A Phase 2a Study to Assess Safety & Pharmacokinetics of Sustained Release Sodium Nitrite in Patients With Diabetic Pain

Study Overview
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Brief Summary
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In this study, subjects with diabetic neuropathic pain (DNP) will be treated for 12 weeks with either placebo, 40 or 80 mg sustained release sodium nitrite (TV1001sr) twice daily. Primary endpoints will be safety and pharmacokinetics. Assessment of the study medications affects on pain following treatment will also be recorded.

Detailed Description
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This is a dose-ranging study to evaluate the safety, pharmacokinetics, and tolerability of multiple doses of an oral, sustained release formulation of sodium nitrite (TV1001sr) in subjects with DNP. The primary objective is to assess the safety and tolerability of multiple doses of twice daily 40 mg and 80 mg TV1001sr compared with placebo over a 12 week treatment period and the pharmacokinetics of the sustained release formulation of sodium nitrite. Secondary objectives are to evaluate the pharmacokinetics and markers of functional improvement including pain questionnaires, quantitative sensory testing and changes in markers of diabetes.

Official Title
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A Randomized, Double-blinded, Phase 2a Study to Assess the Safety and Pharmacokinetics of a Sustained Release Formulation of Sodium Nitrite (TV1001sr) in Patients With Diabetic Neuropathic Pain (DNP)

Conditions
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Diabetes

Intervention / Treatment
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* Drug: Sodium nitrite
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female subjects must be post-menopausal, sterilized or using suitable birth control Diagnosis of diabetes (HbA1c > 6.0) Diagnosis of diabetic peripheral neuropathy pain in feet Presence of ongoing diabetic neuropathic for at least 3 months A pain score of greater than or equal to 4 on the Numerical Pain Rating Scale at screening Ability to provide written informed consent Exclusion Criteria: Patients with fibromyalgia or regional pain caused by lumbar or cervical compression History or diagnosis of significant neurological disease History and diagnosis of clinically significant psychiatric diseases Serious liver disease Poorly controlled diabetes Hypersensitivity to sodium nitrite or related compounds Life expectancy < 6 months A chronic illness that may increase the risks associated with this study Active malignancy requiring active anti-neoplastic therapy that will, in the opinion of the investigator, interfere with study treatment or participation Pregnant or nursing women Current diagnosis of alcohol or other substance abuse Current use of sildenafil or other phosphodiesterase Type 5 Inhibitors History of methemoglobinemia, (met-Hb ≥ 15%) Subject is involved in litigation or receives worker's compensation Inability to speak English

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>One placebo tablet administered twice daily for 12 weeks. | Drug: Placebo<br>* Placebo tablets containing same excipients and coatings used in the active tablets, without sodium nitrite being added.<br>|
| Active Comparator: 40 mg TV1001sr<br>One 40 mg enteric coated sustained release, sodium nitrite tablets administered twice daily. | Drug: Sodium nitrite<br>* Sustained release formulation of sodium nitrite<br>* Other names: TV1001sr;|
| Placebo Comparator: Placebo (2)<br>Two placebo tablets administered twice daily for 12 weeks. | Drug: Placebo<br>* Placebo tablets containing same excipients and coatings used in the active tablets, without sodium nitrite being added.<br>|
| Active Comparator: 80 mg TV1001sr<br>Two 40 mg enteric coated sustained release, sodium nitrite tablets administered twice daily. | Drug: Sodium nitrite<br>* Sustained release formulation of sodium nitrite<br>* Other names: TV1001sr;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reporting of Adverse Events During 12 Week Study Period | The primary objective of this clinical study is to evaluate the safety and tolerability of multiple doses of twice daily 40mg and 80mg sustained release sodium nitrite compared with placebo over a 12 week treatment period. The following safety parameters will also be assessed: concomitant medication usage, physical examination, vital signs, Comprehensive Metabolic Panel, and complete blood count. Assessment of acute adverse events (i.e., drop in blood pressure, dizziness) after administration of each dose level. Counts are number of subjects reporting at least 1 Adverse Event. The total Adverse Events recorded in each cohort is also reported. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (Blood Levels of Nitrite) | Blood levels of nitrite will be assessed for 6 hours post-administration on the initial dosing visit. | 1 day | 
| The Number of Participants Who Reported Use of Analgesic or Medications for Neuropathic Pain. | Daily patient reported use of analgesic or medications for neuropathic pain. The use of medications were recorded at the baseline visit and during both the intermediate and final visit for each subject. All subjects used at least one prescription pain medication, other than one subject in the 80-mg dose cohort who used only ibuprofen to control pain. Most subjects used more than one prescription pain medication. There was no change in use of pain medications during the trial period. | 12 weeks | 
| Assessment of Patients Reported Pain Through Composite Analysis of Pain Questionaires. | Subjects completed the Brief pain inventory (BPI), RAND 36 questionnaire, neuropathic pain symptom inventory (NPSI) and Short Form McGill Pain Questionnaire at each visit for these self-reported questionnaires. The BPI is a questionnaire that measures the patient's subjective perception of pain, its exacerbating and alleviating factors, and perceived effect on functional status; the NPSI is a questionnaire that measures the symptoms associated with neuropathic pain; the Short Form McGill Questionnaire subjectively assesses the patients perception of pain described by commonly used adjectives associated with pain. NPSI is average of 12 questions, range from 0 (no pain) to 120 (maximal pain); For BPI severity and interference, questions are scored from 0-10, then there average score for each subsection is calculated (the higher the score, the worse the response); Scores on McGill range from 0-10, lower associated for less pain, then averaged for each sub score and total score. | Baseline (visit 1) and 12 weeks (visit 3) | 
| Clinical Assessment of Pain. (Quantitative Sensory Testing) | Quantitative sensory testing (QST) was conducted at each visit to determine patients sensitivity to pain. QST was assessed using a quantitative nerve conductance machine where nerves in the distal extremity are subjected to electrical stimulation to determine the sensory threshold of the skin. Nerve conductance measures how fast an electrical impulse moves through the nerve, and nerve velocity measures the speed at which an electrical impulse moves down a neuronal pathway. | 12 weeks | 
| Assessment of Diabetes. (HbA1C Levels) | HbA1C levels will be monitored at each visit to determine whether treatment reduces circulating glucose levels. | 12 weeks | 
| Assessment of Blood Oxygenation. (Pulse Oximetry) | Pulse oximetry will be used at each visit to determine whether treatment improves oxygen levels in the blood. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neuropathy