since it is a non-toxic mineral supplement
      routinely given to preterm infants to improve bone health. The majority of fetal uptake of
      calcium and phosphorus occurs during the third trimester of pregnancy and so preterm infants
      are born with reduced body stores of these minerals. Hypophosphataemia (low blood phosphorus)
      results in increased levels of calcitriol, the active form of vitamin D, and subsequent
      demineralisation of bone (osteopenia). The association between low birth weight,
      hypercalcaemia (high blood calcium) and hypophosphataemia was first identified in the early
      1980s. It was identified that active demineralisation of bone was occurring in order to
      maintain the blood levels of phosphate required for other cellular functions and tissue
      growth. Reduced bone mineral density or metabolic bone disease in very low birth weight
      premature infants can lead to complications such as fractures and reduced growth. Preterm
      infant milk formulas and human breast milk fortifiers are supplemented with phosphate, and in
      addition within NHS Greater Glasgow and Clyde it is routine clinical practice to provide all
      preterm infants born before 32 weeks' gestational age with an oral phosphate supplement.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Serum phosphate
time frame: Participants will be followed from birth until the end of the study period, approximately 6 weeks on average
description: The aim of this research is to demonstrate that oral thin films (OTFs) containing potassium acid phosphate are equivalent to standard oral phosphate supplementation using an oral solution in the prevention of hypophosphataemia (low blood phosphorus). The primary outcome measure will be plasma phosphate. We will assume an equivalent therapeutic effect using OTFs if individual plasma levels for these babies are found to lie within an acceptable physiological range, and the difference between the means of the two groups (as determined by a statistical t-test) lies within 20% of the mean plasma level for the control group.
measure: Age-appropriateness
time frame: Participants will be followed from birth until the end of the study period, approximately 6 weeks on average
description: Secondary objectives will be in terms of age-appropriateness and general acceptability. A lack of any observable adverse effects e.g. choking, vomiting, diarrhoea, will indicate the safety of oral thin films in this age group. Acceptability will be assessed in terms of observed discomfort/distress e.g. grimacing, crying, associated with treatment administration and will be assessed using visual analogue scales.
arm group label: Oral thin film therapy
arm group type: Experimental
description: One or more oral thin films (OTFs) containing potassium acid phosphate administered to the inside cheek, tongue or palate at a dose of 0.5 mmol/kg body weight twice daily. Dosages will be rounded to the nearest 0.1 mM/kg. Where more than one OTF is required to achieve a dosage of 0.5mmol/kg, strips will be administered consecutively with time allowed between doses to allow for complete dissolving of the previous strip. Treatment will continue until the participant has received OTF therapy for 14 consecutive days.
arm group label: Standard therapy
arm group type: Active Comparator
description: Standard oral phosphate supplementation as per NHS Greater Glasgow and Clyde Guidelines. An oral solution containing potassium acid phosphate (1 mmol/mL) will be administered at a dosage of 0.5 mM/kg body weight twice daily. Dosages will be rounded to the nearest 0.1 mM/kg. Standard therapy will continue until the participant has received treatment for 14 consecutive days.
intervention type: Drug
intervention name: Oral thin film therapy (Potassium acid phosphate oral thin films)
description: Orally dissolving thin film. White, square oral thin film. 15 mm x 15 mm surface area. 1-2 mm film thickness. No markings.
Place a single OTF on the tongue, inside cheek or palate and allow to dissolve.
arm group label: Oral thin film therapy
other name: Potassium acid phosphate oral thin films 0.2, 0.3 and 0.4 mM
intervention type: Drug
intervention name: Standard therapy (Potassium acid phosphate oral solution)
description: Each millilitre contains approximately 136mg Monobasic Potassium Phosphate Ph.Eur. (KH2PO4) equivalent to 1mmol Potassium (39mg) and 1mmol Phosphate (31mg Phosphorus). Manufacturer: Specials Products Ltd., Surrey, UK.
arm group label: Standard therapy
other name: Potassium acid phosphate 1mmol in 1ml oral solution
criteria: 
gender: All
minimum age: 26 Weeks
maximum age: 40 Weeks
healthy volunteers: Accepts Healthy Volunteers
last name: Alex Mullen
role: Principal Investigator
affiliation: University of Strathclyde
last name: Helen Mactier, MB ChB
phone: 011441412115249
email: Helen.Mactier@ggc.scot.nhs.uk
last name: Stewart I Watts, MPharm
phone: 011441415483577
email: stewart.watts@strath.ac.uk
facility: 
contact: 
contact backup: 
investigator: 
country: United Kingdom
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PMID: 15701577
citation: Lyon AJ, McIntosh N, Wheeler K, Brooke OG. Hypercalcaemia in extremely low birthweight infants. Arch Dis Child. 1984 Dec;59(12):1141-4. doi: 10.1136/adc.59.12.1141.
PMID: 6441525
citation: Mitchell SM, Rogers SP, Hicks PD, Hawthorne KM, Parker BR, Abrams SA. High frequencies of elevated alkaline phosphatase activity and rickets exist in extremely low birth weight infants despite current nutritional support. BMC Pediatr. 2009 Jul 29;9:47. doi: 10.1186/1471-2431-9-47.
PMID: 19640269
citation: Zhong B. How to calculate sample size in randomized controlled trial? J Thorac Dis. 2009 Dec;1(1):51-4.
PMID: 22263004
citation: Marks J, Srai SK, Biber J, Murer H, Unwin RJ, Debnam ES. Intestinal phosphate absorption and the effect of vitamin D: a comparison of rats with mice. Exp Physiol. 2006 May;91(3):531-7. doi: 10.1113/expphysiol.2005.032516. Epub 2006 Jan 23.
PMID: 16431934
citation: Walton J, Gray TK. Absorption of inorganic phosphate in the human small intestine. Clin Sci (Lond). 1979 May;56(5):407-12. doi: 10.1042/cs0560407.
PMID: 477225
citation: Chen TC, Castillo L, Korycka-Dahl M, DeLuca HF. Role of vitamin D metabolites in phosphate transport of rat intestine. J Nutr. 1974 Aug;104(8):1056-60. doi: 10.1093/jn/104.8.1056. No abstract available.
PMID: 4854171
citation: Uribarri J. Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake. Semin Dial. 2007 Jul-Aug;20(4):295-301. doi: 10.1111/j.1525-139X.2007.00309.x.
PMID: 17635818
citation: Borowitz SM, Ghishan FK. Phosphate transport in human jejunal brush-border membrane vesicles. Gastroenterology. 1989 Jan;96(1):4-10. doi: 10.1016/0016-5085(89)90757-9.
PMID: 2909436
responsible party type: Principal Investigator
investigator affiliation: University of Strathclyde
investigator full name: Professor Alex Mullen
investigator title: Principal Investigator
mesh term: Bone Diseases, Metabolic
mesh term: Premature Birth
mesh term: Hypophosphatemia
mesh term: Pharmaceutical Solutions
mesh term: Potassium phosphate