Medication AbsorptionPhase 1NCT03093090
Evaluating Predictive Methods & Product Performance in Healthy Adults for Pediatric Patients, A Case Study: Furosemide
A Phase 1 study testing Water, Parmalat™ Whole Milk and Similac Pro-Advance™ in people with Medication Absorption, run by Yale University at 1 site in United States.
Trial summary
Poorly absorbed medications such as furosemide are common and recent experiments suggest that improvement in absorption can occur if these types of medications are consumed with liquids such as milk. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Medication Absorption
- What is being tested?
- Water, Parmalat™ Whole Milk and Similac Pro-Advance™
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 31 Dec 2018to 1 Jun 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Age 18-40
- 4 females and 4 males will be recruited
- Free from known significant chronic medical illness (i.e., hypertension, diabetes, atherosclerosis, chronic kidney disease, liver disease, lupus, taking medications with known interactions with furosemide, a history of syncope/falls, or any acute illness, such as influenza, gastroenteritis, dehydration, electrolyte imbalance, or thrombosis risks).
- Systolic Blood Pressure ≥90 mmHg at Screening Visit
Who cannot join
- Inability to read English or give informed consent
- Recent hospitalization within 6 months
- Pregnant or lactating
- Allergy or intolerance to furosemide
- Allergy or intolerance to milk, milk products or soy
- Inability to return for 4 consecutive weekly overnight visits at the study site
- Female subjects with low, or borderline low blood pressure, will be evaluated carefully prior to enrollment, to ensure the safety of all subjects involved in the research study.
Trial locations and contacts
1 site in 1 country.
About this study
Poorly absorbed medications such as furosemide are common and recent experiments suggest that improvement in absorption can occur if these types of medications are consumed with liquids such as milk. The purpose of this study is to evaluate the absorption of furosemide in normal adults when taken with bottled water, milk (Parmalat™ Whole Milk), baby formula (Similac Pro-Advance™), or Ensure Plus™. These results will be used to make models that predict how these liquids will affect drug absorption in children, potentially providing ways to improve medication absorption in children.
Read the detailed description
Low solubility drugs are common in the pharmacopeia and it has been estimated that more than 40% of new chemical entities developed by the pharmaceutical industry are practically insoluble in water. Exploratory in vitro studies by the CDER have recently demonstrated that the solubility, and thus potentially the bioavailability, of poorly soluble drugs may be highly enhanced when administered with milk (Parmalat™ Whole Milk) or baby formula (Similac Pro-Advance™).
While the reasons for variable bioavailability of furosemide are not well characterized, the effect of gastric pH, food and dosing liquids are commonly observed on the absorption of BCS Class IV drugs. Absorption variability is much greater in children due to developmental changes in factors such as gastric fluid, blood flow to the intestine, bile acid composition/secretion, intestinal surface area and drug metabolizing enzyme and transporter abundance. Therefore, it is critical to determine the physio-chemical physiological interactions for furosemide that can explain inter-subject and inter-dosing variability. An integrated in vitro, in silico and in vivo pharmacology approach to study the effect of dosing liquids on PK and PD of furosemide is novel. Quantitative understanding of factors affecting furosemide absorption will first be evaluated using in vitro tests such as solubility, dissolution and protein binding with the dosing liquids. The physiochemical information relevant to drug absorption and elimination will be curated from the literature to build the PBPK model. Such in vitro- in vivo extrapolation (IVIVE) linked PBPK modeling approach is crucial to better characterize furosemide's variable bioavailability. Another novel aspect of this study is that we will include renal metabolism of furosemide in the PBPK modeling. While plasma concentration will be critical in determining rate and extent of furosemide absorption, the renal elimination is the primary contributor to the PD response of furosemide as delivery of drug to the luminal surface of the renal tubule is required. PBPK modeling allows extrapolation of model to special population. For example, once the model is optimized and validated to predict effect of dosing liquids on adult PK of furosemide from in vitro data, this approach can be further extrapolated to children using pediatric gut physiological parameters. This novel approach will allow prediction of furosemide PK and PD in children without conducting a clinical study in this difficult to study population.
- Conditions
- Medication Absorption
- Being tested
- Water, Parmalat™ Whole Milk, Similac Pro-Advance™, Ensure Plus™, Furosemide 20 MG
- Keywords
- furosemide
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
WaterDietary supplement
6 oz
Parmalat™ Whole MilkDietary supplement
Also called Milk
6 oz
Similac Pro-Advance™Dietary supplement
Also called baby formula
6 oz
Ensure Plus™Dietary supplement
Also called Ensure
6 oz
Furosemide 20 MGDrug
Also called Lasix
Furosemide is a loop diuretic (water pill) that prevents your body from absorbing too much salt.
| Study group | Role | What they receive |
|---|---|---|
| Water First | Active comparator | 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid Receives: Dietary Supplement: Water; Dietary Supplement: Parmalat™ Whole Milk; Dietary Supplement: Similac Pro-Advance™; Dietary Supplement: Ensure Plus™; Drug: Furosemide 20 MG |
| Milk First | Active comparator | Parmalat™ Whole Milk 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid Receives: Dietary Supplement: Water; Dietary Supplement: Parmalat™ Whole Milk; Dietary Supplement: Similac Pro-Advance™; Dietary Supplement: Ensure Plus™; Drug: Furosemide 20 MG |
| Baby formula first | Active comparator | Similac Pro-Advance™ 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid Receives: Dietary Supplement: Water; Dietary Supplement: Parmalat™ Whole Milk; Dietary Supplement: Similac Pro-Advance™; Dietary Supplement: Ensure Plus™; Drug: Furosemide 20 MG |
| Ensure Plus first | Active comparator | Ensure Plus™ 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid Receives: Dietary Supplement: Water; Dietary Supplement: Parmalat™ Whole Milk; Dietary Supplement: Similac Pro-Advance™; Dietary Supplement: Ensure Plus™; Drug: Furosemide 20 MG |
What is being measured
The primary outcome is the main question the study is designed to answer.
area under the plasma concentration curve
The primary analysis will test for overall differences in bioavailability (area under the plasma concentration curve) of furosemide between different liquids. This will be accomplished using a repeated measures ANOVA, or if the distribution is not normally distributed a Wilcoxon-matched pairs sign-rank test.
Measured: 4 weeks
Secondary outcomes (2)
differences in the peak plasma concentration in furosemide (C-max)
Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose. It is a standard measurement in pharmacokinetics. Cmax is the opposite of Cmin, which is the minimum (or trough) concentration that a drug achieves after dosing.
Measured: 4 weeks
total urinary sodium output
collected via urine this is a standard metric of diuretic response
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Mar 2017
- Study start31 Dec 2018 (estimated)
- Primary completion1 Jun 2019 (estimated)
- Study completion1 Jun 2019 (estimated)
Why it stopped: Study never officially began
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Medication AbsorptionStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- A four-way randomized crossover PK study
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jeffrey Testani, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03093090
- Sponsor's protocol ID
- 2000020010
- Status last verified
- Jan 2019
- First submitted
- 22 Mar 2017
- Last updated
- 18 Jan 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluating Predictive Methods & Product Performance in Healthy Adults for Pediatric Patients, A Case Study: Furosemide
- ClinicalTrials.gov ID
- NCT03093090
- Acronym / sponsor ID
- 2000020010
- Conditions
- Medication Absorption
- Keywords
- furosemide
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Study never officially began
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Study start
- 31 Dec 2018 (estimated)
- Primary completion
- 1 Jun 2019 (estimated)
- Study completion
- 1 Jun 2019 (estimated)
- First posted
- 28 Mar 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Poorly absorbed medications such as furosemide are common and recent experiments suggest that improvement in absorption can occur if these types of medications are consumed with liquids such as milk. The purpose of this study is to evaluate the absorption of furosemide in normal adults when taken with bottled water, milk (Parmalat™ Whole Milk), baby formula (Similac Pro-Advance™), or Ensure Plus™. These results will be used to make models that predict how these liquids will affect drug absorption in children, potentially providing ways to improve medication absorption in children.
Detailed description
Low solubility drugs are common in the pharmacopeia and it has been estimated that more than 40% of new chemical entities developed by the pharmaceutical industry are practically insoluble in water. Exploratory in vitro studies by the CDER have recently demonstrated that the solubility, and thus potentially the bioavailability, of poorly soluble drugs may be highly enhanced when administered with milk (Parmalat™ Whole Milk) or baby formula (Similac Pro-Advance™).
While the reasons for variable bioavailability of furosemide are not well characterized, the effect of gastric pH, food and dosing liquids are commonly observed on the absorption of BCS Class IV drugs. Absorption variability is much greater in children due to developmental changes in factors such as gastric fluid, blood flow to the intestine, bile acid composition/secretion, intestinal surface area and drug metabolizing enzyme and transporter abundance. Therefore, it is critical to determine the physio-chemical physiological interactions for furosemide that can explain inter-subject and inter-dosing variability. An integrated in vitro, in silico and in vivo pharmacology approach to study the effect of dosing liquids on PK and PD of furosemide is novel. Quantitative understanding of factors affecting furosemide absorption will first be evaluated using in vitro tests such as solubility, dissolution and protein binding with the dosing liquids. The physiochemical information relevant to drug absorption and elimination will be curated from the literature to build the PBPK model. Such in vitro- in vivo extrapolation (IVIVE) linked PBPK modeling approach is crucial to better characterize furosemide's variable bioavailability. Another novel aspect of this study is that we will include renal metabolism of furosemide in the PBPK modeling. While plasma concentration will be critical in determining rate and extent of furosemide absorption, the renal elimination is the primary contributor to the PD response of furosemide as delivery of drug to the luminal surface of the renal tubule is required. PBPK modeling allows extrapolation of model to special population. For example, once the model is optimized and validated to predict effect of dosing liquids on adult PK of furosemide from in vitro data, this approach can be further extrapolated to children using pediatric gut physiological parameters. This novel approach will allow prediction of furosemide PK and PD in children without conducting a clinical study in this difficult to study population.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 4
- Model description
- A four-way randomized crossover PK study
| Arm | Type | Receives |
|---|---|---|
| Water First | Active comparator | Dietary Supplement: Water, Dietary Supplement: Parmalat™ Whole Milk, Dietary Supplement: Similac Pro-Advance™, Dietary Supplement: Ensure Plus™, Drug: Furosemide 20 MG20mg furosemide administered PO with 6 oz of randomly-assigned study liquid |
| Milk First | Active comparator | Dietary Supplement: Water, Dietary Supplement: Parmalat™ Whole Milk, Dietary Supplement: Similac Pro-Advance™, Dietary Supplement: Ensure Plus™, Drug: Furosemide 20 MGParmalat™ Whole Milk 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid |
| Baby formula first | Active comparator | Dietary Supplement: Water, Dietary Supplement: Parmalat™ Whole Milk, Dietary Supplement: Similac Pro-Advance™, Dietary Supplement: Ensure Plus™, Drug: Furosemide 20 MGSimilac Pro-Advance™ 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid |
| Ensure Plus first | Active comparator | Dietary Supplement: Water, Dietary Supplement: Parmalat™ Whole Milk, Dietary Supplement: Similac Pro-Advance™, Dietary Supplement: Ensure Plus™, Drug: Furosemide 20 MGEnsure Plus™ 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Age 18-40
- 4 females and 4 males will be recruited
- Free from known significant chronic medical illness (i.e., hypertension, diabetes, atherosclerosis, chronic kidney disease, liver disease, lupus, taking medications with known interactions with furosemide, a history of syncope/falls, or any acute illness, such as influenza, gastroenteritis, dehydration, electrolyte imbalance, or thrombosis risks).
- Systolic Blood Pressure ≥90 mmHg at Screening Visit
Key exclusion criteria (7 listed)
- Inability to read English or give informed consent
- Recent hospitalization within 6 months
- Pregnant or lactating
- Allergy or intolerance to furosemide
- Allergy or intolerance to milk, milk products or soy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Water6 oz | Dietary supplement | Baby formula first, Ensure Plus first, Milk First, Water First |
| Parmalat™ Whole MilkAlso: Milk6 oz | Dietary supplement | Baby formula first, Ensure Plus first, Milk First, Water First |
| Similac Pro-Advance™Also: baby formula6 oz | Dietary supplement | Baby formula first, Ensure Plus first, Milk First, Water First |
| Ensure Plus™Also: Ensure6 oz | Dietary supplement | Baby formula first, Ensure Plus first, Milk First, Water First |
| Furosemide 20 MGAlso: LasixFurosemide is a loop diuretic (water pill) that prevents your body from absorbing too much salt. | Drug | Baby formula first, Ensure Plus first, Milk First, Water First |
Primary outcome
area under the plasma concentration curve
Time frame: 4 weeks
The primary analysis will test for overall differences in bioavailability (area under the plasma concentration curve) of furosemide between different liquids. This will be accomplished using a repeated measures ANOVA, or if the distribution is not normally distributed a Wilcoxon-matched pairs sign-rank test.
2 secondary outcomes
differences in the peak plasma concentration in furosemide (C-max)
Time frame: 4 weeks
total urinary sodium output
Time frame: 4 weeks
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2019.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeffrey Testani, MD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Water, Parmalat™ Whole Milk and Similac Pro-Advance™ in people with Medication Absorption, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 18 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
area under the plasma concentration curve (time frame: 4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jan 2019.