Pharmacologic Treatment of Congenital Nephrogenic Diabetes Insipidus

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ClinicalTrials.gov Identifier: NCT00478335

Recruitment Status : Completed

First Posted : May 24, 2007

Results First Posted : February 12, 2018

Last Update Posted : February 12, 2018

Sponsor:

Collaborator:

University of Aarhus

Information provided by (Responsible Party):

University of Colorado, Denver

Study Description

Brief Summary:

The purpose of this research study is to determine if two investigational medications will be more effective in decreasing urine output than the currently available and routinely used medications in patients with congenital nephrogenic diabetes insipidus (NDI).

Condition or disease	Intervention/treatment	Phase
Nephrogenic Diabetes Insipidus	Drug: sildenafil Drug: calcitonin Drug: hydrochlorothiazide/amiloride Drug: indomethacin Drug: Placebo for sildenafil Drug: placebo for calcitonin	Not Applicable

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Detailed Description:

The study involves the use of the investigational medications sildenafil and calcitonin. These medications have shown promise as treatment for NDI in laboratory (non-human) studies but have not been used for treatment of NDI in humans. At this time, there is no guarantee that these investigational medications will provide additional benefit to people with NDI.

The study is open to males, between the ages of 5 and 25 years who have been diagnosed with Nephrogenic diabetes insipidus (NDI) and who have normal kidney and bladder function. A total of 40 patients with NDI will be enrolled in the study. The study will involve two outpatient clinic visits, followed by a 9-night hospital stay, followed by a final follow-up outpatient clinic visit. All visits will take place within a 20-day time period.

At the first clinic visit, blood and urine testing for kidney and liver function and blood count will be performed. If the genetic alteration which causes your NDI has not been previously identified, blood for DNA testing will also be obtained. If a kidney and bladder ultrasound has not been performed in the past 6 months, it will be obtained. The ultrasound is to make sure that there is no problem with drainage of urine from the kidneys and bladder. Subjects will be asked to fill out food preference questionnaires to use for planning of meals for the hospital stay. Subjects will be given containers to collect two consecutive 24-hour urine samples at home. These urine collections will help determine how well the subjects routine medicines are working to control their NDI.

At the second clinic visit, subjects will bring in the two 24-hour urine samples. Blood will again be collected for further testing of kidney function. Subjects will be given containers to collect another 24-hour urine just prior to the hospital visit.

The third visit requires hospital admission and will be scheduled at the study site closest to the subjects home (The Children's Hospital, Denver, Colorado; University of Aarhus, Denmark). For the hospital visit, subjects will need to stop their usual NDI medications for 48 hours prior to the visit. Subjects will perform another 24-hour urine collection on the day prior to your hospital admission. This urine sample will be turned in to the laboratory when you are admitted to the hospital for the research study. The length of the hospital stay is 10 days/9 nights. During the stay, subjects can expect to have their weight, heart rate, and blood pressure checked three times a day. All urine will be collected. Blood testing will be performed every other day. Subjects will need to eat the meals provided at the hospital; all meals will be provided according to a low-salt diet restriction. Subjects may drink fluids as desired but they will need to avoid caffeine-containing beverages and alcohol.

On the first day of the hospital stay, testing will be performed to confirm the diagnosis of NDI. This test involves administration of the medicine dDAVP (Desmopressin) through an IV catheter (into a vein) with collection of urine every 30 minutes for 4 hours. subjects will be randomized (like the toss of a coin) to receive either the investigational medication treatment for 4 days followed by the routine medication treatment for 4 days or vice versa. When subjects receive the routine medication treatment, they will receive placebos (inactive substances like a sugar pill) in place of the investigational medicines. In this way, neither the subject nor the investigator will know whether the subjects are receiving the investigational or the routine medication treatment first. Medicines will be given twice a day during the hospital stay. On the last day of the hospital stay, subjects will be instructed to resume their normal diet and medications.

At a final outpatient clinic visit, blood testing and urinalysis will be performed.

Potential benefits of participation include a no-cost health examination, laboratory studies, and an evaluation of current management of NDI. There is no cost for participation in this research study. No pay will be given to participants in this research study.

This research study has been approved by the ethical review boards of the following institutions: Colorado Multiple Institutional Review Board (#06-0588), Emory University Institutional Review Board (#729-2005), and the University of Aarhus (#20050183). Individuals who decide to take part in this research study will need to sign a specific consent form at a participating institution as well as a release for use of personal health information (HIPAA form).

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	4 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Pharmacologic Treatment of Congenital Nephrogenic Diabetes Insipidus
Study Start Date :	May 2007
Actual Primary Completion Date :	October 2012
Actual Study Completion Date :	October 2012

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Neurohypophyseal diabetes insipidus Nephrogenic diabetes insipidus

MedlinePlus related topics: Diabetes Insipidus Urine and Urination

Genetic and Rare Diseases Information Center resources: Nephrogenic Diabetes Insipidus

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Active Therapy 4-day treatment with hydrochlorothiazide/amiloride, indomethacin, calcitonin, sildenafil	Drug: sildenafil 25 mg quaque die (QD) or 50 mg QD x 4 days based on subject weight Other Name: Viagra Drug: calcitonin one nasal spray daily for 4 days Other Name: Miacalcic Drug: hydrochlorothiazide/amiloride 25 mg/2.5 mg BID or 50 mg/5 mg BID x 8 days depending on subject weight Other Name: Moduret, Moduretic Drug: indomethacin 50 mg QD or 50 mg BID x 8 days depending on subject weight Other Name: Indocin
Placebo Comparator: Placebo Control 4-day treatment with hydrochlorothiazide/amiloride, indomethacin, placebo for calcitonin, placebo for sildenafil	Drug: hydrochlorothiazide/amiloride 25 mg/2.5 mg BID or 50 mg/5 mg BID x 8 days depending on subject weight Other Name: Moduret, Moduretic Drug: indomethacin 50 mg QD or 50 mg BID x 8 days depending on subject weight Other Name: Indocin Drug: Placebo for sildenafil one tablet daily for 4 days Drug: placebo for calcitonin one nasal spray daily

Arm

Intervention/treatment

Experimental: Active Therapy

4-day treatment with hydrochlorothiazide/amiloride, indomethacin, calcitonin, sildenafil

Drug: sildenafil

25 mg quaque die (QD) or 50 mg QD x 4 days based on subject weight

Other Name: Viagra

Drug: calcitonin

one nasal spray daily for 4 days

Other Name: Miacalcic

Drug: hydrochlorothiazide/amiloride

25 mg/2.5 mg BID or 50 mg/5 mg BID x 8 days depending on subject weight

Other Name: Moduret, Moduretic

Drug: indomethacin

50 mg QD or 50 mg BID x 8 days depending on subject weight

Other Name: Indocin

Placebo Comparator: Placebo Control

4-day treatment with hydrochlorothiazide/amiloride, indomethacin, placebo for calcitonin, placebo for sildenafil

Drug: hydrochlorothiazide/amiloride

25 mg/2.5 mg BID or 50 mg/5 mg BID x 8 days depending on subject weight

Other Name: Moduret, Moduretic

Drug: indomethacin

50 mg QD or 50 mg BID x 8 days depending on subject weight

Other Name: Indocin

Drug: Placebo for sildenafil

one tablet daily for 4 days

Drug: placebo for calcitonin

one nasal spray daily

Outcome Measures

Primary Outcome Measures :

24h Urine Volume [ Time Frame: 4-days ]
urine volume in mL/d

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:	5 Years to 25 Years (Child, Adult)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Known diagnosis of Congenital Nephrogenic Diabetes Insipidus (CNDI)
Age 5 to 25 years
Normal kidney function
Post-void residual urine < 200 ml (determined by bladder ultrasound)

Exclusion Criteria:

Impaired kidney function
Known urinary retention or bladder dysfunction
High blood pressure
Other significant chronic medical disease (e.g., heart failure, liver disease, etc.)
Allergy to study drugs

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00478335

Locations

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United States, Colorado
University of Colorado at Denver and Health Sciences Center
Aurora, Colorado, United States, 80045
Denmark
University of Aarhus
Aarhus, Denmark

Sponsors and Collaborators

University of Colorado, Denver

University of Aarhus

Investigators

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Principal Investigator:	Melissa A Cadnapaphornchai, MD	University of Colorado, Denver

More Information

Additional Information:

Nephrogenic Diabetes Insipidus Foundation This link exits the ClinicalTrials.gov site

Publications:

Bichet DG. Nephrogenic diabetes insipidus. Adv Chronic Kidney Dis. 2006 Apr;13(2):96-104. Review.

Fujiwara TM, Bichet DG. Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol. 2005 Oct;16(10):2836-46. Epub 2005 Aug 10. Review.

Schrier RW, Cadnapaphornchai MA. Renal aquaporin water channels: from molecules to human disease. Prog Biophys Mol Biol. 2003 Feb;81(2):117-31. Review.

Schrier RW, Cadnapaphornchai MA, Umenishi F. Water-losing and water-retaining states: role of water channels and vasopressin receptor antagonists. Heart Dis. 2001 May-Jun;3(3):210-4. Review.

Nielsen S, Kwon TH, Frøkiaer J, Agre P. Regulation and dysregulation of aquaporins in water balance disorders. J Intern Med. 2007 Jan;261(1):53-64. Review.

Kotnik P, Nielsen J, Kwon TH, Krzisnik C, Frøkiaer J, Nielsen S. Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus. Am J Physiol Renal Physiol. 2005 May;288(5):F1053-68. Epub 2005 Jan 11.

Nielsen S, Frøkiaer J, Marples D, Kwon TH, Agre P, Knepper MA. Aquaporins in the kidney: from molecules to medicine. Physiol Rev. 2002 Jan;82(1):205-44. Review.

Bouley R, Pastor-Soler N, Cohen O, McLaughlin M, Breton S, Brown D. Stimulation of AQP2 membrane insertion in renal epithelial cells in vitro and in vivo by the cGMP phosphodiesterase inhibitor sildenafil citrate (Viagra). Am J Physiol Renal Physiol. 2005 Jun;288(6):F1103-12. Epub 2005 Jan 11.

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Responsible Party:	University of Colorado, Denver
ClinicalTrials.gov Identifier:	NCT00478335
Other Study ID Numbers:	06-0588
First Posted:	May 24, 2007 Key Record Dates
Results First Posted:	February 12, 2018
Last Update Posted:	February 12, 2018
Last Verified:	February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by University of Colorado, Denver:


congenital nephrogenic diabetes insipidus polyuria urine osmolality aquaporin-2 vasopressin V2 receptor

Additional relevant MeSH terms:

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Diabetes Insipidus Diabetes Insipidus, Nephrogenic Diabetes Mellitus Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Kidney Diseases Urologic Diseases Pituitary Diseases Calcitonin Salmon calcitonin Indomethacin Hydrochlorothiazide Amiloride Sildenafil Citrate	Calcitonin Gene-Related Peptide Katacalcin Vasodilator Agents Phosphodiesterase 5 Inhibitors Phosphodiesterase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Urological Agents Antihypertensive Agents Diuretics Natriuretic Agents Physiological Effects of Drugs Sodium Chloride Symporter Inhibitors Membrane Transport Modulators Anti-Inflammatory Agents, Non-Steroidal

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