The Haem and Nitrite Study - The Effects of Haemoglobin NO-blockade on Nitrite-induced Forearm Vessel Dilatation

The Effects of Free Haemoglobin NO-blockade on Nitrite Forearm Vessel Dilatation Under Normoxia and Hypoxia in Healthy Volunteers

The study is a pharmacodynamic random order cross-over trial investigating the physiological effects of intra-arterial infusion of nitrite following a haemolysed autologous blood transfusion.

Study Overview

• Status: Unknown
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Sodium Nitrite

Detailed Description

This is a healthy volunteer study.

Following entry into this cross-over trial, participants will be randomized to undergo experiments under either normoxic followed by hypoxic conditions, or hypoxic followed by normoxic conditions.

Subjects will donate whole blood as an autologous unit at a preselected NHSBT donation site. The unit will transported back to the NNUH blood bank after a minimum of 30 days (maximum 35 days) after donation.

Volunteers will be tested for baseline bloods. Volunteers will be randomised to normoxia or hypoxia. The will then undergo a nitrite infusion, followed by an autologous whole blood transfusion and a second nitrite infusion (which will co-infuse at the end of the transfusion). During the protocol, the participants will undergo repeated FBFR measurements using strain-gauge plethysmography.

After a minimum of 12 weeks rest period after their initial donation, participants will cross-over to the opposite oxygen condition (as per initial randomization) and the above protocol will be repeated. All interventions will be performed by fully trained and competent medical staff.

• Study Type: Interventional
• Enrollment (Anticipated): 41
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Nicholas D Gollop, MRCP(UK); Phone Number: 1790 01603 591790; Email: n.gollop@uea.ac.uk

Study Locations

• United Kingdom
  • Norfolk
    • Norwich, Norfolk, United Kingdom, NR4 7UQ
      • Recruiting
      • University of East Anglia
      • Contact: Nicholas D Gollop, MRCP; Phone Number: 1790 01603 591790; Email: n.gollop@uea.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, aged greater than or equal to 18 years
2. If between 18-20 years of age, calculate total blood volume should be more than >3.5L (http://www.blood.co.uk/giving-blood/who-can-give-blood/)
3. Body weight > 50kg weight (8 stone 12lbs)
4. Not known to have any significant past medical history and not having regular follow up (Check Donor Selection Guidelines (http://www.transfusionguidelines.org.uk/)
5. Willing to provide blood donation and receive autologous blood transfusion
6. After assessment for eligibility pass all blood donor eligibility criteria
7. Able to provide informed consent
8. Should inform overseas travel plan during study period (Check Geographical Disease Risk Index on http://www.transfusionguidelines.org.uk/dsg/gdri) e.g. unable to donate blood for 6 months if travel in a malaria endemic country. Similar guidelines for West Nile virus and T. Cruzi endemic countries.

Exclusion Criteria:

1. Significant medical, surgical or psychiatric disease that in the opinion of the Clinical Research Fellow would affect subject safety or significantly impact his/her ability to comply with follow-up. This would include any known clotting disorders.
2. Known allergy or intolerance to Nitrites
3. Known glucose-6-phosphate dehydrogenase (G6PD) deficiency
4. Female subjects must be of non-childbearing potential, defined as follows: postmenopausal females who have had at least 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhoea with serum FSH>40mIU/ml or females who have had a hysterectomy, bilateral salpingectomy or bilateral oophorectomy at least 6 weeks prior to enrolment
5. Receipt of an investigational drug or biological agent within the 4 weeks prior to study entry or 5 times the drug half-life, whichever is the longer
6. Predisposed to acute on chronic limb ischemia evident from a history of claudication or known peripheral arterial disease.
7. No past history of significant adverse events post blood donation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Normoxia and Nitrite (3umol/min-1); Sodium nitrite stock solution: 100umol/10ml, prepared to concentration according to oxygen sequence. Normoxia (3umol/min-1).	Drug: Sodium Nitrite
Active Comparator: Hypoxia and Nitrite (1umol/min-1); This will be repeated as per the normoxia cohort, but at a reduced dose of sodium nitrite (1umol/min-1 for 30 minutes) and the volunteers will be asked to breathe 12% oxygen/88% nitrogen for 1-5 minutes before Plethysmography is performed (to get the volunteer to an oxygen saturation of 83-88% peripherally).	Drug: Sodium Nitrite

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in FBFR during intra-brachial nitrite and haemolysed blood co-infusion in normoxia vs hypoxia.	Up to 18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in FBFR during haemolysed blood infusion vs baseline	Up to 18 months
Change in FBFR during nitrite infusion in normoxia vs nitrite infusion in hypoxia	Up to 18 months
Change in FBFR during nitrite infusion in normoxia vs baseline	Up to 18 months
Change in FBFR during nitrite infusion in hypoxia vs baseline	Up to 18 months
Blood analysis (cell free haemoglobin, nitrate, nitrite and nitroso species levels)	Up to 18 months

Collaborators and Investigators

• Sponsor: University of East Anglia
• Investigators: Principal Investigator: Michael P Frenneaux, FRCP, FESC, Dean of Medicine, Norwich Medical School, The University of East Anglia, UK

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Anticipated): March 1, 2018
• Study Completion (Anticipated): March 1, 2018

Study Registration Dates

• First Submitted: September 20, 2016
• First Submitted That Met QC Criteria: March 7, 2017
• First Posted (Actual): March 13, 2017

Study Record Updates

• Last Update Posted (Actual): March 20, 2017
• Last Update Submitted That Met QC Criteria: March 17, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: blood; hypoxia; nitrite; haemoglobin; normoxia; vasodilatation
• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Dilatation, Pathologic
• Other Study ID Numbers: 206995

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No