The acute effect of beta-guanidinopropionic acid versus creatine or placebo in healthy men (ABC Trial): study protocol for a randomized controlled trial

Abstract

BackgroundDespite adequate treatment, up to 30% of treated antihypertensive patients with primary, uncomplicated hypertension remain uncontrolled. We proposed that high intracellular activity of the ATP regenerating enzyme creatine kinase (CK) increases pressor responses and hypertension risk. In line with this, we found that plasma CK activity after rest, a surrogate measure of tissue activity, is the main predictor of blood pressure levels and failure of antihypertensive therapy in the general population. In addition, the creatine analog and competitive oral creatine kinase inhibitor beta-guanidinopropionic acid effectively and safely reduced blood pressure in the spontaneously hypertensive rat. However, to our knowledge there are no human data on the safety of oral supplementation with this substance. Therefore, we will assess the tolerability of beta-guanidinopropionic acid in men, compared to creatine and placebo.Methods/DesignThis is a randomized, active and placebo controlled, triple blind, double dummy, single center clinical intervention trial in 24 healthy male volunteers, 18 to 50 years old, recruited in the Netherlands. The intervention consists of one week of daily oral administration of beta-guanidinopropionic acid 100 mg, creatine 5 gram, or placebo. The primary outcome is the tolerability of beta-guanidinopropionic acid as a descriptive measure, in an intent-to-treat analysis. Other outcomes include the placebo-adjusted differences with baseline in biochemical and hemodynamic parameters, including plasma markers of muscle tissue damage, urine sodium excretion, resting sitting systolic and diastolic brachial blood pressure, supine systolic and diastolic central blood pressure, pulse wave velocity and augmentation index, heart rate, cardiac contractility, cardiac output, and total peripheral resistance.DiscussionThere is an unfulfilled need for new conservative options to treat resistant hypertension. This study will provide first-in-men data on creatine kinase inhibition as a potential new class of antihypertensive drugs.Trial registrationThe Netherlands National Trial Register Trialregister.nl (identifier NTR 4444), registered 9 March 2014.

The acute effect of beta‐guanidinopropionic acid versus creatine or placebo in healthy men (ABC‐Trial): A randomized controlled first‐in‐human trial

“…We used 5 g as recommended in studies on creatine supplementation. No side effects are apparent at this dose .…”

“…Exclusion criteria included high blood pressure defined as systolic ≥140 mmHg or diastolic ≥90 mmHg or the use of antihypertensive drugs, (history of) cardiovascular disease including transient ischaemic attack and stroke; the use of plasma CK‐increasing drugs including statins; use of acetylsalicylic acid or nonsteroidal anti‐inflammatory drugs in the 2 weeks prior to the first visit; neuromuscular or endocrine disorders; vasculitis; HIV infection; infectious hepatitis; personal or family history of bleeding disorders; sickle cell anaemia or other hereditary anaemia; current use or use within 2 months prior to start of the trial of creatine or other guanidino compounds; and abnormalities in glucose, lipid spectrum, thyroid, kidney or liver biochemistry parameters in the plasma. To stabilize and standardize plasma CK activity during the trial, participants were instructed to refrain from intensive physical exercise 3 days prior to the baseline visit or during the intervention in the first week . All study participants gave written informed consent, and the full study protocol was approved by the AMC Amsterdam Medical Ethics Review Committee on 25 November 2013 (MERC reference number 38368.018.12) .…”

“…To stabilize and standardize plasma CK activity during the trial, participants were instructed to refrain from intensive physical exercise 3 days prior to the baseline visit or during the intervention in the first week . All study participants gave written informed consent, and the full study protocol was approved by the AMC Amsterdam Medical Ethics Review Committee on 25 November 2013 (MERC reference number 38368.018.12) . The study complies with the Declaration of Helsinki (64th World Medical Association, General Assembly, Fortaleza, Brazil, October 2013).…”

“…After 24 h and after 7 days of trial supplements (day 8), the baseline measurements were repeated. The last visit was at day 21, to assess potential side effects …”

“…GPA and creatine were considered by the MERC to be food supplements as previously described . GPA was ordered from Sequoia (Sequoia Research Products, Oxford, UK).…”