Official Title: “Pharmacologic Treatment of Congenital Nephrogenic Diabetes Insipidus”

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).

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Safety/Efficacy Study

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 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.

You will be asked to fill out food preference questionnaires to use for planning of meals for the hospital stay. You will be given containers to collect two consecutive 24-hour urine samples at home. These urine collections will help determine how well your routine medicines are working to control your NDI.

At the second clinic visit, you will bring in the two 24-hour urine samples. Blood will again be collected for further testing of kidney function. You 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 your home (The Children's Hospital, Denver, Colorado; Emory University, Atlanta, GA; University of Aarhus, Denmark). For the hospital visit, you will need to stop your usual NDI medications for 48 hours prior to the visit. You 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, you can expect to have your weight, heart rate, and blood pressure checked three times a day. All urine will be collected. Blood testing will be performed every other day. You will need to eat the meals provided at the hospital; all meals will be provided according to a low-salt diet restriction. You may drink fluids as desired but you will need to avoid caffeine-containing beverages and alcohol.

On the first day of the hospital stay, testing will be performed to confirm your 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. You 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 you receive the routine medication treatment, you will receive placebos (inactive substances like a sugar pill) in place of the investigational medicines. In this way, neither you nor the investigator will know whether you 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, you will be instructed to resume your 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).

Intervention(s) in this Clinical Trial

• Drug: sildenafil
  • 25 mg QD or 50 mg QD x 4 days based on subject weight
• Drug: calcitonin
  • one nasal spray daily for 4 days
• Drug: hydrochlorothiazide/amiloride
  • 25 mg/2.5 mg BID or 50 mg/5 mg BID x 8 days depending on subject weight
• Drug: indomethacin
  • 50 mg QD or 50 mg BID x 8 days depending on subject weight
• Drug: Placebo for sildenafil
  • one tablet daily for 4 days
• Drug: placebo for calcitonin
  • one nasal spray daily

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • 4-day treatment with hydrochlorothiazide/amiloride, indomethacin, calcitonin, sildenafil
• Placebo Comparator: 2
  • 4-day treatment with hydrochlorothiazide/amiloride, indomethacin, placebo for calcitonin, placebo for sildenafil

Primary Measures

• Urine volume
  • Time Frame: 24-hour
    Safety Issue?: No

Secondary Measures

• Frequency of urination
  • Time Frame: 24-hour
    Safety Issue?: No
• Urine osmolality
  • Time Frame: 24-hour
    Safety Issue?: No

Inclusion Criteria:

• Known diagnosis of 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

Gender Eligibility for this Clinical Trial: Male

Minimum Age for this Clinical Trial: 5 Years

Maximum Age for this Clinical Trial: 25 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Colorado at Denver and Health Sciences Center

Overall Clinical Trial Officials and Contacts

Melissa A Cadnapaphornchai, MD Principal Investigator University of Colorado at Denver and Health Sciences Center  

Overall Contact: Melissa A Cadnapaphornchai, MD 720-777-6263 melissa.cadnapaphornchai@uchsc.edu

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00478335

Study ID Number: 06-0588

ClinicalTrials.gov Identifier: NCT00478335

Health Authority: United States: Food and Drug Administration

Nephrogenic Diabetes Insipidus Foundation